ORCID Profile
0000-0002-9317-9526
Current Organisations
University of Western Australia
,
Sir Charles Gairdner Hospital
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Publisher: Elsevier BV
Date: 06-2018
DOI: 10.1016/J.JTHO.2018.02.012
Abstract: Over the past two decades, the International Association for the Study of Lung Cancer (IASLC) Staging Project has been a steady source of evidence-based recommendations for the TNM classification for lung cancer published by the Union for International Cancer Control and the American Joint Committee on Cancer. The Staging and Prognostic Factors Committee of the IASLC is now issuing a call for participation in the next phase of the project, which is designed to inform the ninth edition of the TNM classification for lung cancer. Following the case recruitment model for the eighth edition database, volunteer site participants are asked to submit data on patients whose lung cancer was diagnosed between January 1, 2011, and December 31, 2019, to the project by means of a secure, electronic data capture system provided by Cancer Research And Biostatistics in Seattle, Washington. Alternatively, participants may transfer existing data sets. The continued success of the IASLC Staging Project in achieving its objectives will depend on the extent of international participation, the degree to which cases are entered directly into the electronic data capture system, and how closely externally submitted cases conform to the data elements for the project.
Publisher: Springer Science and Business Media LLC
Date: 02-2016
DOI: 10.1038/NN.4228
Publisher: Wiley
Date: 27-09-2022
DOI: 10.1002/PON.6028
Abstract: This study aimed to describe patient self‐reported distress over time and how this was associated with wellbeing, and supportive care needs over a 6‐month period from commencing chemoradiotherapy for high grade glioma (HGG). In this prospective cohort study, participants completed surveys at three time points: before chemoradiotherapy, at 3 and 6 months. These included Distress Thermometer, Functional Assessment of Cancer/Brain Cancer Treatment‐general (Fact‐G/FACT‐BR), Supportive Care Needs Scale (SF‐34) and Brain Tumour Specific subscale. Patient survival time was also collected. Group‐based trajectory modelling was performed. Multinominal logistic regression assessed variables associated with different distress trajectory groups. One hundred and sixteen participants completed assessments at baseline, 89 participants at 3 and 64 at 6 months. Four distress trajectory groups were identified consistent low distress (18%), low to high distress (38%), high‐to low distress (24%) and consistent high distress (19%). Younger participants tended to report decreased distress over time, whereas older participants reported consistently high distress. High distress trajectory participants had less education, lower physical wellbeing, more unmet needs, but higher functional wellbeing compared to the low to high distress trajectory. The number of unmet needs paralleled the patterns of distress over time. The highest unmet needs in people with HGG and high distress were disease specific changes in mental ability and physical side effects. This study demonstrates people with HGG experience ongoing distress and highlights a need for continuous distress and unmet needs screening and referrals.
Publisher: Springer Science and Business Media LLC
Date: 14-09-2012
Publisher: Springer Science and Business Media LLC
Date: 15-09-2020
DOI: 10.1186/S13104-020-05284-Y
Abstract: There is substantial evidence that exercise can safely reduce the risk of cancer and improve survival in different human cancer populations. Long latency periods associated with carcinogen–induced cancers like asbestos induced mesothelioma provide an opportunity to implement exercise as an intervention to delay or prevent disease development. However, there are limited studies investigating the ability of exercise to prevent or delay cancer, and exercise as a preventive strategy has never been assessed in models with a known carcinogen. We investigated the potential of voluntary exercise (VE) to delay development of asbestos related disease (ARD) in our well-characterised, asbestos induced MexTAg model of mesothelioma. Asbestos exposed MexTAg mice were given continuous or delayed access to VE and ARD assessed over time. We found that the addition of VE did not affect ARD development in asbestos exposed MexTAg mice. However, non–asbestos exposed, aged matched control mice participated in significantly more VE behaviours, suggesting subclinical development of ARD after asbestos exposure had a greater impact on VE participation than age alone. These data highlight the importance of model choice and the potential limitation that some pre–clinical studies may not accurately represent the clinical paradigm, particularly in the context of prevention studies.
Publisher: Elsevier BV
Date: 12-2016
Publisher: Elsevier BV
Date: 2020
DOI: 10.1016/J.JTHO.2019.08.2506
Abstract: Molecular and immunologic breakthroughs are transforming the management of thoracic cancer, although advances have not been as marked for malignant pleural mesothelioma where pathologic diagnosis has been essentially limited to three histologic subtypes. A multidisciplinary group (pathologists, molecular biologists, surgeons, radiologists, and oncologists), sponsored by European Network for Rare Adult Solid Cancers/International Association for the Study of Lung Cancer, met in 2018 to critically review the current classification. Recommendations include: (1) classification should be updated to include architectural patterns and stromal and cytologic features that refine prognostication (2) subject to data accrual, malignant mesothelioma in situ could be an additional category (3) grading of epithelioid malignant pleural mesotheliomas should be routinely undertaken (4) favorable/unfavorable histologic characteristics should be routinely reported (5) clinically relevant molecular data (programmed death ligand 1, BRCA 1 associated protein 1 [BAP1], and cyclin dependent kinase inhibitor 2A) should be incorporated into reports, if undertaken (6) other molecular data should be accrued as part of future trials (7) resection specimens (i.e., extended pleurectomy/decortication and extrapleural pneumonectomy) should be pathologically staged with smaller specimens being clinically staged (8) ideally, at least three separate areas should be s led from the pleural cavity, including areas of interest identified on pre-surgical imaging (9) image-acquisition protocols/imaging terminology should be standardized to aid research/refine clinical staging (10) multidisciplinary tumor boards should include pathologists to ensure appropriate treatment options are considered (11) all histologic subtypes should be considered potential candidates for chemotherapy (12) patients with sarcomatoid or biphasic mesothelioma should not be excluded from first-line clinical trials unless there is a compelling reason (13) tumor subtyping should be further assessed in relation to duration of response to immunotherapy and (14) systematic screening of all patients for germline mutations is not recommended, in the absence of a family history suspicious for BAP1 syndrome. These multidisciplinary recommendations for pathology classification and application will allow more informative pathologic reporting and potential risk stratification, to support clinical practice, research investigation and clinical trials.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 05-2015
Publisher: Elsevier BV
Date: 12-2016
Publisher: Elsevier BV
Date: 12-2016
Publisher: Elsevier BV
Date: 09-2017
Publisher: Elsevier BV
Date: 08-2009
Publisher: Hindawi Limited
Date: 28-09-2022
DOI: 10.1111/ECC.13716
Abstract: Palliative care improves outcomes for patients with thoracic cancer however, limited evidence exists for the benefits of this approach for caregivers. This study aimed to advance understanding of the experiences of palliative care described by bereaved caregivers. Fifteen adult caregivers completed semi-structured interviews following prior participation in a randomised controlled trial of early referral to palliative care versus discretionary referral to palliative care. Interviews explored caregiver experiences of palliative care delivery. Interview transcripts were thematically analysed. Four related themes about the experiences of palliative care were identified, each of which required sufficient time between palliative care first contact and death: 'relationship building' 'clear communication and information' 'access to practical support' and 'access to psychosocial support'. The core category underpinning these themes was palliative care facilitates caregiver preparedness. Caregivers noted that palliative care played a critical role in preparing them for the future and described a sense of practical and emotional 'relief' associated with the support services made available to them. Our findings emphasise that palliative care can have a positive impact on caregivers' preparedness for providing the care needed by thoracic cancer patients and that this can improve the experiences of both caregivers and patients.
Publisher: Oxford University Press (OUP)
Date: 24-06-2023
DOI: 10.1093/NOP/NPAD035
Abstract: People living with high-grade glioma (HGG) have erse and complex needs. Screening aims to detect patients with some level of unmet need requiring triaging and further assessment. However, most existing measures of unmet need are not suitable for screening in this population due to their length. We aimed to explore the clinical utility of a brief screening tool (SCNS-ST9) in people with HGG in detecting unmet needs. Secondary analysis of data collected in a prospective cohort study of 116 people with HGG who completed the Supportive Care Needs Survey (SCNS-SF34) and a brain cancer-specific needs survey (BrTSCNS) during chemoradiation (T1) and 6 months later (T2). The SCNS-ST9 contains a subset of 9 items from the SCNS-SF34. Data analysis determined the number of in iduals with unmet needs on the SCNS-SF34 and the BrTSCNS, not identified as having some level of need by the SCNS-ST9. Overall, 3 in iduals (T1: 2.6% [3/116] T2: 4.8% [3/63]) at each time point reported other unmet needs on the SCNS-SF34 that were missed by the SCNS-ST9. Domain-specific screening items missed a higher proportion of in iduals (3.2%–26%), particularly in the psychological and health systems domains. Only 1 in idual with brain cancer-specific needs was missed by SCNS-ST9 overall. Findings demonstrate the sensitivity and clinical utility of a brief screening tool (SCNS-ST9) of unmet needs in people with HGG. Routine use of this screening tool, supported by clinical pathways, may improve access to support services, potentially reducing the burden of disease for these patients.
Publisher: Oxford University Press (OUP)
Date: 20-06-2023
DOI: 10.1093/NOP/NPAD032
Abstract: Inadequate knowledge and skills and a lack of confidence to provide care have been identified as major unmet needs for carers of people with brain cancer. An online intervention was developed to address the unmet needs of carers of people with high-grade glioma. Ten carers evaluated the intervention through multiple methods. Acceptability and usability were measured through online data analytics (unique page views, time on page), surveys, and interviews. Questionnaires measured potential impacts on distress (Distress Thermometer), depression, anxiety (Hospital Anxiety and Depression Scale), carer competence (Carer Competence Scale), carer preparedness (Caregiving Preparedness Scale), unmet needs (Supportive Care Needs Scale – Brain Tumor Specific for carers), usability and acceptability (USE). Results suggested the intervention had high levels of usability (usability scales’ means range = 5.1 to 6.7 out of 7) and acceptability (M = 76.3/100). Correlations indicated the potential to impact depression. Qualitative findings highlighted benefits of the intervention as a comprehensive reliable resource that could validate and normalize carer experiences. Interview findings guided further improvements (eg, additional carer videos, content organization). The study indicated high acceptability and usability of an online intervention for carers of people with high-grade glioma. This exploratory study also provided preliminary indications of a potential to decrease depression. However, a more robust, potentially longitudinal, investigation is needed with a larger and broader s le. Informed by this study, the intervention has been amended and a randomized controlled trial will further evaluate the enhanced intervention.
Publisher: Oxford University Press (OUP)
Date: 13-06-2023
DOI: 10.1093/NOP/NPAD031
Abstract: The objective of this scoping review was to describe the intervention characteristics and effectiveness of psychosocial interventions aimed at managing personality and behavior changes in people with brain tumors. A secondary objective was to explore if these interventions had an impact on outcomes for carers. Personality and behavior changes considered included aggression, apathy, paranoia, disinhibition, and emotional lability. This review was conducted following the Joanna Briggs Institute methodology for scoping reviews and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) extension for scoping reviews. Searches were conducted in PsycINFO, CINAHL, Medline (Ovid), and Scopus. We synthesized studies published from 1996 to 2022 that evaluated interventions to manage brain tumor related personality and behavioral changes in adults. A data extraction tool were used based on the Joanna Briggs Institute template. Results are presented in a summary table and a narrative synthesis was conducted. Three thousand and five hundred and ninety-four records were screened. Title and abstract screening resulted in 29 potentially eligible studies. Full screening excluded 24 articles and 5 interventions met the inclusion criteria. The interventions were erse in duration, delivery modality, setting, and participation (eg, the patient in idually or patient and carer). The interventions reported improvements in the targeted personality and behavior change symptoms for patients with primary brain tumors. Four studies included a measure of personality and behavior change symptoms and two studies included a measure of outcomes for carers and reported improvements in carer knowledge and a reduction in carer distress. All studies s led fewer than 100 participants. Studies had limited follow-up data and different tools were used to assess the presence and nature of personality and behavior changes. There is a dearth of psychosocial interventions to support patients and their carers to manage brain tumor related personality and behavior changes.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.C.6532518
Abstract: AbstractPurpose: In a i ost hoc /i analysis of the CATNON trial (NCT00626990), we explored whether adding temozolomide to radiotherapy improves outcome in patients with i IDH1/2 /i wildtype (wt) anaplastic astrocytomas with molecular features of glioblastoma [redesignated as glioblastoma, isocitrate dehydrogenase–wildtype ( i IDH /i -wt) in the 2021 World Health Organization (WHO) classification of central nervous system tumors]. Patients and Methods: From the randomized phase III CATNON study examining the addition of adjuvant and concurrent temozolomide to radiotherapy in anaplastic astrocytomas, we selected a subgroup of i IDH1/2 /i wt and i H3F3A /i wt tumors with presence of i TERT /i promoter mutations and/or i EGFR /i lifications and/or combined gain of chromosome 7 and loss of chromosome 10. Molecular abnormalities including i MGMT /i promoter methylation status were determined by next-generation sequencing, DNA methylation profiling, and SNaPshot analysis. Results: Of the 751 patients entered in the CATNON study, 670 had fully molecularly characterized tumors. A total of 159 of these tumors met the WHO 2021 molecular criteria for glioblastoma, i IDH /i -wt. Of these patients, 47 received radiotherapy only and 112 received a combination of radiotherapy and temozolomide. There was no added effect of temozolomide on either overall survival [HR, 1.19 95% confidence interval (CI), 0.82–1.71] or progression-free survival (HR, 0.87 95% CI, 0.61–1.24). i MGMT /i promoter methylation was prognostic for overall survival, but was not predictive for outcome to temozolomide treatment either with respect to overall survival or progression-free survival. Conclusions: In this cohort of patients with glioblastoma, i IDH /i -wt temozolomide treatment did not add benefit beyond that observed from radiotherapy, regardless of i MGMT /i promoter status. These findings require a new well-powered prospective clinical study to explore the efficacy of temozolomide treatment in this patient population. /
Publisher: American Chemical Society (ACS)
Date: 26-06-2009
DOI: 10.1021/JP903023C
Abstract: Molecules acting as antioxidants capable of scavenging reactive oxygen species (ROS) are of the utmost importance in the living cell. The antioxidative properties of pyridoxine (vitamin B6) have recently been discovered. Previous theoretical calculations have shown a high reactivity of pyridoxine toward hydroxyl radicals, where the latter preferably abstract H from either carbon of the two methanol substituents (C8 or C9). In this study, we have explored the reactivity of pyridoxine toward further hydroxyl radicals, considering as the first step the H abstraction from either C8 or C9, also including addition reactions and cyclization. Many of the reactions display similar DeltaG, and hence, the quenching of hydroxyl radicals by pyridoxine may undergo different pathways leading to a mix of products. In addition, we observe that pyridoxine, under high hydroxyl radical concentrations, may scavenge up to eight radicals, supporting its observed high antioxidant activity.
Publisher: Wiley
Date: 05-07-2017
DOI: 10.1002/CNCR.30838
Abstract: Bevacizumab has been associated with prolonged progression-free survival for patients with recurrent glioblastoma however, not all derive a benefit. An early indicator of efficacy or futility may allow early discontinuation for nonresponders. This study prospectively assessed the role of early magnetic resonance imaging (eMRI) and its correlation with subsequent routine magnetic resonance imaging (MRI) results and survival. Patients were part of a randomized phase 2 clinical trial (CABARET) comparing bevacizumab with bevacizumab plus carboplatin for recurrent glioblastoma. eMRI was conducted after 4 weeks in the trial (after 2 treatments with bevacizumab [10 mg/kg every 2 weeks]). The results were compared with the results of the subsequent 8-week MRI standard. For 119 of 122 patients, eMRI was available, and 111 had subsequent MRI for comparison. Thirty-six (30%) had an early radiological response, and 17 (14%) had progressive disease. The concordance between eMRI and 8-week MRI was moderate (κ = 0.56), with most providing the same result (n = 79 [71%]). There was strong evidence that progression-free survival and overall survival were predicted by the eMRI response (both P values < .001). The median survival was 8.6 months for an eMRI response, 6.6 months for stable disease, and 3.7 months for progressive disease the hazard ratio (progressive disease vs stable disease) was 3.4 (95% confidence interval, 1.9-6.0). Landmark analyses showed that eMRI progression was a strong predictor of mortality independent of other potential baseline predictors. In this study, early progression on MRI appears to be a robust marker of a poor prognosis for patients on bevacizumab. Cancer 2017 :3576-82. © 2017 American Cancer Society.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22487421.V1
Abstract: Supplementary Figure from Temozolomide and Radiotherapy versus Radiotherapy Alone in Patients with Glioblastoma, i IDH /i -wildtype: i Post Hoc /i Analysis of the EORTC Randomized Phase III CATNON Trial
Publisher: Springer International Publishing
Date: 2019
Publisher: Elsevier BV
Date: 04-2013
Publisher: Springer Netherlands
Date: 15-08-2013
Publisher: BMJ
Date: 11-02-2014
Publisher: Elsevier BV
Date: 03-2014
DOI: 10.1016/J.JOCN.2013.07.042
Abstract: Gliosarcoma (GSM) is a rare primary malignant brain tumour accounting for less than 0.5% of all intracranial tumours. It has a biphasic histological composition, demonstrating both gliomatous and sarcomatous elements. In clinical practice GSM are generally managed similarly to glioblastoma multiforme (GBM). However, unique features including its clinical propensity for extra-cranial metastasis, distinct radiological features and possible worse prognosis than GBM suggest that GSM may be a distinct clinico-pathological entity. Hence we reviewed patterns of care and outcomes for a series of Australian patients diagnosed with GSM in the era of combined chemo-radiotherapy. Patients were identified by searching the Australian Genomics and Clinical Outcomes of Glioma (AGOG) database and the Western Australian Interhospital Neurosurgical database. Nineteen patients with GSM were identified. Of these, 15 patients were diagnosed with primary GSM and four patients developed secondary GSM after radiation therapy for primary GBM. For comparative purposes, 408 primary GBM patients were identified from the AGOG database during the same study period. The overall median survival for all primary GSM patients was 9.7 months. In comparison the overall median survival for GBM patients recruited to the AGOG database over the same period was 12.2 months. The median survival for secondary GSM patients from the time of diagnosis was 5 months. Primary and secondary GSM pose a great clinical challenge due to their rarity. Our study adds further evidence to support GSM as a unique clinical entity with a likely worse prognosis than GBM.
Publisher: Frontiers Media SA
Date: 20-07-2015
Publisher: Springer Science and Business Media LLC
Date: 31-05-2021
DOI: 10.1186/S12967-021-02905-3
Abstract: Malignant pleural mesothelioma (MPM) is a rare and aggressive tumour. For patients with inoperable disease, few treatment options are available after first line chemotherapy. The combination of ipilimumab and nivolumab has recently shown increased survival compared to standard chemotherapy, but most patients do not respond and improvements are called for. Telomerase is expressed in mesothelioma cells, but only sparsely in normal tissues and is therefore an attractive target for therapeutic vaccination. Vaccination against telomerase is tolerable and has shown to induce immune responses associated with increased survival in other cancer types. There is a well-founded scientific rationale for the combination of a telomerase vaccine and checkpoint inhibition to improve treatment response in MPM patients. NIPU is a randomized, multi-centre, open-label, phase II study comparing the efficacy and safety of nivolumab and ipilimumab with or without telomerase vaccine in patients with inoperable malignant pleural mesothelioma after first-line platinum-based chemotherapy. Participants (n = 118) are randomized 1:1 into two treatment arms. All participants receive treatment with nivolumab (240 mg every 2 weeks) and ipilimumab (1 mg/kg every 6 weeks) until disease progression, unacceptable toxicity or for a maximum of 2 years. Patients randomised to the experimental arm receive 8 intradermal injections of UV1 vaccine during the first three months of treatment. Tumour tissue, blood, urine, faeces and imaging will be collected for biomarker analyses and exploration of mechanisms for response and resistance to therapy. Checkpoint inhibition is used for treatment of mesothelioma, but many patients still do not respond. Increasing therapy response to immunotherapy is an important goal. Possible approaches include combination with chemotherapy, radiotherapy, targeted therapy and other immunotherapeutic agents. Predictive biomarkers are necessary to ensure optimal treatment for each patient and to prevent unnecessary side effects. This trial seeks to improve treatment response by combining checkpoint inhibition with a telomerase vaccine and also to explore mechanisms for treatment response and resistance. Knowledge gained in the NIPU study may be transferred to the first line setting and to other cancers with limited benefit from immunotherapy. Trial registration : ClinicalTrials.gov: NCT04300244, registered March 8th, 2020, t2/show/NCT04300244?term=NIPU& draw=2& rank=1 .
Publisher: American Society of Clinical Oncology (ASCO)
Date: 20-11-2019
DOI: 10.1200/JCO.19.01414
Abstract: The brain is a common site of metastasis for patients with high-risk melanoma. Although surgery or stereotactic radiosurgery are highly effective local treatments for a small number of metastases, there is a high risk of developing additional brain metastases. The role of adjuvant whole-brain radiotherapy (WBRT) in reducing new metastases is controversial, with a lack of high-level evidence specifically for melanoma. In this randomized phase III trial, patients who had local treatment of one to three melanoma brain metastases were randomly assigned to WBRT or observation. The primary end point was distant intracranial failure within 12 months, and secondary end points included time to intracranial failure, survival, and time to deterioration in performance status. Between April 2009 and September 2017, 215 patients were randomly assigned from 24 centers. Median follow-up was 48.1 months (range, 39.6 to 68 months). Forty-two percent of patients in the WBRT group and 50.5% of those in the observation developed distant intracranial failure within 12 months (odds ratio, 0.71 95% CI, 0.41 to 1.23 P = .22) and the rates over the entire follow-up period were 52.0% and 57.9%, respectively (odds ratio, 0.79 95% CI, 0.45 to 1.36 P = .39). Local failure rate was lower after WBRT (20.0% v 33.6% P = .03). At 12 months, 41.5% of patients in the WBRT group and 51.4% of patients in the observation group had died ( P = .28), with no difference in the rate of neurologic death. Median time to deterioration in performance status was 3.8 months after WBRT and 4.4 months with observation ( P = .32). WBRT was associated with more grade 1 to 2 acute toxicity. After local treatment of one to three melanoma brain metastases, adjuvant WBRT does not provide clinical benefit in terms of distant intracranial control, survival, or preservation of performance status.
Publisher: SAGE Publications
Date: 20-03-2014
Abstract: Aims: The aim of this study was to explore and describe the experiences of persons attending a cancer support center, providing emotional support to cancer patients through self-selected complementary therapies offered free of charge through qualified volunteer therapists. A grounded theory methodology was used. Sources of data were 16 semistructured interviews with persons attending the center. Interviews were digitally recorded and transcribed verbatim. Analysis was conducted using the constant comparative method. Findings: The overarching theme that emerged in this study was the benefits attributed to attendance at the cancer support center. The center was described as an “oasis” in the hospital, and three aspects relating to this were identified: (a) facilitating comfort, (b) increasing personal control, and (c) helping make sense of the cancer experience. Conclusion: A drop-in center offering complementary therapies appeared to enable coping with the diagnosis and treatment of cancer by facilitating comfort and increasing perceptions of personal control. The center also helped some participants to make sense of their experience with cancer. This research has provided a unique insight into the ongoing emotional needs of cancer patients, and directions for further development and research into the provision of holistic care for patients within a hospital setting.
Publisher: Elsevier BV
Date: 03-2016
DOI: 10.1016/J.LUNGCAN.2015.12.006
Abstract: The immune effects of EGFR tyrosine kinase inhibitors (EGFR-TKIs) are poorly understood. Identifying immune biomarkers could guide patient selection and optimisation of EGFR-TKI-immunotherapy combinations. 33 patients with NSCLC treated with an EGFR-TKI were prospectively enrolled. Peripheral blood mononuclear cells were collected pre-treatment, and after 1, 3 and 8 weeks. Flow cytometry was used to identify immune cell subsets, including PD-1 and PD-L1 expressing T cells. Immune parameters were correlated with clinical outcomes. Compared to healthy donors (n=10), patients had higher pre-treatment proportions of proliferating and PD-L1(+)CD3(+) T cells (p<0.001). Compared to patients with an EGFR mutation (n=12), patients without a known mutation (n=21) had higher proportions of proliferating CD4(+) and PD-L1(+)CD3(+) T cells (p=0.03). There was a significant increase in PD-L1(+) T cells after 1 week of EGFR-TKI in patients whose disease progressed compared to non-progressors. Patients with higher PD-L1(+)CD3(+) T cells at 1-week were more likely to progress (OR 30.3, p<0.01) and had shorter PFS (1.6 vs. 8.8m p<0.01) and OS (3.8 vs 23.2m p<0.001) than those with fewer PD-L1(+)CD3(+) T cells. On multivariate analysis, high PD-L1(+)CD3(+) T cells was the only independent predictor for PFS (HR 3.7, p=0.01), while for OS independent predictors were high PD-L1(+)CD3(+) T cells (HR 6.5, p<0.01) and EGFR-negative status (HR 3.3, p=0.04). There was a significant correlation between PD-L1 expression on peripheral T cells and clinical outcomes in EGFR-TKI-treated NSCLC. This warrants further validation as a blood-based biomarker that may identify candidates for PD-1 inhibitors or immunotherapy-EGFR-TKI combinations.
Publisher: Wiley
Date: 02-09-2019
Publisher: Wiley
Date: 17-10-2007
Publisher: Springer Netherlands
Date: 2013
Publisher: Elsevier BV
Date: 10-2017
Publisher: Springer Science and Business Media LLC
Date: 27-02-2019
DOI: 10.1038/S41598-019-39427-4
Abstract: Recurrence in patients with glioblastoma (GBM) is inevitable resulting in short survival times, even in patients with O-6-Methylguanine-DNA Methyltransferase ( MGMT ) methylation. Other pathways must be activated to escape from temozolomide (TMZ) treatment, however acquired resistance mechanisms to TMZ are not well understood. Herein, frozen tumors from 36 MGMT methylated patients grouped according to overall survival were extracted and proteins were profiled using surface-enhanced laser desorption/ionization (SELDI) with time-of flight (TOF) proteomics to identify low molecular weight proteins that associated with poor survival outcomes. Overexpression of macrophage migration inhibitory factor (MIF) was identified in human GBM specimens that were MGMT methylated but showed poor survival. This correlation was confirmed in an independent cohort of human GBM. MIF overexpression has been reported in several cancer types, including GBM. We repurposed ibudilast, a specific MIF inhibitor, and treated patient derived cell lines. Ibudilast showed modest anti-proliferative activity however, when combined with TMZ, significant synergism was observed, resulting in cell cycle arrest and apoptosis. In vivo , combined ibudilast and TMZ treatment of a patient derived xenograft (PDX) model resulted in significantly longer overall survival. Our findings have significant clinical implications for people with GBM. Since clinical trials involving ibudilast have shown no adverse side effects and the drug readily penetrates the blood brain barrier, treatment of GBM with this combination is clinically achievable.
Publisher: Informa UK Limited
Date: 30-07-2018
Publisher: BMJ
Date: 02-04-2014
DOI: 10.1136/JCLINPATH-2014-202173
Abstract: Glioblastoma (GBM) is a highly aggressive malignancy and the most effective treatment regime has a high relapse rate. Increasingly, the development of therapies involves defining drug-diagnostic combinations where the presence of a molecular target or marker identifies patients who are most likely to respond to a specific therapy. Trials in other solid cancers have demonstrated clear utility in the incorporation of biomarkers to stratify patients to targeted treatment, however, there are no mutations that are currently used to inform treatment options for GBM. We piloted the use of high-throughput next-generation sequencing technology to identify genetic mutations in 44 GBM specimens that may be amenable to current or future targeted therapeutic strategies. Somatic mutation profiling was performed using the AmpliSeq Cancer Hotspot Panel v2 and semiconductor sequencing technology. A total of 66 mutations were detected in 35/44 (80%) patients. The number of mutations per tumour ranged from 0 to 4 (average per tumour=1.5). The most frequent mutations were in TP53 (n=12), PTEN (n=9), EGFR (n=8) and PIK3CA (n=5). Clinically actionable somatic mutations were detected in 24/35 (69%) patients. This study demonstrates that the use of an 'off-the-shelf' oncogene primer panel and benchtop next-generation sequencer can identify mutations and potentially actionable targets in the majority of GBM patients. Data from this pilot highlights the potential for targeted genetic resequencing to identify mutations that may inform treatment options and predict outcomes.
Publisher: Springer Science and Business Media LLC
Date: 27-05-2021
DOI: 10.1186/S12913-021-06476-3
Abstract: Current international consensus is that ‘early’ referral to palliative care services improves cancer patient and family carer outcomes. In practice, however, these referrals are not routine. An approach which directly addresses identified barriers to early integration of palliative care is required. This protocol details a trial of a standardized model of early palliative care (Care Plus) introduced at key defined, disease-specific times or transition points in the illness for people with cancer. Introduced as a ‘whole of system’ practice change for identified advanced cancers, the key outcomes of interest are population health service use change. The aims of the study are to examine the effect of Care Plus implementation on (1) acute hospitalisation days in the last 3 months of life (2) timeliness of access to palliative care (3) quality and (4) costs of end of life care and (5) the acceptability of services for people with advanced cancer. Multi-site stepped wedge implementation trial testing usual care (control) versus Care Plus (practice change). The design stipulates ‘control’ periods when usual care is observed, and the process of implementing Care Plus which includes phases of planning, engagement, practice change and evaluation . During the practice change phase, all patients with targeted advanced cancers reaching the transition point will, by default, receive Care Plus. Health service utilization and unit costs before and after implementation will be collated from hospital records, and state and national health service administrative datasets. Qualitative data from patients, consumers and clinicians before and after practice change will be gathered through interviews and focus groups. The study outcomes will detail the impact and acceptability of the standardized integration of palliative care as a practice change, including recommendations for ongoing sustainability and broader implementation. Australian New Zealand Clinical Trials Registry ACTRN 12619001703190 . Registered 04 December 2019.
Publisher: Wiley
Date: 08-11-2018
DOI: 10.1111/AJCO.12806
Abstract: Assessment of magnetic resonance imaging (MRI) in glioblastoma can be challenging. For patients with recurrent glioblastoma managed on the CABARET trial, we compared disease status assessed at hospitals and subsequent blinded central expert radiological review. MRI results and clinical status at specified time points were used for site and central assessment of disease status. Clinical status was determined by the site. Response Assessment in Neuro-Oncology (RANO) criteria were used for both assessments. Site and central assessments of progression-free survival (PFS) and response rates were compared. Inter-rater variability for central review progression dates was assessed. Central review resulted in shorter PFS in 45% of 89 evaluable patients (n = 40). Median PFS was 3.6 (central) versus 3.9 months (site) (hazard ratio 1.5, 95% confidence interval 1.3-1.8, P < 0.001). Responses were documented more frequently by sites (n = 16, 18%) than centrally (n = 11, 12%). Seven of 120 patients continued on trial without site-determined progression for more than 6 months beyond the central review determination of progression. Of scans reviewed by all three central reviewers, 33% were fully concordant for progression date. While the difference between site and central PFS dates was statistically significant, the 0.3-month median difference is small. The variability within central review is consistent with previous studies, highlighting the challenges in MRI interpretation in this context. A small proportion of patients benefited from treatment well beyond the centrally determined progression date, reinforcing that clinical status together with radiology results are important determinants of whether a therapy is effective for an in idual.
Publisher: Oxford University Press (OUP)
Date: 20-12-2022
Abstract: Glioma accounts for approximately 80% of malignant adult brain cancer and its most common subtype, glioblastoma, has one of the lowest 5-year cancer survivals. Fifty risk-associated variants within 34 glioma genetic risk regions have been found by genome-wide association studies (GWAS) with a sex difference reported for 8q24.21 region. We conducted an Australian GWAS by glioma subtype and sex. We analyzed genome-wide data from the Australian Genomics and Clinical Outcomes of Glioma (AGOG) consortium for 7 573 692 single nucleotide polymorphisms (SNPs) for 560 glioma cases and 2237 controls of European ancestry. Cases were classified as glioblastoma, non-glioblastoma, astrocytoma or oligodendroglioma. Logistic regression analysis was used to assess the associations of SNPs with glioma risk by subtype and by sex. We replicated the previously reported glioma risk associations in the regions of 2q33.3 C2orf80, 2q37.3 D2HGDH, 5p15.33 TERT, 7p11.2 EGFR, 8q24.21 CCDC26, 9p21.3 CDKN2BAS, 11q21 MAML2, 11q23.3 PHLDB1, 15q24.2 ETFA, 16p13.3 RHBDF1, 16p13.3 LMF1, 17p13.1 TP53, 20q13.33 RTEL, and 20q13.33 GMEB2 (P & .05). We also replicated the previously reported sex difference at 8q24.21 CCDC26 (P = .0024) with the association being nominally significant for both sexes (P & .05). Our study supports a stronger female risk association for the region 8q24.21 CCDC26 and highlights the importance of analyzing glioma GWAS by sex. A better understanding of sex differences could provide biological insight into the cause of glioma with implications for prevention, risk prediction and treatment.
Publisher: Springer Science and Business Media LLC
Date: 25-01-2014
Publisher: Elsevier BV
Date: 07-2017
DOI: 10.1016/J.JTHO.2017.04.011
Abstract: Revisions to the TNM stage classifications for lung cancer, informed by the international database (N = 94,708) of the International Association for the Study of Lung Cancer (IASLC) Staging and Prognostic Factors Committee, need external validation. The objective was to externally validate the revisions by using the National Cancer Data Base (NCDB) of the American College of Surgeons. Cases presenting from 2000 through 2012 were drawn from the NCDB and reclassified according to the eighth edition stage classification. Clinically and pathologically staged subsets of NSCLC were analyzed separately. The T, N, and overall TNM classifications were evaluated according to clinical, pathologic, and "best" stage (N = 780,294). Multivariate analyses were carried out to adjust for various confounding factors. A combined analysis of the NSCLC cases from both databases was performed to explore differences in overall survival prognosis between the two databases. The databases differed in terms of key factors related to data source. Survival was greater in the IASLC database for all stage categories. However, the eighth edition TNM stage classification system demonstrated consistent ability to discriminate TNM categories and stage groups for clinical and pathologic stage. The IASLC revisions made for the eighth edition of lung cancer staging are validated by this analysis of the NCDB database by the ordering, statistical differences, and homogeneity within stage groups and by the consistency within analyses of specific cohorts.
Publisher: Informa UK Limited
Date: 11-05-2015
Publisher: Springer Science and Business Media LLC
Date: 14-12-2011
DOI: 10.1007/S11060-010-0495-Z
Abstract: This study sought the views of patients and their caregivers on their experience of being diagnosed with high grade glioma. Purposive s ling was used to recruit 19 patients and 21 caregivers from the medical oncology unit of a tertiary hospital. A semi-structured face-to-face interview was conducted. Interviews were audio-taped and transcribed verbatim. Data was analysed based on Grounded Theory and using the constant comparison method. This paper focuses on patient and carer perceptions of the initial communication about the diagnosis of high grade glioma and its prognosis. Themes identified included: (a) shock at hearing the diagnosis (b) trying to understand and process prognostic information when still in shock (c) the perception of hope being taken away (d) in idualizing prognostic information and (e) clinicians' lack of communication skills. This study shows that the first communication of prognosis to patients with high grade glioma and their caregivers requires careful negotiation. It illustrates the inability of in iduals to process detailed prognostic information when in a state of initial shock and distress. The importance of balancing honesty with hope in the communication of a poor prognosis is highlighted. We recommend that clinicians seek patient preferences for the amount and type of information they require and that prognostic information be in idualized. Detailed discussions of prognosis should only take place with senior medical staff, or advanced trainees who have demonstrated acceptable communication skills.
Publisher: Elsevier BV
Date: 09-2016
DOI: 10.1016/J.JTHO.2016.06.028
Abstract: Stage classification provides a consistent language to describe the anatomic extent of disease and is therefore a critical tool in caring for patients. The Staging and Prognostic Factors Committee of the International Association for the Study of Lung Cancer developed proposals for revision of the classification of lung cancer for the eighth edition of the tumor, node, and metastasis (TNM) classification, which takes effect in 2017. An international database of 94,708 patients with lung cancer diagnosed in 1999-2010 was assembled. This article describes the process and statistical methods used to refine the lung cancer stage classification. Extensive analysis allowed definition of tumor, node, and metastasis categories and stage groupings that demonstrated consistent discrimination overall and within multiple different patient cohorts (e.g., clinical or pathologic stage, R0 or R-any resection status, geographic region). Additional analyses provided evidence of applicability over time, across a spectrum of geographic regions, histologic types, evaluative approaches, and follow-up intervals. An extensive analysis has produced stage classification proposals for lung cancer with a robust degree of discriminatory consistency and general applicability. Nevertheless, external validation is encouraged to identify areas of strength and weakness a sound validation should have discriminatory ability and be based on an independent data set of adequate size and sufficient follow-up with enough patients for each subgroup.
Publisher: Oxford University Press (OUP)
Date: 08-2019
DOI: 10.1093/NEUONC/NOZ126.006
Abstract: The 1st interim analysis of the CATNON trial showed benefit from adjuvant (adj) temozolomide (TMZ) on overall survival (OS) but remained inconclusive about concurrent (conc) TMZ. A 2nd interim analysis was planned after 356 events. The 2x2 factorial design phase III CATNON trial randomized 751 adult patients with newly diagnosed non-codeleted anaplastic glioma to either 59.4 Gy radiotherapy (RT) alone the same RT with concTMZ the same RT and 12 cycles of adjTMZ or the same RT with both concTMZ and adjTMZ (doi: 10.1016/S0140-6736(17)31442-3). MGMT promoter methylation (MGMTmeth) status was re-assessed with the Infinium Methylation EPIC Beadchip using the MGMT_STP27 model. Isocitrate dehydrogenase 1 and 2 (IDH) mutation (mt) status was assessed with glioma targeted Agilent SureSelect baits sequence using an Illumina HiSeq2500 Rapid PE100. With a median follow-up of 56 months and 356 events, the hazard ratio (HR) for OS adjusted for stratification factors after concTMZ was 0.968 (99.1% CI 0.73, 1.28). 5-year OS was 50.2% with and 52.7% without concTMZ (95% CI [44.4, 55.7] and [46.9, 58.1]). An IDHmt was found in 335 of 480 assessed cases (70%). Median OS was 19 mo (95% CI 16.3, 22.3) in IDHwt tumors and 116 mo (95% CI 82.0, 116.6) in IDHmt tumors. The interaction test based on IDH status was significant (p=0.016) in the univariate HR analysis for OS after concTMZ (IDHwt, n=145, events=120, HR = 1.27, 95% CI 0.89, 1.82, p=0.19 IDHmt, n=335, events=92, HR= 0.67, 95% CI 0.44, 1.03, p=0.06). IDHmt was predictive of benefit from adjTMZ (IDHmt HR: 0.41, 95% CI 0.27, 0.64 IDHwt: HR 1.05, 95% CI 0.73, 1.52 interaction test p = 0.001). In IDHmt patients that received adjTMZ, the HR for OS after concTMZ was 0.71 (95% CI 0.35, 1.42, p=0.32). MGMTmeth was found in 288 of 410 assessed cases (70%), interaction test for concTMZ (p = 0.092) and adjTMZ (p = 0.166) did not reach statistical significance. In the entire study cohort, concTMZ did not increase OS. However, in IDHmt tumors a trend towards benefit of concTMZ is present. AdjTMZ increased OS in IDHmt but not in IDHwt tumors. Further analyses and follow-up will allow full assessment of efficacy in the molecular subgroups.
Publisher: American Society of Clinical Oncology (ASCO)
Date: 10-2013
Abstract: To determine the accuracy and usefulness of oncologists' estimates of survival time in in idual patients with advanced cancer. Twenty-one oncologists estimated the “median survival of a group of identical patients” for each of 114 patients with advanced cancer. Accuracy was defined by the proportions of patients with an observed survival time bounded by prespecified multiples of their estimated survival time. We expected 50% to live longer (or shorter) than their oncologist's estimate (calibration), 50% to live from half to double their estimate (typical scenario), 5% to 10% to live ≤ one quarter of their estimate (worst-case scenario), and 5% to 10% to live three or more times their estimate (best-case scenario). Estimates within 0.67 to 1.33 times observed survival were deemed precise. Discriminative value was assessed with Harrell's C-statistic and prognostic significance with proportional hazards regression. Median survival time was 11 months. Oncologists' estimates were relatively well-calibrated (61% shorter than observed), imprecise (29% from 0.67 to 1.33 times observed), and moderately discriminative (Harrell C-statistic 0.63 P = .001). The proportion of patients with an observed survival half to double their oncologist's estimate was 63%, ≤ one quarter of their oncologist's estimate was 6%, and three or more times their oncologist's estimate was 14%. Independent predictors of observed survival were oncologist's estimate (hazard ratio [HR] = 0.92 P = .004), dry mouth (HR = 5.1 P .0001), alkaline phosphatase more than 101U/L (HR = 2.8 P = .0002), Karnofsky performance status ≤ 70 (HR = 2.3 P = .007), prostate primary (HR = 0.23 P = .002), and steroid use (HR = 2.4 P = .02). Oncologists' estimates of survival time were relatively well-calibrated, moderately discriminative, independently associated with observed survival, and a reasonable basis for estimating worst-case, typical, and best-case scenarios for survival.
Publisher: Elsevier BV
Date: 07-2005
DOI: 10.1016/J.LUNGCAN.2005.03.030
Abstract: The unique growth pattern of malignant pleural mesothelioma (MPM) presents challenges for clinical investigators assessing tumour response to treatment. Assessment of response is an important surrogate for patient benefit, particularly in phase II clinical trials. Neither the previous WHO criteria nor the more recent RECIST criteria are well suited to tumour measurement in this disease. This paper discusses uni-dimensional measurement of tumour response in pleural mesothelioma, and the development and validation of the modified RECIST criteria for MPM, which attempt to overcome some of the shortcomings of the RECIST criteria in this setting.
Publisher: Elsevier BV
Date: 11-2003
Publisher: Elsevier BV
Date: 07-2023
Publisher: Elsevier BV
Date: 10-2013
Publisher: Elsevier BV
Date: 07-2007
Publisher: Public Library of Science (PLoS)
Date: 10-09-2009
Publisher: Frontiers Media SA
Date: 18-02-2020
Publisher: American Society of Clinical Oncology (ASCO)
Date: 09-2019
DOI: 10.1200/JCO.19.01208
Publisher: American Association for Cancer Research (AACR)
Date: 11-03-2022
DOI: 10.1158/1078-0432.CCR-21-4283
Abstract: In a post hoc analysis of the CATNON trial (NCT00626990), we explored whether adding temozolomide to radiotherapy improves outcome in patients with IDH1/2 wildtype (wt) anaplastic astrocytomas with molecular features of glioblastoma [redesignated as glioblastoma, isocitrate dehydrogenase–wildtype (IDH-wt) in the 2021 World Health Organization (WHO) classification of central nervous system tumors]. From the randomized phase III CATNON study examining the addition of adjuvant and concurrent temozolomide to radiotherapy in anaplastic astrocytomas, we selected a subgroup of IDH1/2wt and H3F3Awt tumors with presence of TERT promoter mutations and/or EGFR lifications and/or combined gain of chromosome 7 and loss of chromosome 10. Molecular abnormalities including MGMT promoter methylation status were determined by next-generation sequencing, DNA methylation profiling, and SNaPshot analysis. Of the 751 patients entered in the CATNON study, 670 had fully molecularly characterized tumors. A total of 159 of these tumors met the WHO 2021 molecular criteria for glioblastoma, IDH-wt. Of these patients, 47 received radiotherapy only and 112 received a combination of radiotherapy and temozolomide. There was no added effect of temozolomide on either overall survival [HR, 1.19 95% confidence interval (CI), 0.82–1.71] or progression-free survival (HR, 0.87 95% CI, 0.61–1.24). MGMT promoter methylation was prognostic for overall survival, but was not predictive for outcome to temozolomide treatment either with respect to overall survival or progression-free survival. In this cohort of patients with glioblastoma, IDH-wt temozolomide treatment did not add benefit beyond that observed from radiotherapy, regardless of MGMT promoter status. These findings require a new well-powered prospective clinical study to explore the efficacy of temozolomide treatment in this patient population.
Publisher: BMJ
Date: 10-2015
Publisher: Research Square Platform LLC
Date: 20-05-2022
DOI: 10.21203/RS.3.RS-1613398/V1
Abstract: Immune checkpoint therapy (ICT) causes durable tumor responses in a subgroup of patients. Profiling T cell receptor beta (TCRβ) repertoire structure in ICT responders and non-responders provides mechanistic insight into what constitutes an effective anti-tumor response, and could result in the development of predictive biomarkers of response to identify and stratify patients for ICT. To examine how the TCRβ repertoire dynamics contribute to ICT response, we utilized an established murine model that excludes variation in host genetics, environmental factors and tumor mutation burden, limiting variation between animals to naturally erse TCRβ repertoires. Oligoclonal expansion of TCRβ clonotypes that corresponded with a low TCRβ ersity was observed in responding tumors prior to ICT. We modeled TCRβ cluster dynamics during ICT and found that select clonotypes expanded slower in responders compared to non- responders. Clonally expanded CD8+ tumor infiltrating T cells in non-responders exhibited a T cell exhaustion phenotype. We conclude that an early burst of clonal expansion followed by a contraction during ICT is associated with response.
Publisher: Springer Science and Business Media LLC
Date: 15-06-2017
Publisher: Oxford University Press (OUP)
Date: 11-12-2014
Abstract: Glioblastoma is the most common and most aggressive primary brain malignancy. The current initial standard of care consists of maximal safe surgical resection followed by radical radiotherapy and adjuvant temozolomide. Despite optimal therapy, median survival is ~15 months from diagnosis in molecularly unselected patients, and <6 months for patients with recurrent disease. Therefore, clinical treatments are currently palliative, not curative. Collectively, current knowledge suggests that the continued tumor growth and recurrence is in part due to the presence of glioma stem-like cells, which display self-renewal and tumorigenic potential. They differ from their more differentiated progeny, as they are more resistant to current treatments. Recurrent disease may be a consequence of the enhancement and/or gain of stem cell-like characteristics during disease progression, together with preferential death of more differentiated tumor cells during treatment, signifying that the cancer stem cell phenotype is a crucial therapeutic target. The limited knowledge of the characteristics of these cells and their response to current clinical treatments warrants intensive investigation with the aim to improve patient survival and/or develop a cure for this disease.
Publisher: Elsevier BV
Date: 02-2020
DOI: 10.1016/J.LUNGCAN.2019.12.018
Abstract: Currently, there is no optimal salvage therapy for patients with malignant pleural mesothelioma (MPM) who relapse after treatment with first-line chemotherapy. In line with the strong preclinical rationale for targeting fibroblast growth factor receptor (FGFR) signalling in malignant mesothelioma, we conducted a phase II study assessing the efficacy of AZD4547, an oral tyrosine multi-kinase FGFR 1-3 inhibitor, as a second or third-line treatment. We conducted a single-center, open-label, single-arm phase II study of AZD4547 in eligible patients with confirmed, measurable MPM and radiological progression after first or second-line systemic chemotherapy. Patients received continuous, twice-daily oral AZD4547 on a 3-weekly cycle. The primary end point was 6-month progression free survival (PFS6). Response was assessed with CT scan every 6 weeks according to the modified RECIST criteria for mesothelioma (mRECIST) and toxicities were also assessed. The study used a Simon's two-stage design: 26 patients would be recruited to the first stage and more than 7 (27 %) of 26 patients were required to achieve PFS6 to continue to stage two, for a potential total cohort of 55 patients. 3 of 24 patients (12 %) were progression-free at 6 months. Hence, the study fulfilled stopping criteria regardless of further recruitment and warranted discontinuation. The most common toxicities (across all grades) were hyperphosphatemia, xerostomia, mucositis, retinopathy, dysgeusia, and fatigue. Maximum toxicities were grade 2 or below for all patients across all cycles. There was no association between tumour BAP1 protein loss and clinical outcomes. The FGFR 1-3 inhibitor AZD4547 did not demonstrate efficacy in patients with MPM who had progressed after first line treatment with platinum-based chemotherapy.
Publisher: Society of Nuclear Medicine
Date: 17-08-2007
DOI: 10.2967/JNUMED.107.042333
Abstract: The aim of chemotherapy for mesothelioma is to palliate symptoms and improve survival. Measuring response using CT is challenging because of the circumferential tumor growth pattern. This study aims to evaluate the role of serial (18)F-FDG PET in the assessment of response to chemotherapy in patients with mesothelioma. Patients were prospectively recruited and underwent both (18)F-FDG PET and conventional radiological response assessment before and after 1 cycle of chemotherapy. Quantitative volume-based (18)F-FDG PET analysis was performed to obtain the total glycolytic volume (TGV) of the tumor. Survival outcomes were measured. Twenty-three patients were suitable for both radiological and (18)F-FDG PET analysis, of whom 20 had CT measurable disease. After 1 cycle of chemotherapy, 7 patients attained a partial response and 13 had stable disease on CT assessment by modified RECIST (Response Evaluation Criteria in Solid Tumors) criteria. In the 7 patients with radiological partial response, the median TGV on quantitative PET analysis fell to 30% of baseline (range, 11%-71%). After 1 cycle of chemotherapy, Cox regression analysis demonstrated a statistically significant relationship between a fall in TGV and improved patient survival (P = 0.015). Neither a reduction in the maximum standardized uptake value (P = 0.097) nor CT (P = 0.131) demonstrated a statistically significant association with patient survival. Semiquantitative (18)F-FDG PET using the volume-based parameter of TGV is feasible in mesothelioma and may predict response to chemotherapy and patient survival after 1 cycle of treatment. Therefore, metabolic imaging has the potential to improve the care of patients receiving chemotherapy for mesothelioma by the early identification of responding patients. This technology may also be useful in the assessment of new systemic treatments for mesothelioma.
Publisher: Springer Science and Business Media LLC
Date: 17-04-2011
Abstract: Cerebral metastases are a common cause of death in patients with melanoma. Systemic drug treatment of these metastases is rarely effective, and where possible surgical resection and/or stereotactic radiosurgery (SRS) are the preferred treatment options. Treatment with adjuvant whole brain radiotherapy (WBRT) following neurosurgery and/or SRS is controversial. Proponents of WBRT report prolongation of intracranial control with reduced neurological events and better palliation. Opponents state melanoma is radioresistant that WBRT yields no survival benefit and may impair neurocognitive function. These opinions are based largely on studies in other tumour types in which assessment of neurocognitive function has been incomplete. This trial is an international, prospective multi-centre, open-label, phase III randomised controlled trial comparing WBRT to observation following local treatment of intracranial melanoma metastases with surgery and/or SRS. Patients aged 18 years or older with 1-3 brain metastases excised and/or stereotactically irradiated and an ECOG status of 0-2 are eligible. Patients with leptomeningeal disease, or who have had previous WBRT or localised treatment for brain metastases are ineligible. WBRT prescription is at least 30 Gy in 10 fractions commenced within 8 weeks of surgery and/or SRS. Randomisation is stratified by the number of cerebral metastases, presence or absence of extracranial disease, treatment centre, sex, radiotherapy dose and patient age. The primary endpoint is the proportion of patients with distant intracranial failure as determined by MRI assessment at 12 months. Secondary end points include: survival, quality of life, performance status and neurocognitive function. Accrual to previous trials for patients with brain metastases has been difficult, mainly due to referral bias for or against WBRT. This trial should provide the evidence that is currently lacking in treatment decision-making for patients with melanoma brain metastases. The trial is conducted by the Australia and New Zealand Melanoma Trials Group (ANZMTG-study 01-07), and the Trans Tasman Radiation Oncology Group (TROG) but international participation is encouraged. Twelve sites are open to date with 43 patients randomised as of the 31st March 2011. The target accrual is 200 patients. Australia and New Zealand Clinical Trials Register (ANZCTR): ACTRN12607000512426
Publisher: Elsevier BV
Date: 11-2016
Publisher: MDPI AG
Date: 04-02-2021
Abstract: We have developed a platform, termed PathoFusion, which is an integrated system for marking, training, and recognition of pathological features in whole-slide tissue sections. The platform uses a bifocal convolutional neural network (BCNN) which is designed to simultaneously capture both index and contextual feature information from shorter and longer image tiles, respectively. This is analogous to how a microscopist in pathology works, identifying a cancerous morphological feature in the tissue context using first a narrow and then a wider focus, hence bifocal. Adjacent tissue sections obtained from glioblastoma cases were processed for hematoxylin and eosin (H& E) and immunohistochemical (CD276) staining. Image tiles cropped from the digitized images based on markings made by a consultant neuropathologist were used to train the BCNN. PathoFusion demonstrated its ability to recognize malignant neuropathological features autonomously and map immunohistochemical data simultaneously. Our experiments show that PathoFusion achieved areas under the curve (AUCs) of 0.985 ± 0.011 and 0.988 ± 0.001 in patch-level recognition of six typical pathomorphological features and detection of associated immunoreactivity, respectively. On this basis, the system further correlated CD276 immunoreactivity to abnormal tumor vasculature. Corresponding feature distributions and overlaps were visualized by heatmaps, permitting high-resolution qualitative as well as quantitative morphological analyses for entire histological slides. Recognition of more user-defined pathomorphological features can be added to the system and included in future tissue analyses. Integration of PathoFusion with the day-to-day service workflow of a (neuro)pathology department is a goal. The software code for PathoFusion is made publicly available.
Publisher: Elsevier BV
Date: 04-2022
Publisher: Wiley
Date: 14-01-2011
DOI: 10.1111/J.1743-7563.2010.01374.X
Abstract: We report two cases of the rare neurological paraneoplastic syndrome, limbic encephalitis, as the initial presentation of small cell lung cancer. The first case responded to treatment of the underlying malignancy, while the second required more acute treatment in the intensive care setting. In this case, initial treatment was with immunosuppression to achieve a degree of stability before the underlying malignancy could be treated. Both cases had significant improvement in neurological function. These cases highlight the importance of directed investigation to try and identify an underlying malignancy in patients in whom a diagnosis of limbic encephalitis is made, and the difficulty in managing such patients.
Publisher: Wiley
Date: 12-2009
DOI: 10.1111/J.1445-5994.2009.02019.X
Abstract: Abstract Patients with inoperable non-small cell lung cancer diagnosed and managed at a single institution over a one-year period were identified. Those whose case had been discussed at a multidisciplinary meeting had better survival than those whose case was not discussed (mean survival 280 days vs. 205 days, log-rank P= 0.048).
Publisher: Informa UK Limited
Date: 17-07-2012
DOI: 10.3109/08830185.2012.698338
Abstract: Agonistic anti-CD40 antibody is a potent stimulator of anti-tumor immune responses due to its action on both immune and tumor cells. It has the ability to "precondition" dendritic cells, allowing them to prime effective cytotoxic T-cell responses. Thus, anti-CD40 antibody provides an ideal therapy for combination with traditional cancer treatments (i.e., chemotherapy, surgery) in order to elicit immune-mediated anti-tumor effects. This review summarizes the mechanisms of action of agonistic anti-CD40, the use of mouse models to investigate its effects and combinations with other therapies in vivo, and current clinical trials combining humanized anti-CD40 antibody with chemotherapy and/or other immunotherapies.
Publisher: Wiley
Date: 07-02-2018
Publisher: Elsevier BV
Date: 07-2005
DOI: 10.1016/J.LUNGCAN.2005.03.020
Abstract: Identification of tumor marker for mesothelioma (MM) might prove useful in diagnosis as well as for monitoring tumor in response to therapy and for screening at-risk in iduals. We tested the hypothesis that soluble mesothelin-related protein (SMRP), a mesothelin family member, in the serum would be such a marker. Our data show that determination of SMRP in serum is a marker of MM with a sensitivity of sensitivity 83% and specificity 95% in the first 48 MM patients tested. Changes in serum SMRP levels parallel clinical course/tumor size and SMRP is elevated in 75% of patients at diagnosis. SMRP should also be useful for monitoring disease progression, and importantly, may prove useful for screening asbestos-exposed in iduals for early MM.
Publisher: Elsevier BV
Date: 07-2005
DOI: 10.1016/J.LUNGCAN.2005.03.021
Abstract: Australasia has a strong record in clinical trials in malignant pleural mesothelioma (MPM), driven by the relatively high incidence of this disease in the region. Two current and three proposed trials in mesothelioma in this region are discussed, covering the erse clinical scenarios of diagnosis and staging, health-related quality of life, maintenance therapy, prediction of response and combined modality treatment.
Publisher: Wiley
Date: 30-10-2012
DOI: 10.1111/AJCO.12030
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22487439.V1
Abstract: Supplementary Figure from Temozolomide and Radiotherapy versus Radiotherapy Alone in Patients with Glioblastoma, i IDH /i -wildtype: i Post Hoc /i Analysis of the EORTC Randomized Phase III CATNON Trial
Publisher: Elsevier BV
Date: 10-2019
DOI: 10.1016/J.JOCN.2019.07.063
Abstract: There is limited information on the patterns of care and outcomes of high grade gliomas (HGGs) in young adults, in particular, the impact it has on a person's employment. We retrospectively identified young adult patients (age ≤ 40 years old) with newly diagnosed high grade gliomas treated between January 2013 and June 2018 across four major neuro-oncology centres in Australia. Patient demographics, tumour characteristics and treatment parameters were collected and outcomes determined. A total of 113 patients were identified with a median follow up of 27.0 months (range 1.0-70.2 months). The median age was 31 years, majority were male (65%) and employed (71.6%). IDH mutations were detected in 66 (62%) cases. The median progression-free survival (PFS) was 38.0 months (95% CI 23.3-52.7 months) and median overall survival (OS) was not reached. Patients with IDH wild type anaplastic astrocytoma and glioblastoma had a significantly shorter median PFS (19.3 months vs. NR, p = 0.001) and median OS (43.5 months vs NR, p = 0.007) than those with IDH mutated grade III anaplastic astrocytoma and oligodendroglioma. There was no significant difference in median OS or PFS between patients who underwent gross or subtotal tumour resection. Significantly, after diagnosis only 36 (32%) patients reported being employed. Young patients with IDH wild type astrocytomas and glioblastoma had better outcomes than reported historical controls. Most patients did not continue in employment post diagnosis.
Publisher: Springer Science and Business Media LLC
Date: 09-04-2022
DOI: 10.1007/S11060-022-03991-Z
Abstract: This study aimed to: determine the supportive care available for Australian patients with High Grade Glioma (HGG) and their carers identify service gaps and inform changes needed to implement guidelines and Optimal Care Pathways. This cross-sectional online survey recruited multidisciplinary health professionals (HPs) who were members of the Cooperative Trials Group for Neuro-Oncology involved in management of patients diagnosed with HGG in Australian hospitals. Descriptive statistics were calculated. Fisher's exact test was used to explore differences between groups. 42 complete responses were received. A majority of MDT meetings were attended by a: neurosurgeon, radiation oncologist, medical oncologist, radiologist, and care coordinator. Less than 10% reported attendance by a palliative care nurse physiotherapist neuropsychologist or speech therapist. Most could access referral pathways to a cancer care coordinator (76%), neuropsychologist (78%), radiation oncology nurse (77%), or psycho-oncologist (73%), palliative care (93–100%) and mental health professionals (60–85%). However, few routinely referred to an exercise physiologist (10%), rehabilitation physician (22%), dietitian (22%) or speech therapist (28%). Similarly, routine referrals to specialist mental health services were not standard practice. Nearly all HPs (94%) reported HGG patients were advised to present to their GP for pre-existing conditions/comorbidities however, most HPs took responsibility (≤ 36% referred to GP) for social issues, mental health, symptoms, cancer complications, and treatment side-effects. While certain services are accessible to HGG patients nationally, improvements are needed. Psychosocial support, specialist allied health, and primary care providers are not yet routinely integrated into the care of HGG patients and their carers despite these services being considered essential in clinical practice guidelines and optimal care pathways.
Publisher: Elsevier BV
Date: 08-2016
DOI: 10.1016/J.JTHO.2016.03.025
Abstract: This article proposes codes for the primary tumor categories of adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma (MIA) and a uniform way to measure tumor size in part-solid tumors for the eighth edition of the tumor, node, and metastasis classification of lung cancer. In 2011, new entities of AIS, MIA, and lepidic predominant adenocarcinoma were defined, and they were later incorporated into the 2015 World Health Organization classification of lung cancer. To fit these entities into the T component of the staging system, the Tis category is proposed for AIS, with Tis (AIS) specified if it is to be distinguished from squamous cell carcinoma in situ (SCIS), which is to be designated Tis (SCIS). We also propose that MIA be classified as T1mi. Furthermore, the use of the invasive size for T descriptor size follows a recommendation made in three editions of the Union for International Cancer Control tumor, node, and metastasis supplement since 2003. For tumor size, the greatest dimension should be reported both clinically and pathologically. In nonmucinous lung adenocarcinomas, the computed tomography (CT) findings of ground glass versus solid opacities tend to correspond respectively to lepidic versus invasive patterns seen pathologically. However, this correlation is not absolute so when CT features suggest nonmucinous AIS, MIA, and lepidic predominant adenocarcinoma, the suspected diagnosis and clinical staging should be regarded as a preliminary assessment that is subject to revision after pathologic evaluation of resected specimens. The ability to predict invasive versus noninvasive size on the basis of solid versus ground glass components is not applicable to mucinous AIS, MIA, or invasive mucinous adenocarcinomas because they generally show solid nodules or consolidation on CT.
Publisher: Elsevier BV
Date: 09-2012
Publisher: Research Square Platform LLC
Date: 24-09-2021
DOI: 10.21203/RS.3.RS-892399/V1
Abstract: Little is known about the dynamic biological events that underpin therapeutic efficacy in immune checkpoint blockade (ICB) in cancer, due to the inability to frequently s le tumors in patients. Here, we mapped the transcriptional profiles of 144 responding and non-responding tumors within two mouse models at four time points during ICB. We found that responding tumors displayed on/fast-off kinetics of type-I-interferon (IFN) signaling. Phenocopying of this kinetics using time-dependent sequential dosing of recombinant IFNs and neutralizing anti-bodies markedly improved ICB efficacy, but only when IFNβ was targeted, not IFNα. We identified Ly6C+/CD11b+ inflammatory monocytes as the primary source of IFNβ and found that active type-I-IFN signaling in tumor-infiltrating inflammatory monocytes was associated with T cell expansion in patients treated with ICB. Together, our results suggest that on/fast-off modulation of IFNβ signaling is critical to the therapeutic response to ICB, which can be exploited to drive clinical outcomes towards response.
Publisher: Springer Science and Business Media LLC
Date: 22-03-2011
DOI: 10.1007/S11864-011-0149-1
Abstract: Novel targeted therapies have found a niche in the treatment of many cancers, although the most responsive populations, best biomarkers of response, and appropriate treatment settings are still under investigation. With few exceptions, cancer vaccination strategies have not entered into routine management. In malignant mesothelioma, combination first-line chemotherapy with a platinum and pemetrexed remains the standard of care when systemic therapy is considered. Second-line chemotherapy is used but benefits are uncertain in the absence of appropriately controlled randomized trials. Currently, there are no novel targeted therapies or vaccinations that should be used in this disease outside the context of a clinical trial.
Publisher: Elsevier BV
Date: 10-2019
DOI: 10.1016/J.JTHO.2019.08.012
Abstract: Detailed guidelines pertaining to radiological assessment of malignant pleural mesothelioma are currently lacking due to the rarity of the disease, complex morphology, propensity to invade multiple planes simultaneously, and lack of specific recommendations within the radiology community about assessment, reporting, and follow-up. In March 2017, a multidisciplinary meeting of mesothelioma experts was co-sponsored by the National Cancer Institute Thoracic Malignancy Steering Committee, International Association for the Study of Lung Cancer, and the Mesothelioma Applied Research Foundation. One of the outcomes of this conference was the foundation of detailed, multidisciplinary consensus imaging and management guidelines. Here, we present the recommendations for radiologic assessment of malignant pleural mesothelioma in the setting of clinical trial enrollment. We discuss optimization of imaging parameters across modalities, standardized reporting, and response assessment within clinical trials.
Publisher: Elsevier BV
Date: 11-2022
DOI: 10.1016/J.CELL.2022.09.039
Abstract: Human brain development is underpinned by cellular and molecular reconfigurations continuing into the third decade of life. To reveal cell dynamics orchestrating neural maturation, we profiled human prefrontal cortex gene expression and chromatin accessibility at single-cell resolution from gestation to adulthood. Integrative analyses define the dynamic trajectories of each cell type, revealing major gene expression reconfiguration at the prenatal-to-postnatal transition in all cell types followed by continuous reconfiguration into adulthood and identifying regulatory networks guiding cellular developmental programs, states, and functions. We uncover links between expression dynamics and developmental milestones, characterize the erse timing of when cells acquire adult-like states, and identify molecular convergence from distinct developmental origins. We further reveal cellular dynamics and their regulators implicated in neurological disorders. Finally, using this reference, we benchmark cell identities and maturation states in organoid models. Together, this captures the dynamic regulatory landscape of human cortical development.
Publisher: Wiley
Date: 24-02-2009
Publisher: Oxford University Press (OUP)
Date: 29-04-2021
Abstract: Survival in patients with IDH1/2-mutant (mt) anaplastic astrocytomas is highly variable. We have used the prospective phase 3 CATNON trial to identify molecular factors related to outcome in IDH1/2mt anaplastic astrocytoma patients. The CATNON trial randomized 751 adult patients with newly diagnosed 1p/19q non-codeleted anaplastic glioma to 59.4 Gy radiotherapy +/− concurrent and/or adjuvant temozolomide. The presence of necrosis and/or microvascular proliferation was scored at central pathology review. Infinium MethylationEPIC BeadChip arrays were used for genome-wide DNA methylation analysis and the determination of copy number variations (CNV). Two DNA methylation-based tumor classifiers were used for risk stratification. Next-generation sequencing (NGS) was performed using 1 of the 2 glioma-tailored NGS panels. The primary endpoint was overall survival measured from the date of randomization. Full analysis (genome-wide DNA methylation and NGS) was successfully performed on 654 tumors. Of these, 432 tumors were IDH1/2mt anaplastic astrocytomas. Both epigenetic classifiers identified poor prognosis patients that partially overlapped. A predictive prognostic Cox proportional hazard model identified that independent prognostic factors for IDH1/2mt anaplastic astrocytoma patients included age, mini-mental state examination score, treatment with concurrent and/or adjuvant temozolomide, the epigenetic classifiers, PDGFRA lification, CDKN2A/B homozygous deletion, PI3K mutations, and total CNV load. Independent recursive partitioning analysis highlights the importance of these factors for patient prognostication. Both clinical and molecular factors identify IDH1/2mt anaplastic astrocytoma patients with worse outcome. These results will further refine the current WHO criteria for glioma classification.
Publisher: Elsevier BV
Date: 09-2015
Publisher: Informa UK Limited
Date: 16-09-2015
Publisher: Elsevier BV
Date: 02-2019
DOI: 10.1016/J.JTHO.2018.10.005
Abstract: Malignant pleural mesothelioma (MPM) is an uncommon cancer with a poor prognosis and heterogeneous survival. Surgery for MPM is offered in some specialist centers to highly selected patients. A previously described classification and regression tree (CART) model stratified survival in unselected MPM patients using routinely collected clinical data. This study aimed to examine the performance of this CART model on a highly selected surgical population. Data were collected from subjects undergoing cytoreductive surgery for MPM from specialist centers in Hyõgo, Japan, and Sydney, Australia, between 1991 and 2016. The CART model was applied using the combination of clinical variables to stratify subjects into risk groups (1 through 4) survival characteristics were then compared. Two hundred eighty-nine cases were included (205 from Australia, 84 from Japan). Overall median survival was 34.6 (interquartile range: 17.5-56.1) months median age was 63.0 (interquartile range: 57.0-67.8) years, and 83.0% (n = 240) were male. There were no clinically meaningful differences between the two cohorts. Survival across the four risk groups was significantly different (p 153 g/L and serum albumin > 43 g/L at time of referral to the surgical center. Using routinely available clinical variables, the CART model was able to stratify surgical patients into risk groups with statistically different survival characteristics with fair to good performance. Presence of weight loss, anemia, and low albumin should confer caution when considering surgical therapy for MPM.
Publisher: Elsevier BV
Date: 04-2016
DOI: 10.1016/J.COI.2015.12.003
Abstract: Cancer immunotherapy, and in particular checkpoint blockade, is now standard clinical care for a growing number of cancers. Cytotoxic drugs have been the primary weapon against cancer for a long time and have typically been understood because of their capacity to directly kill tumour cells. It is now clear that these drugs are potential partners for checkpoint blockade and different drugs can influence the immune response to cancer through a wide variety of mechanisms. Some of these relate to immunogenic cell death, whilst others relate to changes in antigen-presentation, tumour cell targeting, or depletion of immunosuppressive cells. Here, we review some recent advances in our understanding of the immunological changes associated with chemotherapy, discuss progress in combining chemotherapy with checkpoint blockade, and comment on the difficulties encountered in translating promising preclinical data into successful treatments for cancer patients.
Publisher: American Chemical Society (ACS)
Date: 09-11-2006
DOI: 10.1021/JP065115P
Abstract: Molecules acting as antioxidants capable of scavenging reactive oxygen species (ROS) are of utmost importance in the living cell. The antioxidative properties of pyridoxine (vitamin B6) have recently been discovered. In this study, we have analyzed the reactivity of pyridoxine toward the ROS (.-)OH, (.-)OOH, and (.-)O(2)- at the density functional theory level (functionals B3LYP and MPW1B95). Two reaction types have been studied as follows: addition to the aromatic ring atoms and hydrogen roton abstraction. Our results show that (.-)OH is the most reactive species, while (.-)OOH displays low reactivity and (.-)O2(-) does not react at all with pyridoxine. The most exergonic reactions are those where (.-)H is removed from the CH(2)OH groups or the ring-bound OH group and range from -33 to -39 kcal/mol. The most exergonic addition reactions occur by attacking the carbon atoms bonded to nitrogen but with an energy gain of only 6 kcal/mol.
Publisher: Elsevier BV
Date: 05-2018
Publisher: Springer Science and Business Media LLC
Date: 11-03-2020
Publisher: Elsevier BV
Date: 05-2022
DOI: 10.1016/J.LUNGCAN.2022.03.012
Abstract: In CheckMate 743 (NCT02899299), nivolumab + ipilimumab significantly prolonged overall survival in patients with unresectable malignant pleural mesothelioma (MPM). We present patient-reported outcomes (PROs). Patients (N = 605) were randomized to nivolumab + ipilimumab or chemotherapy. Changes in disease-related symptom burden and health-related quality of life (HRQoL) were evaluated descriptively using the Lung Cancer Symptom Scale (LCSS)-Mesothelioma (Meso) average symptom burden index (ASBI), LCSS-Meso 3-item global index (3-IGI), 3-level EuroQol 5-dimensional (EQ-5D-3L) visual analog score (VAS), and EQ-5D-3L utility index. PROs were assessed at baseline and every 2 (nivolumab + ipilimumab) or 3 weeks (chemotherapy) through 12 weeks, every 6 weeks through 12 months, every 12 weeks thereafter, and at specified follow-ups. Mixed-effect model repeated measures (MMRM) and time to deterioration analyses were conducted. Completion rates were generally >80%. LCSS-Meso ASBI mean changes from baseline trended to improve over time with nivolumab + ipilimumab and deteriorate with chemotherapy, but did not meet clinically important difference thresholds [±10 score change]. EQ-5D-3L VAS mean scores improved over time with nivolumab + ipilimumab by week 60, patients had scores consistent with United Kingdom normal population values. MMRM analyses favored nivolumab + ipilimumab for all in idual symptoms except cough. Nivolumab + ipilimumab delayed time to definitive deterioration in HRQoL (hazard ratio 0.52 [95% confidence interval 0.36-0.74]) and showed a trend in symptom delay versus chemotherapy. Nivolumab + ipilimumab decreased the risk of deterioration in disease-related symptoms and HRQoL versus chemotherapy and maintained QoL in patients with unresectable MPM.
Publisher: CSIRO Publishing
Date: 2016
DOI: 10.1071/WF14193
Abstract: Bushfire survival plans are a valuable tool for residents living in fire-prone landscapes. Plans include assigning trigger points for action, roles for all household members, and alternate approaches should the original plan fail. Fire agencies advocate that residents write, practise and discuss these plans before the fire season. In this study we use a multiple-methods approach to examine the theoretical and actual application of bushfire survival plans in south-east Australia. First, we review agency advice regarding survival plans to determine the consistency, clarity and specificity of the advice. Second, an online survey of residents examines the relationships between types of plans, with the planned action during a wildfire, gender and past experience with fire. Finally, semi-structured interviews with residents who have experienced wildfire examine the reality of decision-making, triggers used for actions and the role of survival plans. The study concludes that: a) fire agencies provide clear and concise information around survival plans despite some variation between states b) preparation of survival plans is limited by the same range of factors that limit the extent of overall wildfire preparedness and c) without a written, discussed and practised plan, decision-making during a wildfire may be impaired with potentially fatal consequences.
Publisher: Springer Science and Business Media LLC
Date: 19-08-2022
DOI: 10.1038/S41467-022-32567-8
Abstract: The biological determinants of the response to immune checkpoint blockade (ICB) in cancer remain incompletely understood. Little is known about dynamic biological events that underpin therapeutic efficacy due to the inability to frequently s le tumours in patients. Here, we map the transcriptional profiles of 144 responding and non-responding tumours within two mouse models at four time points during ICB. We find that responding tumours display on/fast-off kinetics of type-I-interferon (IFN) signaling. Phenocopying of this kinetics using time-dependent sequential dosing of recombinant IFNs and neutralizing antibodies markedly improves ICB efficacy, but only when IFNβ is targeted, not IFNα. We identify Ly6C + /CD11b + inflammatory monocytes as the primary source of IFNβ and find that active type-I-IFN signaling in tumour-infiltrating inflammatory monocytes is associated with T cell expansion in patients treated with ICB. Together, our results suggest that on/fast-off modulation of IFNβ signaling is critical to the therapeutic response to ICB, which can be exploited to drive clinical outcomes towards response.
Publisher: Springer Science and Business Media LLC
Date: 17-06-2019
Publisher: Elsevier BV
Date: 10-2006
Publisher: Oxford University Press (OUP)
Date: 28-09-2018
DOI: 10.1634/THEONCOLOGIST.2018-0290
Abstract: We assessed the efficacy and safety of bevacizumab (BEV) through multiple lines in patients with recurrent glioblastoma who had progressed after first-line treatment with radiotherapy, temozolomide, and BEV. TAMIGA (NCT01860638) was a phase II, randomized, double-blind, placebo-controlled, multicenter trial in adult patients with glioblastoma. Following surgery, patients with newly diagnosed glioblastoma received first-line treatment consisting of radiotherapy plus temozolomide and BEV, followed by six cycles of temozolomide and BEV, then BEV monotherapy until disease progression (PD1). Randomization occurred at PD1 (second line), and patients received lomustine (CCNU) plus BEV (CCNU + BEV) or CCNU plus placebo (CCNU + placebo) until further disease progression (PD2). At PD2 (third line), patients continued BEV or placebo with chemotherapy (investigator's choice). The primary endpoint was survival from randomization. Secondary endpoints were progression-free survival in the second and third lines (PFS2 and PFS3) and safety. Of the 296 patients enrolled, 123 were randomized at PD1 (CCNU + BEV, n = 61 CCNU + placebo, n = 62). The study was terminated prematurely because of the high drop-out rate during first-line treatment, implying underpowered inferential testing. The proportion of patients receiving corticosteroids at randomization was similar (BEV 33%, placebo 31%). For the CCNU + BEV and CCNU + placebo groups, respectively, median survival from randomization was 6.4 versus 5.5 months (stratified hazard ratio [HR], 1.04 95% confidence interval [CI], 0.69–1.59), median PFS2 was 2.3 versus 1.8 months (stratified HR, 0.70 95% CI, 0.48–1.00), median PFS3 was 2.0 versus 2.2 months (stratified HR, 0.70 95% CI, 0.37–1.33), and median time from randomization to a deterioration in health-related quality of life was 1.4 versus 1.3 months (stratified HR, 0.76 95% CI, 0.52–1.12). The incidence of treatment-related grade 3 to 4 adverse events was 19% (CCNU + BEV) versus 15% (CCNU + placebo). There was no survival benefit and no detriment observed with continuing BEV through multiple lines in patients with recurrent glioblastoma. Previous research suggested that there may be value in continuing bevacizumab (BEV) beyond progression through multiple lines of therapy. No survival benefit was observed with the use of BEV through multiple lines in patients with glioblastoma who had progressed after first-line treatment (radiotherapy + temozolomide + BEV). No new safety concerns arose from the use of BEV through multiple lines of therapy.
Publisher: Springer Science and Business Media LLC
Date: 14-08-2017
DOI: 10.1007/S00520-017-3846-X
Abstract: The aim of the current study was to determine how carer needs changed longitudinally and understand associations between unmet needs and distress. Family carers of patients with high-grade glioma (HGG) were recruited. Carers completed questionnaires during patients' chemoradiotherapy (T1), 3 months (T2) and 6 months (T3) including the following: the Distress Thermometer, the General Health Questionnaire-12, the Partner and Carer Supportive Care (PCS) Needs Scale and its supplement the Access to Services Needs Scale and the Brain Tumour Specific Supportive Care Needs Scale. Linear latent growth models were applied. The time 1 questionnaire was completed by 118 carers 70 carers provided responses at time 3. While the mean numbers of elevated (moderate to high) needs remained stable over time, the specific needs changed. The most frequently reported PCS needs included the impact of caring on the carer's working life or usual activities, finding more accessible parking, making life decisions in the context of uncertainty, reducing stress in the patient's life and understanding the patient's experience. The most frequently reported need unique to carers of a brain tumour patient was for information on adjusting to cognitive changes in the patient. Other prominent needs included managing difficult aspects of the patient's behaviour and adjusting to changes in the patient's personality, both of which increased over time. Higher numbers of unmet needs were associated cross-sectionally with higher distress levels. Carers of people with HGG remain highly distressed and their needs evolve over time, indicating a requirement for ongoing evaluation of unmet needs and interventions to address carer psychological morbidities.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.C.6532518.V1
Abstract: AbstractPurpose: In a i ost hoc /i analysis of the CATNON trial (NCT00626990), we explored whether adding temozolomide to radiotherapy improves outcome in patients with i IDH1/2 /i wildtype (wt) anaplastic astrocytomas with molecular features of glioblastoma [redesignated as glioblastoma, isocitrate dehydrogenase–wildtype ( i IDH /i -wt) in the 2021 World Health Organization (WHO) classification of central nervous system tumors]. Patients and Methods: From the randomized phase III CATNON study examining the addition of adjuvant and concurrent temozolomide to radiotherapy in anaplastic astrocytomas, we selected a subgroup of i IDH1/2 /i wt and i H3F3A /i wt tumors with presence of i TERT /i promoter mutations and/or i EGFR /i lifications and/or combined gain of chromosome 7 and loss of chromosome 10. Molecular abnormalities including i MGMT /i promoter methylation status were determined by next-generation sequencing, DNA methylation profiling, and SNaPshot analysis. Results: Of the 751 patients entered in the CATNON study, 670 had fully molecularly characterized tumors. A total of 159 of these tumors met the WHO 2021 molecular criteria for glioblastoma, i IDH /i -wt. Of these patients, 47 received radiotherapy only and 112 received a combination of radiotherapy and temozolomide. There was no added effect of temozolomide on either overall survival [HR, 1.19 95% confidence interval (CI), 0.82–1.71] or progression-free survival (HR, 0.87 95% CI, 0.61–1.24). i MGMT /i promoter methylation was prognostic for overall survival, but was not predictive for outcome to temozolomide treatment either with respect to overall survival or progression-free survival. Conclusions: In this cohort of patients with glioblastoma, i IDH /i -wt temozolomide treatment did not add benefit beyond that observed from radiotherapy, regardless of i MGMT /i promoter status. These findings require a new well-powered prospective clinical study to explore the efficacy of temozolomide treatment in this patient population. /
Publisher: Oxford University Press (OUP)
Date: 25-05-2017
DOI: 10.1093/NOP/NPW025
Abstract: In patients with recurrent glioblastoma, the benefit of bevacizumab beyond progression remains uncertain. We prospectively evaluated continuing or ceasing bevacizumab in patients who progressed while on bevacizumab. CABARET, a phase II study, initially randomized patients to bevacizumab with or without carboplatin (Part 1). At progression, eligible patients underwent a second randomization to continue or cease bevacizumab (Part 2). They could also receive additional chemotherapy regimens (carboplatin, temozolomide, or etoposide) or supportive care. Of 120 patients treated in Part 1, 48 (80% of the anticipated 60-patient s le size) continued to Part 2. Despite randomization, there were some imbalances in patient characteristics. The best response was stable disease in 7 (30%) patients who continued bevacizumab and 2 (8%) patients who stopped receiving bevacizumab. There were no radiological responses. Median progression-free survival was 1.8 vs 2.0 months (bevacizumab vs no bevacizumab hazard ratio [HR], 1.08 95% CI, .59–1.96 P = .81). Median overall survival was 3.4 vs 3.0 months (HR, .84 95% CI, .47–1.50 P = .56 and HR .70 95% CI .38–1.29 P = .25 after adjustment for baseline factors). Quality-of-life scores did not significantly differ between arms. While the maximum daily steroid dose was lower in the continuation arm, the difference was not statistically significant. Patients who continued bevacizumab beyond disease progression did not have clear survival improvements, although the study was not powered to detect other than very large differences. While these data provide the only randomized evidence related to continuing bevacizumab beyond progression in recurrent glioblastoma, the small s le size precludes definitive conclusions and suggests this remains an open question.
Publisher: Springer Science and Business Media LLC
Date: 24-06-2021
DOI: 10.1038/S41467-021-23931-1
Abstract: Land-use intensification is a major driver of bio ersity loss. However, understanding how different components of land use drive bio ersity loss requires the investigation of multiple trophic levels across spatial scales. Using data from 150 agricultural grasslands in central Europe, we assess the influence of multiple components of local- and landscape-level land use on more than 4,000 above- and belowground taxa, spanning 20 trophic groups. Plot-level land-use intensity is strongly and negatively associated with aboveground trophic groups, but positively or not associated with belowground trophic groups. Meanwhile, both above- and belowground trophic groups respond to landscape-level land use, but to different drivers: aboveground ersity of grasslands is promoted by erse surrounding land-cover, while belowground ersity is positively related to a high permanent forest cover in the surrounding landscape. These results highlight a role of landscape-level land use in shaping belowground communities, and suggest that revised agroecosystem management strategies are needed to conserve whole-ecosystem bio ersity.
Publisher: Springer Science and Business Media LLC
Date: 28-01-2011
DOI: 10.1007/S00281-011-0246-Z
Abstract: The immune system plays an important role in the surveillance of neoplastic cells by eliminating them before they manifest as full-blown cancer. Despite this, tumors do develop in the presence of a functioning immune system. Conventional chemotherapy and its ability to directly kill tumor cells is one of the most effective weapons in the fight against cancer, however, increasing evidence suggests that the therapeutic efficacy of some cytotoxic drugs relies on their capacity to interact with the immune system. Killing of tumor cells in a manner that favors their capture by immune cells or selective targeting of immunosuppressive pathways by specific chemotherapies promotes the generation of an effective anti-cancer response however, this alone is rarely sufficient to cause elimination of advanced disease. An understanding of the immunological events occurring in both animal models and patients undergoing chemotherapy will guide decisions for the development of appropriate combinations and scheduling for the integration of chemotherapy with immunotherapy.
Publisher: Impact Journals, LLC
Date: 03-02-2017
Publisher: American Association for the Advancement of Science (AAAS)
Date: 17-07-2019
DOI: 10.1126/SCITRANSLMED.AAV7816
Abstract: A STAT1-driven inflammatory phenotype associated with response to checkpoint blocking antibodies sensitizes cancers to immunotherapy.
Publisher: American Society of Clinical Oncology (ASCO)
Date: 20-05-2010
Publisher: Informa UK Limited
Date: 31-08-2016
Publisher: MDPI AG
Date: 17-12-2022
DOI: 10.3390/CURRONCOL29120781
Abstract: The aim of this project was to determine research priorities, barriers, and enablers for adult primary brain tumour research in Australia and New Zealand. Consumers, health professionals, and researchers were invited to participate in a two-phase modified Delphi study. Phase 1 comprised an initial online survey (n = 91) and then focus groups (n = 29) which identified 60 key research topics, 26 barriers, and 32 enablers. Phase 2 comprised two online surveys to (1) reduce the list to 37 research priorities which achieved consensus ( % 2-point agreement) and had high mean importance ratings (n = 116 participants) and (2) determine the most important priorities, barriers, and enablers (n = 90 participants). The top ten ranked research priorities for the overall s le and sub-groups (consumers, health professionals, and researchers) were identified. Priorities focused on: tumour biology, pre-clinical research, clinical and translational research, and supportive care. Variations were seen between sub-groups. The top ten barriers to conducting brain tumour research related to funding and resources, accessibility and awareness of research, collaboration, and process. The top ten research enablers were funding and resources, collaboration, and workforce. The broad list of research priorities identified by this Delphi study, together with how consumers, health professionals, and researchers prioritised items differently, and provides an evidence-based research agenda for brain tumour research that is needed across a wide range of areas.
Publisher: BMJ
Date: 03-2020
DOI: 10.1136/BMJRESP-2019-000551
Abstract: Cachexia is common in malignant mesothelioma (MM) half of patients have malnutrition and low skeletal muscle mass. Malnourished patients have worse quality of life (QoL). Weight loss is strongly associated with poor survival. Anamorelin is an oral ghrelin receptor agonist that improves appetite, body weight and QoL in advanced cancer. The aim of this study is to examine the efficacy of anamorelin in improving appendicular skeletal muscle mass (ASM) and patient-reported outcomes in patients with MM with cachexia. A single-centre, phase II, randomised, placebo-controlled cross-over pilot study with 28-day treatment periods and 3-day washout. Forty patients will be randomised. Primary outcome is change in ASM relative to height measured by dual energy X-ray absorptiometry at end of period 1. Secondary outcomes include cancer-specific and cachexia-related QoL, objective physical activity, dietary intake and adverse events. Eligible patients will have confirmed MM, Eastern Cooperative Oncology Group 0–2, expected survival months and cachexia (defined as % weight loss in 6 months or body mass index kg/m 2 with weight loss %). Ethical approval has been granted. Results will be reported in peer-reviewed publications. Australian New Zealand Clinical Trials Registry (U1111-1240-6828).
Publisher: Elsevier BV
Date: 10-2005
Publisher: Elsevier BV
Date: 09-2020
Publisher: Informa UK Limited
Date: 02-2012
DOI: 10.1080/01635581.2012.649100
Abstract: Epidemiological evidence indicates that supplementation with some dietary factors is associated with a lower incidence of cancer. An effective cancer prevention strategy for the millions of people worldwide who have been exposed to asbestos could have enormous benefit. We tested whether dietary supplementation of the antioxidants vitamin A, E, and selenium could alter the pattern of disease in the MexTAg transgenic mouse model, in which mice uniformly develop mesothelioma after asbestos exposure. We focused on antioxidants because one of the most widely accepted hypotheses for the mechanism by which asbestos fibers cause cancer proposes the involvement of reactive oxygen and nitrogen species. We compared the survival of MexTAg mice that had been inoculated with asbestos fed on diets supplemented with 250,000 IU/kg vitamin A (retinoic acid), or 1,000 mg/kg vitamin E (α-tocopherol acetate) or 3 mg/kg selenium, or both vitamin E and selenium concurrently and, additionally, diets deficient in each antioxidant. We found that neither the time to develop symptoms of disease nor overall survival times were altered by any of the diets. We conclude that the data do not support the notion that dietary antioxidants will moderate the rate of mesothelioma in asbestos-exposed populations.
Publisher: Elsevier BV
Date: 04-2010
DOI: 10.1016/J.PEC.2009.08.013
Abstract: To understand patients' experiences of High Grade Glioma and identify and describe information and support needs along the disease trajectory. Semi-structured interviews were conducted with 19 patients. Data was analysed using grounded theory and the constant comparative method. Four major themes were identified: (1) feelings of uncertainty around prognosis and quality of life (2) the need for in idualised information (3) dependence on carers due to cognitive deficits, loss of balance and inability to drive and (4) communication with health professionals around prognostic uncertainty and disease progression with communication barriers due to complex language deficits. Previous studies in HGG pre-date the current combined modality standard of care, or examined a mixed population. This study has found that patients with HGG have needs that differ from other patients with terminal malignancy and that these needs change over time with disease progression. This study has identified that patients with brain tumours may have unique needs. Health professionals need to clarify patients' information and support needs and be aware that these change over and within time.
Publisher: Elsevier BV
Date: 09-2013
DOI: 10.1016/J.LUNGCAN.2013.05.006
Abstract: BNC105P is a tubulin polymerisation inhibitor that selectively disrupts tumour vasculature and suppresses cancer cell proliferation. This agent has exhibited preclinical and phase I activity in Malignant Pleural Mesothelioma (MPM). This phase II, single arm trial investigated the efficacy and safety of BNC105P as second line therapy in MPM. Participants had progressive MPM after first line pemetrexed latinum chemotherapy, ECOG PS 0-1, adequate organ function, and measurable disease. BNC105P 16 mg/m(2) was administered intravenously on day 1 and 8 every 21 days until progression or undue toxicity. The primary endpoint was centrally reviewed objective response rate (RR). Tumour response was assessed every two cycles using modified RECIST. 30 patients were enrolled in 10 months, predominantly male (90%), ECOG PS 1 (77%), epithelioid histology (67%), and non-metastatic disease (67%). All patients received at least one dose of study drug, with a median of 2 cycles. No significant haematologic, biochemical, or cardiac adverse events (AEs) were observed. Grade 3 or 4 AEs occurred in 10 patients (33%). There were 2 deaths on study: 1 cardiorespiratory, the other to pneumonia. We observed 1 partial response (3%) 13 patients had stable disease (43%). Median progression free survival was 1.5 months (95% CI 1.4-2.4) median overall survival was 8.2 months (95% CI 3.8-11.9). BNC105P was safe and tolerable. The sole response was insufficient to warrant further research as a single agent.
Publisher: Elsevier BV
Date: 11-2022
Publisher: Public Library of Science (PLoS)
Date: 05-08-2014
Publisher: Elsevier BV
Date: 11-2018
DOI: 10.1016/J.JTHO.2018.08.007
Abstract: There is no approved second-line treatment for malignant pleural mesothelioma (MPM). On the basis of promising early results, pembrolizumab was used off-label in Switzerland and Australia. We investigated outcomes in association with clinicopathological features and expression of programmed death ligand 1 (PD-L1). Registry data in Australia and Switzerland were pooled. Patient characteristics, including age, sex, histological subtype, and previous treatments were captured. Outcomes were assessed locally. PD-L1 expression was categorized as negative (<5%), intermediate (5%-49%), and high (≥50%). A total of 93 patients (48 from Switzerland and 45 from Australia) were treated 68 patients (73%) had epithelioid MPM, and 67 (72%) had an Eastern Cooperative Oncology Group performance status of 0 or 1. Pembrolizumab was the second-line treatment in 48 of 93 patients (52%). PD-L1 expression results were available for 66 patients (71%). Most (68%) were negative, 18% were intermediate, and 14% were high for PD-L1 expression. In the full cohort, the overall response rate (ORR) was 18%, the median progression-free survival (mPFS) was 3.1 months, and the median overall survival was 7.2 months. In patients with an Eastern Cooperative Oncology Group performance status of 0 or 1 and only one previous systemic treatment (n = 35), the ORR was 37%, the mPFS was 3.7 months, and the median overall survival was 10.2 months. The nonepitheloid histological subtype showed an improved ORR (24% versus 16% [p = 0.54) and mPFS (5.6 versus 2.8 months [p = 0.02]). Compared with intermediate and negative PD-L1 expression, high PD-L1 expression was associated with an improved ORR (44% versus 42% versus 11% [p = 0.01]) and mPFS (6.2 versus 3.9 versus 2.7 months [p = 0.04]). Toxicity was as expected. These real-world data demonstrate similar response rates but inferior survival compared with those in early-phase trials. High PD-L1 expression and nonepitheloid histological subtype were associated with greater activity. Anti-PD-L1 immunotherapy is a reasonable second-line therapy in patients with MPM.
Publisher: Oxford University Press (OUP)
Date: 30-06-2015
Publisher: Elsevier BV
Date: 04-2016
DOI: 10.1016/J.JTHO.2015.12.108
Abstract: Malignant pleural mesothelioma (MPM) is a rare cancer with a heterogeneous prognosis. Prognostic models are not widely utilized clinically. Classification and regression tree (CART) analysis examines the interaction of multiple variables with a given outcome. Between 2005 and 2014, all cases with pathologically confirmed MPM had routinely available histological, clinical, and laboratory characteristics recorded. Classification and regression tree analysis was performed using 29 variables with 18-month survival as the dependent variable. Risk groups were refined according to survival and clinical characteristics. The model was then tested on an external international cohort. A total of 482 cases were included in the derivation cohort the median survival was 12.6 months, and the median age was 69 years. The model defined four risk groups with clear survival differences (p < 0.0001). The strongest predictive variable was the presence of weight loss. The group with the best survival at 18 months (86.7% alive, median survival 34.0 months, termed risk group 1) had no weight loss, a hemoglobin level greater than 153 g/L, and a serum albumin level greater than 43 g/L. The group with the worst survival (0% alive, median survival 7.5 months, termed risk group 4d) had weight loss, a performance score of 0 or 1, and sarcomatoid histological characteristics. The C-statistic for the model was 0.761, and the sensitivity was 94.5%. Validation on 174 external cases confirmed the model's ability to discriminate between risk groups in an alternative data set with fair performance (C-statistic 0.68). We have developed and validated a simple, clinically relevant model to reliably discriminate patients at high and lower risk of death using routinely available variables from the time of diagnosis in unselected populations of patients with MPM.
Publisher: Elsevier BV
Date: 05-1995
Publisher: Springer Science and Business Media LLC
Date: 18-03-2019
DOI: 10.1038/S41430-019-0418-9
Abstract: Malignant pleural mesothelioma (MPM) is an incurable cancer and optimizing daily physical activity and quality of life are key goals of patient management. Little is known about the prevalence of pre-sarcopenia and malnutrition in MPM or their associations with patient outcomes. This study aimed to determine the prevalence of pre-sarcopenia and malnutrition in MPM and investigate if activity levels and quality of life differed according to body composition and nutritional status. Patients with a diagnosis of MPM were recruited. Pre-sarcopenia was defined as low appendicular skeletal muscle mass (≤ 7.26 kg/m Sixty-one people participated (79% male, median age 69 [IQR 62-74] years and median BMI 25.8 [IQR 24.3-28.4] kg/m Participants with MPM had high rates of pre-sarcopenia and malnutrition. Pre-sarcopenia was associated with poorer activity levels, whilst malnutrition was associated with poorer quality of life. Interventions that aim to address reduced muscle mass and weight loss, should be tested in MPM to assess their impact on patient outcomes.
Publisher: Elsevier BV
Date: 12-2020
Publisher: Elsevier BV
Date: 2011
DOI: 10.1016/J.EJCA.2010.08.015
Abstract: Animal models provide an important tool for investigating the biology of cancer and for testing the efficacy of novel treatments. Here we describe several aspects of the transgenic MexTAg mouse that develops asbestos-induced mesothelioma. Targeted expression of the TAg transgene causes mesothelioma to develop more rapidly after asbestos exposure in wild-type mice with 100% incidence compared to 30% incidence in wild-type mice. MexTAg mice do not develop spontaneous mesothelioma and exhibit a very low incidence of other tumours. Here we show that TAg does not affect the aggressiveness or rate of progression of the mesotheliomas, suggesting that the oncogene alters only the rate at which disease is initiated. The instillation of an alternative inflammatory agent, thioglycollate, did not induce mesotheliomas, demonstrating acute inflammation is not sufficient for tumour development in MexTAg mice. We found that neither the age of a mouse at the time of exposure nor its gender were prognostic factors. MexTAg mice with mesotheliomas respond to treatment with a cytotoxic drug in a similar way to that of patients with mesothelioma, demonstrating the validity of the model. We also show that long-term treatment with a COX-2 inhibitor prior to the development of disease does not have a survival benefit, suggesting that this is not a useful cancer prevention therapy for asbestos-exposed in iduals. The model is robust and suitable for testing a wide variety of protocols and a range of translational studies.
Publisher: Informa UK Limited
Date: 09-02-2021
Publisher: SAGE Publications
Date: 12-2015
DOI: 10.1037/GPR0000055
Abstract: An integrative model of approach and avoidance goals in achievement contexts is proposed based on the concepts and principles of nonlinear dynamical systems. These goals are conceptualized as self-organizing systems in which information relevant to competence expectancies and perceptions of benefit and threat for the self is integrated with respect to either a single coherent state ( static integration) or 2 conflicting coherent states ( dynamic integration). Mathematical equations depict the emergence of approach and avoidance attractor dynamics from the proposed integration process. The model specifies the conditions under which states of goal involvement will display patterns of resistance (stability), oscillation between approach and avoidance (instability), or reversal (nonlinear change). As a result, this model of approach and avoidance goals equips previous dynamical models of self-regulation with greater social–cognitive substance. It also provides a parsimonious account of achievement motivation and resolves lingering inconsistencies and uncertainties in the achievement goal literature. Moreover, the dynamical systems approach, on which the model is based, provides a heuristic framework for generating new predictions regarding the ebb and flow of approach and avoidance in achievement contexts.
Publisher: Wiley
Date: 12-2007
Publisher: Elsevier BV
Date: 06-2021
Publisher: Wiley
Date: 24-03-2014
DOI: 10.1111/RESP.12263_8
Publisher: Elsevier BV
Date: 05-2013
Publisher: Wiley
Date: 2020
DOI: 10.1002/CTI2.1169
Publisher: Elsevier BV
Date: 04-2013
Publisher: Elsevier BV
Date: 05-2016
DOI: 10.1016/J.JTHO.2015.12.114
Abstract: Separate tumor nodules with the same histologic appearance occur in the lungs in a small proportion of patients with primary lung cancer. This article addresses how such tumors can be classified to inform the eighth edition of the anatomic classification of lung cancer. Separate tumor nodules should be distinguished from second primary lung cancer, multifocal ground glass/lepidic tumors, and pneumonic-type lung cancer, which are addressed in separate analyses. Survival of patients with separate tumor nodules in the International Association for the Study of Lung Cancer database were analyzed. This was compared with a systematic literature review. Survival of clinically staged patients decreased according to the location of the separate tumor nodule relative to the index tumor (same lobe > same side > other side) in N0 and N-any cohorts (all M0 except possible other-side nodules). However, there was also a decrease in the proportion of patients resected among only surgically resected or among nonresected patients no survival differences were noted. There were no survival differences between patients with same-lobe nodules and those with other T3 tumors, between patients with same-side nodules and those with T4 tumors, and patients with other-side nodules and those with other M1a tumors. The data correlated with those identified in a literature review. Tumors with same-lobe separate tumor nodules (with the same histologic appearance) are recommended to be classified as T3, same-side nodules as T4, and other-side nodules as M1a. Thus, there is no recommended change between the seventh and eighth edition of the TNM classification of lung cancer.
Publisher: Elsevier BV
Date: 07-2004
Publisher: Wiley
Date: 26-05-2021
DOI: 10.1111/CEO.13940
Abstract: To describe ocular adverse events and retinal changes during fibroblast growth factor receptor (FGFR) inhibitor (AZD4547) anticancer therapy. This is a sub‐study examining ocular adverse effects from AZD4547 therapy (single‐centre, open‐label, single arm phase II clinical trial). Comprehensive ocular examinations were performed 3 weekly in 24 patients. Macular optical coherence tomography (OCT) scan (30 0 × 25 0 ) was obtained at each visit and OCT parameters [central 1 mm retinal thickness (CRT) and total macular volume in central 6 mm] extracted. OCT scans were sub ided into outer (ELM to RPE) and inner (ELM to ILM) layers to compare outer and inner retinal changes. In 24 patients, AZD4547 was associated with eyelash elongation ( n = 5, 21%) and punctate corneal erosion ( n = 2, 8%). One patient developed clinically significant posterior capsular opacification during the study. OCT data were available in 23 patients, retinal changes ranged from an asymptomatic increased visibility of the interdigitation zone (IDZ) ( n = 10, 43%) to multilobular subretinal fluid pockets ( n = 5, 22%), which was associated with mild visual acuity loss. In a subset of patients ( n = 9) with pre‐AZD4547 dosing OCT baseline, CRT increased by mean ( SD ) of 9 (4) μm in those with IDZ change only compared with 64 (38) μm in those with other retinal changes. Retinal changes tended to be bilateral, self‐limiting and improved over time without medical intervention. The ocular signs and symptoms did not result in dose cessation. Posteriorly, FGFR inhibition leads to outer retinal changes ranging from increased visibility of IDZ to distinct, multiple fluid pockets.
Publisher: Elsevier BV
Date: 05-2016
DOI: 10.1016/J.JTHO.2015.12.113
Abstract: Application of tumor, node, and metastasis (TNM) classification is difficult in patients with lung cancer presenting as multiple ground glass nodules or with diffuse pneumonic-type involvement. Clarification of how to do this is needed for the forthcoming eighth edition of TNM classification. A subcommittee of the International Association for the Study of Lung Cancer Staging and Prognostic Factors Committee conducted a systematic literature review to build an evidence base regarding such tumors. An iterative process that included an extended workgroup was used to develop proposals for TNM classification. Patients with multiple tumors with a prominent ground glass component on imaging or lepidic component on microscopy are being seen with increasing frequency. These tumors are associated with good survival after resection and a decreased propensity for nodal and extrathoracic metastases. Diffuse pneumonic-type involvement in the lung is associated with a worse prognosis, but also with a decreased propensity for nodal and distant metastases. For multifocal ground glass/lepidic tumors, we propose that the T category be determined by the highest T lesion, with either the number of tumors or m in parentheses to denote the multifocal nature, and that a single N and M category be used for all the lesions collectively-for ex le, T1a(3)N0M0 or T1b(m)N0M0. For diffuse pneumonic-type lung cancer we propose that the T category be designated by size (or T3) if in one lobe, as T4 if involving an ipsilateral different lobe, or as M1a if contralateral and that a single N and M category be used for all pulmonary areas of involvement.
Publisher: AMPCo
Date: 02-2016
DOI: 10.5694/MJA15.01072
Publisher: Springer Science and Business Media LLC
Date: 10-05-2022
DOI: 10.1007/S00520-022-07107-1
Abstract: People with advanced cancer often experience greater physical and psychosocial morbidity compared to those with early disease. Limited research has focused on their experiences within the Australian health system. The aim of this study was to explore the lived experiences of adults receiving care for advanced cancer. A qualitative design with a descriptive phenomenological approach was used to explore the lived experiences of people with advanced cancer following their diagnosis. Twenty-three people living with an advanced solid malignancy receiving care were referred by their oncologists to take part in an interview conducted at their home, the hospital, or over the phone. Three key themes emerged relating to participants’ experiences of living with advanced cancer: (1) living with a life-limiting diagnosis and uncertainty, (2) living with symptom burden and side effects, and (3) living within the health system, with two subthemes, the patient-clinician relationship, and care coordination. Participant relationships with their health professionals were particularly important and had a defining impact on whether patient experiences living with cancer were positive or negative. People with advanced cancer experienced broad variation in their experiences navigating the health system, and their relationships with clinicians and other health professionals were important factors affecting their perceptions of their experiences. Attention to the coordination of care for people with advanced cancer is necessary to improve their experiences and improve symptom control and the management of their psychosocial burden.
Publisher: Elsevier BV
Date: 09-2022
Publisher: Elsevier BV
Date: 11-2011
DOI: 10.1016/J.JOCN.2011.02.026
Abstract: Concurrent and post-radiotherapy temozolomide (T) significantly improves survival in patient with newly diagnosed glioblastoma multiforme. We aimed to assess the activity of the combination of T and pegylated liposomal doxorubicin (PLD) in this population. A combination of T (days 1-5, 200mg/m(2) orally) and PLD (day 1, 40 mg/m(2) intravenous) was given every 4 weeks for six cycles following chemo-radiotherapy as a post-operative treatment. The primary endpoint was 6-month progression free survival (6PFS). Of the 40 patients who enrolled (53 years median age, 73% male), the 6PFS was 58% (95% confidence interval [CI], 41-72%). The median time to progression was 6.2 months (95% CI, 5.6-8.0 months) and overall survival (OS) was 13.4 months (95% CI, 12.7-15.8 months). Thirty-four patients had measurable disease: one had a complete response (3%), 28 had stable disease (82%), and five had progressive disease (15%). Treatment was well tolerated: hematological toxicity included grade 3 neutropenia (8%). Grade 3 non-hematologic toxicity included nausea and vomiting (8%) and palmar-plantar toxicity (5%). We concluded that combination T and PLD is well tolerated but does not add significant clinical benefit regarding 6PFS and OS.
Publisher: Wiley
Date: 15-05-2007
Abstract: Singlet oxygen is known to cause oxidative stress in cells, leading to severe damage (e.g., lipid peroxidation, membrane degradation, mutagenic alterations to DNA, protein misfunctionality). Recently, pyridoxine has been discovered to be capable of quenching singlet oxygen, however, the mechanism of this reaction remains essentially unknown. In this work, we have investigated four sets of reactions: 1) 1,3-addition to a double bond connected to a hydrogen-carrying group, resulting in the formation of allylic hydroperoxides 2) [pi2+pi2] 1,2-cycloaddition to an isolated double bond, resulting in the formation of 1,2-peroxides 3) 1,4-cycloaddition to a system containing at least two conjugated double bonds, resulting in the formation of the so-called 1,4-peroxides 4) 1,4-addition to phenols and naphthols with the formation of hydroperoxide ketones. Thermodynamically, reaction 4 and the 6(9), 3(8), and 5(8) cases of reaction 1 are the most exergonic ones, with energies ranging from -16 to -18 kcal mol(-1). Furthermore, reaction 4 shows the lowest barrier through the reaction path, and is predicted to be the preferred mechanism for the pyridoxine + singlet-oxygen reaction, which is in agreement with previous experimental results.
Publisher: Oxford University Press (OUP)
Date: 15-10-2015
DOI: 10.1093/NOP/NPV039
Abstract: Few studies have explored the unmet needs of carers of people with high-grade glioma. We aimed to determine carers' levels of distress during treatment, understand their support needs and explore predictors of distress. Carers of people with high-grade glioma undergoing chemoradiotherapy were recruited to this prospective, longitudinal cohort study. Carers completed the validated Supportive Care Needs Survey, Brain Tumour Specific Supportive Care Needs Scale, Distress Thermometer (DT), and General Health Questionnaire (GHQ-12). Questionnaires were administered during patients' chemoradiotherapy and 3 and 6 months later. We recruited 118 carers who were mainly female (72%) and caring for spouse (82%). The mean age was 53 years (SD = 13.6 range, 21-89). Thirty-one percent of carers reported moderate distress (DT score 5-6/10) and 31% reported extreme distress (score 7-10/10) during combined chemoradiotherapy. Carer distress was associated with adverse GHQ scores (r = 0.61, P .001). Seventy-two percent reported a negative financial impact of caring and 51% of those previously working full-time had taken leave or reduced working hours. The top 5 moderate/high unmet needs were: accessing prognostic information accessing financial support and government benefits accessible hospital parking impact of caring on usual life reducing stress in the patients' life. Carers reported substantial distress, and high distress levels were correlated with greater psychological impact and increased self-reporting of unmet needs. Future research should focus on interventions that aid in reducing carer distress.
Publisher: AME Publishing Company
Date: 08-2021
Publisher: BMJ
Date: 12-2011
Publisher: Springer Science and Business Media LLC
Date: 04-2020
DOI: 10.1038/S41596-020-0299-3
Abstract: The therapeutic response to immune checkpoint blockade (ICB) is highly variable, not only between different cancers but also between patients with the same cancer type. The biological mechanisms underlying these differences in response are incompletely understood. Identifying correlates in patient tumor s les is challenging because of genetic and environmental variability. Murine studies usually compare different tumor models or treatments, introducing potential confounding variables. This protocol describes bilateral murine tumor models, derived from syngeneic cancer cell lines, that display a symmetrical yet dichotomous response to ICB. These models enable detailed analysis of whole tumors in a highly homogeneous background, combined with knowledge of the therapeutic outcome within a few weeks, and could potentially be used for mechanistic studies using other (immuno-)therapies. We discuss key considerations and describe how to use two cell lines as fully optimized models. We discuss experimental details, including proper inoculation technique to achieve symmetry and one-sided surgical tumor removal, which takes only 5 min per mouse. Furthermore, we outline the preparation of bulk tissue or single-cell suspensions for downstream analyses such as bulk RNA-seq, immunohistochemistry, single-cell RNA-seq and flow cytometry.
Publisher: Informa UK Limited
Date: 24-02-2014
DOI: 10.1080/01635581.2013.878733
Abstract: Epidemiological studies suggest that vitamin and mineral intake is associated with cancer incidence. A prevention strategy based on diet or dietary supplementation could have enormous benefit, both directly, by preventing disease, and indirectly by alleviating fear in millions of people worldwide who have been exposed to asbestos. We have previously shown that dietary supplementation with the antioxidants vitamins A, E, and selenium does not affect overall survival nor the time to progression of asbestos-induced mesothelioma in MexTAg mice. Here we have extended our analysis to vitamin D. We compared survival of asbestos-exposed MexTAg mice provided with diets that were deficient or supplemented with 4500 IU/kg vitamin D (cholecalciferol). Survival of supplemented mice was significantly shorter than mice given a standard AIN93 diet containing 1000 IU/kg cholecalciferol (median survival was 29 and 32.5 weeks respectively). However, mice deficient in vitamin D had the same rate of mesothelioma development as control mice. Neither the latency time from asbestos exposure to diagnosis nor disease progression after diagnosis were significantly different between mice on these diets. We conclude that vitamin D is unlikely to moderate the incidence of disease in asbestos-exposed populations or to ameliorate the pathology in patients with established mesothelioma.
Publisher: Elsevier BV
Date: 03-2023
Publisher: Springer Science and Business Media LLC
Date: 14-11-2016
DOI: 10.1007/S00520-016-3478-6
Abstract: This study aimed to determine how carer distress and psychological morbidity change over time following a patient's diagnosis of high-grade glioma (HGG) and identify factors associated with changes in carers' psychological status. Carers of patients with HGG planned for chemoradiotherapy were recruited to this longitudinal cohort study. Carers completed questionnaires during patients' chemoradiotherapy and 3 and 6 months later including the following: the Distress Thermometer (DT) General Health Questionnaire-12 (GHQ-12) and three single-item questions about understanding of information presented by health professionals, confidence to care and preparedness to care for their relative/friend. Linear latent growth models were applied. The time 1 questionnaire was completed by 118 carers, of these 70 carers provided responses to the third time point. Carer distress and psychological morbidity were most prominent proximal to diagnosis, but remained high over time. Sixty-two percent of participants had moderate or high distress on the DT at time 1, 61% at time 2 and 58% at time 3. Scores on the DT and the GHQ-12 correlated significantly at all time points as did changes in scores over time (p < .001). However, for in idual carers, the DT or GHQ-12 scores at one time point did not strongly predict scores at subsequent time points. In carers of patients with HGG, distress levels are consistently high and cannot be predicted at any time point. Carers should be monitored over time to identify evolving psychological morbidity. The single-item DT correlates highly with GHQ-12 scores and is a suitable tool for rapid repeated screening.
Publisher: Springer Science and Business Media LLC
Date: 16-10-2013
DOI: 10.1007/S00262-012-1360-Z
Abstract: There is a complex interplay between the immune system and a developing tumor that is manifest in the way that the balance of T cell subsets in the local tumor environment reflects clinical outcome. Tumor infiltration by CD8(+) T cells and regulatory T cells (Treg) is associated with improved and reduced survival, respectively, in many cancer types. However, little is known of the prognostic value of immunological parameters measured in peripheral blood. In this study, peripheral CD8(+) T cells and Treg from 43 patients with malignant mesothelioma or advanced non-small-cell lung cancer scheduled to commence palliative chemotherapy were assessed by flow cytometry and evaluated for association with patient survival. Patients had a higher proportion of peripheral Treg, proliferating CD8(+) T cells and CD8(+) T cells with an activated effector phenotype compared with age-matched healthy controls. Higher proportions of Treg and proliferating CD8(+) T cells were both associated with poor survival in univariate analyses (hazard ratio [HR] 3.81, 95 % CI 1.69-8.57 p < 0.01 and HR 2.86, 95 % CI 1.26-6.50 p < 0.05, respectively). CD8(+) T cell proliferation was independently predictive of reduced survival in multivariate analysis (HR 2.58, 95 % CI 1.01-6.61 p < 0.05). These findings suggest that peripheral CD8(+) T cell proliferation can be a useful prognostic marker in patients with thoracic malignancies planned for palliative chemotherapy.
Publisher: Springer Science and Business Media LLC
Date: 21-07-2015
DOI: 10.1038/SREP12298
Abstract: Cancer immunotherapy has shown impressive results, but most patients do not respond. We hypothesized that the effector response in the tumour could be visualized as a complex network of interacting gene products and that by mapping this network we could predict effective pharmacological interventions. Here, we provide proof of concept for the validity of this approach in a murine mesothelioma model, which displays a dichotomous response to anti-CTLA4 immune checkpoint blockade. Network analysis of gene expression profiling data from responding versus non-responding tumours was employed to identify modules associated with response. Targeting the modules via selective modulation of hub genes or alternatively by using repurposed pharmaceuticals selected on the basis of their expression perturbation signatures dramatically enhanced the efficacy of CTLA4 blockade in this model. Our approach provides a powerful platform to repurpose drugs and define contextually relevant novel therapeutic targets.
Publisher: Oxford University Press (OUP)
Date: 26-08-2015
DOI: 10.1093/NOP/NPV033
Abstract: Diagnostic pathology reports inform management plans for patients with glioma, and there is an increasing clinical need for molecular testing. We assessed the quality of histopathology reports of grade III/IV gliomas. Reports were obtained as part of a tumor biobank. From 720 pathology reports, 594 eligible reports were assessed for 28 elements derived from published checklists. A summary quality score incorporated 9 critical parameters for clinical decision making: diagnosis using World Health Organization 2007 criteria cell type grade narrative supporting cell type and grade absence of equivocal language conclusion reporting cell type and grade and conclusion aligned with report narrative. Of 594 eligible reports, the final conclusion was not supported by the report narrative in 122 (21%). Tumor classification and grade were not supported by the narrative in 105 (18%) and 36 (6%) reports, respectively. Only 145 (24%) reports fulfilled all 9 quality criteria, while 25% contained 6 or fewer key quality indices. Report quality was higher when pathologists had neuropathology subspecialization, when a grade IV tumor was reported, and when the specimen was from an initial resection or grade-progressed tumor rather than recurrent high-grade glioma. Use of molecular testing increased over time, from 29% to 48% over four quartiles of the study. Molecular testing was more frequently done where oligodendroglial elements were reported. A significant proportion of reports failed to meet key indicators of report quality. Pathology reporting is critical in communicating between pathologists and treating clinicians. Clinicians should be aware of reporting quality and seek clarification when required.
Publisher: Elsevier BV
Date: 02-2022
Publisher: Springer Science and Business Media LLC
Date: 20-06-2012
DOI: 10.1007/S00262-012-1307-4
Abstract: Cytotoxic chemotherapies may expose the immune system to high levels of tumor antigens and expand the CD8(+) T-cell response to include weak or subdominant antigens. Here, we evaluated the in vivo CTL response to tumor antigens using a murine mesothelioma tumor cell line transfected with a neotumor antigen, ovalbumin, that contains a known hierarchy of epitopes for MHC class I molecules. We show that as tumors progress, effector CTLs are generated in vivo that focus on the dominant epitope SIINFEKL, although a weak response was seen to one (KVVRFDKL) subdominant epitope. These CTLs did not prevent tumor growth. Cisplatin treatment slowed tumor growth, slightly improved in vivo SIINFEKL presentation to T cells and reduced SIINFEKL-CTL activity. However, the CTL response to KVVRFDKL was lified, and a response to another subdominant epitope, NAIVFKGL, was revealed. Similarly, gemcitabine cured most mice, slightly enhanced SIINFEKL presentation, reduced SIINFEKL-CTL activity yet drove a significant CTL response to NAIVFKGL, but not KVVRFDKL. These NAIVFKGL-specific CTLs secreted IFNγ and proliferated in response to in vitro NAIVFKGL stimulation. IL-2 treatment during chemotherapy refocused the response to SIINFEKL and simultaneously degraded the cisplatin-driven subdominant CTL response. These data show that chemotherapy reveals weaker tumor antigens to the immune system, a response that could be rationally targeted. Furthermore, while integrating IL-2 into the chemotherapy regimen interfered with the hierarchy of the response, IL-2 or other strategies that support CTL activity could be considered upon completion of chemotherapy.
Publisher: BMJ
Date: 08-2023
DOI: 10.1136/BMJOPEN-2022-071327
Abstract: Glioblastoma is the most common aggressive primary central nervous system cancer in adults characterised by uniformly poor survival. Despite maximal safe resection and postoperative radiotherapy with concurrent and adjuvant temozolomide-based chemotherapy, tumours inevitably recur. Imaging with O-(2-[ 18 F]-fluoroethyl)-L-tyrosine (FET) positron emission tomography (PET) has the potential to impact adjuvant radiotherapy (RT) planning, distinguish between treatment-induced pseudoprogression versus tumour progression as well as prognostication. The FET-PET in Glioblastoma (FIG) study is a prospective, multicentre, non-randomised, phase II study across 10 Australian sites and will enrol up to 210 adults aged ≥18 years with newly diagnosed glioblastoma. FET-PET will be performed at up to three time points: (1) following initial surgery and prior to commencement of chemoradiation (FET-PET1) (2) 4 weeks following concurrent chemoradiation (FET-PET2) and (3) within 14 days of suspected clinical and/or radiological progression on MRI (performed at the time of clinical suspicion of tumour recurrence) (FET-PET3). The co-primary outcomes are: (1) to investigate how FET-PET versus standard MRI impacts RT volume delineation and (2) to determine the accuracy and management impact of FET-PET in distinguishing pseudoprogression from true tumour progression. The secondary outcomes are: (1) to investigate the relationships between FET-PET parameters (including dynamic uptake, tumour to background ratio, metabolic tumour volume) and progression-free survival and overall survival (2) to assess the change in blood and tissue biomarkers determined by serum assay when comparing FET-PET data acquired prior to chemoradiation with other prognostic markers, looking at the relationships of FET-PET versus MRI-determined site/s of progressive disease post chemotherapy treatment with MRI and FET-PET imaging and (3) to estimate the health economic impact of incorporating FET-PET into glioblastoma management and in the assessment of post-treatment pseudoprogression or recurrence/true progression. Exploratory outcomes include the correlation of multimodal imaging, blood and tumour biomarker analyses with patterns of failure and survival. The study protocol V.2.0 dated 20 November 2020 has been approved by a lead Human Research Ethics Committee (Austin Health, Victoria). Other clinical sites will provide oversight through local governance processes, including obtaining informed consent from suitable participants. The study will be conducted in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice. Results of the FIG study (TROG 18.06) will be disseminated via relevant scientific and consumer forums and peer-reviewed publications. ANZCTR ACTRN12619001735145
Publisher: Elsevier BV
Date: 12-2019
DOI: 10.1016/J.JOCN.2019.08.044
Abstract: The CABARET trial (ACTRN12610000915055) reported no difference in overall survival (OS) between patients with recurrent glioblastoma (GBM) randomized to either bevacizumab monotherapy or bevacizumab plus carboplatin. However, a subset of patients showed durable responses and prolonged survival, with recorded survival times of over 30 months in five of 122 patients (4%). Patient selection for bevacizumab therapy would be enhanced if a predictive biomarker of response or survival could be identified this biomarker sub-study attempted to identify novel biomarkers. Patients who opted to participate in this sub-study and who had adequate biospecimens for analysis (n = 54) were retrospectively evaluated for the expression of a series of tumor proteins. Immunohistochemistry (IHC) was used to measure the expression of 19 proteins previously implicated in cancer treatment response to bevacizumab. MGMT promoter methylation was also assessed. Tumor DNA from five patients with outlying survival duration ('poor' and 'exceptional' survivors) was subjected to whole genome sequencing (WGS). No single protein expression level, including VEGF-A, predicted OS in the cohort. WGS of poor and exceptional survivors identified a gain in Chromosome 19 that was exclusive to the exceptional survivors. Validation of this finding requires examination of a larger independent cohort.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22487424
Abstract: Supplementary Figure from Temozolomide and Radiotherapy versus Radiotherapy Alone in Patients with Glioblastoma, i IDH /i -wildtype: i Post Hoc /i Analysis of the EORTC Randomized Phase III CATNON Trial
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22487433.V1
Abstract: Supplementary Figure from Temozolomide and Radiotherapy versus Radiotherapy Alone in Patients with Glioblastoma, i IDH /i -wildtype: i Post Hoc /i Analysis of the EORTC Randomized Phase III CATNON Trial
Publisher: Wiley
Date: 24-06-2021
DOI: 10.1111/AJCO.13606
Abstract: The neuro‐oncology community in Australia is well positioned to collaborate internationally, with a motivated trials group, strong regulatory bodies and an attractive fiscal environment. We sought to identify gaps in the Australian neuro‐oncology clinical trials landscape and describe strategies to increase international trial access in Australia. We searched clinical trial registries to identify active adult primary brain cancer trials. We compared the participation rate and phase of these trials between tumour types and countries. A survey was distributed to the Cooperative Trials Group for Neuro‐Oncology membership to identify barriers and solutions to effective international collaboration. Globally, 307 trials for adult primary brain cancers were identified. These included 50% pharmaceutical agents, 18% cellular therapies and 9% radiation therapy. Twelve adult primary brain cancer trials were actively recruiting in Australia at the time the survey was sent out. There were more early phase brain cancer trials (34%) compared with colorectal and breast cancer (21% and 24%, respectively). In Australia, 92% of brain cancer trials were involving pharmaceutical agents. The most commonly cited barrier was lack of funding for international trials (86%) and insufficient research time (75%). High ranking solutions included increasing the availability of funding for international trials and creating opportunities to develop personal relationships with collaborators. Accreditation of clinical research key performance indicators into practice (88%) and hospital accreditation (73%) also ranked highly. Participation in international research in Australia could be improved by embedding clinical research targets into institutional funding, provision of funding for early phase studies and streamlining mutual ethics schemes.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22487421
Abstract: Supplementary Figure from Temozolomide and Radiotherapy versus Radiotherapy Alone in Patients with Glioblastoma, i IDH /i -wildtype: i Post Hoc /i Analysis of the EORTC Randomized Phase III CATNON Trial
Publisher: American Society of Clinical Oncology (ASCO)
Date: 08-2004
Abstract: To assess the feasibility and validity of using the European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life Questionnaire (QLQ-C30) and Lung Cancer Module (QLQ-LC13) to describe health-related quality of life (HRQL) in patients with pleural mesothelioma undergoing combination chemotherapy, to identify the most impaired aspects of HRQL, and to assess the impact of chemotherapy on HRQL. Fifty-three patients received cisplatin on day 1 and gemcitabine on days 1, 8, and 15 of a 28-day cycle for a maximum of six cycles. HRQL was assessed using the EORTC QLQ-C30 and QLQ-LC13. Compliance was 100% at baseline but subsequently decreased. At baseline, role function and social function were the most impaired domains, and the worst-rated symptoms were fatigue, dyspnea, pain, insomnia, appetite loss, and cough. Dyspnea, pain, insomnia, and cough improved with chemotherapy, although functional domains and chemotherapy-related symptoms deteriorated. Fatigue remained unchanged. Few patients reported hemoptysis. Functional domains and symptoms scales from the QLQ-C30 demonstrated predictive validity for survival. The predictive value of QLQ-LC13 pain scores was improved by combining three pain items into a single score. Dyspnea scores were correlated strongly with lung function as measured by forced vital capacity. This study supports the validity of the EORTC QLQ-C30 and LC13 as outcome measures for trials of chemotherapy in mesothelioma. Although the most prominent symptoms reported were concordant with clinical experience, impairments in role and social function and insomnia were worse than expected. Future research should focus on how best to apply, analyze, and interpret existing, validated HRQL instruments in mesothelioma research and practice, not on the development of new ones.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22487427.V1
Abstract: Supplementary Figure from Temozolomide and Radiotherapy versus Radiotherapy Alone in Patients with Glioblastoma, i IDH /i -wildtype: i Post Hoc /i Analysis of the EORTC Randomized Phase III CATNON Trial
Publisher: Springer New York
Date: 17-11-2012
Publisher: Springer New York
Date: 2013
Publisher: Spandidos Publications
Date: 2015
DOI: 10.3892/OL.2015.2980
Publisher: Springer Science and Business Media LLC
Date: 19-09-2017
DOI: 10.1038/BJC.2017.310
Publisher: BMJ
Date: 2022
DOI: 10.1136/BMJOPEN-2021-057663
Abstract: There is a strong theoretical rationale for combining checkpoint blockade with cytotoxic chemotherapy in pleural mesothelioma and other cancers. Two recent single-arm, phase 2 trials [DuRvalumab with chEmotherapy as first-line treAtment in advanced pleural Mesothelioma (DREAM) and Phase II multicenter study of anti-PD-L1, durvalumab, in combination with cisplatin and pemetrexed for the first-line treatment of unresectable malignant pleural mesothelioma (PrE0505)] combining the programmed death ligand-1 (PD-L1) inhibitor durvalumab with standard first-line chemotherapy exceeded prespecified safety and activity criteria to proceed to a phase 3 confirmatory trial to assess this combination. We present the protocol of the DREAM3R trial. This multicentre open-label randomised trial will recruit 480 treatment-naïve adults with advanced pleural mesothelioma, randomised (2:1) to either 3-weekly durvalumab 1500 mg plus 3-weekly doublet chemotherapy (cisplatin 75 mg/m 2 or carboplatin, Area Under the Curve,AUC 5 and pemetrexed 500 mg/m 2 ) 4–6 cycles, followed by 4-weekly durvalumab 1500 mg until disease progression, unacceptable toxicity or patient withdrawal OR doublet chemotherapy alone for 4–6 cycles, followed by observation. The target accrual time is 27 months, with follow-up for an additional 24 months. This provides over 85% power if the true HR for overall survival (OS) is 0.70, with two-sided alpha of 0.05, assuming a median OS of 15 months in the control group. Randomisation is stratified by age (18–70 years vs ), sex, histology (epithelioid vs non-epithelioid), platinum agent (cisplatin vs carboplatin) and region (USA vs Australia/New Zealand vs Other). The primary endpoint is OS. Secondary endpoints include progression-free survival, objective tumour response (by mRECIST V.1.1 and iRECIST), adverse events, health-related quality of life and healthcare resource use. Tertiary correlative objectives are to explore and validate potential prognostic and/or predictive biomarkers (including features identified in the DuRvalumab with chEmotherapy as first-line treAtment in advanced pleural Mesothelioma (DREAM) and PrE0505 studies, PD-L1 expression, tumour mutational burden, genomic characteristics and human leukocyte antigen subtypes) in tissue and serial blood s les. An imaging databank will be assembled for validation of radiological measures of response, and studies of possible radiomic biomarkers in mesothelioma. The protocol was approved by human research ethics review committees for all participating sites. Results will be disseminated in peer-reviewed journals and at scientific conferences. AstraZeneca. CTC 0231 / TOGA 18/001 / PrE0506 3.0, 29 July 2021. ClinicalTrials.gov Identifier: NCT04334759 ACTRN 12620001199909.
Publisher: Springer Science and Business Media LLC
Date: 26-06-2020
DOI: 10.1186/S12889-020-09084-8
Abstract: Relative survival is the most common method used for measuring survival from population-based registries. However, the relative survival concept of ‘survival as far as the cancer is concerned’ can be biased due to differing non-cancer risk of death in the population with cancer (competing risks). Furthermore, while relative survival can be stratified or standardised, for ex le by sex or age, adjustment for a broad range of sociodemographic variables potentially influencing survival is not possible. In this paper we propose Fine and Gray competing risks multivariable regression as a method that can assess the probability of death from cancer, incorporating competing risks and adjusting for sociodemographic confounders. We used whole of population, person-level routinely linked Western Australian cancer registry and mortality data for in iduals diagnosed from 1983 to 2011 for major cancer types combined, female breast, colorectal, prostate, lung and pancreatic cancers, and grade IV glioma. The probability of death from the index cancer (cancer death) was evaluated using Fine and Gray competing risks regression, adjusting for age, sex, Indigenous status, socio-economic status, accessibility to services, time sub-period and (for all cancers combined) cancer type. When comparing diagnoses in 2008–2011 to 1983–1987, we observed substantial decreases in the rate of cancer death for major cancer types combined ( N = 192,641, − 31%), female breast (− 37%), prostate (− 76%) and colorectal cancers (− 37%). In contrast, improvements in pancreatic (− 15%) and lung cancers (− 9%), and grade IV glioma (− 24%) were less and the cumulative probability of cancer death for these cancer types remained high. Considering the justifiable expectation for confounder adjustment in observational epidemiological studies, standard methods for tracking population-level changes in cancer survival are simplistic. This study demonstrates how competing risks and sociodemographic covariates can be incorporated using readily available software. While cancer has been focused on here, this technique has potential utility in survival analysis for other disease states.
Publisher: SAGE Publications
Date: 12-02-2016
Abstract: Malignant pleural mesothelioma (MPM) represents a significant diagnostic and therapeutic challenge and is almost always a fatal disease. Imaging abnormalities are common, but have a limited role in distinguishing mesothelioma from metastatic pleural disease. Similarly, minimally invasive biomarkers have shown promise but also have limitations in the diagnosis of mesothelioma. In experienced centers, cytology and immunohistochemistry are now sufficient to diagnose the epithelioid subtype of mesothelioma, which can reduce the need for more invasive diagnostic investigations. Prognosis of MPM is modestly impacted by oncological treatments. Chemotherapy with cisplatin and pemetrexed is considered the standard of care, though the addition of bevacizumab to the platinum doublet may be the new standard of care. New targeted therapies have demonstrated some promise and are being addressed in clinical trials. This review focuses on the current data on the diagnostic and therapeutic issues of MPM.
Publisher: Elsevier BV
Date: 2016
DOI: 10.1016/J.JOCN.2015.05.038
Abstract: Following the widely publicized presentation of the Radiation Therapy Oncology Group (RTOG) 9802 data, we sought to understand how these data had been translated to the management of low grade gliomas (LGG) by Australian neuro-oncology clinicians. The de novo management of LGG is transitioning to include postoperative radiotherapy and chemotherapy after the RTOG 9802 study results demonstrated a survival benefit in this setting. In 2014, neurosurgeons, radiation oncologists and neuro-oncologists who were members of the Australian Cooperative Trials Group for Neuro-oncology (COGNO), as well as additional attendants of the COGNO annual scientific meeting, were surveyed. The survey presented six LGG clinical scenarios and asked respondents to select their preferred management strategy. Some additional questions included the respondents' approach to 1p/19q testing and chemotherapy preferences. The response rate was 30.2% (61/202), with the majority (77%) working in tertiary referral neuro-oncology centers. There was no consensus regarding the management approach for each scenario, with postsurgery observation alone remaining a popular strategy. Only 25% of respondents reported that their institution routinely tests for 1p/19q status in LGG, although 69% were of the opinion that all LGG patients should be tested. The majority (81%) preferred to use temozolomide rather than the procarbazine, lomustine, and vincristine combination as the first line chemotherapy for LGG, but only 44% would actually use it in this setting. Up front chemotherapy, prior to radiotherapy, would be considered by 52% of respondents for certain LGG patients. This survey assessed the management strategies for LGG since the updated RTOG 9802 data were presented. It demonstrates no consensus in the postoperative treatment approaches for LGG.
Publisher: BMJ
Date: 17-09-2014
Publisher: SAGE Publications
Date: 02-2010
Abstract: Patients diagnosed with high-grade gliomas have a poor prognosis and limited life expectancy, and often experience rapid decline in function. Caring for a patient with high-grade glioma is particularly stressful because caregivers are faced not only with cancer-related caregiving issues, but also issues relating to caring for someone with cognitive impairment. This study aimed to articulate the experiences of family caregivers of people diagnosed with high-grade glioma and to describe their information and support needs. A grounded theory method was adopted. Twenty-one family caregivers of people with high-grade glioma were interviewed using a semi-structured interview guide. A constant comparison method of data analysis was employed. A central theme, A Time of Rapid Change and two sub-themes, Renegotiating Relationships and Learning to be a Caregiver, emerged to describe the experiences of participants. Caregiving was characterised by numerous role and life changes from the moment of diagnosis. Caregivers in this study reported experiences similar to those described by caregivers of people with other cancers. What differed for this group was the rapidity of change and the need for immediate information and support to assist with caring for a person with high-grade glioma.
Publisher: American Chemical Society (ACS)
Date: 29-07-2006
DOI: 10.1021/JP062800N
Abstract: The key electronic and spectroscopic properties of vitamin B(6) (pyridoxine) and some of its main charged and protonated/deprotonated species are explored using hybrid density functional theory (DFT) methods including polarized solvation models. It is found that the dominant species at low pH is the N(1)-protonated form and, at high pH, the O(3)(')-deprotonated compound. Computed and experimental UV-spectra for these species (experimental spectra recorded at pH 1.7 and 11.1, respectively) show a very close resemblance. At pH 4.3, the protonated species dominates, but with onset of the zwitterionic oxo form which is also the dominant species at neutral pH. The computational studies furthermore show that neither a polarized continuum model of the polar aqueous solvent or explicit hydrogen bonding through additional water molecules are sufficient to describe accurately the spectrum at physiological pH. Instead, Na(+) and Cl(-) counterions were required to give a blue-shift of approximately 0.15 eV.
Publisher: Springer Science and Business Media LLC
Date: 05-08-2019
Publisher: Public Library of Science (PLoS)
Date: 13-04-2018
Publisher: Elsevier BV
Date: 12-2021
DOI: 10.1016/J.LUNGCAN.2021.11.006
Abstract: Mesothelioma is a rare and universally fatal cancer linked to exposure to asbestos. Until recently, standard of care treatment was chemotherapy a treatment resulting in a minimal survival extension, and not improved upon for almost twenty years. However, the advent of cancer immunotherapy - and in particular the immune checkpoint inhibitor class of drugs - has resulted in recently approved new treatment options, with more currently under investigation. Here, we review clinical trials of both single agent and combination checkpoint inhibitors in mesothelioma, plus studies investigating their combination with chemotherapy. We also describe current advances in biomarker identification regarding prediction of patient response to checkpoint inhibitors. Finally, we assess the probable future direction of the field including where current and developing technologies are likely to lead - in terms of both biomarker discovery and treatment options.
Publisher: Springer Science and Business Media LLC
Date: 25-07-2020
Publisher: Elsevier BV
Date: 02-2011
DOI: 10.1016/J.JOCN.2010.05.009
Abstract: Previous surgical patterns of care reports in high grade glioma (HGG) antedated the use of chemo-radiotherapy. This study, from an elective neurosurgical centre serving an isolated population of over 2 million, identified adult patients with HGG from a prospective multidisciplinary database. Of 328 patients in Western Australia who were diagnosed with HGG between 1 June 2006 and 30 June 2008, 283 patients (86%) received care at the study site. A total of 4% were diagnosed on imaging and clinical factors alone 12% had surgery outside the study site. The remaining 231 patients had 264 surgical procedures 78% resection and 22% biopsy. Median survival (grade IV) was 9.4 months. Resection predicted improved survival (hazard ratio 0.64 95% confidence interval 0.4-0.89) however, in multivariable analysis, only age and grade predicted outcome. The proportion of patients having no tissue diagnosis, or biopsy alone, compares favourably with data before the use of chemo-radiotherapy, as does survival. The therapeutic nihilism surrounding HGG may have decreased since the introduction of temozolomide.
Publisher: American Society of Clinical Oncology (ASCO)
Date: 11-2017
Abstract: LUME-Meso is a phase II/III randomized, double-blind trial designed to assess efficacy and safety of nintedanib plus chemotherapy as first-line treatment of malignant pleural mesothelioma (MPM). Phase II results are reported here. Chemotherapy-naïve patients with unresectable, nonsarcomatoid MPM (Eastern Cooperative Oncology Group performance status 0 to 1), stratified by histology (epithelioid or biphasic), were randomly assigned in a 1:1 ratio to up to six cycles of pemetrexed and cisplatin plus nintedanib (200 mg twice daily) or placebo followed by nintedanib plus placebo monotherapy until progression. The primary end point was progression-free survival (PFS). Eighty-seven patients were randomly assigned. The median number of pemetrexed and cisplatin cycles was six the median treatment duration for nintedanib was 7.8 months and 5.3 months for placebo. Primary PFS favored nintedanib (hazard ratio [HR], 0.56 95% CI, 0.34 to 0.91 P = .017), which was confirmed in updated PFS analyses (HR, 0.54 95% CI, 0.33 to 0.87 P = .010). A trend toward improved overall survival also favored nintedanib (HR, 0.77 95% CI, 0.46 to 1.29 P = .319). Benefit was evident in epithelioid histology, with a median overall survival gain of 5.4 months (HR, 0.70 95% CI, 0.40 to 1.21 P = .197 median [nintedanib v placebo], 20.6 months v 15.2 months) and median PFS gain of 4.0 months (HR, 0.49 95% CI, 0.30 to 0.82 P = .006 median [nintedanib v placebo], 9.7 v 5.7 months). Neutropenia was the most frequent grade ≥ 3 adverse event (AE nintedanib 43.2% v placebo 12.2%) rates of febrile neutropenia were low (4.5% in nintedanib group v 0% in placebo group). AEs leading to discontinuation were reported in 6.8% of those receiving nintedanib versus 17.1% of those in the placebo group. Addition of nintedanib to pemetrexed plus cisplatin resulted in PFS improvement. AEs were manageable. The clinical benefit was evident in patients with epithelioid histology. The confirmatory phase III part of the study is ongoing.
Publisher: Springer Science and Business Media LLC
Date: 17-10-2019
Publisher: Elsevier BV
Date: 10-2010
DOI: 10.1016/J.LUNGCAN.2010.05.016
Abstract: Imaging of malignant pleural mesothelioma (MPM) poses many challenges for imaging specialists and clinicians due to the anatomic location and unique growth pattern of this tumor. Nevertheless, imaging in MPM plays a critical role in diagnosis, prognostication, prediction or measurement of response to therapy, and monitoring of disease recurrence after aggressive surgical management. Imaging-based studies presented at the 9th International Conference of the International Mesothelioma Interest Group (IMIG) in October 2008 sought to further define the current practice and future potential of imaging for the mesothelioma patient. The Imaging Session was dominated by presentations that addressed the use of fluorodeoxyglucose positron emission tomography (FDG-PET), a clear indication of the expanding role of this modality. These uses included FDG-PET imaging at the point of diagnosis, in prognostication, and in the assessment of response to chemotherapy. Often FDG-PET studies were combined with computed tomography (CT) scans in an attempt to overcome limitations associated with either imaging modality alone. At diagnosis, FDG-PET parameters had a high sensitivity and specificity for differentiation of benign from malignant pleural disease. The use of FDG-PET to extract quantitative features from metabolically active tumor volume was shown to be a significant factor in the prediction of patient survival. The prognostic value of FDG-PET was not confounded by prior talc pleurodesis, despite the inflammatory response associated with the procedure. Metabolic response based on FDG-PET was found to be significantly correlated with progression-free survival. CT-based assessment of mesothelioma was determined to be inconsistent with spherical-model-based criteria so that changes in tumor area, a presumably more complete assessment of tumor burden, exhibited a 46% concordance rate with changes in linear measurements.
Publisher: Elsevier BV
Date: 10-2019
Publisher: BENTHAM SCIENCE PUBLISHERS
Date: 02-2016
Publisher: Elsevier BV
Date: 09-2017
DOI: 10.1016/J.CLLC.2017.03.010
Abstract: Malignant pleural mesothelioma (MPM) is a rare but aggressive disease: median survival is 6 to 9 months if untreated. Standard first-line treatment for patients with unresectable MPM is cisplatin emetrexed, with a median overall survival (OS) of approximately 1 year. Improvements in first-line treatment options are needed. With the benefit of combining bevacizumab with standard therapy shown in the Mesothelioma Avastin Cisplatin Pemetrexed Study (MAPS), vascular endothelial growth factor (VEGF) pathway inhibition has gained renewed interest as a treatment approach. Nintedanib is an oral angiokinase inhibitor targeting multiple signaling pathways implicated in the pathogenesis of MPM, including the VEGF receptor. The phase III part of the international, phase II/III LUME-Meso study is evaluating the efficacy and safety of nintedanib plus pemetrexed/cisplatin in patients with unresectable epithelioid MPM. Originally, this was a double-blind, randomized, phase II exploratory study and was amended to include a confirmatory phase III part following the recommendation of an internal Data Monitoring Committee and review of phase II data. The phase III part plans to enroll 450 chemotherapy-naive patients, who will be randomized to receive pemetrexed/cisplatin on day 1 and nintedanib or placebo on days 2 to 21, for a maximum of 6 cycles. Patients without disease progression who are eligible to continue study treatment will receive maintenance treatment with nintedanib or placebo until disease progression or undue toxicity. The primary end point is progression-free survival OS is the key secondary end point. The study will use an adaptive design, including an interim analysis to reassess the number of OS events required to ensure sufficient power for OS analysis. The study is currently enrolling patients.
Publisher: Elsevier BV
Date: 04-2013
Publisher: Springer Science and Business Media LLC
Date: 12-2018
Publisher: Wiley
Date: 14-06-2022
Abstract: Previous preclinical and clinical trials have shown promising antitumour activity and toxicity profile when employing the ‘Synergy between Immunotherapy and Radiotherapy’ (SITAR) strategy. Approximately, one in seven radiation therapy studies currently recruiting is investigating SITAR. This article reviews the range of cancers known to respond to immunotherapy and publications analysing SITAR. It sets the background for work that needs to be done in future clinical trials. It also reviews the potential toxicities of immunotherapy and discusses areas where caution is required when combining treatments.
Publisher: Springer Science and Business Media LLC
Date: 19-01-2023
DOI: 10.1007/S11060-023-04239-0
Abstract: High-grade glioma (HGG) is a rapidly progressing and debilitating disease. Family carers take on multiple responsibilities and experience high levels of distress. We aimed to deliver a nurse-led intervention (Care-IS) to carers to improve their preparedness to care and reduce distress. We conducted a randomised controlled trial (ACTRN:12612001147875). Carers of HGG patients were recruited during patients’ combined chemoradiation treatment. The complex intervention comprised four components: (1) initial telephone assessment of carer unmet needs (2) tailored hard-copy resource folder (3) home visit and, (4) monthly telephone support for up to 12 months. Primary outcomes included preparedness for caregiving and distress at 2, 4, 6 and 12 months. Intervention effects were estimated using linear mixed models which included a time by group interaction. Secondary outcomes included anxiety, depression, quality of life, carer competence and strain. We randomised 188 carers (n = 98 intervention, n = 90 control). The intervention group reported significantly higher preparedness for caregiving at 4 months (model β = 2.85, 95% CI 0.76–4.93) and all follow-up timepoints including 12 months (model β = 4.35, 95% CI 2.08–6.62), compared to the control group. However, there was no difference between groups in carer distress or any secondary outcomes. This intervention was effective in improving carer preparedness. However, carer distress was not reduced, potentially due to the debilitating rogressive nature of HGG and ongoing caring responsibilities. Future research must explore whether carer interventions can improve carer adjustment, self-efficacy and coping and how we support carers after bereavement. Additionally, research is needed to determine how to implement carer support into practice.
Publisher: BMJ
Date: 12-2022
DOI: 10.1136/BMJGH-2022-010553
Abstract: Mesothelioma is a key asbestos-related disease (ARD) but can be difficult to diagnose. Countries presumably ban asbestos to reduce future ARD burdens, but it is unknown if countries ban asbestos as a consequence of ARD burdens. We assessed if and to what extent mesothelioma burden has an impact on a country banning asbestos and obtaining targets for preventative strategies. We analysed the status of asbestos ban and mesothelioma burden during 1990–2019 in 198 countries. We assessed mesothelioma burden by age-adjusted mortality rates (MRs) estimated by the Global Burden of Disease Study (GBD) and mesothelioma identification by the WHO mortality database. For GBD-estimated mesothelioma MR, the pre-ban period in the asbestos-banned countries was compared with the 1990–2019 period in the not-banned countries. For mesothelioma identification, the 1990–2019 period was applied to both banned and not-banned countries. The association of mesothelioma MR with ban status increased as the ban year approached. Logistic regression analyses showed that the odds of a country banning asbestos increased 14.1-fold (95% CI 5.3 to 37.9) for mesothelioma identification combined with a 26% (12% to 42%) increase per unit increase of mesothelioma MR (one death per million per year) during the period 1–5 year before ban (model p .0001). Mesothelioma burden had an impact on, and together with its identification, explained the banning of asbestos in many countries. Asbestos-banned countries likely learnt lessons from their historical policies of using asbestos because mesothelioma burden and identification follow historical asbestos use. Prevention targets for ARD elimination should combine asbestos ban with mesothelioma identification.
Publisher: Elsevier BV
Date: 12-2022
Publisher: Elsevier BV
Date: 09-2019
Publisher: Springer Science and Business Media LLC
Date: 20-09-2010
DOI: 10.1038/ONC.2010.437
Abstract: It is well established that the immune system has the capacity to attack malignant cells. During malignant transformation cells acquire numerous molecular and biochemical changes that render them potentially vulnerable to immune cells. Yet it is self-evident that a growing tumour has managed to evade these host defence mechanisms. The exact ways in which the immune system interacts with tumour cells and how cancers are able to escape immunological eradication have only recently started to be fully elucidated. Understanding the relationship between the tumour and the anti-tumour immune response and how this can be altered with conventional treatments and immune-targeted therapies is crucial to developing new treatments for patients with cancer. In this review, focusing on the anti-tumour T-cell response, we summarize our understanding of how tumours, cancer treatments and the immune system interact, how tumours evade the immune response and how this process could be manipulated for the benefit of patients with cancer.
Publisher: Environmental Health Perspectives
Date: 05-2022
DOI: 10.1289/EHP11148
Publisher: Frontiers Media SA
Date: 18-02-2020
Publisher: Frontiers Media SA
Date: 24-03-2022
Abstract: With immune checkpoint therapy (ICT) having reshaped the treatment of many cancers, the next frontier is to identify and develop novel combination therapies to improve efficacy. Previously, we and others identified beneficial immunological effects of the vitamin A derivative tretinoin on anti-tumour immunity. Although it is known that tretinoin preferentially depletes myeloid derived suppressor cells in blood, little is known about the effects of tretinoin on the tumour microenvironment, h ering the rational design of clinical trials using tretinoin in combination with ICT. Here, we aimed to identify how tretinoin changed the tumour microenvironment in mouse tumour models, using flow cytometry and RNAseq, and we sought to use that information to establish optimal dosing and scheduling of tretinoin in combination with several ICT antibodies in multiple cancer models. We found that tretinoin rapidly induced an interferon dominated inflammatory tumour microenvironment, characterised by increased CD8+ T cell infiltration. This phenotype completely overlapped with the phenotype that was induced by ICT itself, and we confirmed that the combination further lified this inflammatory milieu. The addition of tretinoin significantly improved the efficacy of anti-CTLA4/anti-PD-L1 combination therapy, and staggered scheduling was more efficacious than concomitant scheduling, in a dose-dependent manner. The positive effects of tretinoin could be extended to ICT antibodies targeting OX40, GITR and CTLA4 monotherapy in multiple cancer models. These data show that tretinoin induces an interferon driven, CD8+ T cell tumour microenvironment that is responsive to ICT.
Publisher: Springer Science and Business Media LLC
Date: 22-05-2017
DOI: 10.1007/S11060-017-2479-8
Abstract: In recurrent glioblastoma, health-related quality of life (HRQL) is a crucial trial endpoint. We examined HRQL outcomes as a secondary endpoint for patients in the CABARET randomized phase 2 trial. 122 patients were randomly allocated to bevacizumab monotherapy or bevacizumab plus carboplatin. We calculated change scores from baseline for each HRQL measure on the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) and the Brain Cancer Module (QLQ-BN20), together with time to deterioration in HRQL, and the proportion of participants with clinically meaningful improvements in specific disease-related symptoms. At baseline, 117 of 122 randomized patients (96%) attempted questionnaires. Questionnaire participation rates were >90% for patients continuing on treatment, however at the end-of-treatment visit only 72 (64% of eligible participants) returned a form. There were no differences between arms in change scores over the treatment period. Time to ≥10 point deterioration in scores from baseline was also similar between arms. HRQL deterioration occurred largely before progression for the domains tested, but scores in HRQL domains specifically relevant to symptoms of recurrent glioblastoma also improved for about 50% of patients with symptoms at baseline. Neither detrimental nor beneficial effects on HRQL were seen with carboplatin added to bevacizumab, with a proportion of patients on both arms experiencing symptomatic benefit. Given the reduced questionnaire completion at end of treatment, time to HRQL deterioration is a feasible and robust clinical trial endpoint in this patient population. Clinical trials registration number: ACTRN12610000915055.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22487439
Abstract: Supplementary Figure from Temozolomide and Radiotherapy versus Radiotherapy Alone in Patients with Glioblastoma, i IDH /i -wildtype: i Post Hoc /i Analysis of the EORTC Randomized Phase III CATNON Trial
Publisher: Wiley
Date: 10-02-2021
DOI: 10.1111/AJCO.13508
Abstract: The FACT COST is a patient‐rated measure of financial toxicity, developed and validated in a North American population. We aimed to confirm the validity and reliability of the FACT COST in Australian cancer patients, because the Australian healthcare funding structure is different to that in North America. A single center, cross‐sectional study design investigated financial toxicity in oncology outpatients. Eligible adults had current malignancy, with or without active cancer treatment. The primary endpoint was the degree of financial toxicity experienced via the COST questionnaire secondary endpoints included health‐related quality of life (Functional Assessment of Cancer Therapy‐General), anxiety, and depression (Hospital Anxiety and Depression Scale). Clinical and demographic data were recorded. Statistical analysis determined the internal consistency, test‐retest reliability and validity of COST, and correlations between COST score and secondary endpoints. A total of 257 patients participated (79% response rate). Fifty‐three percent were female median age 63 years (range 19‐88). COST scores were skewed toward less financial toxicity, median 26 (SD 10.3, range 1‐43), lower scores indicating higher toxicity. High internal consistency (Cronbach's α = 0.884), test‐retest reliability (ICC = 0.801), and convergent validity were demonstrated. Financial toxicity was greatest in younger participants, those with more inpatient admissions, those with a change in employment status following diagnosis, and those in the lowest income quintile. Financial toxicity was associated with worse health‐related quality of life, and greater depression and anxiety. The COST measure of financial toxicity demonstrated acceptable validity parameters in an Australian outpatient population. Greater financial toxicity was associated with worse psychological well‐being and with certain patient demographics.
Publisher: Elsevier BV
Date: 05-2011
DOI: 10.1016/J.LUNGCAN.2010.08.007
Abstract: We sought (i) lung cancer clinicians' judgements about the smallest survival benefits that would make the harms of adjuvant chemotherapy for non-small-cell lung cancer (NSCLC) worthwhile, (ii) factors associated with their judgements, and (iii) comparisons with breast cancer and colon cancer clinicians surveyed similarly in 2002-2003. Delegates at the Australian Lung Cancer Conference 2008 were invited to complete a validated, self-administered questionnaire that used the time trade-off method to determine the minimum survival benefits judged sufficient to make adjuvant chemotherapy worthwhile. The baseline survival times were 3 and 5 years, and the baseline 5-year survival rates were 50% and 65%. Chemotherapy was 4 cycles of cisplatin and vinorelbine. Characteristics of the 156 respondents were: median age 41 years (range 23-62), female 55%, married 83%, with dependent children 62%, respiratory physician 28%, nurse 24%, medical oncologist 14%, radiation oncologist 12%, trial nurse/coordinator 12%, thoracic surgeon 4%. Moderate survival benefits were judged sufficient to make chemotherapy worthwhile. The median benefit judged sufficient was an extra 9 months beyond a baseline survival time of 3 or 5 years. The median benefit judged sufficient was an extra 5% for a baseline survival rate of 65%, versus an extra 10% for a baseline survival rate of 50% (p<0.001). Smaller benefits were judged sufficient by clinicians who were married (p=0.02) or had dependants (p=0.04). Lung cancer clinicians judged smaller benefits sufficient than breast cancer (n=89) and colon cancer (n=72) clinicians in similar prior studies (median required benefit of 9 months versus 12 months, p<0.001). Most lung cancer clinicians attending a national lung cancer conference judged moderate improvements in survival sufficient to make adjuvant chemotherapy worthwhile. Smaller benefits were judged sufficient by lung cancer clinicians in 2008 than by breast cancer and colon cancer clinicians 5-6 years earlier. Clinicians should be aware of their own preferences, and explore their patients' preferences, when discussing adjuvant chemotherapy.
Publisher: Elsevier BV
Date: 04-2015
DOI: 10.1016/J.PEC.2015.01.002
Abstract: To determine High Grade Glioma (HGG) patients' levels of distress and QOL during combined chemoradiotherapy, explore predictors of distress and QOL and prioritize patients' supportive care needs. Patients diagnosed with HGG who were referred for combined chemoradiotherapy were recruited. Participants completed demographics and questionnaires assessing distress, function, and supportive care needs. Descriptive statistics, correlation coefficients, t-tests and linear and logistic regression analyses were performed. 116 participants completed the questionnaire. Participants scored lower for QOL in physical, functional and emotional domains than the general Australian population. Poor physical function, lower education levels, loss of employment and financial impact associated with diagnosis were consistently linked with multiple domains of distress, poor QOL and high unmet needs. Having a carer who was their partner predicted lower emotional well-being. Patients with HGG experience a poor QOL, increased levels of distress and high unmet needs when commencing chemoradiotherapy. Patients who experience a financial impact and those with lower education levels may report higher levels of distress and increased unmet needs. Poor function, lower education and limited financial resources may help identify those who require additional screening and may benefit from additional information and psychological support at this time.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22487442
Abstract: Supplementary Data from Temozolomide and Radiotherapy versus Radiotherapy Alone in Patients with Glioblastoma, i IDH /i -wildtype: i Post Hoc /i Analysis of the EORTC Randomized Phase III CATNON Trial
Publisher: Oxford University Press (OUP)
Date: 14-09-2016
Publisher: Wiley
Date: 30-11-2010
DOI: 10.1111/J.1743-7563.2010.01316.X
Abstract: Malignant pleural mesothelioma (MPM) is a devastating malignancy that until recently has had no effective treatment. Pemetrexed in combination with cisplatin entered routine clinical practice following reports of efficacy in 2003. We performed a retrospective analysis of all patients with malignant mesothelioma at a single institution treated with pemetrexed in any combination or as monotherapy between 2004 and 2007. During this period, 62 patients received pemetrexed-based chemotherapy for MPM, most of whom were male (87%), treated in the palliative setting (84%) and received pemetrexed in combination with a platinum agent (95%). Pemetrexed was found to be well tolerated and produced clinical benefit and response rates similar to other published studies for its use in MPM in the phase IV or community practice settings. Patients with progressive disease as their best radiological response had very poor outcomes, while patients with stable disease had similar outcomes to those with responses. We confirmed that survival after commencement of pemetrexed-based chemotherapy remains under one year in this group of patients, somewhat less than the survival reported in phase III trials that currently inform clinical decision making. Further research is required to identify those patients who might benefit from pemetrexed based on molecular predictive markers.
Publisher: American Society of Clinical Oncology (ASCO)
Date: 02-2022
DOI: 10.1200/OP.21.00426
Abstract: The management of pleural mesothelioma has changed with the demonstration that first-line checkpoint blockade therapy improves survival. This review covers issues of relevance to the practicing medical oncologist, with an emphasis on the palliative setting and on new information. Until recently, standard systemic therapy for mesothelioma was combination chemotherapy with platinum and pemetrexed. In 2020, combination immunotherapy with ipilimumab and nivolumab was approved as first-line systemic therapy for mesothelioma following release of the results from the CheckMate 743 trial. This trial showed improved overall survival for patients receiving ipilimumab and nivolumab over those treated with platinum and pemetrexed chemotherapy. When the survival results were examined by histologic subtype, the survival benefit was most significant in those with nonepithelioid mesothelioma, a group for which combination immunotherapy is now standard of care. The most important outstanding issue from CheckMate-743 is a better understanding, through translational studies, of which patients with epithelioid mesothelioma may benefit from combination immunotherapy. The next generation of first-line clinical trials in mesothelioma will report the results of first-line combination chemoimmunotherapy. For those patients who receive first-line dual checkpoint blockade, there is no evidence as to the efficacy of subsequent chemotherapy. However, given the known first-line efficacy of cisplatin or carboplatin and pemetrexed, combination chemotherapy is an appropriate subsequent choice for those who progress on or after dual immunotherapy. For those who previously received chemotherapy without immunotherapy, single-agent nivolumab provides benefit over best supportive care. In summary, both chemotherapy and immunotherapy should be considered for all patients during their disease course. Another topical issue is the growing appreciation that some in iduals have an inherited predisposition to mesothelioma referral to a clinical geneticist should be considered under some circumstances. The role of surgery and multimodality therapy is controversial, with results awaited from the fully recruited MARS-2 clinical trial. Patient selection, staging, and multidisciplinary review are critical to identify those who might benefit from a multimodality approach. Finally, a proactive, multidisciplinary approach to symptom management and the principles of management of pleural effusions are critical to manage the symptom burden of mesothelioma and optimize patient well-being.
Publisher: SAGE Publications
Date: 08-07-2023
DOI: 10.1177/02692163231186177
Abstract: Despite global support, there remain gaps in the integration of early palliative care into cancer care. The methods of implementation whereby evidence of benefits of palliative care is translated into practice deserve attention. To identify implementation frameworks utilised in integrated palliative care in hospital-based oncology services and to describe the associated enablers and barriers to service integration. Systematic review with a narrative synthesis including qualitative, mixed methods, pre-post and quasi experimental designs following the guidance by the Centre for Reviews and Dissemination (PROSPERO registration CRD42021252092). Six databases searched in 2021: EMBASE, EMCARE, APA PsycINFO, CINAHL, Cochrane Library and Ovid MEDLINE searched in 2023. Included were qualitative or quantitative studies, in English language, involving adults years, and implementing hospital-based palliative care into cancer care. Critical appraisal tools were used to assess the quality and rigour. Seven of the 16 studies explicitly cited the use of frameworks including those based on RE-AIM, Medical Research Council evaluation of complex interventions and WHO constructs of health service evaluation. Enablers included an existing supportive culture, clear introduction to the programme across services, adequate funding, human resources and identification of advocates. Barriers included a lack of communication with the patients, caregivers, physicians and palliative care team about programme goals, stigma around the term ‘palliative’, a lack of robust training, or awareness of guidelines and undefined staff roles. Implementation science frameworks provide a method to underpin programme development and evaluation as palliative care is integrated within the oncology setting.
Publisher: American Association for Cancer Research (AACR)
Date: 03-2011
DOI: 10.1158/1078-0432.CCR-10-1929
Abstract: Purpose: To examine the clinical utility of soluble mesothelin in patients with malignant pleural mesothelioma. Experimental Design: A total of 97 patients (female: 11 male: 86) were prospectively enrolled, longitudinal serum s les collected, and mesothelin concentrations determined. Baseline mesothelin levels were analyzed relative to tumor stage, presence of metastatic disease, the positron emission tomography (PET) parameters maximum standardized uptake value, tumor volume, total glycolytic volume, and survival. Changes in mesothelin level were correlated to objective response to chemotherapy, as assessed radiologically and by PET imaging, and with patient survival. Results: Baseline mesothelin levels greater than 5 nmol/L were a significant negative prognostic indicator (HR = 2.25 95% CI, 1.20–4.21) and correlated with tumor stage and volume. In 55 patients who received chemotherapy, change in mesothelin correlated with radiological response (χ2 = 11.32 P = 0.023) and change in metabolically active tumor volume (r = 0.58 P & 0.01). Median survival for patients with a reduction in mesothelin following chemotherapy (19 months) was significantly longer than for patients with increased mesothelin (5 months P & 0.001). Conclusion: These findings show the potential value of changes in mesothelin levels for prognostication and monitoring of treatment response in mesothelioma. Clin Cancer Res 17(5) 1181–9. ©2010 AACR.
Publisher: Wiley
Date: 21-10-2020
DOI: 10.1002/PON.5569
Publisher: Elsevier BV
Date: 10-2005
Publisher: Springer Science and Business Media LLC
Date: 11-02-2017
DOI: 10.1007/S13187-017-1175-X
Abstract: The aim of this pilot study was to test the feasibility and acceptability of a family carer intervention for carers of patients with high-grade glioma (HGG). The intervention consisted of: (1) an initial telephone assessment of carer needs (2) a personalised tabbed resource file (3) nurse-led home visit and (4) ongoing telephone support. Two consumer representatives reviewed the intervention resources. The intervention was then piloted with participants who were the primary carer for patients undergoing treatment for HGG in Western Australia. Two consumers provided feedback on the resource, and 10 carers participated in the pilot. Positive feedback was received about the resource manual and intervention. Suggestions were also made for changes which were implemented into the trial. The surveys were shortened based on feedback. Participants identified a large range of issues during nursing assessments which would not otherwise be identified or addressed for carers receiving routine care. As a result of providing the intervention, the nurse was able to make referrals to address needs that were identified. This pilot study enabled us to refine and test the Care-IS intervention and test the feasibility and acceptability of proposed survey instruments. We were also able to estimate recruitment and retention and the overall study timeline required for the randomised controlled trial we are now conducting. It has also demonstrated the role of the nurse who delivered the intervention and allowed us to refine communication and referral pathways.
Publisher: Elsevier BV
Date: 03-2020
DOI: 10.1016/J.JTHO.2019.10.019
Abstract: Our aim was to validate the prognostic relevance in NSCLC of potential residual tumor (R) descriptors, including the proposed International Association for the Study of Lung Cancer definition for uncertain resection, referred to as R(un). A total of 14,712 patients undergoing resection with full R status and survival were analyzed. The following were also evaluated: whether fewer than three N2 stations were explored, lobe-specific nodal dissection, extracapsular extension, highest lymph node station status, carcinoma in situ at the bronchial resection margin, and pleural lavage cytologic examination result. Revised categories of R0, R(un), R1, and R2 were tested for survival impact. In all, 14,293 cases were R0, 263 were R1, and 156 were R2 (median survivals not reached, 33 months, and 29 months, respectively). R status correlated with T and N categories. A total of 9290 cases (63%) had three or more N2 stations explored and 6641 cases (45%) had lobe-specific nodal dissection, correlated with increasing pN2. Extracapsular extension was present in 62 of 364 cases with available data (17%). The highest station was positive in 942 cases (6.4%). The pleural lavage cytologic examination result was positive in 59 of 1705 cases (3.5%): 13 had carcinoma in situ at the bronchial resection margin. After reassignment because of inadequate nodal staging in 56% of cases, 6070 cases were R0, 8185 were R(un), 301 were R1, and 156 were R2. In node-positive cases, the median survival times were 70, 50, and 30 months for R0, R(un) (p < 0.0001), and R1 (p < 0.001), respectively, with no significant difference between R0 and R(un) in pN0 cases. R descriptors have prognostic relevance, with R(un) survival stratifying between R0 and R1. Therefore, a detailed evaluation of R factor is of particular importance in the design and analyses of clinical trials of adjuvant therapies.
Publisher: Wiley
Date: 20-04-2018
DOI: 10.1002/PATH.5080
Publisher: Informa UK Limited
Date: 13-07-2019
Publisher: Springer Science and Business Media LLC
Date: 12-2015
DOI: 10.1038/BJC.2015.427
Publisher: Springer Science and Business Media LLC
Date: 04-12-2009
DOI: 10.1007/S00262-008-0628-9
Abstract: Tumor cell death potentially engages with the immune system. However, the efficacy of anti-tumor chemotherapy may be limited by tumor-driven immunosuppression, e.g., through CD25+ regulatory T cells. We addressed this question in a mouse model of mesothelioma by depleting or reconstituting CD25+ regulatory T cells in combination with two different chemotherapeutic drugs. We found that the efficacy of cyclophosphamide to eradicate established tumors, which has been linked to regulatory T cell depletion, was negated by adoptive transfer of CD25+ regulatory T cells. Analysis of post-chemotherapy regulatory T cell populations revealed that cyclophosphamide depleted cycling (Ki-67(hi)) T cells, including foxp3+ regulatory CD4+ T cells. Ki-67(hi) CD4+ T cells expressed increased levels of two markers, TNFR2 and ICOS, that have been associated with a maximally suppressive phenotype according to recently published studies. This suggest that cyclophosphamide depletes a population of maximally suppressive regulatory T cells, which may explain its superior anti-tumor efficacy in our model. Our data suggest that regulatory T cell depletion could be used to improve the efficacy of anti-cancer chemotherapy regimens. Indeed, we observed that the drug gemcitabine, which does not deplete cycling regulatory T cells, eradicates established tumors in mice only when CD25+ CD4+ T cells are concurrently depleted. Cyclophosphamide could be used to achieve regulatory T cell depletion in combination with chemotherapy.
Publisher: Future Medicine Ltd
Date: 12-2014
DOI: 10.2217/LMT.14.37
Abstract: SUMMARY Given the impressive efficacy of immune checkpoint blockade in thoracic malignancies, and the recently discovered immune-stimulating properties of many cytotoxic drugs, a logical next step would be to combine these treatments. However, the rational design of clinical trials investigating these combinations is h ered by a lack of knowledge regarding the overall immunogenic effects of the different chemotherapeutics. Here, we give an overview of the field with regard to checkpoint blockade and the immunological effects of cytotoxic chemotherapeutics, with particular focus on preclinical and clinical studies investigating the combination of these two treatment modalities. We discuss the hurdles that need to be overcome in order to optimally exploit chemotherapy and immune checkpoint blockade combinations in thoracic cancers.
Publisher: Elsevier BV
Date: 07-2011
DOI: 10.1016/J.CPET.2011.04.002
Abstract: Assessment of response is important to interpret early phase clinical trial results and to guide in idual patient management. In malignant pleural mesothelioma (MPM), the circumferential growth pattern of the disease, the presence of pleural effusion and atelectasis, and the common use of pleurodesis make this a challenging task for imaging specialists and clinicians. This article reviews the current evidence for radiological and positron emission tomography (PET) response assessment in MPM, and the pitfalls and challenges in its application. Current research and future directions in radiological and PET response are discussed, including the use of novel radiotracers.
Publisher: Elsevier BV
Date: 07-2011
DOI: 10.1016/J.CPET.2011.04.001
Abstract: Early diagnosis and accurate disease staging in patients with malignant pleural mesothelioma (MPM) are essential in classifying such patients into prognostic subgroups to allow delivery of stage-specific therapies. This review addresses the current status of multimodality imaging in the diagnosis and staging of MPM. Clinical, research, and future directions in computed tomography (CT), magnetic resonance imaging, and PET/CT diagnosis and staging of MPM are discussed, including the use of novel PET probes. The article concludes with important take-home messages summarized as the pearls and pitfalls of each diagnostic modality in the diagnosis and staging of patients with MPM.
Publisher: Oxford University Press (OUP)
Date: 30-01-2013
Abstract: Previous studies have focused on the treatment received by rural cancer patients and have not examined their diagnostic pathways as reasons for poorer outcomes in rural Australia. To compare and explore symptom appraisal and help-seeking behaviour in patients with breast, lung, prostate or colorectal cancer from rural Western Australia (WA). A mixed-methods study of people recently diagnosed with breast, lung, prostate or colorectal cancer from rural WA. The time from first symptom to diagnosis (i.e. total diagnostic interval, TDI) was calculated from interviews and medical records. Sixty-six participants were recruited (24 breast, 20 colorectal, 14 prostate and 8 lung cancer patients). There was a highly significant difference in time from symptom onset to seeking help between cancers (P = 0.006). Geometric mean symptom appraisal for colorectal cancer was significantly longer than that for breast and lung cancers [geometric mean differences: 2.58 (95% confidence interval, CI: 0.64-4.53), P = 0.01 3.97 (1.63-6.30), P = 0.001, respectively]. There was a significant overall difference in arithmetic mean TDI (P = 0.046) breast cancer TDI was significantly shorter than colorectal or prostate cancer TDI [mean difference : 266.3 days (95% CI: 45.9-486.8), P = 0.019 277.0 days, (32.1-521.9), P = 0.027, respectively]. These differences were explained by the nature and personal interpretation of symptoms, perceived as well as real problems of access to health care, optimism, stoicism, machismo, fear, embarrassment and competing demands. Longer symptom appraisal was observed for colorectal cancer. Participants defined core characteristics of rural Australians as optimism, stoicism and machismo. These features, as well as access to health care, contribute to later presentation of cancer.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22487427
Abstract: Supplementary Figure from Temozolomide and Radiotherapy versus Radiotherapy Alone in Patients with Glioblastoma, i IDH /i -wildtype: i Post Hoc /i Analysis of the EORTC Randomized Phase III CATNON Trial
Publisher: Elsevier BV
Date: 12-2021
DOI: 10.1016/J.JOCN.2021.10.022
Abstract: Assessment of neurocognitive function (NCF) is important in brain tumor clinical trials, however there are varying methodologies available. We used the Cogstate computerized NCF testing battery and the mini-mental state examination (MMSE) to prospectively assess cognition in adult patients with recurrent glioblastoma (GBM) enrolled in the CABARET randomized phase II clinical trial of bevacizumab versus bevacizumab plus carboplatin chemotherapy. We determined completion rates compared NCF results between trial arms and assessed baseline NCF as a predictor of survival outcome. 93 of 103 eligible patients completed baseline Cogstate NCF testing. Completion rates were between 60 and 100% across each timepoint, and 38% at disease progression. There was no evidence of difference between arms in time to deterioration in NCF using either test. Prior to disease progression, deterioration on the Cogstate tests was substantially more common (90%) than deterioration on the MMSE (37%), and decline in the Cogstate composite score within the first 8 weeks was associated with shorter overall survival. This testing methodology may be useful when determining net clinical benefit for therapies in patients with recurrent GBM.
Publisher: Future Medicine Ltd
Date: 05-2014
DOI: 10.2217/FON.14.75
Abstract: ABSTRACT: Glioblastoma has a poor prognosis accompanied by debilitating neurological symptoms and impaired quality of life. Effective treatment strategies are needed, beyond the current standard of care (SOC), to improve outcomes. Glioblastomas are highly vascularized with elevated levels of VEGF, representing an appropriate target for selective therapies. The role of the anti-VEGF agent bevacizumab in newly diagnosed and recurrent glioblastoma is not fully clear at this time. Although bevacizumab has demonstrated improvements in progression-free survival in newly diagnosed and recurrent glioblastoma, there remain challenges in assessing disease progression after antiangiogenic treatment. The bevacizumab mechanism of action suggests a rationale for continuing bevacizumab treatment through multiple lines of therapy, strengthened by longer progression-free and overall survival observed with bevacizumab continuation beyond progression in a Phase III study in metastatic colorectal cancer and in pooled analyses of Phase II trials in glioblastoma. A novel study (randomized, double-blind, Phase IIIb TAMIGA [MO28347]) aims to evaluate whether continuing bevacizumab plus lomustine (as second-line therapy) and SOC (third line and beyond) improves survival compared with placebo plus lomustine and then placebo plus SOC in patients with glioblastoma who progressed after first-line bevacizumab plus SOC.
Publisher: BMJ
Date: 18-07-2014
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22487433
Abstract: Supplementary Figure from Temozolomide and Radiotherapy versus Radiotherapy Alone in Patients with Glioblastoma, i IDH /i -wildtype: i Post Hoc /i Analysis of the EORTC Randomized Phase III CATNON Trial
Publisher: Elsevier BV
Date: 08-2014
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22487430
Abstract: Supplementary Figure from Temozolomide and Radiotherapy versus Radiotherapy Alone in Patients with Glioblastoma, i IDH /i -wildtype: i Post Hoc /i Analysis of the EORTC Randomized Phase III CATNON Trial
Publisher: Elsevier BV
Date: 06-2021
Publisher: Elsevier BV
Date: 12-2015
Abstract: Data from murine models suggest that CD40 activation may synergize with cytotoxic chemotherapy. We aimed to determine the maximum tolerated dose (MTD) and toxicity profile and to explore immunological biomarkers of the CD40-activating antibody CP-870,893 with cisplatin and pemetrexed in patients with malignant pleural mesothelioma (MPM). Eligible patients had confirmed MPM, ECOG performance status 0-1, and measurable disease. Patients received cisplatin 75 mg/m(2) and pemetrexed 500 mg/m(2) on day 1 and CP-870,893 on day 8 of a 21-day cycle for maximum 6 cycles with up to 6 subsequent cycles single-agent CP-870,893. Immune cell subset changes were examined weekly by flow cytometry. Fifteen patients were treated at three dose levels. The MTD of CP-870,893 was 0.15 mg/kg, and was exceeded at 0.2 mg/kg with one grade 4 splenic infarction and one grade 3 confusion and hyponatraemia. Cytokine release syndrome (CRS) occurred in most patients (80%) following CP-870,893. Haematological toxicities were consistent with cisplatin and pemetrexed chemotherapy. Six partial responses (40%) and 9 stable disease (53%) as best response were observed. The median overall survival was 16.5 months the median progression-free survival was 6.3 months. Three patients survived beyond 30 months. CD19+ B cells decreased over 6 cycles of chemoimmunotherapy (P < 0.001) with a concomitant increase in the proportion of CD27+ memory B cells (P < 0.001) and activated CD86+CD27+ memory B cells (P < 0.001), as an immunopharmacodynamic marker of CD40 activation. CP-870,893 with cisplatin and pemetrexed is safe and tolerable at 0.15 mg/kg, although most patients experience CRS. While objective response rates are similar to chemotherapy alone, three patients achieved long-term survival. ACTRN12609000294257.
Publisher: Springer Science and Business Media LLC
Date: 08-04-2014
DOI: 10.1038/BJC.2014.187
Publisher: Elsevier BV
Date: 03-2016
Publisher: Oxford University Press (OUP)
Date: 12-09-2021
DOI: 10.1093/NOP/NPAA057
Abstract: Emerging evidence supports the clinical impact of sleep disturbance (SD) on cancer patients. This study aimed to determine the prevalence and predictors of SD in people with malignant brain tumors and caregivers, and explore any relationship between the patient-caregiver dyad’s sleep. Eighty-one adults with primary malignant (91%) or metastatic (9%) brain tumors and their family caregivers (n = 44) completed a series of self-report questionnaires, including the Pittsburgh Sleep Quality Index (PSQI), the Insomnia Severity Index, and the drowsiness item of The MD Anderson Symptom Inventory-Brain Tumor in an Australian ambulatory neuro-oncology setting. Participants were grouped by the PSQI cutoff (SD & 5), and binary logistic regression analyses were performed to identify risk factors. Of patients, 53% reported SD and 15% of those clinically significant insomnia, and 27% reported moderate to severe daytime drowsiness. Whereas anxiety, depression, fatigue, pain, neurocognitive symptoms, and antiemetic use were higher in patients with SD, fatigue and KPS were strong predictors of SD. In caregivers, 55% reported poor sleep and 13% clinical insomnia. Anxiety, caregiver burden, and comorbid illness were significantly associated with caregivers’ SD. The in idual’s SD did not affect the chance of the other member of the patient-caregiver dyad experiencing SD. More than half the s le had sleep disturbance, which was linked to many concomitant symptoms, such as fatigue in patients and anxiety in caregivers, potentially contributing to distress and functional impairment. Understanding underlying mechanisms of SD, the potential use of these clinical predictors in care settings, and options for management is warranted.
Publisher: Elsevier BV
Date: 07-2018
DOI: 10.1016/J.JTHO.2018.04.034
Abstract: Malignant pleural mesothelioma poses unique difficulties in tumor measurement and response assessment however, robust and reproducible assessment of response is critically important in the conduct, interpretation, and reporting of clinical trials. The current de facto standard for the assessment of mesothelioma tumor response, "modified RECIST" (Response Evaluation Criteria in Solid Tumors), was published in 2004 as a research paper. Practical application of the modified RECIST guidelines has suffered from varied interpretations, resulting in inaccuracies and inconsistencies in tumor response assessment across and within mesothelioma clinical trials. The presented "modified RECIST 1.1 for mesothelioma" response assessment guidelines provide a much-needed update that incorporates recommendations from RECIST 1.1 and approaches to other practical issues, including: (1) definition of minimally measurable disease (2) definition of measurable lesions (3) acceptable measurement location (4) non-pleural disease considerations (5) characterization of non-measurable pleural disease (6) assessment of pathological lymph nodes (7) establishing progressive disease and (8) accommodations for bilateral pleural disease. These modified RECIST 1.1 guidelines for mesothelioma tumor response collate and apply research published since the development of modified RECIST, align modified RECIST with RECIST 1.1, address those aspects of tumor measurement that were neglected or not well characterized in the modified RECIST paper, and clarify ambiguous or difficult measurement issues that have been highlighted through the subsequent decade of clinical trials research. Adoption of the modified RECIST 1.1 guidelines for mesothelioma is recommended to harmonize the application of tumor measurement and response assessment across the next generation of clinical trials in this disease.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22487442.V1
Abstract: Supplementary Data from Temozolomide and Radiotherapy versus Radiotherapy Alone in Patients with Glioblastoma, i IDH /i -wildtype: i Post Hoc /i Analysis of the EORTC Randomized Phase III CATNON Trial
Publisher: Elsevier BV
Date: 04-2019
DOI: 10.1053/J.SEMINONCOL.2019.06.001
Abstract: Malignant pleural mesothelioma (MPM) is a global health issue, the principal cause of which is exposure to asbestos. The prevalence is anticipated to rise over the next 2 decades, particularly in developing countries, due to the 30-50-year latency period between exposure to asbestos and carcinogenic development. Unresectable MPM has a poor prognosis and limited treatment options and, as such, there is a broad range of therapeutic targets of interest, including angiogenesis, immune checkpoints, mesothelin, as well as chemotherapeutic agents. Recently, the results of several randomized trials in the first-line setting combining antiangiogenic agents with chemotherapy have been reported. This review examines the scientific rationale for targeting angiogenesis in the treatment of unresectable MPM and analyzes recent clinical results with antiangiogenic agents in development (bevacizumab, nintedanib, and cediranib) for the management of MPM.
Publisher: Future Medicine Ltd
Date: 12-2015
DOI: 10.2217/LMT.15.32
Abstract: For most patients with mesothelioma, symptom control and palliative chemotherapy are mainstays of care. First-line cisplatin emetrexed chemotherapy has demonstrated survival and quality-of-life benefits. A randomized controlled trial adding bevacizumab to cisplatin and pemetrexed recently reported improved survival and time to progression, and may constitute a new standard of care where economically viable. Immunotherapy is under active investigation and positive results have been reported from single-arm studies of the anti-CTLA4 antibody tremelimumab the anti-PD-1 antibody pembrolizumab and mesothelin-targeting strategies. Symptom control remains critical for patient well-being, and includes management of pleural effusion, analgesia, treatment of symptomatic masses and management of systemic symptoms. There is increasing evidence that tunneled pleural catheters are preferred over talc pleurodesis for recurrent pleural effusion.
Publisher: Hindawi Limited
Date: 20-04-2021
DOI: 10.1111/ECC.13453
Publisher: Oxford University Press (OUP)
Date: 27-08-2019
DOI: 10.1093/NOP/NPZ036
Abstract: A key component of cancer research is the availability of clinical s les with appropriately annotated clinical data. Biobanks facilitate research by collecting/storing various types of clinical s les for research. Brain Cancer Biobanking Australia (BCBA) was established to facilitate the networking of brain cancer biobanking operations Australia-wide. Maximizing biospecimen utility in a networked biobanking environment requires the standardization of procedures and data across different sites. The aim of this research was to scope and develop a recommended clinical annotation dataset both for pediatric and adult brain cancer biobanks. A multidisciplinary working group consisting of members from the BCBA Consortium was established to develop clinical dataset recommendations for brain cancer biobanks. A literature search was undertaken to identify any published clinical dataset recommendations for brain cancer biobanks. An audit of data items collected and stored by BCBA member biobanks was also conducted to survey current clinical data collection practices across the BCBA network. BCBA has developed a clinical annotation dataset recommendation for pediatric and adult brain cancer biobanks. The clinical dataset recommendation has 5 clinical data categories: demographic, clinical and radiological diagnosis and surgery, neuropathological diagnosis, patient treatment, and patient follow-up. The data fields have been categorized into 1 of 3 tiers essential, preferred, and comprehensive. This enables biobanks and researchers to prioritize appropriately where resources are limited. This dataset can be used to guide the integration of data from multiple existing biobanks for research studies and for planning prospective brain cancer biobanking activities.
Publisher: Elsevier BV
Date: 07-2010
DOI: 10.1016/J.EJCA.2009.12.032
Abstract: We sought to determine the minimum survival benefits that patients judged sufficient to make adjuvant chemotherapy for early colon cancer worthwhile, factors associated with these judgments and, to compare a self-administered questionnaire with a validated, scripted interview. One twenty three subjects who completed adjuvant chemotherapy for early colon cancer 3-60 months earlier completed a questionnaire 97 were randomised to complete an interview before or after the questionnaire. Preferences were elicited by the time trade-off method in 4 hypothetical scenarios. Concordance between the interview and questionnaire was assessed with the intraclass correlation coefficient (ICC). Median age was 65 years (range 19-86), 52% were female and 74% had involved lymph nodes. Over 60% of patients judged an additional 1 month beyond life expectancies of 5 years or 15 years, and an additional 1-2% beyond 5-year survival rates of 85% or 65%, sufficient to make chemotherapy worthwhile. Subjects with tertiary education (p=0.003) or aged 75 years or less (p=0.02) judged larger benefits necessary to make chemotherapy worthwhile. Concordance between the interview and questionnaire was high (ICCs 0.71-0.82). Most subjects judged small survival benefits sufficient to make adjuvant chemotherapy worthwhile. A self-administered questionnaire was a valid and acceptable way of eliciting preferences.
Publisher: Elsevier BV
Date: 05-2022
DOI: 10.1016/J.ANNONC.2022.01.074
Abstract: In the phase III CheckMate 743 study (NCT02899299), first-line nivolumab plus ipilimumab significantly improved overall survival (OS) versus chemotherapy in patients with unresectable malignant pleural mesothelioma (MPM). We report updated data with 3-year minimum follow-up. Adults with previously untreated, histologically confirmed, unresectable MPM and Eastern Cooperative Oncology Group performance status of ≤1 were randomized 1 : 1 to nivolumab (3 mg/kg every 2 weeks) plus ipilimumab (1 mg/kg every 6 weeks) for up to 2 years, or six cycles of platinum plus pemetrexed chemotherapy. This report includes updated efficacy and safety outcomes, exploratory biomarker analyses including four-gene inflammatory expression signature score, and a post hoc efficacy analysis in patients who discontinued treatment due to treatment-related adverse events (TRAEs). With a median follow-up of 43.1 months, nivolumab plus ipilimumab continued to prolong OS versus chemotherapy. Median OS was 18.1 versus 14.1 months [hazard ratio (95% confidence interval), 0.73 (0.61-0.87)], and 3-year OS rates were 23% versus 15%, respectively. Three-year progression-free survival rates were 14% versus 1%, and objective response rates were 40% versus 44%. At 3 years, 28% versus 0% of responders had an ongoing response. Improved survival benefit with nivolumab plus ipilimumab versus chemotherapy was observed across subgroups, including histology. A high score of the four-gene inflammatory signature appeared to correlate with improved survival benefit with nivolumab plus ipilimumab. No new safety signals were observed with nivolumab plus ipilimumab, despite patients being off therapy for 1 year. In patients who discontinued nivolumab plus ipilimumab due to TRAEs, median OS was 25.4 months, and 34% of responders maintained their responses for ≥3 years after discontinuation. With 3 years' minimum follow-up, nivolumab plus ipilimumab continued to provide long-term survival benefit over chemotherapy and a manageable safety profile, supporting the regimen as standard-of-care treatment for unresectable MPM, regardless of histology.
Publisher: Springer Science and Business Media LLC
Date: 16-10-2017
Publisher: Elsevier BV
Date: 06-2016
Publisher: Elsevier BV
Date: 10-2006
Publisher: Frontiers Media SA
Date: 08-04-2015
Publisher: Springer Science and Business Media LLC
Date: 13-04-2018
Publisher: Elsevier BV
Date: 10-2018
Publisher: Elsevier BV
Date: 06-2004
Publisher: Springer Science and Business Media LLC
Date: 04-2007
Publisher: Frontiers Media SA
Date: 14-10-2020
Publisher: BMJ
Date: 17-02-2023
DOI: 10.1136/SPCARE-2022-004119
Abstract: Symptoms of raised intracranial pressure (ICP) in recurrent high-grade glioma (HGG) generally require corticosteroid treatment, often causing toxicity with variable effects on ICP symptoms. Acetazolamide reduces ICP when used in other clinical non-cancer settings. The aim of the study was to explore whether the addition of oral acetazolamide enables safe dexamethasone dose reduction in management of raised ICP in recurrent HGG. Participants had recurrent HGG with any of dexamethasone recommencement, dose increase or dependency prior/current bevacizumab was an exclusion. Eligible participants were randomised 1:1 to acetazolamide or placebo for 8 weeks. Standardised protocols were used for dexamethasone dosing, with planned dose decrease from day 5 once ICP symptoms were stable. The primary endpoint was a composite of dexamethasone dose reduction and stable Karnofsky Performance Status Secondary endpoints included toxicity and feasibility. Thirty participants (15 per group) were enrolled (mean age 58 years) from seven Australian sites. The mean baseline dexamethasone dose was 6.2 mg. Mean duration on study treatment was 38 days (placebo group) and 31 days (acetazolamide group) with nine participants (30%) completing all study treatments (six placebo, three acetazolamide). Study withdrawal was due to adverse events (n=6 one placebo, five acetazolamide) and disease progression (n=6 (three per arm)). Four participants (13%) (two per arm) were stable responders. Ten participants experienced a total of 13 serious adverse events (acetazolamide arm: five participants (33%), six events, two related). The study closed early due to poor accrual and increasing availability of bevacizumab. The addition of acetazolamide did not facilitate dexamethasone reduction. ACTRN12615001072505.
Publisher: Wiley
Date: 10-2009
DOI: 10.1111/J.1445-2197.2009.05060.X
Abstract: Trimodality therapy (TMT extrapleural pneumonectomy (EPP), chemotherapy and radiation therapy) offers the potential of optimal survival in selected patients with Brigham stage I-II epitheliod mesothelioma based on CT, MRI and PET scanning. We hypothesized that these scanning modalities were inadequate to accurately stage these patients. Patients suitable for TMT, in addition to CT, MRI and PET scanning, prior to EPP, underwent bilateral thoracoscopy, mediastinoscopy and laparoscopy (surgical staging). Follow-up CT scans were performed, six monthly, quality of life assessments yearly. From 1 June 2004 to 28 February 2007, 34 patients were referred mean age was 66 years (range: 44-69). Surgical staging was performed in 30 patients 24 patients were confirmed as Brigham Stage I-II. However, six were upstaged, five as stage IV disease (one contralateral chest, two contralateral chest and abdomen, two abdomen) and one as mediastinal node positive two further patients were reclassified histologically (one sarcomatoid, one biphasic). These eight patients fared poorly, 50% dying within 1 year from mesothelioma. Following surgical staging, 3 patients declined further surgery thus, 19 patients proceeded to surgery, 3 were unresectable and 16 received EPP. Follow-up of all 34 patients is complete. Surgical staging identified 26% of patients who would have received no benefit from TMT.
Publisher: Springer Science and Business Media LLC
Date: 06-01-2017
DOI: 10.1038/NRD.2016.233
Abstract: Recently, there has been a coordinated effort from academic institutions and the pharmaceutical industry to identify biomarkers that can predict responses to immune checkpoint blockade in cancer. Several biomarkers have been identified however, none has reliably predicted response in a sufficiently rigorous manner for routine use. Here, we argue that the therapeutic response to immune checkpoint blockade is a critical state transition of a complex system. Such systems are highly sensitive to initial conditions, and critical transitions are notoriously difficult to predict far in advance. Nevertheless, warning signals can be detected closer to the tipping point. Advances in mathematics and network biology are starting to make it possible to identify such warning signals. We propose that these dynamic biomarkers could prove to be useful in distinguishing responding from non-responding patients, as well as facilitate the identification of new therapeutic targets for combination therapy.
Publisher: Elsevier BV
Date: 03-2008
DOI: 10.1016/J.LUNGCAN.2007.09.027
Abstract: The diagnosis, staging, and response assessment of mesothelioma pose unique challenges to radiologic imaging. No single, conventional imaging approach captures the information necessary to direct all aspects of patient management. Instead, the complexities of this unique disease demand the integration of elements cleverly adapted from different modalities. Imaging-based studies presented at the 8th International Conference of the International Mesothelioma Interest Group (IMIG) in October 2006 sought to further define the current practice and future potential of radiology for the mesothelioma patient. The imaging studies selected through a peer-review process for presentation at the 2006 IMIG Conference were intended to frame this research in the context of the unique imaging challenges presented by mesothelioma while stimulating dialogue on the future resolution of these challenges. This communication conveys the pitfalls and potential of pleural mesothelioma imaging based on work presented at the Conference. From diagnosis to response, PET/CT to molecular bioprobes, volumetric analysis to computerized tumor assessment, imaging promises to provide valuable insight for patients with mesothelioma and the physicians who treat them.
Publisher: American Society of Clinical Oncology (ASCO)
Date: 09-2015
Abstract: Little benefit was seen for a shared care model in the majority of domains including empowerment, symptom prevalence, and psychological adjustment to cancer. The shared care model showed efficacy in clinically anxious patients.
Publisher: Elsevier BV
Date: 12-2016
DOI: 10.1016/J.JTHO.2016.08.147
Abstract: The current T component for malignant pleural mesothelioma (MPM) has been predominantly informed by surgical data sets and consensus. The International Association for the Study of Lung Cancer undertook revision of the seventh edition of the staging system for MPM with the goal of developing recommendations for the eighth edition. Data elements including detailed T descriptors were developed by consensus. Tumor thickness at three pleural levels was also recorded. An electronic data capture system was established to facilitate data submission. A total of 3519 cases were submitted to the database. Of those eligible for T-component analysis, 509 cases had only clinical staging, 836 cases had only surgical staging, and 642 cases had both available. Survival was examined for T categories according to the current seventh edition staging system. There was clear separation between all clinically staged categories except T1a versus T1b (hazard ratio = 0.99, p = 0.95) and T3 versus T4 (hazard ratio = 1.22, p = 0.09), although the numbers of T4 cases were small. Pathological staging failed to demonstrate a survival difference between adjacent categories with the exception of T3 versus T4. Performance improved with collapse of T1a and T1b into a single T1 category no current descriptors were shifted or eliminated. Tumor thickness and nodular or rindlike morphology were significantly associated with survival. A recommendation to collapse both clinical and pathological T1a and T1b into a T1 classification will be made for the eighth edition staging system. Simple measurement of pleural thickness has prognostic significance and should be examined further with a view to incorporation into future staging.
Publisher: Springer Science and Business Media LLC
Date: 02-01-2021
Publisher: Wiley
Date: 02-03-2005
DOI: 10.1002/CNCR.20963
Abstract: Hepatocellular carcinoma (HCC) is the third most common cause of cancer mortality worldwide. Survival is poor for patients with advanced-stage HCC, and small trials of tamoxifen for patients with this disease have shown conflicting results. The authors conducted a systematic review of randomized clinical trials to compare the effect of a tamoxifen-containing arm with a nontamoxifen-containing arm in advanced HCC. Eligible trials were identified from the Cochrane Hepato-Biliary Group register and other databases. Studies were selected for inclusion and their methodologic quality assessed by three independent reviewers. Hazard ratios (HR) were derived for overall survival where possible. Metaanalysis was performed using a fixed-effect model. The authors identified 10 randomized trials with a total of 1709 patients. Use of tamoxifen had no effect on median survival (HR, 1.05 95% confidence interval, 0.94-1.16 P = 0.4) or tumor response rate. The findings were stable in sensitivity analyses and were not affected by publication bias or inclusion of low-quality studies or studies reported in abstract form only. Few adverse events or withdrawals were noted. There was no support for the therapeutic use of tamoxifen in advanced HCC, nor for its use as a control arm in future clinical trials.
Publisher: Frontiers Media SA
Date: 12-11-2020
Publisher: Future Medicine Ltd
Date: 10-2015
DOI: 10.2217/LMT.15.23
Abstract: Malignant pleural mesothelioma is an aggressive, treatment-resistant tumor, which continues to increase in frequency throughout the world because the causative agent, asbestos, has high economic importance, particularly in developing countries. Patients typically present with breathlessness and chest pain with pleural effusions. Median survival is around 12 months from diagnosis. Palliative chemotherapy is beneficial for mesothelioma patients with high performance status. The role of aggressive surgery remains controversial. This review will outline some of the recent advances in the development of novel therapies for malignant pleural mesothelioma, with a focus on immunological approaches.
Publisher: Elsevier BV
Date: 10-2014
DOI: 10.1016/J.LUNGCAN.2014.08.005
Abstract: Non-steroidal anti-inflammatory drugs (NSAIDs) and COX-2 inhibitors have been associated with lower incidence rates of some cancers. Because asbestos can cause chronic inflammation at the pleural and peritoneal surfaces we hypothesised that NSAID and COX-2 inhibitors would inhibit the development of asbestos-induced mesothelioma. A murine model of asbestos-induced mesothelioma was used to test this hypothesis by providing the NSAID, aspirin, daily in the feed at 50mg/kg or 250 mg/kg. In a parallel study, the relationship between the use of NSAID and COX-2 inhibitors and mesothelioma was investigated in a human cohort of 1738 asbestos exposed people living or working in Wittenoom, Western Australia (a crocidolite mine site). Aspirin did not alter the rate of disease development or increase the length of time that mice survived. Aspirin had a small but significant effect on disease latency (the time between asbestos exposure and first evidence of disease p<0.05) but disease progression was not affected by the continued presence of the drug. In the Wittenoom cohort, in iduals who reported use of NSAIDs, COX-2 inhibitors or both did not have a lower incidence of mesothelioma (HR=0.85 95% CI=0.53-1.37, p=0.50), (HR=0.69 95% CI=0.21-2.30, p=0.55) and (HR=0.43 95% CI=0.16-1.13, p=0.087) respectively. We conclude that NSAIDs and COX-2 inhibitors do not moderate mesothelioma development or progression in a human cohort exposed to asbestos and this result is confirmed in an autochthonous mouse model.
Publisher: Elsevier BV
Date: 02-2022
DOI: 10.1016/J.LUNGCAN.2021.12.008
Abstract: Imaging of mesothelioma plays a role in all aspects of patient management, including disease detection, staging, evaluation of treatment options, response assessment, pre-surgical evaluation, and surveillance. Imaging in this disease impacts a wide range of disciplines throughout the healthcare enterprise. Researchers and clinician-scientists are developing state-of-the-art techniques to extract more of the information contained within these medical images and to utilize it for more sophisticated tasks moreover, image-acquisition technology is advancing the inherent capabilities of these images. This paper summarizes the imaging-based topics presented orally at the 2021 International Conference of the International Mesothelioma Interest Group (iMig), which was held virtually from May 7-9, 2021. These topics include an update on the mesothelioma staging system, novel molecular targets to guide therapy in mesothelioma, special considerations and potential pitfalls in imaging mesothelioma in the immunotherapy setting, tumor measurement strategies and their correlation with patient survival, tumor volume measurement in MRI and CT, CT-based texture analysis for differentiation of histologic subtype, diffusion-weighted MRI for the assessment of biphasic mesothelioma, and the prognostic significance of skeletal muscle loss with chemotherapy.
Publisher: American Society of Clinical Oncology (ASCO)
Date: 12-2011
Abstract: We compared oral capecitabine, administered intermittently or continuously, versus classical cyclophosphamide, methotrexate, and fluorouracil (CMF) as first-line chemotherapy for women with advanced breast cancer unsuited to more intensive regimens. Three hundred twenty-three eligible women were randomly assigned to capecitabine administered intermittently (1,000 mg/m 2 twice daily for 14 of every 21 days n = 107) or continuously (650 mg/m 2 twice daily for 21 of every 21 days n = 107), or to classical CMF (oral cyclophosphamide 100 mg/m 2 days 1 to 14 with intravenous methotrexate 40 mg/m 2 and fluorouracil 600 mg/m 2 on days 1 and 8 every 28 days n = 109). The primary end point was quality-adjusted progression-free survival (PFS) secondary end points included PFS, overall survival (OS), objective tumor response, and adverse events. Intermittent and continuous capecitabine were to be compared first and, if similar (P .05), combined for definitive comparisons versus CMF. Quality-adjusted PFS (P = .2), objective tumor response rate (20% P = .8), and PFS (median, 6 months hazard ratio [HR], 0.86 95% CI, 0.67 to 1.10 P = .2) were similar in women assigned capecitabine versus CMF. OS was longer in women assigned capecitabine rather than CMF (median, 22 v 18 months HR, 0.72 95% CI, 0.55 to 0.94 P = .02). Febrile neutropenia, infection, stomatitis, and serious adverse events were more common with CMF hand-foot syndrome was more common with capecitabine. Capecitabine improved OS by being similarly active, less toxic, and more tolerable than CMF. Capecitabine is a good first-line chemotherapy option for women with advanced breast cancer who are unsuited to more intensive regimens.
Publisher: Elsevier BV
Date: 12-2015
Publisher: Springer Science and Business Media LLC
Date: 14-11-2022
DOI: 10.1038/S41559-022-01918-5
Abstract: The impact of local bio ersity loss on ecosystem functioning is well established, but the role of larger-scale bio ersity dynamics in the delivery of ecosystem services remains poorly understood. Here we address this gap using a comprehensive dataset describing the supply of 16 cultural, regulating and provisioning ecosystem services in 150 European agricultural grassland plots, and detailed multi-scale data on land use and plant ersity. After controlling for land-use and abiotic factors, we show that both plot-level and surrounding plant ersity play an important role in the supply of cultural and aboveground regulating ecosystem services. In contrast, provisioning and belowground regulating ecosystem services are more strongly driven by field-level management and abiotic factors. Structural equation models revealed that surrounding plant ersity promotes ecosystem services both directly, probably by fostering the spill-over of ecosystem service providers from surrounding areas, and indirectly, by maintaining plot-level ersity. By influencing the ecosystem services that local stakeholders prioritized, bio ersity at different scales was also shown to positively influence a wide range of stakeholder groups. These results provide a comprehensive picture of which ecosystem services rely most strongly on bio ersity, and the respective scales of bio ersity that drive these services. This key information is required for the upscaling of bio ersity-ecosystem service relationships, and the informed management of bio ersity within agricultural landscapes.
Publisher: Elsevier BV
Date: 07-2015
Publisher: Elsevier BV
Date: 07-2014
Publisher: Wiley
Date: 09-06-2009
DOI: 10.1111/J.1399-0039.2009.01275.X
Abstract: Whether the immune system can recognize malignant and premalignant cells and eliminate them to prevent the development of cancer is still a matter of open debate, but in our view, the balance of evidence favours this concept. Nonetheless, the International Agency for Research on Cancer has now predicted that cancer will overtake heart disease as the leading cause of death worldwide by 2010, showing that this protective mechanism often fails. Malignant mesothelioma has traditionally been considered a relatively non-immunogenic cancer. However, mesothelioma cells do express a set of well-defined tumour antigens that have been shown to engage with the host immune system. Mesothelioma should therefore be considered a target for immunotherapy. A variety of anticancer immunotherapies have been investigated in mesothelioma and in other malignancies, although these have been largely ineffective when used in isolation. Over recent years, there has been increasing interest in the possibility of combining immunotherapy with chemotherapy in the fight against cancer. Here, we discuss the rationale behind combining these two, long considered antagonistic, treatment options in the context of malignant mesothelioma.
Publisher: Elsevier BV
Date: 05-2016
DOI: 10.1016/J.JTHO.2016.01.024
Abstract: Patients with lung cancer who harbor multiple pulmonary sites of disease have been challenging to classify a subcommittee of the International Association for the Study of Lung Cancer Staging and Prognostic Factors Committee was charged with developing proposals for the eighth edition of the tumor, node, and metastasis (TNM) classification to address this issue. A systematic literature review and analysis of the International Association for the Study of Lung Cancer database was performed to develop proposals for revision in an iterative process involving multispecialty international input and review. Details of the evidence base are summarized in other articles. Four patterns of disease are recognized the clinical presentation, pathologic correlates, and biologic behavior of these suggest specific applications of the TNM classification rules. First, it is proposed that second primary lung cancers be designated with a T, N, and M category for each tumor. Second, tumors with a separate tumor nodule of the same histologic type (either suspected or proved) should be classified according to the location of the separate nodule relative to the index tumor-T3 for a same-lobe, T4 for a same-side (different lobe), and M1a for an other-side location-with a single N and M category. Third, multiple tumors with prominent ground glass (imaging) or lepidic (histologic) features should be designated by the T category of the highest T lesion, the number or m in parentheses (#/m) to indicate the multiplicity, and a collective N and M category for all. Finally, it is proposed that diffuse pneumonic-type lung cancers be designated by size (or T3) if in one lobe, T4 if involving multiple same-side lobes, and M1a if involving both lungs with a single N and M category for all areas of involvement. We propose to tailor TNM classification of multiple pulmonary sites of lung cancer to reflect the unique aspects of four different patterns of presentation. We hope that this will lead to more consistent classification and clarity in communication and facilitate further research in the nature and optimal treatment of these entities.
Publisher: Elsevier BV
Date: 05-2016
DOI: 10.1016/J.JTHO.2016.01.025
Abstract: It can be difficult to distinguish between a second primary and a metastasis in patients with lung cancer who have more than one pulmonary site of cancer. A systematic review of the literature was conducted by a subcommittee of the International Association for the Study of Lung Cancer Staging and Prognostic Factors Committee to develop recommendations to identify second primary lung cancers. The process entailed review of knowledge relating to the mechanism of metastasis, determination of clonality, and outcomes of patients with resected tumors. It is easier to determine that two tumors are different than that they are the same finding similarities does not establish that they are the same. For ex le, most second primary lung cancers are of the same histotype. Few criteria are reliable by themselves these include different histologic cancer types or matching DNA breakpoints by sequencing and a comprehensive histologic assessment of resected specimens. Characteristics that are suggestive but associated with potential misclassification include the presence or absence of biomarkers, imaging characteristics, and the presence or absence of nodal involvement. Clinical and pathologic (i.e., after resection) criteria are presented to identify two foci as separate primary lung cancers versus a metastasis. Few features are definitive many commonly used characteristics are suggestive but associated with a substantial rate of misclassification. Careful review by a multidisciplinary tumor board, considering all available information, is recommended.
Publisher: Elsevier BV
Date: 03-2011
Publisher: Springer Science and Business Media LLC
Date: 05-09-2006
Publisher: Elsevier BV
Date: 11-2015
Publisher: Elsevier BV
Date: 05-2023
Publisher: Oxford University Press (OUP)
Date: 17-01-2018
DOI: 10.1111/BJD.16098
Abstract: Health-related quality of life (HRQOL) in melanoma is affected by cancer stage. Previous studies have reported limited data on utility-based HRQOL. To determine pooled estimates of utility-based HRQOL (utilities) for people with American Joint Cancer Committee stage I/II, III or IV melanoma for use in economic evaluations. We performed a systematic review, meta-analysis and metaregression of utilities for patients with melanoma. HRQOL scores reported with the QLQ-C30, SF-36, SF-12, FACT-G and FACT-M instruments were converted to utilities using published mapping algorithms. Meta-analysis was used to calculate mean utilities. Metaregression was used to examine the effects of baseline patient and study characteristics. We identified 33 studies reporting 213 utilities. From meta-analyses, the mean utility for stage I/II melanoma was 0·97 [95% confidence interval (CI) 0·90-0·98] for stage III melanoma it was 0·77 (95% CI 0·70-0·83) for stage III/IV 0·76 (95% CI 0·76-0·77) and for stage IV melanoma 0·76 (95% CI 0·71-0·81). The difference in utility between stage III and stage IV was not statistically significant (P = 0·52). For patients with stage I/II, the utility estimate at the time of surgery was 0·77 (95% CI 0·75-0·79), and at 3-12 months postsurgery it was 0·85 (95% CI 0·84-0·86). Utility estimates for patients with stage IV melanoma were 0·65 (95% CI 0·62-0·69) during the first 3 months of treatment and 0·83 (95% CI 0·81-0·86) at 4-12 months on treatment. For patients with stage IV melanoma treated with chemotherapy, the utility estimate was 0·52 (95% CI 0·51-0·52), while for those treated with targeted therapy it was 0·83 (95% CI 0·82-0·85). These robust, evidence-based estimates of health state utility can be used in economic evaluations of new treatments for patients with early-stage or advanced-stage melanoma.
Publisher: Elsevier BV
Date: 10-2019
DOI: 10.1016/J.JTHO.2019.06.020
Abstract: The accurate diagnosis of mesothelioma is critical for the appropriate clinical management of this cancer. Many issues complicate making the diagnosis of mesothelioma including the presence of reactive mesothelial cells in benign pleural effusions, the heterogeneity of mesothelioma histopathology, the relatively high incidence of other epithelial malignancies that metastasize to the pleura, and primary sarcomas that arise within the pleura. Given the rapidly evolving field of molecular profiling and the need for translational correlates in mesothelioma clinical trials, the National Cancer Institute (NCI)-International Association for the Study of Lung Cancer-Mesothelioma Applied Research Foundation Clinical Trials Planning Meeting was convened in March 2017 to develop a consensus on standard pathology guidelines for future NCI-sponsored clinical trials in mesothelioma. This consensus statement covers recommendations for specimen handling, pathologic classification and diagnosis, biobanking, and tissue correlative studies.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 08-2014
Publisher: BMJ
Date: 12-2021
DOI: 10.1136/BMJOPEN-2021-054075
Abstract: Grades 2 and 3 gliomas (G2/3 gliomas), when combined, are the second largest group of malignant brain tumours in adults. The outcomes for G2/3 gliomas at progression approach the dismal outcomes for glioblastoma (GBM), yet there is a paucity of trials for Australian patients with relapsed G2/3 gliomas compared with patients with GBM. LUMOS will be a pilot umbrella study for patients with relapsed G2/3 gliomas that aims to match patients to targeted therapies based on molecular screening with contemporaneous tumour tissue. Participants in whom no actionable or no druggable mutation is found, or in whom the matching drug is not available, will form a comparator arm and receive standard of care chemotherapy. The objective of the LUMOS trial is to assess the feasibility of this approach in a multicentre study across five sites in Australia, with a view to establishing a national molecular screening platform for patient treatment guided by the mutational analysis of contemporaneous tissue biopsies This study will be a multicentre pilot study enrolling patients with recurrent grade 2/3 gliomas that have previously been treated with radiotherapy and chemotherapy at diagnosis or at first relapse. Contemporaneous tumour tissue at the time of first relapse, defined as tissue obtained within 6 months of relapse and without subsequent intervening therapy, will be obtained from patients. Molecular screening will be performed by targeted next-generation sequencing at the reference laboratory (PathWest, Perth, Australia). RNA and DNA will be extracted from representative formalin-fixed paraffin embedded tissue scrolls or microdissected from sections on glass slides tissue sections following a review of the histology by pathologists. Extracted nucleic acid will be quantified by Qubit Fluorometric Quantitation (Thermo Fisher Scientific). Library preparation and targeted capture will be performed using the TruSight Tumor 170 (TST170) kit and s les sequenced on NextSeq 550 (Illumina) using NextSeq V.2.5 hi output reagents, according to the manufacturer’s instructions. Data analysis will be performed using the Illumina BaseSpace TST170 app v1.02 and a custom tertiary pipeline, implemented within the Clinical Genomics Workspace software platform from PierianDx (also refer to section 3.2). Primary outcomes for the study will be the number of patients enrolled and the number of patients who complete molecular screening. Secondary outcomes will include the proportion of screened patients enrolled proportion of patients who complete molecular screening the turn-around time of molecular screening and the value of a brain tumour specific multi-disciplinary tumour board, called the molecular tumour advisory panel as measured by the proportion of patients in whom the treatment recommendation was refined compared with the recommendations from the automated bioinformatics platform of the reference laboratory testing. The study was approved by the lead Human Research Ethics Committee of the Sydney Local Health District: Protocol No. X19-0383. The study will be conducted in accordance with the principles of the Declaration of Helsinki 2013, guidelines for Good Clinical Practice and the National Health and Medical Research Council National Statement on Ethical Conduct in Human Research (2007, updated 2018 and as amended periodically). Results will be disseminated using a range of media channels including newsletters, social media, scientific conferences and peer-reviewed publications. ACTRN12620000087954 Pre-results.
Publisher: Frontiers Media SA
Date: 29-07-2022
Abstract: Chemotherapy has historically been the mainstay of cancer treatment, but our understanding of what drives a successful therapeutic response remains limited. The erse response of cancer patients to chemotherapy has been attributed principally to differences in the proliferation rate of the tumor cells, but there is actually very little experimental data supporting this hypothesis. Instead, other mechanisms at the cellular level and the composition of the tumor microenvironment appear to drive chemotherapy sensitivity. In particular, the immune system is a critical determinant of chemotherapy response with the depletion or knock-out of key immune cell populations or immunological mediators completely abrogating the benefits of chemotherapy in pre-clinical models. In this perspective, we review the literature regarding the known mechanisms of action of cytotoxic chemotherapy agents and the determinants of response to chemotherapy from the level of in idual cells to the composition of the tumor microenvironment. We then summarize current work toward the development of dynamic biomarkers for response and propose a model for a chemotherapy sensitive tumor microenvironment.
Publisher: Elsevier BV
Date: 06-2021
Publisher: Springer Science and Business Media LLC
Date: 08-2002
Publisher: AME Publishing Company
Date: 11-2020
DOI: 10.21037/JTD-20-1831
Publisher: Springer Science and Business Media LLC
Date: 27-08-2013
DOI: 10.1038/BJC.2013.504
Publisher: Informa UK Limited
Date: 25-02-2015
Publisher: Archives of Pathology and Laboratory Medicine
Date: 05-2018
DOI: 10.5858/ARPA.2017-0245-RA
Abstract: The Staging and Prognostic Factors Committee of the International Association for the Study of Lung Cancer, in conjunction with the International Mesothelioma Interest Group, the International Thymic Malignancy Interest Group, and the Worldwide Esophageal Cancer Collaboration, developed proposals for the 8th edition of their respective tumor, node, metastasis (TNM) staging classification systems. To review these changes and discuss issues for the reporting pathologist. Proposals were based on international databases of lung (N = 94 708), with an external validation using the US National Cancer Database mesothelioma (N = 3519) thymic epithelial tumors (10 808) and epithelial cancers of the esophagus and esophagogastric junction (N = 22 654). These proposals have been mostly accepted by the Union for International Cancer Control and the American Joint Committee on Cancer and incorporated into their respective staging manuals (2017). The Union for International Cancer Control recommended implementation beginning in January 2017 however, the American Joint Committee on Cancer has deferred deployment of the eighth TNM until January 1, 2018, to ensure appropriate infrastructure for data collection. This manuscript summarizes the updated staging of thoracic malignancies, specifically highlighting changes from the 7th edition that are relevant to pathologic staging. Histopathologists should become familiar with, and start to incorporate, the 8th edition staging in their daily reporting of thoracic cancers henceforth.
Publisher: Springer Science and Business Media LLC
Date: 18-08-2009
DOI: 10.1007/S11060-009-9976-3
Abstract: A randomized, multicenter, open-label, phase 3 study of patients with progressive, recurrent glioblastoma multiforme (GBM) for whom front-line therapy had failed was conducted. This study was designed to determine whether combination therapy with imatinib and hydroxyurea (HU) has superior antitumor activity compared with HU monotherapy in the treatment of recurrent GBM. The target population consisted of patients with confirmed recurrent GBM and an Eastern Cooperative Oncology Group performance status of 0-2 who had completed previous treatment comprising surgical resection, irradiation therapy, and first-line chemotherapy (preferably temozolomide (TMZ) containing regimen) and who have progressed despite treatment. If first-line chemotherapy did not contain TMZ, a second completed chemotherapy was acceptable. The primary efficacy parameter was progression-free survival (PFS). The primary comparison of combination therapy versus monotherapy for PFS was not significant (adjusted P = 0.56). The hazard ratio (HR) (adjusted HR = 0.93) was not clinically relevant. The median PFS for the combination arm was low at 6 weeks and similar to the median PFS in the monotherapy arm (6 weeks). The 6-month PFS for the two treatment groups was very similar (5% in the combination arm vs. 7% in the monotherapy arm). No clinically meaningful differences were found between the two treatment arms, and the primary study end point was not met. Among the patients receiving imatinib, no adverse events were reported that were either previously unknown or unexpected as a consequence of the disease.
Publisher: Elsevier BV
Date: 10-2006
Publisher: Elsevier BV
Date: 02-2004
Publisher: Elsevier BV
Date: 10-2015
DOI: 10.1016/J.LUNGCAN.2015.07.015
Abstract: Malignant pleural mesothelioma (MPM) is a chemotherapy resistant tumor with a poor prognosis. Hypoxia is increasingly recognized as an important factor in tumor aggressiveness and cellular resistance to chemotherapy and radiation treatment. This prospective pilot study was performed with [F-18] fluoromisonidazole (FMISO) PET-CT to characterize hypoxia in patients with MPM. Twenty prospectively recruited patients with histologically or cytologically confirmed MPM not currently receiving systemic or local treatment underwent both FMISO and fluorodeoxyglucose (FDG) PET-CT scans within 2 weeks. FMISO and FDG PET-CT scans were independently analyzed visually and semi-quantitatively using SUVmax and tumor to background ratio (TBR) in order to assess tumor hypoxia and metabolic activity. Lesion by lesion analysis was performed in sites of measurable pleural masses. Visual analysis demonstrated tumor FMISO activity in 17 of 20 patients, and tumor FDG activity in 19 of 20 patients. Focal areas of bulky tumor were most likely to demonstrate hypoxia. In 19 patients suitable for semi-quantitative analysis the median FDG SUVmax was 6.4 (range 1.9-19.1), median FMISO SUVmax was 2.5 (range 1.4-3.7) and median FMISO TBR was 1.8 (1.1-2.5). There was a positive correlation between intensity of metabolic activity and hypoxia (r=0.72, p=0.001). Lesion by lesion analysis demonstrated a positive correlation between tumor thickness and FMISO activity (r=0.77, p<0.001). This pilot study confirms that MPM is a tumor with significant areas of hypoxia, particularly in dominant tumor masses. The relationship of tumor hypoxia to effectiveness of chemotherapy and/or radiation therapy warrants prospective assessment.
Publisher: Wiley
Date: 03-2008
Publisher: Oxford University Press (OUP)
Date: 29-11-2020
DOI: 10.1093/NOP/NPAA081
Abstract: Sleep is an important element in health-related quality of life of cancer patients and caregivers. This study aimed to explore the experience of sleep disturbance in people with malignant brain tumors (BT) and their family caregivers. Participants were recruited from ambulatory neuro-oncology clinics. Semi-structured interviews were conducted with 24 patients (67% with high-grade gliomas) and 14 caregivers. Data were analyzed thematically using a framework synthesis. We identified six themes relating to perceptions of the nature, impact, causal factors, and interventions for sleep disturbance, beliefs about sleep and impact, and personal coping strategies. Participants described their sleep disturbance in terms of insomnia symptoms most commonly difficulties initiating and maintaining sleep. Participants had varied views on causal factors including the BT diagnosis and treatment and caregiver burden. However, excessive thinking and BT-related anxiety were evident in both patients and caregivers. The described impact on daytime functioning due to non-restful sleep and fatigue appeared to be significant and many participants needed daytime naps, although they understated the impact on in idual functioning. Some participants were reluctant to seek help from clinicians for sleep disturbance due to previous experiences where sleep disturbance was overlooked, or because they held negative views toward pharmacological interventions. Participants reported various coping strategies, ranging from relaxation-promoting techniques to behaviors to distract thinking at night that may instead disturb sleep. Psychological factors contribute to sleep disturbance in patients with BT and caregivers. This population may benefit from information about sleep disturbance and interventions targeting anxiety.
Publisher: Wiley
Date: 15-12-2015
Abstract: Cross-presentation defines the unique capacity of an APC to present exogenous Ag via MHC class I molecules to CD8(+) T cells. DCs are specialized cross-presenting cells and as such have a critical role in antitumor immunity. DCs are routinely found within the tumor microenvironment, but their capacity for endogenous or therapeutically enhanced cross-presentation is not well characterized. In this study, we examined the tumor and lymph node DC cross-presentation of a nominal marker tumor Ag, HA, expressed by the murine mesothelioma tumor AB1-HA. We found that tumors were infiltrated by predominantly CD11b(+) DCs with a semimature phenotype that could not cross-present tumor Ag, and therefore, were unable to induce tumor-specific T-cell activation or proliferation. Although tumor-infiltrating DCs were able to take up, process, and cross-present exogenous cell-bound and soluble Ags, this was significantly impaired relative to lymph node DCs. Importantly, however, systemic chemotherapy using gemcitabine reversed the defect in Ag cross-presentation of tumor DCs. These data demonstrate that DC cross-presentation within the tumor microenvironment is defective, but can be reversed by chemotherapy. These results have important implications for anticancer therapy, particularly regarding the use of immunotherapy in conjunction with cytotoxic chemotherapy.
Publisher: Springer Science and Business Media LLC
Date: 08-05-2015
Publisher: The American Association of Immunologists
Date: 15-05-2003
DOI: 10.4049/JIMMUNOL.170.10.4905
Abstract: Cross-presentation of cell-bound Ags from established, solid tumors to CD8 cells is efficient and likely to have a role in determining host response to tumor. A number of investigators have predicted that when tumor Ags are derived from apoptotic cells either no response, due to Ag “sequestration,” or CD8 cross-tolerance would ensue. Because the crucial issue of whether this happens in vivo has never been addressed, we induced apoptosis of established hemagglutinin (HA)-transfected AB1 tumors in BALB/c mice using the apoptosis-inducing reagent gemcitabine. This shrank the tumor by ∼80%. This induction of apoptosis increased cross-presentation of HA to CD8 cells yet neither gross deletion nor functional tolerance of HA-specific CD8 cells were observed, based on tetramer analysis, proliferation of specific CD8 T cells, and in vivo CTL activity. Interestingly, apoptosis primed the host for a strong antitumor response to a second, virus-generated HA-specific signal in that administration of an HA-expressing virus after gemcitabine administration markedly decreased tumor growth compared with viral administration without gemcitabine. Thus tumor cell apoptosis in vivo neither sequesters tumor Ags nor cross-tolerizes tumor-specific CD8 cells. This observation has fundamental consequences for the development of tumor immunotherapy protocols and for understanding T cell reactivity to tumors and the in vivo immune responses to apoptotic cells.
Publisher: American Association for Cancer Research (AACR)
Date: 14-04-2010
DOI: 10.1158/1078-0432.CCR-09-2313
Abstract: Purpose: Existing prognostic systems for malignant pleural mesothelioma do not incorporate imaging information. We aimed to identify the contribution of quantitative fluorodeoxyglucose positron emission tomography (FDG-PET) analysis to other prognostic variables in this disease. Experimental Design: Patients with malignant pleural mesothelioma underwent helical thoracoabdominal computed tomography and FDG-PET scans at baseline. Patients were treated as clinically indicated and followed for survival. FDG-PET variables derived included total glycolytic volume, a composite of tumor volume and glycolytic activity. Results: Ninety-three patients were accrued from 2003 to 2006. Of 89 eligible assessable patients, 28 had undergone pleurodesis before enrolment. Seventeen patients remained alive at analysis median survival is 15.4 months. On univariate analysis, significant prognostic factors were: total glycolytic volume on FDG-PET (P = 0.003), sarcomatoid histology (P & 0.0005), weight loss (P = 0.031), computed tomography stage (P = 0.015), and European Organization for Research and Treatment of Cancer good prognostic score (P = 0.049). In patients with epithelioid or biphasic histology, baseline total glycolytic volume remained predictive of survival in patients with (P = 0.01) or without (P = 0.018) previous pleurodesis. In multivariate analysis, no variable other than histology contributed to the model in patients with sarcomatoid histology total glycolytic volume and weight loss contributed to the models in patients with nonsarcomatoid histology. computed tomography–assessed tumor-node-metastasis stage did not contribute to the model. A nomogram, which incorporates quantitative PET parameters and pleurodesis into prognostic information, is presented. Conclusions: Sarcomatoid histology remains the strongest prognostic factor. In patients with non sarcomatoid disease, volumetric FDG-PET parameters are more predictive of survival than tumor-node-metastasis staging, suggesting that tumor volume and glycolytic activity may be more important determinants of prognosis in malignant pleural mesothelioma than anatomic extent of disease. Clin Cancer Res 16(8) 2409–17. ©2010 AACR.
Publisher: Elsevier BV
Date: 11-2015
DOI: 10.1016/J.LUNGCAN.2015.07.011
Abstract: Imaging of malignant pleural mesothelioma is essential to patient management, prognostication, and response assessment. From animal models to clinical trials, the gamut of research activities and clinical standards relies on imaging to provide information on lesion morphology and the growing number of physiologic characteristics amenable to capture through imaging techniques. The complex morphology, growth pattern, and biological mechanisms of mesothelioma, however, present challenges for image acquisition and interpretation. Nevertheless, novel approaches to image acquisition and subsequent image analysis have expanded the opportunities for (as well as the need for) imaging in this disease. This paper summarizes the imaging-based research presented orally at the 2014 International Conference of the International Mesothelioma Interest Group (iMig) in Cape Town, South Africa, October 2014. Presented topics include the imaging of hypoxia in a murine model through positron emission tomography (PET), the use of diffusion-weighted magnetic resonance imaging (MRI) to assess the histologic composition of biphasic mesothelioma and to assess early response to chemotherapy, the correlation of CT-based tumor volume with the volume of the post-surgical tumor specimen, the development of volumetric tumor response criteria, and pre-treatment tumor volume growth considerations for tumor response assessment.
Publisher: Elsevier BV
Date: 07-2019
Publisher: Oxford University Press (OUP)
Date: 24-04-2015
Publisher: Elsevier BV
Date: 10-2006
Publisher: American Society of Clinical Oncology (ASCO)
Date: 04-2019
Abstract: Inhibition of focal adhesion kinase has been shown to selectively kill mesothelioma cells that express low levels of moesin-ezrin-radixin-like protein (merlin). On this basis, we designed a randomized, phase II trial to investigate whether defactinib as maintenance therapy after standard first-line chemotherapy could improve progression-free survival (PFS) in patients with malignant pleural mesothelioma (MPM). This global, double-blind, randomized, placebo-controlled trial was conducted in patients with advanced MPM and disease control after at least four cycles of first-line chemotherapy. Patients were stratified for merlin and then randomly assigned (in a 1:1 fashion) to receive either oral defactinib or placebo until disease progression, unacceptable toxicity, or withdrawal occurred. The coprimary end points were PFS and overall survival (OS). Quality of life (QoL) was assessed using the Lung Cancer Symptom Scale for Mesothelioma tool. Three hundred forty-four patients were randomly assigned to receive either defactinib (n = 173) or placebo (n = 171). The median PFS was 4.1 months (95% CI, 2.9 to 5.6 months) for defactinib versus 4.0 months (95% CI, 2.9 to 4.2 months) for placebo. The median OS was 12.7 months (95% CI, 9.1 to 21 months) for defactinib versus 13.6 months (95% CI, 9.6 to 21.2 months) for placebo (hazard ratio, 1.0 95% CI, 0.7 to 1.4). Although shorter survival for both defactinib- and placebo-treated patients was observed, in the patients who had merlin-low MPM compared with the patients who had merlin-high MPM, there were no statistical differences in response rate, PFS, OS, or QoL between the treatment groups. The most common grade 3 or worse adverse events were nausea, diarrhea, fatigue, dyspnea, and decreased appetite. Neither PFS nor OS was improved by defactinib after first-line chemotherapy in patients with merlin-low MPM. Defactinib cannot be recommended as maintenance therapy for advanced MPM.
Publisher: Elsevier
Date: 2007
Publisher: Informa UK Limited
Date: 02-05-2019
DOI: 10.1080/14712598.2019.1606209
Abstract: Combination chemotherapy is currently standard care for advanced mesothelioma. Checkpoint blockade is a promising new treatment. This review covers clinical use and biomarkers of checkpoint blockade. Medline search used keywords 'mesothelioma' combined with 'checkpoint blockade' OR 'PD-L1' OR 'PD1' OR 'anti-CTLA4' the search terms AND 'clinical trial' or AND 'biomarker*' were added. Handsearching covered abstracts from relevant meetings from 2016 to 2018 and reference lists. Data informed a narrative review. Single agent anti-CTLA4 blockade is inactive in mesothelioma. Single agent PD-1 blockade as second or subsequent treatment gives 20-29% partial responses no randomized comparisons against placebo or chemotherapy are available. Biomarkers of response have been difficult to identify. There is no consensus as to whether tumor PD-L1 expression predicts outcomes. Combination checkpoint inhibitors (CTLA4 and PD1 blockade) provide a small incremental increase in response rates and progression-free survival. Chemoimmunotherapy is the next frontier.
Publisher: Wiley
Date: 26-10-2020
DOI: 10.1002/RCR2.675
Publisher: Oxford University Press (OUP)
Date: 22-05-2013
Abstract: Previous studies have focused on the treatment received by rural cancer patients and have not examined their diagnostic pathways as reasons for poorer outcomes in rural Australia. To compare and explore diagnostic pathways and diagnostic intervals in patients with breast, lung, prostate or colorectal cancer from rural Western Australia (WA) to inform future interventions aimed at reducing time to cancer diagnosis. Mixed methods study of people recently diagnosed with breast, lung, prostate or colorectal cancer from the Goldfields and Great Southern Regions of WA. Qualitative interviews explored participants' diagnostic pathways and factors underlying differences observed between in iduals and cancers. Data were extracted from general practice and hospital records to calculate intervals from first presentation in general practice to final diagnosis. Sixty-six participants were recruited (43 Goldfields and 23 Great Southern region 24 breast, 20 colorectal, 14 prostate and 8 lung cancers). There were significant overall differences between cancers in time from presentation in general practice to referral (P = 0.045), from referral to seeing a specialist (P = 0.010) and from specialist appointment to cancer diagnosis (P ≤ 0.001). These differences were due to the nature of presenting symptoms, access to diagnostic tests and multiple visits to specialists. Breast cancer was diagnosed more quickly because its symptoms are more specific and due to better access to diagnostic tests and specialist one-stop clinics. Interventions to improve cancer diagnosis in rural Australia should focus on better case selection in general practice and better access to diagnostic tests, especially for prostate and colorectal cancers.
Publisher: Frontiers Media SA
Date: 18-11-2022
DOI: 10.3389/FIMMU.2022.969678
Abstract: We assessed the murine Stimulator of Interferon Genes (STING) agonist, DMXAA, for anti-mesothelioma potential using the AE17-sOVA model that expresses ovalbumin (OVA) as a neo tumor antigen. Dose response experiments alongside testing different routes of administration identified a safe effective treatment regimen that induced 100% cures in mice with small or large tumors. Three doses of 25mg/kg DMXAA given intra-tumorally every 9 days induced tumor regression and long-term survival (& months). Re-challenge experiments showed that tumor-free mice developed protective memory. MTT and propidium-iodide assays showed that DMXAA exerted direct cytotoxic effects at doses & mg/ml on the murine AE17 and AB1 mesothelioma cell lines. In-vivo studies using a CFSE-based in-vivo proliferation assay showed that DMXAA improved tumor-antigen presentation in tumor-draining lymph nodes, evidenced by OVA-specific OT-1 T cells undergoing more isions. An in-vivo cytotoxic T lymphocyte (CTL) assay showed that DMXAA blunted the lytic quality of CTLs recognizing the dominant (SIINFEKL) and a subdominant (KVVRFDKL) OVA epitopes. DMXAA reduced tumor vessel size in-vivo and although the proportion of T cells infiltrating tumors reduced, the proportion of tumor-specific T cells increased. These data show careful dosing and treatment protocols reduce mesothelioma cell viability and modulate tumor vessels such that tumor-antigen specific CTLs access the tumor site. However, attempts to enhance DMXAA-induced anti-tumor responses by combination with an agonist anti-CD40 antibody or IL-2 reduced efficacy. These proof-of-concept data suggest that mesothelioma patients could benefit from treatment with a STING agonist, but combination with immunotherapy should be cautiously undertaken.
Publisher: Informa UK Limited
Date: 14-02-2023
Publisher: Elsevier BV
Date: 07-2021
Publisher: Springer Science and Business Media LLC
Date: 19-03-2021
DOI: 10.1007/S00401-021-02291-6
Abstract: Somatic mutations in the isocitrate dehydrogenase genes IDH1 and IDH2 occur at high frequency in several tumour types. Even though these mutations are confined to distinct hotspots, we show that gliomas are the only tumour type with an exceptionally high percentage of IDH1 R132H mutations. Patients harbouring IDH1 R132H mutated tumours have lower levels of genome-wide DNA-methylation, and an associated increased gene expression, compared to tumours with other IDH1/2 mutations (“non-R132H IDH1/2 mutations”). This reduced methylation is seen in multiple tumour types and thus appears independent of the site of origin. For 1p/19q non-codeleted glioma (astrocytoma) patients, we show that this difference is clinically relevant: in s les of the randomised phase III CATNON trial, patients harbouring tumours with IDH mutations other than IDH1 R132H have a better outcome (hazard ratio 0.41, 95% CI [0.24, 0.71], p = 0.0013). Such non-R132H IDH1/2-mutated tumours also had a significantly lower proportion of tumours assigned to prognostically poor DNA-methylation classes ( p 0.001). IDH mutation-type was independent in a multivariable model containing known clinical and molecular prognostic factors. To confirm these observations, we validated the prognostic effect of IDH mutation type on a large independent dataset. The observation that non-R132H IDH1/2-mutated astrocytomas have a more favourable prognosis than their IDH1 R132H mutated counterpart indicates that not all IDH-mutations are identical. This difference is clinically relevant and should be taken into account for patient prognostication.
Publisher: Springer Science and Business Media LLC
Date: 20-02-2022
DOI: 10.1007/S10552-022-01559-W
Abstract: High-grade disease accounts for ~ 70% of all glioma, and has a high mortality rate. Few modifiable exposures are known to be related to glioma risk or mortality. We examined associations between lifetime physical activity and physical activity at different ages (15–18 years, 19–29 years, 30–39 years, last 10 years) with the risk of glioma diagnosis, using data from a hospital-based family case–control study (495 cases 371 controls). We followed up cases over a median of 25 months to examine whether physical activity was associated with all-cause mortality. Physical activity and potential confounders were assessed by self-administered questionnaire. We examined associations between physical activity (metabolic equivalent [MET]-h/wk) and glioma risk using unconditional logistic regression and with all-cause mortality in cases using Cox regression. We noted a reduced risk of glioma for the highest (≥ 47 MET-h/wk) versus lowest ( 24 METh/wk) category of physical activity for lifetime activity (OR = 0.58, 95% CI: 0.38–0.89) and at 15–18 years (OR = 0.57, 95% CI: 0.39–0.83). We did not observe any association between physical activity and all-cause mortality (HR for lifetime physical activity = 0.91, 95% CI: 0.64–1.29). Our findings are consistent with previous research that suggested physical activity during adolescence might be protective against glioma. Engaging in physical activity during adolescence has many health benefits this health behavior may also offer protection against glioma.
Publisher: Public Library of Science (PLoS)
Date: 23-04-2013
Publisher: Frontiers Media SA
Date: 27-04-2021
Abstract: The success of immunotherapy that targets inhibitory T cell receptors for the treatment of multiple cancers has seen the anti-tumor immune response re-emerge as a promising biomarker of response to therapy. Longitudinal characterization of T cells in the tumor microenvironment (TME) helps us understand how to promote effective anti-tumor immunity. However, serial analyses at the tumor site are rarely feasible in clinical practice. Malignant pleural effusions (MPE) associated with thoracic cancers are an abnormal accumulation of fluid in the pleural space that is routinely drained for patient symptom control. This fluid contains tumor cells and immune cells, including lymphocytes, macrophages and dendritic cells, providing a window into the local tumor microenvironment. Recurrent MPE is common, and provides an opportunity for longitudinal analysis of the tumor site in a clinical setting. Here, we review the phenotype of MPE-derived T cells, comparing them to tumor and blood T cells. We discuss the benefits and limitations of their use as potential dynamic biomarkers of response to therapy.
Publisher: Oxford University Press (OUP)
Date: 03-02-2023
DOI: 10.1093/NOP/NPAD006
Abstract: While therapeutically effective, chemoradiotherapy treatment for high-grade glioma (glioblastoma) is often accompanied by side effects. Exercise has been demonstrated to alleviate the adverse effects of such treatments in other cancers. We aimed to evaluate the feasibility and preliminary efficacy of supervised exercise incorporating autoregulation. Thirty glioblastoma patients were recruited, five declined exercise and 25 were provided with a multimodal exercise intervention for the duration of their chemoradiotherapy treatment. Patient recruitment, retention, adherence to training sessions and safety were evaluated throughout the study. Physical function, body composition, fatigue, sleep quality, and quality of life were evaluated before and after the exercise intervention. Eight of the 25 participants commencing exercise withdrew prior to completion of the study (32%). Seventeen patients (68%) demonstrated low to high adherence (33%–100%) and exercise dosage compliance (24%–83%). There were no reported adverse events. Significant improvements were observed for all trained exercises and lower limb muscle strength and function with no significant changes observed for any other physical function, body composition, fatigue, sleep, or quality of life outcomes. Only half of glioblastoma patients recruited were willing or able to commence, complete or meet minimum dose compliance for the exercise intervention during chemoradiotherapy indicating the intervention evaluated may not be feasible for part of this patient cohort. For those who were able to complete the exercise program, supervised, autoregulated, multimodal exercise was safe and significantly improved strength and function and may have prevented deterioration in body composition and quality of life.
Publisher: Frontiers Media SA
Date: 11-05-2022
DOI: 10.3389/FIMMU.2022.872295
Abstract: Antibodies that target immune checkpoints such as cytotoxic T lymphocyte antigen 4 (CTLA‐4) and the programmed cell death protein 1/ligand 1 (PD-1/PD-L1) are now a treatment option for multiple cancer types. However, as a monotherapy, objective responses only occur in a minority of patients. Chemotherapy is widely used in combination with immune checkpoint blockade (ICB). Although a variety of isolated immunostimulatory effects have been reported for several classes of chemotherapeutics, it is unclear which chemotherapeutics provide the most benefit when combined with ICB. We investigated 10 chemotherapies from the main canonical classes dosed at the clinically relevant maximum tolerated dose in combination with anti‐CTLA-4/anti-PD-L1 ICB. We screened these chemo-immunotherapy combinations in two murine mesothelioma models from two different genetic backgrounds, and identified chemotherapies that produced additive, neutral or antagonistic effects when combined with ICB. Using flow cytometry and bulk RNAseq, we characterized the tumor immune milieu in additive chemo-immunotherapy combinations. 5-fluorouracil (5-FU) or cisplatin were additive when combined with ICB while vinorelbine and etoposide provided no additional benefit when combined with ICB. The combination of 5-FU with ICB augmented an inflammatory tumor microenvironment with markedly increased CD8 + T cell activation and upregulation of IFNγ, TNFα and IL-1β signaling. The effective anti‐tumor immune response of 5-FU chemo-immunotherapy was dependent on CD8 + T cells but was unaffected when TNFα or IL-1β cytokine signaling pathways were blocked. Our study identified additive and non-additive chemotherapy/ICB combinations and suggests a possible role for increased inflammation in the tumor microenvironment as a basis for effective combination therapy.
Publisher: Springer Science and Business Media LLC
Date: 21-08-2012
DOI: 10.1038/BJC.2012.362
Publisher: Elsevier BV
Date: 09-2023
Publisher: Elsevier BV
Date: 11-2021
Publisher: BMJ
Date: 09-2022
DOI: 10.1136/BMJOPEN-2021-058107
Abstract: Glioblastoma (GBM) is the most common malignant primary central nervous system cancer in adults. The objective of the Multi-Arm GlioblastoMa Australasia (MAGMA) trial is to test hypotheses in real world setting to improve survival of people with GBM. Initial experimental arms are evaluating the effectiveness of interventions in newly diagnosed GBM (ndGBM). This study will compare maximal surgical resection followed by chemoradiotherapy plus adjuvant chemotherapy for 6 months with the addition of (1) ‘neoadjuvant’ chemotherapy beginning as soon as possible after surgery and/or (2) adjuvant chemotherapy continued until progression within the same study platform. MAGMA will establish a platform for open-label, multiarm, multicentre randomised controlled testing of treatments for GBM. The study began recruiting in September 2020 and recruitment to the initial two interventions in MAGMA is expected to continue until September 2023. Adults aged ≥18 years with ndGBM will be given the option of undergoing randomisation to each study intervention separately, thereby giving rise to a partial factorial design, with two separate randomisation time points, one for neoadjuvant therapy and one for extended therapy. Patients will have the option of being randomised at each time point or continuing on with standard treatment. The primary outcome for the study is overall survival from the date of initial surgery until death from any cause. Secondary outcomes include progression-free survival, time to first non-temozolomide treatment, overall survival from each treatment randomisation, clinically significant toxicity as measured by grade 3 or 4 adverse events and health-related quality-of-life measures. Tertiary outcomes are predictive rognostic biomarkers and health utilities and incremental cost-effectiveness ratio. The primary analysis of overall survival will be performed separately for each study intervention according to the intention to treat principle on all patients randomised to each study intervention. The study (Protocol version 2.0 dated 23 November 2020) was approved by a lead Human Research Ethics Committee (Sydney Local Health District: 2019/ETH13297). The study will be conducted in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice. ACTRN12620000048987.
Publisher: Springer Science and Business Media LLC
Date: 09-04-2021
DOI: 10.1007/S00262-021-02934-3
Abstract: Surgical resection of cancer remains the frontline therapy for millions of patients annually, but post-operative recurrence is common, with a relapse rate of around 45% for non-small cell lung cancer. The tumour draining lymph nodes (dLN) are resected at the time of surgery for staging purposes, and this cannot be a null event for patient survival and future response to immune checkpoint blockade treatment. This project investigates cancer surgery, lymphadenectomy, onset of metastatic disease, and response to immunotherapy in a novel model that closely reflects the clinical setting. In a murine metastatic lung cancer model, primary subcutaneous tumours were resected with associated dLNs remaining intact, completely resected or partially resected. Median survival after surgery was significantly shorter with complete dLN resection at the time of surgery (49 days (95%CI)) compared to when lymph nodes remained intact ( 88 days p 0.05). Survival was partially restored with incomplete lymph node resection and CD8 T cell dependent. Treatment with aCTLA4 whilst effective against the primary tumour was ineffective for metastatic lung disease. Conversely, aPD-1/aCD40 treatment was effective in both the primary and metastatic disease settings and restored the detrimental effects of complete dLN resection on survival. In this pre-clinical lung metastatic disease model that closely reflects the clinical setting, we observe decreased frequency of survival after complete lymphadenectomy, which was ameliorated with partial lymph node removal or with early administration of aPD-1/aCD40 therapy. These findings have direct relevance to surgical lymph node resection and adjuvant immunotherapy in lung cancer, and perhaps other cancer, patients.
Publisher: Wiley
Date: 06-2011
DOI: 10.1118/1.3611864
Publisher: Elsevier BV
Date: 11-2018
DOI: 10.1016/J.JTHO.2018.08.2036
Abstract: On March 28- 29, 2017, the National Cancer Institute (NCI) Thoracic Malignacy Steering Committee, International Association for the Study of Lung Cancer, and Mesothelioma Applied Research Foundation convened the NCI-International Association for the Study of Lung Cancer- Mesothelioma Applied Research Foundation Mesothelioma Clinical Trials Planning Meeting in Bethesda, Maryland. The goal of the meeting was to bring together lead academicians, clinicians, scientists, and the U.S. Food and Drug Administration to focus on the development of clinical trials for patients in whom malignant pleural mesothelioma has been diagnosed. In light of the discovery of new cancer targets affecting the clinical development of novel agents and immunotherapies in malignant mesothelioma, the objective of this meeting was to assemble a consensus on at least two or three practice-changing multimodality clinical trials to be conducted through NCI's National Clinical Trials Network.
Publisher: Elsevier BV
Date: 12-2020
Publisher: Elsevier BV
Date: 09-2016
DOI: 10.1016/J.IJROBP.2016.04.024
Abstract: To report the first comprehensive investigation of patient-reported cosmesis and breast-related quality of life (QOL) outcomes comparing patients randomized to risk-adapted single-dose intraoperative radiation therapy (TARGIT-IORT) versus external beam radiation therapy (EBRT) on the TARGIT-A trial. Longitudinal cosmesis and QOL data were collected from a subset of TARGIT-A participants who received TARGIT-IORT as a separate procedure (postpathology). Patients completed a cosmetic assessment before radiation therapy and annually thereafter for at least 5 years. Patients also completed the combined European Organization for Research and Treatment of Cancer (EORTC) core questionnaire and Breast-Specific Module in addition to the Body Image after Breast Cancer Questionnaire at baseline and annually thereafter. The combined EORTC questionnaires were also collected 3, 6, and 9 months after wide local excision. An Excellent-Good cosmetic result was scored more often than a Fair-Poor result for both treatment groups across all time points. The TARGIT-IORT patients reported better breast-related QOL than EBRT patients. Statistically and clinically significant differences were seen at month 6 and year 1, with EBRT patients having moderately worse breast symptoms (a statistically significant difference of more than 10 in a 100-point scale) than TARGIT-IORT patients at these time points. Patients treated with TARGIT-IORT on the TARGIT-A trial have similar self-reported cosmetic outcome but better breast-related QOL outcomes than patients treated with EBRT. This important evidence can facilitate the treatment decision-making process for patients who have early breast cancer suitable for breast-conserving surgery and inform their clinicians.
Publisher: Wiley
Date: 29-10-2023
Publisher: Elsevier BV
Date: 2021
Publisher: Elsevier BV
Date: 02-2002
Abstract: Although malignant mesothelioma is not a classically immunogenic cancer, there is abundant evidence for immune recognition. The relative ease of obtaining tumor tissue makes mesothelioma ideal for studying surrogate biomarkers such as lymphocytic infiltration or expression of transduced genes. There is evidence that malignant mesothelioma patients as well as asbestos-exposed persons without mesothelioma have impaired immune responsiveness. Substantial progress has been made in animal models using several biological and immunological techniques, but clinical application has been problematic. Systems studied have included lysis by interleukin-2 (IL-2)-activated lymphokine-activated killer (LAK) cells, tumor necrosis factor-alpha (TNF-alpha), a p16-expressing adenovirus vector, suicide gene therapy using the herpes simplex virus-tyrosine kinase (HSV-tk) followed by ganciclovir, and immunomodulatory gene therapy with IL-2, IL-4, interferon-gamma (IFN-gamma), IFN-alpha, TNF-alpha, granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-6, and IL-1beta transfected into tumors. Vaccinia virus has been studied as a vector for cytokine gene transfer. Suicide gene therapy has been combined with a tumor vaccine. The University of Western Australia is initiating a pilot study of autologous vaccination in malignant mesothelioma. Novel agents under study include the angiogenesis inhibitors SU5416, bevacizumab, and thalidomide. ZD1839, an orally administered, highly selective inhibitor of the epidermal growth factor receptor (EGFR) tyrosine kinase, is being tested in a phase II trial. Since platelet-derived growth factor (PDGF) is thought to be an autocrine growth factor for mesothelioma STI-571 (Gleevec Novartis, Basel, Switzerland), a highly selective inhibitor of the PDGF receptor tyrosine kinase, is being tested in a phase II trial. The development of more active cytotoxic combinations in this disease should facilitate further studies of chemoimmunotherapy. It seems likely that no single treatment modality will be effective by itself.
Publisher: Springer New York
Date: 2005
Publisher: Springer Science and Business Media LLC
Date: 29-04-2008
Publisher: Elsevier BV
Date: 04-2013
DOI: 10.1016/J.LUNGCAN.2012.12.008
Abstract: The biomarker mesothelin is a useful diagnostic tool in malignant mesothelioma (MM) patients. It has high specificity but a sensitivity of only 50%. As mesothelin binds CA125, and as CA125 is often elevated in MM, we asked whether this binding affected measurable mesothelin levels in a relevant clinical setting. Mesothelin and CA125 concentrations were measured in the serum of 41 patients with MM. An assay was developed to detect mesothelin bound to CA125. Mesothelin was demonstrated to be bound by CA125 in 9 of 41 MM patients. This binding could be broken by the addition of sodium dodecyl sulphate and diethylenetriaminepenta acetic acid (DTPA) to the s les, however this did not lead to any change in the mesothelin level measured. We therefore conclude that binding of mesothelin to CA125 does not alter the measurement of mesothelin for the detection of MM.
Publisher: Elsevier BV
Date: 2016
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22487430.V1
Abstract: Supplementary Figure from Temozolomide and Radiotherapy versus Radiotherapy Alone in Patients with Glioblastoma, i IDH /i -wildtype: i Post Hoc /i Analysis of the EORTC Randomized Phase III CATNON Trial
Publisher: BMJ
Date: 19-01-2019
DOI: 10.1136/THORAXJNL-2018-212380
Abstract: Malignant pleural mesothelioma (MPM) has a high symptom burden and poor survival. Evidence from other cancer types suggests some benefit in health-related quality of life (HRQoL) with early specialist palliative care (SPC) integrated with oncological services, but the certainty of evidence is low. We performed a multicentre, randomised, parallel group controlled trial comparing early referral to SPC versus standard care across 19 hospital sites in the UK and one large site in Western Australia. Participants had newly diagnosed MPM main carers were additionally recruited. Intervention: review by SPC within 3 weeks of allocation and every 4 weeks throughout the study. HRQoL was assessed at baseline and every 4 weeks with the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30. Primary outcome: change in EORTC C30 Global Health Status 12 weeks after randomisation. Between April 2014 and October 2016, 174 participants were randomised. There was no significant between group difference in HRQoL score at 12 weeks (mean difference 1.8 (95% CI −4.9 to 8.5 p=0.59)). HRQoL did not differ at 24 weeks (mean difference −2.0 (95% CI −8.6 to 4.6 p=0.54)). There was no difference in depression/anxiety scores at 12 weeks or 24 weeks. In carers, there was no difference in HRQoL or mood at 12 weeks or 24 weeks, although there was a consistent preference for care, favouring the intervention arm. There is no role for routine referral to SPC soon after diagnosis of MPM for patients who are cared for in centres with good access to SPC when required. ISRCTN18955704 .
Publisher: Hindawi Limited
Date: 14-01-2019
DOI: 10.1111/ECC.12985
Publisher: Elsevier BV
Date: 10-2006
DOI: 10.1016/J.ADDR.2006.04.002
Abstract: Cytotoxic chemotherapy not only affects the tumour but also targets iding lymphocytes, the very cells required to develop an immune response. Hence, chemo- and immunotherapy have been seen as antagonistic. It is now clear that the way a chemotherapeutic drug kills a tumour cell determines how that dying cell interacts with the immune system and whether the interaction leads to an immune response. Chemotherapy also depletes regulatory T cells, potentially enhancing immune responses. Furthermore, lymphodepletion triggers homeostatic T cell reconstitution, creating new populations of pre-T cells that need education in the thymic environment. Post-chemotherapy immune system reconstitution may provide a unique opportunity for therapeutic intervention by shaping the repertoire towards reactivity to tumour antigens. An understanding of the underlying cellular and immunological events in both animal models and patients undergoing chemotherapy will guide decisions about which immunomodulatory approaches may be effective with different cytostatic drugs and hence to develop appropriate scheduling for integration of the treatment modalities.
Publisher: Wiley
Date: 08-07-2009
Publisher: Frontiers Media SA
Date: 31-10-2022
DOI: 10.3389/FONC.2022.1020493
Abstract: Though immune checkpoint inhibition has recently shown encouraging clinical efficacy in mesothelioma, most patients do not respond. Combining immune checkpoint inhibition with radiotherapy presents an attractive option for improving treatment responses owing to the various immunomodulatory effects of radiation on tumors. However, the ideal dosing and scheduling of combined treatment remains elusive, as it is poorly studied in mesothelioma. The present study characterizes the dose- and time-dependent changes to expression of various immune markers and cytokines important to antitumor responses following irradiation of mesothelioma cell lines. Two murine (AB1, AE17) and two human (BYE, JU77) mesothelioma cell lines were treated with titrated gamma-radiation doses (1-8 Gy) and the expression of MHC class-I, MHC class-II and PD-L1 was measured over a series of post-irradiation timepoints (1-72 hours) by flow cytometry. Levels of cytokines IL-1α, IL-1β, IL-6, IL-10, IL-12p70, IL-17A, IL-23, IL-27, MCP-1, IFN-β, IFN-γ, TNF-α, and GM-CSF were measured by multiplex immunoassay in murine cell lines following 8 Gy radiation. Following irradiation, a dose-dependent upregulation of MHC-I and PD-L1 was observed on three of the four cell lines studied to varying extents. For all cell lines, the increase in marker expression was most pronounced 72 hours after radiation. At this timepoint, increases in levels of cytokines IFN-β, MCP-1 and IL-6 were observed following irradiation with 8 Gy in AB1 but not AE17, reflecting patterns in marker expression. Overall, this study establishes the dose- and time-dependent changes in immune marker expression of commonly studied mesothelioma cell lines following radiation and will inform future study into optimal dosing and scheduling of combined radiotherapy and immune checkpoint inhibition for mesothelioma.
Publisher: Elsevier BV
Date: 11-2012
Publisher: Elsevier
Date: 2013
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22487424.V1
Abstract: Supplementary Figure from Temozolomide and Radiotherapy versus Radiotherapy Alone in Patients with Glioblastoma, i IDH /i -wildtype: i Post Hoc /i Analysis of the EORTC Randomized Phase III CATNON Trial
Publisher: Informa Healthcare
Date: 12-2004
DOI: 10.1517/14656566.5.12.2441
Abstract: Malignant pleural mesothelioma is an aggressive malignancy which is almost always fatal median survival is usually < 1 year. Most patients present with symptoms including pain, dyspnoea, pleural effusions and chest wall masses. Until recently, there has been no effective treatment which can improve symptoms and prolong survival. This article reviews recent developments in the treatment of mesothelioma, particularly advances in drug therapy and the use of the current most active drug combination: pemetrexed and cisplatin. Pemetrexed is a novel antifolate drug with multiple enzyme targets. The combination of pemetrexed and cisplatin demonstrated a survival advantage over cisplatin alone in patients with pleural mesothelioma, and can give symptomatic benefits. This combination has become the standard of care in mesothelioma treatment.
Publisher: Elsevier BV
Date: 2013
Publisher: Wiley
Date: 02-2012
DOI: 10.1111/J.1754-9485.2011.02334.X
Abstract: Radiotherapy (RT) plays an integral role in the management of high-grade glioma (HGG). However, there is little information on the patterns of care in unselected Australian patients with HGG. This prospective cohort study collected information on patients with a diagnosis of HGG managed in Western Australia over a 25-month period from 2006 to 2008. RT treatment and survival data were analysed. 86% of Western Australian patients with HGG were treated at the study site over this period. Of these, 80% were reviewed by a radiation oncologist with RT recommended in 88% of cases. One hundred eighty-seven patients proceeded to have RT, with most receiving 60 Gy in 30 fractions with limited field external beam radiotherapy (LFRT). Median survival from diagnosis was 13.6 months for all patients and 15.4 months for those planned for treatment with 60 Gy in 30 fractions. The median time from surgery to the start of RT was 41 days. Longer waiting times were not predictors of poor survival. Failure to receive all planned treatment (13% of patients) predicted for poor survival (hazard ratio 0.38). Dose and fractionation practices show concordance with published data and guidelines. Survival is also consistent with clinical trial data for patients planned for aggressive therapy. Nevertheless, a substantial number of patients are not suited to aggressive therapy or fail to complete planned therapy, and these patients have poor outcomes. Treatment delays did not affect survival outcomes but are confounded by earlier treatment of those unsuited to LFRT.
No related grants have been discovered for Anna Nowak.