ORCID Profile
0000-0002-1629-4352
Current Organisation
The University of Newcastle
Does something not look right? The information on this page has been harvested from data sources that may not be up to date. We continue to work with information providers to improve coverage and quality. To report an issue, use the Feedback Form.
Publisher: Wiley
Date: 07-2018
DOI: 10.1111/AJCO.13035
Publisher: MDPI AG
Date: 23-04-2020
Abstract: Cannabis has been used to relieve the symptoms of disease for thousands of years. However, social and political biases have limited effective interrogation of the potential benefits of cannabis and polarised public opinion. Further, the medicinal and clinical utility of cannabis is limited by the psychotropic side effects of ∆9-tetrahydrocannabinol (∆9-THC). Evidence is emerging for the therapeutic benefits of cannabis in the treatment of neurological and neurodegenerative diseases, with potential efficacy as an analgesic and antiemetic for the management of cancer-related pain and treatment-related nausea and vomiting, respectively. An increasing number of preclinical studies have established that ∆9-THC can inhibit the growth and proliferation of cancerous cells through the modulation of cannabinoid receptors (CB1R and CB2R), but clinical confirmation remains lacking. In parallel, the anti-cancer properties of non-THC cannabinoids, such as cannabidiol (CBD), are linked to the modulation of non-CB1R/CB2R G-protein-coupled receptors, neurotransmitter receptors, and ligand-regulated transcription factors, which together modulate oncogenic signalling and redox homeostasis. Additional evidence has also demonstrated the anti-inflammatory properties of cannabinoids, and this may prove relevant in the context of peritumoural oedema and the tumour immune microenvironment. This review aims to document the emerging mechanisms of anti-cancer actions of non-THC cannabinoids.
Publisher: MDPI AG
Date: 25-11-2019
DOI: 10.3390/IJMS20235924
Abstract: Metastases in thyroid cancer are associated with aggressive disease and increased patient morbidity, but the factors driving metastatic progression are unclear. The precursor for nerve growth factor (proNGF) is increased in primary thyroid cancers, but its expression or significance in metastases is not known. In this study, we analysed the expression of proNGF in a retrospective cohort of thyroid cancer lymph node metastases (n = 56), linked with corresponding primary tumours, by automated immunohistochemistry and digital quantification. Potential associations of proNGF immunostaining with clinical and pathological parameters were investigated. ProNGF staining intensity (defined by the median h-score) was significantly higher in lymph node metastases (h-score 94, interquartile range (IQR) 50–147) than in corresponding primary tumours (57, IQR 42–84) (p = 0.002). There was a correlation between proNGF expression in primary tumours and corresponding metastases, where there was a 0.68 (95% CI 0 to 1.2) increase in metastatic tumour h-score for each unit increase in the primary tumour h-score. However, larger tumours (both primary and metastatic) had lower proNGF expression. In a multivariate model, proNGF expression in nodal metastases was negatively correlated with lateral neck disease and being male. In conclusion, ProNGF is expressed in locoregional metastases of thyroid cancer and is higher in lymph node metastases than in primary tumours, but is not associated with high-risk clinical features.
Publisher: Public Library of Science (PLoS)
Date: 25-11-2014
Publisher: Wiley
Date: 23-03-2019
DOI: 10.1111/AJCO.12866
Abstract: Many biobanks rely upon patients' willingness to donate biospecimens and healthcare professionals to initiate opt-in consent processes. This study explored if: (1) patients accept opt-in or opt-out consent models with varying levels of professional involvement (2) professionals discuss participation with specific patient groups and (3) this discussion is associated with patient knowledge of biobanking processes. Outpatients completed surveys at a tertiary cancer center in New South Wales, Australia. Eligible participants were English-speaking adults who recently had cancer-related surgery. Participants completed 27 questions exploring acceptable consent models, biobanking experiences, knowledge, and willingness. Logistic regression and chi-square tests examined differences in the characteristics and knowledge of participants who were offered the opportunity to participate versus those who were not. A total of 113 outpatients participated (97% response). Most participants (92%) found opt-out, patient-initiated consent acceptable however, high acceptability was reported for all models except for opt-in, patient-initiated consent (58%). University or technical qualifications (P = 0.001) was associated with increased odds (OR = 4.5) of being offered biobanking. The majority did not know what occurred to s les after surgery (59.3%) or pathology review (81.4%) and ability to answer these questions was associated with discussion of participation (P < 0.001). Of the few outpatients who discussed biobanking with their doctor (29%), all consented. Professional-initiated, opt-in consent resulted in a few educated patients being approached greater professional initiation of consent would be fruitful as most patients were willing to participate if asked. However, other consent approaches minimizing professional involvement were as acceptable to participants warranting further consideration.
Publisher: American Association for Cancer Research (AACR)
Date: 15-04-2008
DOI: 10.1158/0008-5472.CAN-07-5664
Abstract: FoxP3 is a member of the forkhead family of transcription factors critically involved in the development and function of CD25+ regulatory T cells (Treg). Until recently, FoxP3 expression was thought to be restricted to the T-cell lineage. However, using immunohistochemistry and flow cytometric analysis of human melanoma tissue, we detected FoxP3 expression not only in the tumor infiltrating Treg but also in the melanoma cells themselves. FoxP3 is also widely expressed by established human melanoma cell lines (as determined by flow cytometry, PCR, and Western blot), as well as cell lines derived from other solid tumors. Normal B cells do not express FoxP3 however, expression could be induced after transformation with EBV in vitro and in vivo, suggesting that malignant transformation of healthy cells can induce FoxP3. In addition, a FOXP3 mRNA variant lacking exons 3 and 4 was identified in tumor cell lines but was absent from Treg. Interestingly, this alternative splicing event introduces a translation frame-shift that is predicted to encode a novel protein. Together, our results show that FoxP3, a key regulator of immune suppression, is not only expressed by Treg but also by melanoma cells, EBV-transformed B cells, and a wide variety of tumor cell lines. [Cancer Res 2008 (8):3001–9]
Publisher: American Society for Microbiology
Date: 17-06-2020
DOI: 10.1128/CMR.00035-19
Abstract: The past 2 decades have seen a revolution in our approach to therapeutic immunosuppression. We have moved from relying on broadly active traditional medications, such as prednisolone or methotrexate, toward more specific agents that often target a single receptor, cytokine, or cell type, using monoclonal antibodies, fusion proteins, or targeted small molecules. This change has transformed the treatment of many conditions, including rheumatoid arthritis, cancers, asthma, and inflammatory bowel disease, but along with the benefits have come risks.
Publisher: T.M.C. Asser Press
Date: 24-12-2013
Publisher: Royal Society of Chemistry (RSC)
Date: 1992
DOI: 10.1039/C39920000392
Publisher: Elsevier BV
Date: 11-2022
Publisher: Springer Science and Business Media LLC
Date: 28-04-2016
DOI: 10.1038/SREP25220
Abstract: Rare cancer stem cells (CSC) are proposed to be responsible for tumour propagation and re-initiation and are functionally defined by identifying tumour-initiating cells (TICs) using the xenotransplantation limiting dilution assay (LDA). While TICs in clear cell renal cell carcinoma (ccRCC) appeared rare in NOD/SCID/IL2Rγ −/− (NSG) mice, xenografts formed more efficiently from small tumour fragments, indicating the LDA underestimated ccRCC TIC frequency. Mechanistic interrogation of the LDA identified multiple steps that influence ccRCC TIC quantitation. For ex le, tissue disaggregation destroys most ccRCC cells, common assays significantly overestimate tumour cell viability and microenvironmental supplementation with human extracellular factors or pharmacological inhibition of anoikis increase clonogenicity and tumourigenicity of ccRCC cell lines and primary tumour cells. Identification of these previously uncharacterized concerns that cumulatively lead to substantial underestimation of TICs in ccRCC provides a framework for development of more accurate TIC assays in the future, both for this disease and for other cancers.
Publisher: Elsevier BV
Date: 11-2010
DOI: 10.1016/J.UROLONC.2009.06.010
Abstract: There is evolving evidence for the so-called cancer stem cell (CSC) hypothesis, which holds that intra-tumoral heterogeneity in urologic malignancies is hierarchical and that not all cells have the ability to proliferate indefinitely and to generate metastases. This has far-reaching implications for research and the clinical management of urologic malignancies. In this review, we outline the tenets and implications of the CSC hypothesis, summarize existing evidence for CSCs in urologic malignancies, suggest research directions that may better dissect intra-tumoral heterogeneity in urologic cancers, and outline novel therapeutic modalities implied by the CSC hypothesis.
Publisher: American Society of Clinical Oncology (ASCO)
Date: 20-02-2021
DOI: 10.1200/JCO.2021.39.6_SUPPL.TPS367
Abstract: TPS367 Background: Inhibitors of the programmed death-1 pathway (PD-1) are effective in clear cell renal cell cancer (ccRCC). Preclinical data and case reports suggest that denosumab, an inhibitor of Receptor Activator of Nuclear Factor κ-B Ligand (RANKL) signaling, could potentiate the anti-tumour effects of anti-PD1 inhibitors without overlapping toxicities. We aim to determine the activity and safety of combining denosumab and pembrolizumab in advanced ccRCC. Methods: This single arm, multi-center, phase II trial will recruit 70 participants with metastatic or unresectable ccRCC, progressing during or after treatment with vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors, and with no prior treatment with immunotherapy or denosumab. Participants will receive pembrolizumab 200mg IV every 3 weeks plus denosumab 120mg SC on days 1, 8 and 22 and then every 3 weeks until disease progression, prohibitive toxicity or maximum treatment of 24 months. Response will be assessed at weeks 12, 18, 24, then every 12 weeks until disease progression. Bloods for translational studies are collected at baseline, week 6 and on disease progression. The primary endpoint is objective tumour response rate (OTRR) per RECIST 1.1. Secondary endpoints include OTRR per iRECIST, progression free survival (PFS), time to OTRR, time to first skeletal related event, adverse events, and frequency of treatment delays/discontinuations. Correlative studies will include identification of prognostic and/or predictive biomarkers relating to immune and RANKL signaling. A s le size of 70 provides 90% power with a 1-sided type 1 error rate of 10% to distinguish the observed OTRR (and PFS at 6 months) from an OTRR of 40% (worthy of pursuit) versus 25% (not worthy of pursuit). 15 sites are open across Australia. As of September 23, 2020, 40 patients have been recruited. Clinical trial information: NCT03280667 .
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 08-2021
Publisher: Oxford University Press (OUP)
Date: 18-01-2012
DOI: 10.1002/STEM.786
Abstract: The ability of cell lines to accurately represent cancer is a major concern in preclinical research. Culture of glioma cells as neurospheres in stem cell media (SCM) has been shown to better represent the genotype and phenotype of primary glioblastoma in comparison to serum cell lines. Despite the use of neurosphere-like models of many malignancies, there has been no robust analysis of whether other cancers benefit from a more representative phenotype and genotype when cultured in SCM. We analyzed the growth properties, transcriptional profile, and genotype of melanoma cells grown de novo in SCM, as while melanocytes share a common precursor with neural cells, melanoma frequently demonstrates ergent behavior in cancer stem cell assays. SCM culture of melanoma cells induced a neural lineage gene expression profile that was not representative of matched patient tissue s les and which could be induced in serum cell lines by switching them into SCM. There was no enrichment for expression of putative melanoma stem cell markers, but the SCM expression profile did overlap significantly with that of SCM cultures of glioma, suggesting that the observed phenotype is media-specific rather than melanoma-specific. Xenografts derived from either culture condition provided the best representation of melanoma in situ. Finally, SCM culture of melanoma did not prevent ongoing acquisition of DNA copy number abnormalities. In conclusion, SCM culture of melanoma does not provide a better representation of the phenotype or genotype of metastatic melanoma, and the resulting neural bias could potentially confound therapeutic target identification. Disclosure of potential conflicts of interest is found at the end of this article.
Publisher: American Society of Clinical Oncology (ASCO)
Date: 20-05-2014
DOI: 10.1200/JCO.2014.32.15_SUPPL.11127
Abstract: 11127 Background: Rare cancer stem cells (CSC), proposed to be solely responsible for tumor propagation and re-initiation, are functionally identified as tumor-initiating cells (TIC) from ex vivo tumors using xenotransplantation and clonogenic limiting dilution assays (LDA). TIC have not previously been described from ex vivohuman clear cell renal cell carcinoma (ccRCC). Methods: Primary human ccRCC s les (n=120) from patients undergoing nephrectomy were processed and implanted as subcapsular fragments or cell suspension injection LDAs with Matrigel in NOD/SCID/IL2Rγ -/- (NSG) mice, and observed for at least 6 months. In vitro clonogenic LDAs assays were performed from primary cell suspensions and ccRCC cell lines. LDAs were supplemented with human stromal cells and proteins, and the Y-26732 ROCK inhibitor. Multiparametric flow cytometry and immunofluorescence were used to investigate tumor heterogeneity and cell viability. Results: ccRCC TIC appeared rare from injected suspensions, but xenografts engrafted frequently from tiny fragments, and clonogenic frequencies were 10 3 -10 4 greater than TIC frequencies, suggesting that LDAs underestimated ccRCC tumor cell potential. We systematically identified multiple methodological steps that distort quantitation and identification of ccRCC TIC. For ex le cell viability was highly variable prior to processing, disaggregation itself destroyed up to 99% of tumor cells, standard assays substantially overestimated tumor cell viability in suspensions, and supplementation with human extracellular cells or proteins, or inhibition of anoikis by Y-26732 increased clonogenic and TIC frequencies in cell lines and primary ccRCC suspensions. Annexin-V staining revealed that tumor cells were more apoptotic then normal stromal cells, and that tumor cells positive for CD44 (a putative CSC marker) were more viable than CD44- tumor cells. Conclusions: We describe multiple, unappreciated and largely unavoidable observational errors in essential methods used to study TIC in ccRCC. ccRCC TIC may be more common than appreciated. Re-examination of the CSC hypothesis in other solid tumors is warranted in view of these previously unexplored methodological biases.
Publisher: Elsevier BV
Date: 09-2020
Publisher: Public Library of Science (PLoS)
Date: 29-08-2014
Publisher: Portland Press Ltd.
Date: 06-1995
DOI: 10.1042/BJ3080559
Abstract: Myeloperoxidase is the most abundant protein in neutrophils and catalyses the conversion of H2O2 and chloride into HOCl. To help clarify the role of this enzyme in bacterial killing and inflammation, a specific and potent inhibitor needs to be identified. We have studied a series of benzoic acid hydrazides and found that in general they inhibit the peroxidation activity of myeloperoxidase with an IC50 value of less than 10 microM. The IC50 values of derivatives with substituents containing oxygen or nitrogen were related to their Hammett substituent constants. This indicates that myeloperoxidase oxidizes the hydrazide group of these compounds, and the degree to which they inhibit the enzyme is dependent on the ease of their oxidation. Unsubstituted benzoic acid hydrazide and its 4-chloro derivative were poor inhibitors of peroxidation. Thus it is likely that hydrogen-bonding of the enzyme to substituents containing oxygen or nitrogen increases the binding affinity of the hydrazides and enhances their oxidation by myeloperoxidase. 4-Aminobenzoic acid hydrazide (ABAH) was the most potent inhibitor of peroxidation. It irreversibly inhibited HOCl production by the purified enzyme, having an IC50 value of 0.3 microM. With neutrophils stimulated with opsonized zymosan or phorbol myristate acetate, ABAH inhibited HOCl production by up to 90% and the IC50 values were 16 microM and 2.2 microM respectively. In the presence of superoxide dismutase, these values decreased to 6.4 microM and 0.6 microM respectively. ABAH had no effect on superoxide radical (O2-.) production and degranulation by neutrophils, nor did it inhibit catalase or glutathione peroxidase. Thus ABAH is an effective and selective inhibitor that should be useful for determining the contribution of myeloperoxidase to oxidant-mediated reactions of neutrophils.
Publisher: Springer Science and Business Media LLC
Date: 17-02-2009
DOI: 10.1007/S00262-009-0672-0
Abstract: "Cancer stem cells" that resist conventional treatments may be a cause of therapeutic failure in melanoma. We report a subpopulation of clonogenic melanoma cells that are characterized by high prominin-1/CD133 expression in melanoma and melanoma cell lines. These cells have enhanced clonogenicity and self-renewal in vitro, and serve as a limited in vitro model for melanoma stem cells. In some cases clonogenic CD133(+) melanoma cells show increased expression of some cancer/testis (CT) antigens. The expression of NY-ESO-1 in an HLA-A2 expressing cell line allowed CD133(+) clonogenic melanoma cells to be targeted for killing in vitro by NY-ESO-1-specific CD8(+) T-lymphocytes. Our in vitro findings raise the hypothesis that if melanoma stem cells express CT antigens in vivo that immune targeting of these antigens may be a viable clinical strategy for the adjuvant treatment of melanoma.
Publisher: Frontiers Media SA
Date: 22-04-2021
Abstract: Brain and Acute Leukemia, Cytoplasmic (BAALC) is a protein that controls leukemia cell proliferation, differentiation, and survival and is overexpressed in several cancer types. The gene is located in the chromosomal region 8q22.3, an area commonly lified in breast cancer and associated with poor prognosis. However, the expression and potential role of BAALC in breast cancer has not widely been examined. This study investigates BAALC expression in human breast cancers with the aim of determining if it plays a role in the pathogenesis of the disease. BAALC protein expression was examined by immunohistochemistry in breast cancer, and matched lymph node and normal breast tissue s les. The effect of gene expression on overall survival (OS), disease-free and distant metastasis free survival (DMFS) was assessed in silico using the Kaplan-Meier Plotter (n=3,935), the TCGA invasive breast carcinoma (n=960) and GOBO (n=821) data sets. Functional effects of BAALC expression on breast cancer proliferation, migration and invasion were determined in vitro . We demonstrate herein that BAALC expression is progressively increased in primary and breast cancer metastases when compared to normal breast tissue. Increased BAALC mRNA is associated with a reduction in DMFS and disease-free survival, but not OS, in breast cancer patients, even when corrected for tumor grade. We show that overexpression of BAALC in MCF-7 breast cancer cells increases the proliferation, anchorage-independent growth, invasion, and migration capacity of these cells. Conversely, siRNA knockdown of BAALC expression in Hs578T breast cancer cells decreases proliferation, invasion and migration. We identify that this BAALC associated migration and invasion is mediated by focal adhesion kinase (FAK)-dependent signaling and is accompanied by an increase in matrix metalloproteinase (MMP)-9 but not MMP-2 activity in vitro . Our data demonstrate a novel function for BAALC in the control of breast cancer metastasis, offering a potential target for the generation of anti-cancer drugs to prevent breast cancer metastasis.
Publisher: Spandidos Publications
Date: 31-12-2015
DOI: 10.3892/OL.2015.4069
Publisher: Elsevier BV
Date: 12-2020
Publisher: Proceedings of the National Academy of Sciences
Date: 30-03-2011
Abstract: The cancer stem cell (CSC) model proposes that tumors have a hierarchical organization in which only some cells indefinitely self-renew and thereby sustain tumor growth. In addition, the CSC model requires that tumor-initiating cells (TICs) be prospectively isolatable on the basis of their phenotype. Previous studies have suggested that serous ovarian cancer (SOC) conforms to the CSC model, but these used arguably nonfidelitous immortalized cell lines, cultured primary cells, or passaged xenografts as the source of tumor cells. We developed a robust assay for quantifying TICs from primary SOC. Using this assay, we find that TICs are rare when assayed in either NOD/SCID or NOD/SCID/IL2Rγ −/− (NSG) mice. TIC frequency (TICf) varies substantially between patients, although it is similar in primary ovarian masses and omental metastases, suggesting that TICf is an intrinsic property of ovarian tumors. CD133 marks all TICs from several primary SOC cases. However, in other cases, substantial TIC activity is found in both the CD133 + and CD133 − fractions, whereas still other cases have exclusively CD133 − TICs. Furthermore, the TIC phenotype can change in xenografts: primary tumors in which all TICs are CD133 + can give rise to xenografts that contain substantial numbers of CD133 − TICs. Our results highlight the need for quantitative rigor in the evaluation of TICs and for caution when using passaged xenografts for such studies. Furthermore, although our data suggest that SOC conforms to the CSC hypothesis, the heterogeneity of the TIC phenotype may complicate its clinical application.
Publisher: Wiley
Date: 05-2021
DOI: 10.1111/IMJ.15217
Abstract: The COVID‐19 pandemic has challenged cancer care globally, introducing resource limitations and competing risks into clinical practice. To describe the COVID‐19 impact on medical oncology care provision in an Australian setting. Calvary Mater Newcastle and Newcastle Private Hospital medical oncology data from 1 February to 31 April 2019 versus 2020 were retrospectively analysed. Three hundred and sixty‐four inpatient admissions occurred in 2020, 21% less than in 2019. Total inpatient days decreased by 22% (2842 vs 2203). April was most impacted (36% and 44% fewer admissions and inpatient days respectively). Mean length of stay remained unchanged (6.4 vs 6.2 days, P = 0.7). In all, 5072 outpatient consultations were conducted, including 417 new‐patient consultations (4% and 6% increase on 2019 respectively). Telephone consultations (0 vs 1380) replaced one‐quarter of face‐to‐face consultations (4859 vs 3623, −25%), with minimal telehealth use (6 vs 69). Day Treatment Centre encounters remained stable (3751 vs 3444, −8%). The proportion of new patients planned for palliative treatment decreased (35% vs 28%, P = 0.04), observation increased (16% vs 23%, P = 0.04) and curative intent treatment was unchanged (both 41%). Recruiting clinical trials decreased by one‐third (45 vs 30), two trials were activated (vs 5 in 2019) and 45% fewer patients consented to trial participation (62 vs 34). Our medical oncology teams adapted rapidly to COVID‐19 with significant changes to care provision, including fewer hospital admissions, a notable transition to telephone‐based outpatient clinics and reduced clinical trial activity. The continuum of care was largely defended despite pandemic considerations and growing service volumes.
Publisher: Springer Science and Business Media LLC
Date: 16-07-2016
Publisher: Springer Science and Business Media LLC
Date: 17-06-1970
DOI: 10.1186/S12885-022-10407-8
Abstract: Oesophageal and gastrooesophageal junction (GOJ) carcinoma frequently present with dysphagia and de novo metastatic disease. There is scope to improve treatment paradigms to both address symptoms and improve survival. One method is integrating immune checkpoint inhibition with novel treatment combinations. PALEO is a single arm, phase II clinical trial in patients with previously untreated, oligometastatic or locoregionally advanced oesophageal or GOJ carcinoma and dysphagia. PALEO is sponsored by the Australasian Gastro-Intestinal Trials Group (AGITG). Participants receive 2 weeks of therapy with concurrent hypofractionated radiotherapy of 30Gy in 10 fractions to the primary tumour, weekly carboplatin AUC2, weekly paclitaxel 50 mg/m 2 and durvalumab 1500 mg q4 weekly, followed by durvalumab monotherapy continuing at 1500 mg q4weekly until disease progression, unacceptable toxicity or 24 months of therapy. A single metastasis is treated with stereotactic radiotherapy of 24Gy in 3 fractions in week 7. The trial primary endpoint is the progression free survival rate at 6 months. Secondary endpoints include duration of dysphagia relief, nutritional status change, quality of life, response rate, toxicity, progression free survival and overall survival. The tertiary endpoint is prediction of outcome based on biomarkers identified from patient serial blood s les collected pre- and post-radiotherapy. This unique investigator-initiated clinical trial is designed to simultaneously address the clinically relevant problems of dysphagia and distant disease control. The overarching aims are to improve patient nutrition, quality of life and survival with low toxicity therapy. AGITG PALEO is a multidisciplinary collaboration and will add to the understanding of the relationship between radiotherapy and the anti-tumour immune response. Australian and New Zealand Clinical Trials Registry: ACTRN12619001371189 , registered 8 October 2019.
Publisher: Springer Science and Business Media LLC
Date: 03-04-2020
DOI: 10.1186/S12885-020-06733-4
Abstract: Clear cell renal cell carcinoma (ccRCC) is a markedly heterogeneous disease in many aspects, including the tumour microenvironment. Our previous study showed the importance of the tumour microenvironment in ccRCC xeno-transplant success rates. In order to better understand the potential relationship between TICs and the immune microenvironment, we employed a multi-modal approach, examining RNA and protein expression (flow cytometry, immunohistochemistry). We first examined the gene expression pattern of 18 stem rogenitor marker genes in the cancer genome atlas (TCGA) ccRCC cohort. Flow cytometry was next employed to examine lineage-specific expression levels of stem rogenitor markers and immune population makeup in six, disaggregated, primary ccRCC specimens. Immunohistochemistry was performed on a commercial ccRCC tissue microarray (TMA). The 18 genes differed with respect to their correlation patterns with one another and to their prognostic significance. By flow cytometry, correlating expression frequency of 12 stem rogenitor markers and CD10 resulted in two clusters—one with CD10 (marker of proximal tubular differentiation), and second cluster containing mostly mesenchymal stem cell (MSC) markers, including CD146. In turn, these clusters differed with respect to their correlation with different CD45 + lineage markers and their expression of immune checkpoint pathway proteins. To confirm these findings, four stem rogenitor marker expression patterns were compared with CD4, CD8 and CD20 in a ccRCC TMA which showed a number of similar trends with respect to frequency of the different tumour-infiltrating leukocytes. Taken together, we observed heterogeneous but patterned expression levels of different stem rogenitor markers. Our results suggest a non-random relationship between their expression patterns with the immune microenvironment populations in ccRCC.
Publisher: Wiley
Date: 06-07-2021
DOI: 10.1111/BJU.15491
Abstract: To determine the activity and safety of lutetium‐177 ( 177 Lu)‐prostate‐specific membrane antigen (PSMA)‐617 in men with metastatic castration‐resistant prostate cancer (mCRPC) commencing enzalutamide, who are at high risk of early progression, and to identify potential prognostic and predictive biomarkers from imaging, blood and tissue. ENZA‐p (ANZUP 1901) is an open‐label, randomized, two‐arm, multicentre, phase 2 trial. Participants are randomly assigned (1:1) to treatment with enzalutamide 160 mg daily alone or enzalutamide plus 177 Lu‐PSMA‐617 7.5 GBq on Days 15 and 57. Two additional 177 Lu‐PSMA‐617 doses are allowed, informed by Day‐92 Gallium‐68 ( 68 Ga)‐PSMA positron emission tomography (PET up to four doses in total). The primary endpoint is prostate‐specific antigen (PSA) progression‐free survival (PFS). Other major endpoints include radiological PFS, PSA response rate, overall survival, health‐related quality of life, adverse events and cost‐effectiveness. Key eligibility criteria include: biochemical and/or clinical progression 68 Ga‐PSMA PET‐avid disease no prior androgen signalling inhibitor, excepting abiraterone no prior chemotherapy for mCRPC and ≥2 high‐risk features for early enzalutamide failure. Assessments are 4 weekly during study treatment, then 6 weekly until radiographic progression. Response Evaluation Criteria in Solid Tumours (RECIST) are used to assess imaging conducted every 12 weeks, 68 Ga‐PSMA PET at baseline, Days 15 and 92, and at progression, and 18 F‐fluorine deoxyglucose ( 18 F‐FDG) PET at baseline and progression. Translational s les include blood (and optional biopsies) at baseline, Day 92, and first progression. Correlative studies include identification of prognostic and predictive biomarkers from 68 Ga‐PSMA and 18 F‐FDG PET/CT, circulating tumour cells and circulating tumour DNA. The trial will enrol 160 participants, providing 80% power with a two‐sided type‐1 error rate of 5% to detect a hazard ratio of 0.625 assuming a median PSA‐PFS of 5 months with enzalutamide alone. The combination of 177 Lu‐PSMA‐617 and enzalutamide may be synergistic. ENZA‐p will determine the safety and efficacy of the combination in addition to developing predictive and prognostic biomarkers to better guide treatment decisions.
Publisher: Springer Science and Business Media LLC
Date: 30-10-2016
DOI: 10.1007/S12015-015-9630-8
Abstract: Cancer cell lines can be useful to model cancer stem cells. Infection with Mycoplasma species is an insidious problem in mammalian cell culture. While investigating stem-like properties in early passage melanoma cell lines, we noted poorly reproducible results from an aliquot of a cell line that was later found to be infected with Mycoplasma hyorhinis. Deliberate infection of other early passage melanoma cell lines aliquots induced variable and unpredictable effects on expression of putative cancer stem cell markers, clonogenicity, proliferation and global gene expression. Cell lines established in stem cell media (SCM) were equally susceptible. Mycoplasma status is rarely reported in publications using cultured cells to study the cancer stem cell hypothesis. Our work highlights the importance of surveillance for Mycoplasma infection while using any cultured cells to interrogate tumor heterogeneity.
Publisher: Humana Press
Date: 11-10-2013
DOI: 10.1007/978-1-62703-128-8_12
Abstract: The cancer stem cell hypothesis is an appealing concept to account for intratumoral heterogeneity and the observation that systemic metastasis and treatment failure are often associated with the survival of a small number of cancer cells. Whilst in vivo evidence forms the foundation of this concept, in vitro methods and reagents are attractive as they offer opportunities to perform experiments that are not possible in an animal model. While there is abundant evidence that existing cancer cell lines are not reliable models of tumor heterogeneity, recent advances based on well validated novel cancer cell lines established de novo in defined serum-free media are encouraging, particularly in the study of glioblastoma multiforme. In this chapter we wish to broadly outline the process of establishing, characterizing, and managing novel cancer cell lines in defined serum-free media, and discuss the limitations and potential opportunities that may arise from these model systems.
Publisher: Elsevier BV
Date: 07-2022
DOI: 10.1016/J.EJCA.2022.04.016
Abstract: Based on PROfound, olaparib is approved for patients with metastatic castration-resistant prostate cancer following disease progression on at least enzalutamide or abiraterone and who carry relevant alterations in DNA repair genes. To facilitate continued olaparib treatment as long as the patient derives benefit, we describe further safety assessments from PROfound focusing on the four most common adverse events (AEs) and events of special interest. Patients were randomized (2:1) to olaparib tablets (300 mg bid) or control (enzalutamide or abiraterone) until disease progression or unacceptable toxicity. Safety was assessed through AE reporting and laboratory assessments. Safety data were also collected from all patients in the control group who experienced radiographic disease progression and subsequently crossed over to olaparib treatment. 256 patients received olaparib and 130 control. Incidence rates for the four most commonly occurring AEs in the olaparib group (all-causality) were anaemia 50%, nausea 43%, fatigue/asthenia 42% and decreased appetite 31%. All were mostly Grade 1 and 2 and all peaked within the first 2 months of treatment as the events were managed where appropriate, primarily with dose interruptions or dose reductions. The extent of bone metastases at baseline or prior taxane use was not associated with the rate of anaemia. Pneumonitis was reported in 2% and 1.5% of patients in the olaparib and control groups, respectively, and one patient (0.4%) in the olaparib group experienced an event of MDS/AML after a 30-day follow-up period. Venous thromboembolic events occurred in 8% of olaparib and 3% of control patients. The four most common AEs observed in PROfound were generally manageable without the need for treatment discontinuation, allowing patients to remain on treatment for as long as they were deriving clinical benefit. gov registration number: NCT02987543.
Publisher: Elsevier BV
Date: 07-2019
DOI: 10.1016/J.EURURO.2019.03.015
Abstract: Atezolizumab, a humanised monoclonal antibody targeting PD-L1, is approved for locally advanced/metastatic urothelial carcinoma. SAUL evaluated atezolizumab in a broader, pretreated population, including patients ineligible for the pivotal IMvigor211 phase 3 trial of atezolizumab. To determine the safety and efficacy of atezolizumab in an international real-world setting. Between November 2016 and March 2018 (median follow-up 12.7mo), 1004 patients with locally advanced or metastatic urothelial or nonurothelial urinary tract carcinoma who experienced progression during or after one to three prior therapies for inoperable, locally advanced, or metastatic disease were enrolled. Patients with renal impairment, treated central nervous system metastases, or stable controlled autoimmune disease were eligible 10% had Eastern Cooperative Oncology Group performance status (ECOG PS) 2 and 98% were platinum pretreated (Clinicaltrials.gov: NCT02928406). Atezolizumab 1200mg every 3wk until progression or unacceptable toxicity. The primary endpoint was safety. Secondary efficacy endpoints included overall survival (OS), progression-free survival (PFS), and overall response rate (ORR). The median treatment duration was 2.8mo (range 0-19) 22% remained on treatment and 8% discontinued because of toxicity. Grade ≥3 adverse events occurred in 45% of patients. The most common grade ≥3 treatment-related adverse events were fatigue, asthenia, colitis, and hypertension (each in 1%). Median OS was 8.7mo (95% confidence interval [CI] 7.8-9.9). The 6-mo OS rate was 60% (95% CI 57-63%), median PFS was 2.2mo (95% CI 2.1-2.4), and the ORR was 13% (95% CI 11-16% 3% complete responses). Among IMvigor211-like patients (excluding ECOG PS 2 and other IMvigor211 exclusion criteria), median OS was 10.0mo (95% CI 8.8-11.9) and 6-mo OS was 65% (95% CI 61-69%). SAUL confirms the tolerability of atezolizumab in a real-world pretreated population with urinary tract carcinoma. Efficacy overall and in the IMvigor211-like subgroup is consistent with previous pivotal anti-PD-L1/PD-1 urothelial carcinoma trials. These results support the use of atezolizumab in urinary tract carcinoma, including patients with limited treatment options. In this international study we investigated the efficacy and safety of atezolizumab treatment for advanced urinary tract cancer in a large population of pretreated patients, including those who would not normally be candidates for clinical trials. Patients tolerated the treatment well, even if they had autoimmune disease, were being treated with corticosteroids, or had disease that had spread to their brain. Life expectancy in this study for patients typical of everyday clinical practice was similar to that seen in trials that enrolled only selected fitter patients.
Publisher: BMJ
Date: 14-01-1995
Publisher: Elsevier BV
Date: 09-2020
Publisher: EMBO
Date: 07-2010
Publisher: American Association for Cancer Research (AACR)
Date: 04-2012
DOI: 10.1158/1538-7445.AM2012-SY35-02
Abstract: Serous ovarian cancer (SOC) is the leading cause of morbidity/mortality from gynecologic malignancy. Current therapies increase survival significantly, yet the vast majority of SOC patients (70-90%) die of their disease. Patients almost always respond to initial courses of standard-of-care (platinum- and taxane-based) chemotherapy. Unfortunately, however, drug resistance almost always develops, resulting in the death of the patient. Two competing theories have been proposed to account for tumor initiation in SOC (and other malignancies) these theories also have important implications for therapy resistance. In the stochastic model, most, if not all, tumor cells can self-renew indefinitely consequently, nearly all tumor cells provide a target population for the acquisition of drug resistance mutations. By contrast, the cancer stem cell (CSC) hypothesis holds that only a subset of tumor cells can initiate and maintain the tumor. Moreover, CSC might be intrinsically more resistant to some/many drugs that are effective against other (“bulk”) tumor cells. These two models differ fundamentally in their view of tumor-initiating cells (TIC). The essential feature of the CSC model is that tumors are organized hierarchically, such that TIC can be prospectively distinguished from non-TIC by phenotype. If the CSC model holds, it should be possible to identify and purify a stable cell population with the unique ability to generate serially transplantable tumors that recreate the heterogeneity of the initial malignancy. By contrast, the stochastic model predicts that TIC distribute into all cell fractions. Many studies of ovarian carcinogenesis and drug response have used immortalized cell lines grown for long periods of time in serum-containing culture. However, the extent to which these cells represent the biology of SOC is unclear. Many SOC lines do not reproduce serous histology when propagated as xenografts in immune-compromised mice others cannot even give rise to xenografts. Even in culture, few of these lines show evidence of the cytologic and immunologic heterogeneity typically seen in primary tumors. Consequently, these lines might not be adequate for testing new therapies for SOC. Moreover, it is not clear that immortalized cell lines represent valid models for evaluating the CSC model or for studying TIC in SOC. Notably, studies of several other malignancies have shown that TIC as defined using immortalized cell lines do not have the same phenotype as those defined in xenografts using primary patient s les. Improving outcome for SOC patients will require better understanding of SOC pathogenesis and drug resistance, using assay systems that reflect the genetic and cellular ersity of human SOC more faithfully than conventional ovarian cancer cell lines. To this end, we have established a large collection of primary human SOC s les and developed a robust, quantitative assay for SOC tumor-initiating cells (TIC). Using this assay, we find that TICs are rare when assayed in either NOD/SCID or NOD/SCID/IL2Rγ−/− (NSG) mice. TIC frequency varies substantially between patients, although it is similar in primary ovarian masses and omental metastases, suggesting that TIC frequency is an intrinsic property of given ovarian tumor classes. For instance, CD133 marks all TICs from several primary SOC cases. However, in other cases, substantial TIC activity is found in both the CD133+ and CD133− fractions, whereas still other cases have exclusively CD133− TICs. Furthermore, the TIC phenotype can change in xenografts: primary tumors in which all TICs are CD133+ can give rise to xenografts that contain substantial numbers of CD133− TICs. Our results highlight the need for quantitative rigor in the evaluation of TICs and for caution when using passaged xenografts for such studies. Furthermore, although our data suggest that SOC conforms to the CSC hypothesis, the heterogeneity of the TIC phenotype may complicate its clinical application. To address whether instability in the TIC phenotype may be due to the acquisition of genetic alterations in the CD133- compared to the CD133+ fraction, we analyzed copy number alterations in CD133 positive and negative-derived xenografts. Preliminary analysis suggests that most genetic alterations are common in both fractions however, in 3/6 cases, additional genetic alterations were observed in the CD133- fraction, suggesting the emergence of CD133- TIC might be, at least in part, genetically driven. The applicability of this observation to additional cases and primary sorted cells (i.e. those that were used to establish the xenografts), as well as the mechanism of genetic instability is currently under investigation. We used expression microarrays to examine differences between CD133+ and CD133- populations. We find that & probes are differentially expressed in these two cell subsets, confirming that they are distinct cell populations. We have identified several putatively targetable pathways and transcription factor networks with altered expression in TIC-enriched fractions. The biological roles of these pathways in HG-SOC, specifically in the TIC compartment, are under investigation. Finally, we performed high-throughput flow cytometry: involving independent analysis of 365 cell surface markers to identify proteins expressed on all or subsets of HG-SOC cells. We have combined these analyses with mass cytometry (collaboration with Nolan's lab, Stanford University). Mass cytometry allows deep profiling of cell attributes and function using a novel multi-parametric approach combining flow cytometry with mass spectrometry that allows examination of up to 35 cell surface and/or intracellular markers on a single cell. Examination of 40 primary ovarian cancer s les has provided further supportive evidence for inter- and intra-patient heterogeneity in HG-SOC. Current analyses focus on biological validation of identified subpopulations marked by a series of cell surface and putative “stem cell” gene sets. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research 2012 Mar 31-Apr 4 Chicago, IL. Philadelphia (PA): AACR Cancer Res 2012 (8 Suppl):Abstract nr SY35-02. doi:1538-7445.AM2012-SY35-02
Publisher: American Society of Clinical Oncology (ASCO)
Date: 20-02-2022
DOI: 10.1200/JCO.2021.39.6_SUPPL.TPS177
Abstract: TPS177 Background: 177 Lu‐PSMA‐617 (LuPSMA) is a novel radionuclide with promising activity and tolerability in metastatic, castration-resistant prostate cancer (mCRPC). Pre-clinical studies have shown that androgen receptor blockade with enzalutamide upregulates PSMA-receptor expression, and that PSMA-receptor blockade increases treatment response to enzalutamide. We hypothesise that concurrent administration of LuPSMA and enzalutamide will be synergistic in mCRPC. The aims of ENZA-p are to determine the activity and safety of LuPSMA and enzalutamide in men with mCRPC at high-risk of early progression on enzalutamide alone and to identify potential prognostic and predictive biomarkers from imaging, blood, and tissue. Methods: This open-label, randomised, multicentre, phase 2 trial will recruit 160 men with mCRPC. Key eligibility criteria include progression on androgen deprivation therapy, 2 or more high-risk features for early (LDH ≥ULN ALP ≥ULN albumin g/L M1 disease at diagnosis years from initial diagnosis to randomisation bone metastases visceral metastases PSA doubling time days pain requiring opiates days prior abiraterone), no prior treatment with a novel androgen signalling inhibitor (except abiraterone), no prior chemotherapy for mCRPC, and PSMA-avid disease on positron emission tomography (PET) with 68 Ga-PSMA. Participants are randomly assigned (1:1) enzalutamide 160 mg daily or enzalutamide 160 mg daily plus LuPSMA 7.5 GBq on days 15 and 57. Two subsequent doses of Lu-PSMA will be administered if the 68 Ga-PSMA PET on day 92 shows persistent PSMA expression in the tumour. Imaging assessments include CT and technetium bone scan at baseline, day 99, then every 12 weeks 68 Ga-PSMA-11 PET at baseline, days 15, 92, and first progression and 18 F FDG PET at baseline and first progression. Translational s les including circulating tumour cells (CTCs), circulating tumour DNA (ctDNA) and biopsies (optional) will be collected at baseline, day 92, and first progression. The primary endpoint is PSA progression-free survival (PSA-PFS). Secondary endpoints include radiological-PFS, PSA-response rate, pain response and PFS, clinical-PFS, overall survival, health related quality of life, adverse events, and cost-effectiveness. Correlative studies include identification of prognostic and predictive biomarkers from 68 Ga-PSMA, 18 F FDG PET/CT, CTCs, and ctDNA. A s le size of 160 provides 80% power with a 2-sided type 1-error rate of 5% to detect a HR of 0.625 assuming a median PSA-PFS of 5 months with enzalutamide alone. Accrual was 5 on 13 October 2020. ENZA-p is an investigator-initiated, academic trial led by ANZUP in collaboration with the NHMRC Clinical Trials Centre, University of Sydney. Clinical trial information: NCT04419402.
Publisher: American Association for Cancer Research (AACR)
Date: 06-2008
DOI: 10.1158/1078-0432.CCR-07-1322
Abstract: Purpose: Cancer cells recapitulate many behaviors of pluripotent embryonic cells such as unlimited proliferation, and the capacity to self-renew and to migrate. Embryo-cancer sequence A (ECSA), later named developmental pluripotency associated-2 (DPPA2), is an embryonic gene initially isolated from pluripotent human preimplantation embryos. We hypothesized that ECSA/DPPA2 would be quiescent in most normal tissues but expressed in cancers and may therefore be a useful target for immunotherapy. Experimental Design: ECSA/DPPA2 expression was examined in a panel of normal and tumor tissue by reverse transcription PCR, quantitative real-time PCR, and immunohistochemistry. A panel of 110 non–small cell lung cancers (NSCLC) were further investigated for the presence of ECSA/DPPA2 transcripts and several cancer testis antigens (CTA). Sera from 104 patients were analyzed for spontaneous ECSA/DPPA2 antibody production by ELISA and Western blot. Results: ECSA/DPPA2 transcripts were limited to normal testis, placenta, bone marrow, thymus, and kidney but expressed in a variety of tumors most notably in 30% of NSCLC. Enrichment for CTAs in ECSA/DPPA2-positive NSCLC was observed. Immunohistochemistry confirmed nuclear and cytoplasmic localization in subpopulations of cells with coexpression of the CTA MAGE-A3. Antibodies to recombinant ECSA/DPPA2 protein were detected in the sera of 4 of 104 patients with NSCLC but not in healthy controls. Conclusions: The restricted expression in normal tissues, expression in tumors with coexpression of CTAs, and spontaneous immunogenicity indicate that ECSA/DPPA2 is a promising target for antigen-specific immunotherapy in NSCLC.
Publisher: Elsevier BV
Date: 04-1993
DOI: 10.1016/0006-2952(93)90010-T
Abstract: Myeloperoxidase, the most abundant enzyme in neutrophils, catalyses the conversion of hydrogen peroxide and chloride to hypochlorous acid. This potent oxidant has the potential to cause considerable tissue damage in many inflammatory diseases. We have investigated the ability of dapsone, diclofenac, primaquine, sulfapyridine and benzocaine to inhibit hypochlorous acid production by stimulated human neutrophils. The drugs were also tested against purified myeloperoxidase using xanthine oxidase to generate hydrogen peroxide and superoxide. The inhibitory effects of the drugs on hypochlorous acid production, either by cells stimulated with phorbol myristate acetate or by myeloperoxidase and xanthine oxidase, were significantly less than those determined with myeloperoxidase and reagent hydrogen peroxide. Comparable potency was observed only when superoxide dismutase was present to remove superoxide. We also observed that with the xanthine oxidase system, inhibition of hypochlorous acid production by dapsone decreased markedly as the concentration of myeloperoxidase increased. Dapsone was a poor inhibitor of hypochlorous acid production by neutrophils stimulated with opsonized zymosan, regardless of the presence of superoxide dismutase. With this phagocytic stimulus, catalase inhibited hypochlorous acid formation by only 60%, which indicates that a substantial amount of the hypochlorous acid detected originated from within phagosomes. Thus, it is apparent that dapsone is unable to affect intraphagosomal conversion of hydrogen peroxide to hypochlorous acid. All the drugs inhibit myeloperoxidase reversibly by trapping it as its inactive redox intermediate, compound II. We propose that superoxide limits the potency of the drugs by reducing compound II back to the active enzyme. Furthermore, under conditions where the activity of myeloperoxidase exceeds that of the hydrogen peroxide-generating system, which is most likely to occur in phagosomes, partial inhibition of myeloperoxidase need not affect hypochlorous acid production. We conclude that drugs that inhibit myeloperoxidase by converting it to compound II are unlikely to be effective against hypochlorous acid-mediating tissue damage.
Publisher: Wiley
Date: 02-2015
DOI: 10.5694/MJA14.01202
Publisher: Springer Science and Business Media LLC
Date: 10-2022
DOI: 10.1007/S11764-021-01113-8
Abstract: To synthesize existing evidence on the unmet supportive care needs of people affected by kidney cancer, across the cancer care continuum. A systematic review was conducted according to the PRISMA Statement Guidelines. Electronic databases (CINAHL, MEDLINE, and PsychINFO) were searched using key search terms. Articles were assessed according to pre-specified eligibility criteria. Data extraction and quality appraisal were conducted. The findings were integrated in a narrative synthesis. One thousand sixty-three publications were screened, and 18 publications met the inclusion criteria. The following domains of unmet needs in order of frequency included psychological/emotional needs (17/18: 94%), physical needs (10/18: 56%), social needs (4/18: 22%), interpersonal/intimacy needs (4/18: 22%), patient-clinician communication needs (3/18: 17%), family-related needs (3/18: 17%), health system/information needs (3/18: 17%), spiritual needs (3/18: 17%), daily living needs (2/18: 11%), practical needs (1/18: 6%), and cognitive needs (1/18: 6%). There was a wide range of unmet supportive care needs experienced by people diagnosed with kidney cancer. A prominent focus was on psychological and physical needs. Further research is needed to understand how clinical (stage/treatment) and demographic (age/socio-economic/ethnicity) variables may moderate or mediate the relationship with unmet needs over time. With many unmet needs identified, this review provides a starting place to inform future work to address the complex unmet supportive care needs of people affected by kidney cancer. In iduals living with kidney cancer have many unmet supportive care needs, and future research is needed to learn about what are the most pressing needs and how to best address these concerns to ensure holistic person-centered care is delivered.
Publisher: American Society of Clinical Oncology (ASCO)
Date: 20-05-2021
DOI: 10.1200/JCO.2021.39.15_SUPPL.4565
Abstract: 4565 Background: Immunotherapy targeting PD1 is active across many cancers, but many people are failed by PD1 inhibition alone. UNISON (ANZUP 1602/NCT03177239) has previously reported the activity and outcomes of nivolumab monotherapy in people with nccRCC (OTRR 17%, PFS6 45% part 1), and here we report the outcomes of combining ipilimumab (I) and nivolumab (N), in people whose cancers are refractory to N alone (part 2). Methods: Participants (pts) with advanced nccRCC with good performance status (ECOG 0/1), were initially enrolled and took N alone. 41 pts refractory to N were offered the combination I (1mg/kg) + N (3mg/kg) every 3 weeks for up to 4 doses. Pts with disease control after N, or N + I could continue N for up to 1 year. UNISON was powered to distinguish a clinically relevant improvement in objective tumour response rate (OTRR) from 15% to 30% in people taking I+N in part 2. Results: 85 pts were enrolled and received N. 41 pts were refractory to N, were well enough to take I+N, and had a representative spectrum of nccRCC histologies (n=41 papillary 44%, chromophobe 20%, Xp11 translocation 12%, RCC unclassified 7%, other 17%). The median time on treatment was 2.1 months, the median number of doses was 3 median follow up at the time of reporting was 20.3 months. The OTRR of I+N in pts refractory to N was 10% with 1 complete and 3 partial responses. Stable disease was experienced by 36% of pts and disease progression by 52%. The disease control rate at 6 months was 45% (95% CI: 34%, 56%). The median PFS was 2.6 months (95% CI: 2.2, 3.8). The 6 month progression-free survival (PFS) was 25% (95% CI: 13-39). Only 14% of patients were free of progression at 12 months. The safety of I+N appeared similar to previous reports. 68% of pts experienced serious adverse events, 34% treatment related SAE. One pt died from refractory pneumonitis. 11 pts (27%) experienced treatment delays or permanent treatment discontinuation. Conclusions: The primary endpoint of the study was not met. A minority of pts with nccRCC refractory to nivolumab derive benefit from combination I+N but many pts remain refractory to immunotherapy. No new safety issues were identified. More effective therapeutic options are needed for people with rare variant renal cell carcinoma. Clinical trial information: NCT03177239.
Publisher: MDPI AG
Date: 27-04-2023
Abstract: Glioblastoma (GBM) is a devastating brain cancer with no effective treatment, and there is an urgent need for developing innovative biomarkers as well as therapeutic targets for better management of the disease. The membrane protein sortilin has recently been shown to participate in tumor cell invasiveness in several cancers, but its involvement and clinical relevance in GBM is unclear. In the present study, we explored the expression of sortilin and its potential as a clinical biomarker and therapeutic target for GBM. Sortilin expression was investigated by immunohistochemistry and digital quantification in a series of 71 clinical cases of invasive GBM vs. 20 non-invasive gliomas. Sortilin was overexpressed in GBM and, importantly, higher expression levels were associated with worse patient survival, pointing to sortilin tissue expression as a potential prognostic biomarker for GBM. Sortilin was also detectable in the plasma of GBM patients by enzyme-linked immunosorbent assay (ELISA), but no differences were observed between sortilin levels in the blood of GBM vs. glioma patients. In vitro, sortilin was detected in 11 brain-cancer-patient-derived cell lines at the anticipated molecular weight of 100 kDa. Interestingly, targeting sortilin with the orally bioavailable small molecule inhibitor AF38469 resulted in decreased GBM invasiveness, but cancer cell proliferation was not affected, showing that sortilin is targetable in GBM. Together, these data suggest the clinical relevance for sortilin in GBM and support further investigation of GBM as a clinical biomarker and therapeutic target.
Publisher: Springer Science and Business Media LLC
Date: 14-07-2020
DOI: 10.1186/S13063-020-04576-9
Abstract: To determine if lopinavir/ritonavir +/- hydroxychloroquine will reduce the proportion of participants who survive without requiring ventilatory support, 15 days after enrolment, in adult participants with non-critically ill SARS-CoV-2 infection. ASCOT is an investigator-initiated, multi-centre, open-label, randomised controlled trial. Participants will have been hospitalised with confirmed COVID-19, and will be randomised 1:1:1:1 to receive lopinavir /ritonavir, hydroxychloroquine, both or neither drug in addition to standard of care management. Participants will be recruited from hospitals across Australia and New Zealand, representing metropolitan and regional centres in both public and private sectors. Admitted patients will be eligible if aged ≥ 18 years, have confirmed SARS-CoV-2 by nucleic acid testing in the past 12 days and are expected to remain an inpatient for at least 48 hours from the time of randomisation. Potentially eligible participants will be excluded if admitted to intensive care or requiring high level respiratory support, are currently receiving study drugs or their use is contraindicated due to allergy, drug interaction or comorbidities (including baseline QTc prolongation of 470ms for women or 480ms for men), or death is anticipated imminently. Participants will be randomised 1:1:1:1 to: Group 1 : standard of care Group 2 : lopinavir (400mg) / ritonavir (100mg) twice daily for 10 days in tablet form Group 3 : hydroxychloroquine (800mg) 4x200mg administered 12 hours apart on Day 1, followed by 400mg twice a day for 6 days Group 4 : lopinavir /ritonavir plus hydroxychloroquine. Proportion of participants alive and not having required intensive respiratory support (invasive or non-invasive ventilation) at 15 days after enrolment. A range of clinical and virological secondary outcomes will also be evaluated. The randomisation schedule will be generated by an independent statistician. Randomisation will be stratified by site and will be in permuted blocks of variable block size. The randomised sequence allocation will only be accessible to the data management group, and site investigators will have in idual participant allocation provided through a web-based trial enrolment platform. This is an open-label study, with researchers assessing the laboratory outcomes blinded to treatment allocation. No unblinding procedures relating to potential adverse effects are therefore required. We assumed that 5% of participants receiving standard of care would meet the primary outcome, aimed to evaluate whether interventions could lead to a relative risk of 0.5, assuming no interaction between intervention arms. This corresponds to a required s le size of 610 per arm, with a 5% two-sided significance level (alpha) and 80% power. The total s le size therefore is planned to be 2440. ASCOT protocol version 3, May 5, 2020. Recruitment opened April 4, 2020 and is ongoing, with planned completion of enrolment July 31, 2021. Australian New Zealand Clinical Trials Registry ( ACTRN12620000445976 ). Prospectively registered April 6, 2020. The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated this Letter serves as a summary of the key elements of the full protocol.
Publisher: Elsevier BV
Date: 02-2021
Publisher: CMA Joule Inc.
Date: 18-02-2014
DOI: 10.1503/CMAJ.130989
Publisher: Wiley
Date: 07-2015
DOI: 10.1111/IMJ.12653
Abstract: Novel cancer immunotherapy antibodies are moving from clinical trials into routine practice, delivering sustained benefits and prolonged survival to patients with melanoma, lung, kidney and other cancers. These immunostimulatory antibodies non-specifically activate the patient's own immune system by inhibiting immune system checkpoint proteins. This mechanism of action is entirely different to traditional cancer treatments, such as chemotherapy. While there are virtually no immediate toxicities, serious life-threatening autoimmune side-effects such as colitis, dermatitis, hypophysitis, pneumonitis and hepatitis can occur, sometimes starting long after the treatment has been given. Recognition, referral and prompt treatment with immunosuppressive drugs like corticosteroids can control these immune-related side-effects without compromising efficacy. This exciting new class of drugs is defining a new paradigm in cancer therapy.
Publisher: Wiley
Date: 30-10-2006
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: Elsevier BV
Date: 11-2022
Publisher: Wiley
Date: 11-04-2013
DOI: 10.1111/PCMR.12097
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: American Society of Clinical Oncology (ASCO)
Date: 20-02-2021
DOI: 10.1200/JCO.2021.39.6_SUPPL.325
Abstract: 325 Background: Immune checkpoint inhibitors (ICI) are active in many cancers, but people with rare variant, non clear-cell renal cell carcinoma (nccRCC) have been excluded from most clinical trials in RCC. UNISON (NCT03177239) aimed to test 2 hypotheses the activity of nivolumab in nccRCC (Part 1), and the benefit of adding ipilimumab to nivolumab, in people whose cancers progress on nivolumab (Part 2). Methods: 83 participants (pts) with advanced nccRCC with good (ECOG0/1) performance status, were enrolled including papillary type 1 (17%), papillary type 2 (28%), chromophobe (18%), Xp11 translocation (6%), hereditary leiomyomatosis renal cell carcinoma syndrome-associated renal cell carcinoma (6%), RCC unclassified (10%) and other (15%) histological subtypes. Participants took nivolumab (N) 240mg every two weeks in Part 1 in total. If they experienced progression and remained eligible they could take N (3mg/kg) plus ipilimumab (I 1mg/kg) every 3 weeks for up to 4 doses (Part 2). Pts with disease control after N or N + I could continue N for up to 1 year. UNISON was powered to distinguish a clinically-relevant improvement in objective tumor response rate (OTRR) from 15% to 30% in people taking N+I in Part 2 in pts whose cancers were refractory to single-agent first-line N. Here we report results of Part 1. Results: Pts experience of N appeared similar to previous reports, with most experiencing mild adverse events. 12 treatment related SAE occurred in 11 patients (13%). 14 pts (17%) experienced treatment delays, or permanent treatment discontinuation (10%). The median time on treatment was 5.1 months. The OTRR was 17% with 3 complete responses and 11 partial responses. The median duration of response was 21 months. Stable disease occurred in 49% of pts and disease progression in 34%. The disease control rate at 6 months was 45% (95% CI: 34%, 56%). The median PFS was 4.0 months (95% CI: 3.6, 7.4). The 6 month progression-free survival (PFS) was 45% (95% CI: 34-55) and the 12 months PFS was 30% (95% CI: 21%, 40%). Conclusions: Pts with nccRCC treated with N experience similar adverse events compared to pts with other cancers. A substantial minority of people with nccRCC derive benefit, but many pts have cancers refractory to anti-PD1, similar to other reports. The activity of I and N in this PD1-refractory population is of considerable interest and will be reported at a later date. Clinical trial information: NCT03177239 .
Publisher: American Society of Clinical Oncology (ASCO)
Date: 20-02-2021
DOI: 10.1200/JCO.2021.39.6_SUPPL.126
Abstract: 126 Background: The Phase 3 PROfound trial (NCT02987543) met its primary endpoint and key secondary endpoints, including improved overall survival (OS) for olaparib in men with mCRPC with alterations in BRCA1, BRCA2, or ATM (Cohort A). We report gene-by-gene analysis of olaparib antitumor activity among the 15 prespecified homologous recombination repair (HRR) genes. Methods: Pts were randomized to olaparib (300 mg bid n=256) or physician’s choice of enzalutamide or abiraterone (control n=131). Exploratory analyses in pts with alterations in BRCA1 and/or BRCA2 (BRCA, regardless of co-occurring alterations with other HRR genes) or in single genes were conducted. Results: Evidence of olaparib antitumor activity was observed in subgroups with pts (table). Data for pts with alterations in only BRCA1, BRCA2, PPP2R2A, RAD51B, RAD54L, PALB2, BRIP1, CHEK1, BARD1, and RAD51D will be reported (no FANCL or RAD51C enrolled). Conclusions: Small subgroups limit interpretation for some genes. Olaparib antitumor activity is greatest in pts with BRCA alterations, with a spectrum of clinical sensitivity to olaparib as defined by rPFS and OS across the broader population with alterations in other HRR genes. Clinical trial information: NCT02987543. [Table: see text]
Publisher: Mary Ann Liebert Inc
Date: 06-2019
Abstract: Tumor biobanks have become critical components of the cancer research infrastructure. Consideration of how to place appropriate values on tumor biobanks is important for all stakeholders. At the level of in idual biobanks, value is important in determining how to contribute to, utilize, and fund biobanks. At the level of the research system, value is important in determining how to evaluate, rationalize, and sustain or modify the investments in this infrastructure. This review considers approaches and indicators for evaluation of a biobank with a particular focus on utilization, as one important indicator of value, from the perspective of the researcher and funder. The patterns of utilization and the influence of different phases and approaches of research, and types of biobank are described, as well as strategies for biobanks to increase utilization and therefore their value to research.
Publisher: MDPI AG
Date: 13-01-2023
DOI: 10.3390/IJMS24021616
Abstract: Glioblastoma multiforme (GBM) is the most lethal adult brain cancer. Temozolomide (TMZ), the standard chemotherapeutic drug used in GBM, has limited benefit and alternate therapies are needed to improve GBM treatment. Nerve growth factor (NGF) and its precursor proNGF are increasingly recognized as stimulators of human tumor progression. The expression and stimulatory effect of NGF on GBM cell growth has previously been reported, but the status of proNGF in GBM is unreported. In this study, we have investigated proNGF expression and biological activity in GBM. A clinical cohort of GBM (n = 72) and low-grade glioma (n = 20) was analyzed by immunohistochemistry for proNGF and digital quantification. ProNGF expression was significantly increased in GBM compared to low grade gliomas and proNGF was also detected in patient plasma s les. ProNGF was also detected in most GBM cell lines by Western blotting. Although anti-proNGF blocking antibodies inhibited cell growth in GBM cells with methylated MGMT gene promoter, targeting proNGF could not potentiate the efficacy of TMZ. In subcutaneous xenograft of human GBM cells, anti-proNGF antibodies slightly reduced tumor volume but had no impact on TMZ efficacy. In conclusion, this data reveals that proNGF is overexpressed in GBM and can stimulate cancer cell growth. The potential of proNGF as a clinical biomarker and therapeutic target warrants further investigations.
Publisher: American Society of Clinical Oncology (ASCO)
Date: 20-02-2021
DOI: 10.1200/JCO.2021.39.6_SUPPL.6
Abstract: 6 Background: TheraP is a randomized phase 2 trial that showed LuPSMA significantly improved the primary endpoint of PSA≥50% reduction (66% vs. 37%) compared to cabazitaxel in men with docetaxel-treated mCRPC. We now report results on other clinical endpoints and PROs reached the pre-specified target of 170 PFS events. Methods: 200 men with mCRPC (median age 72 y, prior enza/abi 91%) and high PSMA-expression by 68Ga-PSMA-11 and no sites of FDG-positive/PSMA-negative disease, were randomly assigned (1:1) to LuPSMA (6-8.5GBq q6wk up to 6 cycles N = 99) or cabazitaxel (20mg/m2 q3wk up to 10 cycles N = 101). Secondary endpoints include PSA/radiologic PFS (PCWG3), pain response (≥2 point reduction on McGill-Melzack Present Pain Intensity scale, objective response rate (ORR) (RECIST 1.1), adverse events (CTCAE), PROs (EORTC QLQ-C30) and overall survival (OS). Cut-off date for analysis of 20JUL20. Results: At a median follow-up of 18.4 months, PFS was significantly longer in those assigned Lu-PSMA rather than cabazitaxel (rates at 1y 19% [95%CI 12-27%] vs 3% [1-9%], hazard ratio (HR) 0.63, 95%CI 0.46-0.86 p = 0.003 173 events). Similar benefit was seen for rPFS (HR 0.64, 95%CI 0.46-0.88 p = 0.007 160 events) and PSA-PFS (HR 0.60 95%CI 0.44-0.83 p = 0.002 172 events). ORR in 78 men with measurable disease was significantly greater in the LuPSMA arm (49% vs 24%, RR 2.1, 95%CI 1.1-4.1 p = 0.019). In 90 men with pain at baseline, pain responses occurred in 60% in the Lu-PSMA arm vs 43% for cabazitaxel (RR 1.42, 95%CI 0.84-4.48 p = 0.10). Patient-reported global health status was similar (LuPSMA 64 [95%CI 61-67] vs cabazitaxel 60 [57-64]) with significantly better outcomes reported for fatigue (34 [95%CI 31-37] vs 40 [36-43]), social functioning (79 [76-82] vs 73 [69-77]), insomnia (24 [20-27] vs 29 [25-33]) and diarrhoea (8.3 [5.6-11.0] vs 15.6 [12.6-18.6]) domains. No PRO domains were superior for cabazitaxel. G3-4 AEs were similar to previously reported (33% vs 53%). OS data remains immature (90 deaths). Conclusions: In men with docetaxel-treated mCRPC, LuPSMA is a promising alternative to cabazitaxel with significantly higher activity (PSA≥50%, PFS, ORR), fewer G3-4 AEs, similar effects on global health status, and improvements in some PRO domains. Clinical trial information: NCT03392428.
Publisher: Elsevier BV
Date: 10-2017
Publisher: Elsevier BV
Date: 11-2020
Publisher: Elsevier BV
Date: 03-2022
DOI: 10.1016/J.BBCAN.2022.188681
Abstract: Cytotoxic chemotherapy and targeted therapies help people with advanced cancers, but for most, treatment fails. Cancer heterogeneity is one cause of treatment failure, but also suggests an opportunity to improve outcomes reconceptualising cancer therapy as an ecological problem offers the strategy of adaptive therapy. If an agent is active against a patient's cancer, instead of traditional continuous dosing at the maximum tolerated dose until treatment failure, the patient and their oncologist may instead choose to pause treatment as soon as the cancer responds. When tumour burden increases, the cancer is rechallenged with the same agent in hope of delivering another response, ideally before symptoms occur or quality-of-life is impacted. These 'loops' of 'pause/restart' allows an active treatment to be used strategically, to delay the development of evolutionary selection within the cancer, delaying the onset of treatment resistance, controlling the cancer for longer. Modelling predicts patients can navigate several 'loops', potentially increasing the utility of an active treatment by multiples, and early trials suggest at least doubling of progression-free survival. In this narrative review we confront how cancer heterogeneity limits treatment effectiveness, re-examine cancer as an ecological problem, review the data supporting adaptive therapy and outline the challenges and opportunities faced in clinical practice to implement this evolutionary concept. In an era where multiple novel active anti-neoplastic agents are being used with ancient inflexibile maximum tolerated dose for maximum duration approaches, adaptive dosing offers a personalised, n = 1 approach to cancer therapy selection.
Publisher: Elsevier BV
Date: 02-2018
DOI: 10.1016/J.CLGC.2018.09.014
Abstract: Men with progressive, symptomatic metastatic castration-resistant prostate cancer previously treated with antiandrogens (abiraterone and/or enzalutamide) and taxane-based chemotherapy were prospectively enrolled. Eligibility criteria included uptake on PSMA PET above or equal to liver activity, with no Fourteen of 18 men screened underwent Lu-PSMA therapy. Ten (71%) of 14 had a PSA response (mean reduction, 59%). A ≥ 50% reduction in PSA occurred in 5 (36%), and ≥ 30% in 9 (64%). PSMA PET standardized uptake value (SUV) at screening was predictive of ≥ 30% PSA reduction: SUV max value 17 ± 9 versus 44 ± 15 (P < .007), and PSMA SUV mean 6 ± 4 versus 10 ± 4 (P < .04). FDG parameters alone, and volume or site of disease did not predict PSA response. No imaging parameters predicted ≥ 50% PSA reduction. Nine of 14 men were reimaged after treatment, revealing 3 distinct patterns of progression. PSMA PET plays an important role in predicting treatment response to Lu-PSMA and in identifying subsequent patterns of failure, which may aid in determining the next best treatment options.
Publisher: Springer Science and Business Media LLC
Date: 04-10-2016
DOI: 10.1038/BJC.2016.308
Publisher: Springer Science and Business Media LLC
Date: 27-11-2019
DOI: 10.1186/S12902-019-0457-1
Abstract: Nerves and neurotrophic growth factors are emerging promoters of cancer growth. The precursor for Nerve Growth Factor (proNGF) is overexpressed in thyroid cancer, but its potential role as a clinical biomarker has not been reported. Here we have examined the value of proNGF as a serum and biopsy-rinse biomarker for thyroid cancer diagnosis. Patients presenting for thyroid surgery or biopsy were enrolled in separate cohorts examining serum ( n = 204, including 46 cases of thyroid cancer) and biopsy-rinse specimens ( n = 188, including 26 cases of thyroid cancer). ProNGF levels in clinical s les were analysed by ELISA. Univariate and multivariate statistical analyses were used to compare proNGF levels with malignancy status and clinicopathological parameters. ProNGF was not detected in the majority of serum s les (176/204, 86%) and the detection of proNGF was not associated with thyroid cancer diagnosis. In the few cases where proNGF was detected in the serum, thyroidectomy did not affect proNGF concentration, demonstrating that the thyroid was not the source of serum proNGF. Intriguingly, an association between hyperthyroidism and serum proNGF was observed (OR 3.3, 95% CI 1.6–8.7 p = 0.02). In biopsy-rinse, proNGF was detected in 73/188 (39%) cases, with no association between proNGF and thyroid cancer. However, a significant positive association between follicular lesions and biopsy-rinse proNGF was found (OR 3.3, 95% CI 1.2–8.7, p = 0.02). ProNGF levels in serum and biopsy-rinse are not increased in thyroid cancer and therefore proNGF is not a clinical biomarker for this condition.
Publisher: American Association for Cancer Research (AACR)
Date: 12-08-2008
DOI: 10.1158/1078-0432.CCR-07-4170
Abstract: Purpose: Patients with macroscopic stage III melanoma represent a heterogeneous cohort with average 5-year overall survival rates of & %. With current algorithms, it is not possible to predict which patients will achieve longer-term survival. We hypothesized that molecular profiling could be used to identify prognostic groups within patients with stage III melanoma while also providing a greater understanding of the biological programs underpinning these differences. Experimental Design: Lymph node sections from 29 patients with stage IIIB and IIIC melanoma, with ergent clinical outcome including 16 “poor-prognosis” and 13 “good-prognosis” patients as defined by time to tumor progression, were subjected to molecular profiling using oligonucleotide arrays as an initial training set. Twenty-one differentially expressed genes were validated using quantitative PCR and the 15 genes with strongest cross-platform correlation were used to develop two predictive scores, which were applied to two independent validation sets of 10 and 14 stage III tumor s les. Results: Supervised analysis using differentially expressed genes was able to differentiate the prognostic groups in the training set. The developed predictive scores correlated directly with clinical outcome. When the predictive scores were applied to the two independent validation sets, clinical outcome was accurately predicted in 90% and 85% of patients, respectively. Conclusion: We describe a gene expression profile that is capable of distinguishing clinical outcomes in a previously homogeneous group of stage III melanoma patients.
Publisher: American Society of Clinical Oncology (ASCO)
Date: 10-10-2021
DOI: 10.1200/JCO.21.01444
Publisher: Bioscientifica
Date: 06-2017
DOI: 10.1530/ERC-17-0010
Abstract: Recent advances in the arena of theranostics have necessitated a re-examining of previously established fields. The existing paradigm of therapeutic thyroid-stimulating hormone receptor (TSHR) targeting in the post-surgical management of differentiated thyroid cancer using levothyroxine and recombinant human thyroid-stimulating hormone (TSH) is well understood. However, in an era of personalized medicine, and with an increasing awareness of the risk profile of longstanding pharmacological hyperthyroidism, it is imperative clinicians understand the molecular basis and magnitude of benefit for in idual patients. Furthermore, TSHR has been recently re-conceived as a selective target for residual metastatic thyroid cancer, with pilot data demonstrating effective targeting of nanoparticles to thyroid cancers using this receptor as a target. This review examines the evidence for TSHR signaling as an oncogenic pathway and assesses the evidence for ongoing TSHR expression in thyroid cancer metastases. Priorities for further research are highlighted.
Publisher: Elsevier BV
Date: 05-2017
Publisher: American Society of Clinical Oncology (ASCO)
Date: 20-05-2014
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 2017
DOI: 10.1097/CJI.0000000000000146
Abstract: A 72-year-old male patient was receiving second-line chemotherapy for metastatic squamous cell carcinoma of the skin (SCCS) when he was diagnosed with concurrent metastatic melanoma ( BRAF G469E mutant). Chemotherapy was ceased and he was treated with 4 cycles of ipilimumab immunotherapy. The patient experienced clinical benefit and durable remission in both malignancies and remains free of cancer progression 8 months after the last cycle of ipilimumab. Response of SCCS to ipilimumab has not been previously described, however this case and recent reports of pembrolizumab efficacy confirm the critical role of the immune system in SCCS pathogenesis and suggest further exploration of checkpoint immunotherapy for the treatment of this disease.
Publisher: Wiley
Date: 30-03-2018
Publisher: American Association for Cancer Research (AACR)
Date: 28-01-2022
DOI: 10.1158/1078-0432.CCR-21-3940
Abstract: Successful implementation of genomic testing in clinical practice is critical for identification of men with metastatic castration-resistant prostate cancer (mCRPC) eligible for olaparib and future molecularly targeted therapies. An investigational clinical trial assay, based on the FoundationOneCDx tissue test, was used to prospectively identify patients with qualifying homologous recombination repair gene alterations in the phase III PROfound study. Evaluation of next-generation sequencing (NGS) tissue test outcome against preanalytic parameters was performed to identify key factors influencing NGS result generation. A total of 4,858 tissue s les from 4,047 patients were tested and reported centrally. NGS results were obtained in 58% (2,792/4,858) of s les (69% of patients). Of s les submitted, 83% were primary tumor s les (96% were archival and 4% newly obtained). Almost 17% were metastatic tumor s les (60% were archival and 33% newly obtained). NGS results were generated more frequently from newly obtained compared with archival s les (63.9% vs. 56.9%) and metastatic compared with primary s les (63.9% vs. 56.2%). Although generation of an NGS result declined with increasing s le age, approximately 50% of s les ages & years generated results. While higher tumor content and DNA yield resulted in greater success in obtaining NGS results, other factors, including selection and preservation of s les, may also have had an impact. The PROfound study shows that tissue testing to identify homologous recombination repair alterations is feasible and that high-quality tumor tissue s les are key to obtaining NGS results and identifying patients with mCRPC who may benefit from olaparib treatment.
Publisher: Wiley
Date: 17-01-1994
DOI: 10.1016/0014-5793(94)80203-3
Abstract: The Escherichia coli signal transduction protein PII, product of the glnB gene, was overproduced and purified. The predicted molecular weight of the protein based on the correct nucleotide sequence is 12,427 and is very close to the value 12,435 obtained by matrix-assisted laser desorption mass spectrometry. Hexagonal crystals of the unuridylylated form of PII with dimensions 0.2 x 0.2 x 0.3 mm were grown and analysed by X-ray diffraction. The crystals belong to space group P6(3) with a = b = 61.6 A, c = 56.3 A and Vm of 2.5 for one subunit in the asymmetric unit. A low-resolution electron density map showed electron density concentrated around a three-fold axis, suggesting the molecule to be a trimer. A sedimentation equilibrium experiment of the meniscus depletion type was used to estimate a molecular weight of 35,000 +/- 1,000 for PII in solution. This result is consistent with the native protein being a homotrimer.
Publisher: Elsevier BV
Date: 11-2014
Publisher: Frontiers Media SA
Date: 2013
Publisher: Portland Press Ltd.
Date: 15-01-1997
DOI: 10.1042/BJ3210503
Abstract: Hypochlorous acid is the most powerful oxidant generated by neutrophils and is likely to contribute to the damage mediated by these inflammatory cells. The haem enzyme myeloperoxidase catalyses its production from hydrogen peroxide and chloride. 4-Aminobenzoic acid hydrazide (ABAH) is a potent inhibitor of hypochlorous acid production. In this investigation we show that, in the presence of hydrogen peroxide, ABAH irreversibly inactivates myeloperoxidase. ABAH was oxidized by myeloperoxidase, and kinetic analysis of the inactivation conformed to that for a mechanism-based inhibitor. Inactivation was exacerbated by concentrations of hydrogen peroxide greater than 50 ƁM and by the absence of oxygen. Hydrogen peroxide alone caused minimal inactivation. Reduced glutathione inhibited the oxidation of ABAH as well as the irreversible inhibition of myeloperoxidase. In the presence of oxygen, ABAH and hydrogen peroxide initially converted myeloperoxidase into compound III, which susequently lost haem absorbance. In the absence of oxygen, the enzyme was converted into ferrous myeloperoxidase and its haem groups were rapidly destroyed. We propose that myeloperoxidase oxidizes ABAH to a radical that reduces the enzyme to its ferrous intermediate. Ferrous myeloperoxidase reacts either with oxygen to allow enzyme turnover, or with hydrogen peroxide to give irreversible inactivation.
Publisher: Oxford University Press (OUP)
Date: 15-07-2022
Abstract: Approximately 50% of newly diagnosed glioblastomas (GBMs) harbor epidermal growth factor receptor gene lification (EGFR- ). Preclinical and early-phase clinical data suggested efficacy of depatuxizumab mafodotin (depatux-m), an antibody–drug conjugate comprised of a monoclonal antibody that binds activated EGFR (overexpressed wild-type and EGFRvIII-mutant) linked to a microtubule-inhibitor toxin in EGFR- GBMs. In this phase III trial, adults with centrally confirmed, EGFR- newly diagnosed GBM were randomized 1:1 to radiotherapy, temozolomide, and depatux-m lacebo. Corneal epitheliopathy was treated with a combination of protocol-specified prophylactic and supportive measures. There was 85% power to detect a hazard ratio (HR) ≤0.75 for overall survival (OS) at a 2.5% 1-sided significance level (ie traditional two-sided p ≤ 0.05) by log-rank testing. There were 639 randomized patients (median age 60, range 22–84 62% men). Prespecified interim analysis found no improvement in OS for depatux-m over placebo (median 18.9 vs. 18.7 months, HR 1.02, 95% CI 0.82–1.26, 1-sided p = 0.63). Progression-free survival was longer for depatux-m than placebo (median 8.0 vs. 6.3 months HR 0.84, 95% confidence interval [CI] 0.70–1.01, p = 0.029), particularly among those with EGFRvIII-mutant (median 8.3 vs. 5.9 months, HR 0.72, 95% CI 0.56–0.93, 1-sided p = 0.002) or MGMT unmethylated (HR 0.77, 95% CI 0.61–0.97 1-sided p = 0.012) tumors but without an OS improvement. Corneal epitheliopathy occurred in 94% of depatux-m-treated patients (61% grade 3–4), causing 12% to discontinue. Interim analysis demonstrated no OS benefit for depatux-m in treating EGFR- newly diagnosed GBM. No new important safety risks were identified.
Publisher: Oxford University Press (OUP)
Date: 31-05-2016
DOI: 10.1093/JNCI/DJW031
Publisher: SAGE Publications
Date: 2023
DOI: 10.1177/17588359231156392
Abstract: 177 LuPSMA is an effective treatment in metastatic castrate-resistant prostate cancer with trials adopting a standardised dose interval. Adjusting treatment intervals utilising early response biomarkers may improve patient outcomes. This study evaluated progression-free survival (PFS) and overall survival (OS) based on treatment interval adjustment utilising 177 LuPSMA 24-h SPECT/CT ( 177 Lu-SPECT) and early prostate-specific antigen (PSA) response. Retrospective analysis of a clinical 177 Lu-PSMA-I& T treatment programme. In all, 125 men were treated with 6-weekly 177 LuPSMA-I& T [median 3 cycles, interquartile range (IQR): 2–4], median dose 8.0 GBq [95% confidence interval (CI): 7.5–8.0]. Imaging screening involved 68 GaPSMA-11 PET/diagnostic CT. 177 Lu-SPECT/diagnostic CT was acquired following each therapy, and clinical assessments 3-weekly. Following dose 2 (week 6), a composite PSA and 177 Lu-SPECT/CT imaging response [partial response (PR), stable disease (SD), and progressive disease (PD)] determined ongoing management. Response group (RG) 1 (marked reduction in PSA/imaging PR) break in treatment until subsequent PSA rise, then re-treatment. RG 2 (stable or reduced PSA and/or imaging SD) 6-weekly treatments until six doses, or no longer clinically benefitting. RG 3 (rise in PSA and/or imaging PD) recommended for an alternative treatment. Overall PSA50% response rate (PSARR) was 60% (75/125), median PSA-PFS 6.1 months (95%CI: 5.5–6.7), and median OS 16.8 months (95%CI: 13.5–20.1). 35% (41/116) were classified as RG 1, 34% (39/116) RG 2, and 31% (36/116) RG 3. PSARRs by RG were 95% (38/41), 74% (29/39), and 8% (3/36) median PSA-PFS rates were 12.1 months (95%CI: 9.3–17.4), 6.1 months (95%CI: 5.8–9.0), and 2.6 months (95%CI: 1.6–3.1) and OS rates were 19.2 months (95%CI: 16.8–20.7), 13.2 months (95%CI: 12.0–18.8), and 11.2 months (95%CI: 8.7–15.6) for RG 1, 2, and 3, respectively. The median months of ‘treatment holiday’ for RG 1 was 6.1 months (IQR: 3.4–8.7). Nine men had received prior 177 LuPSMA-617 and were retreated with 177 LuPSMA-I& T, with a PSARR of 56% on re-treatment. Personalising dosing regimens using early response biomarkers with 177 LuPSMA has the potential to achieve similar treatment responses to continuous dosing while allowing treatment breaks or intensification. Further evaluation of early response biomarker-guided treatment regimens in prospective trials is warranted. Lutetium-PSMA therapy is a new therapy for metastatic prostate cancer that is well tolerated and effective. However, not all men respond equally, with some responding very well and others progressing early. Personalising treatments require tools that can accurately measure treatment responses, preferably early in the treatment course, so adjustments to treatment can be made. Lutetium-PSMA can measure tumour sites after each therapy by taking whole body 3D images at 24 h using a small radiation wave from the treatment itself. This is called a SPECT scan. Previous work has shown that both prostate-specific antigen (PSA) response and changes in tumour volume on a SPECT scan can predict how patients will respond to treatment as early as dose 2. This study demonstrates that stratifying how men are treated based on the results of the 6-week SPECT scan and PSA response potentially allows a third of men to have break in treatment and that these men have both longer time to disease progression and OS. Men with an increase in tumour volume and increase in PSA early in treatment (6 weeks) had shorter time to disease progression and OS. Men with early biomarker disease progression were offered alternative treatments early in an attempt to allow the opportunity to allow a more effective potential therapy, if one was available. The study is an analysis of a clinical programme, and was not a prospective trial. As such, there are potential biases that could influence results. Hence, while the study is encouraging for the use of early response biomarkers to guide better treatment decisions, this must be validated in a well-designed clinical trial.
Publisher: BMJ
Date: 09-2018
DOI: 10.1136/BMJOPEN-2017-020745
Abstract: Chemotherapy-induced nausea and vomiting (CINV) remains an important issue for patients receiving chemotherapy despite guideline-consistent antiemetic therapy. Trials using delta-9-tetrahydrocannabinol-rich (THC) products demonstrate limited antiemetic effect, significant adverse events and flawed study design. Trials using cannabidiol-rich (CBD) products demonstrate improved efficacy and psychological adverse event profile. No definitive trials have been conducted to support the use of cannabinoids for this indication, nor has the potential economic impact of incorporating such regimens into the Australian healthcare system been established. CannabisCINV aims to assess the efficacy, safety and cost-effectiveness of adding TN-TC11M, an oral THC/CBD extract to guideline-consistent antiemetics in the secondary prevention of CINV. The current multicentre, 1:1 randomised cross-over, placebo-controlled pilot study will recruit 80 adult patients with any malignancy, experiencing CINV during moderate to highly emetogenic chemotherapy despite guideline-consistent antiemetics. Patients receive oral TN-TC11M (THC 2.5mg/CBD 2.5 mg) capsules or placebo capsules three times a day on day −1 to day 5 of cycle A of chemotherapy, followed by the alternative drug regimen during cycle B of chemotherapy and the preferred drug regimen during cycle C. The primary endpoint is the proportion of subjects attaining a complete response to CINV. Secondary and tertiary endpoints include regimen tolerability, impact on quality of life and health system resource use. The primary assessment tool is patient diaries, which are filled from day −1 to day 5. A subsequent randomised placebo-controlled parallel phase III trial will recruit a further 250 patients. The protocol was approved by ethics review committees for all participating sites. Results will be disseminated in peer-reviewed journals and at scientific conferences. Tilray. 2.0, 9 June 2017. ANZCTR12616001036404 Pre-results.
Publisher: American Society of Clinical Oncology (ASCO)
Date: 20-05-2019
DOI: 10.1200/JCO.2019.37.15_SUPPL.4519
Abstract: 4519 Background: Atezo, a monoclonal antibody targeting PD-L1, is an approved therapy for locally advanced/metastatic UC based on IMvigor210 and IMvigor211 phase II and III trials. The single-arm SAUL study (NCT02928406) with a broader patient (pt) population demonstrated median overall survival (OS) of 8.7 months and a safety profile consistent with previous atezo trials. Methods: Pts with locally advanced/metastatic UC or non-UC of the urinary tract received atezo 1200 mg every 3 weeks until disease progression or unacceptable toxicity. Populations excluded from IMvigor211 (renal impairment, ECOG PS 2, treated asymptomatic CNS metastases, stable controlled autoimmune disease, concomitant steroids, HIV positive, non-UC) were eligible. The primary endpoint was safety OS and overall response rate (ORR) were secondary endpoints. Predefined subgroup analyses included outcomes according to PD-L1 status (VENTANA SP142) and age in the overall population (and the IMvigor211-like subgroup for PD-L1). Results: Between Nov 2016 and Mar 2018, 1004 pts were enrolled 997 received atezo. Efficacy is summarized below. Incidences of grade ≥3 treatment-related adverse events were similar irrespective of PD-L1 status (overall IC 0/1 vs 2/3: 11% vs 16% IMvigor211-like IC 0/1 vs 2/3: 11% vs 15%) or age (≥65 y: 13% ≥75 y: 12% ≥80 y: 10%). Conclusions: OS and ORR appear more favorable in IC 2/3 vs IC 0/1 subgroups (overall and in the IMvigor211-like population). Atezo was effective and well tolerated across subgroups including elderly pts. Clinical trial information: NCT02928406. [Table: see text]
Publisher: Informa UK Limited
Date: 04-2013
DOI: 10.4161/ONCI.24185
Publisher: Springer Science and Business Media LLC
Date: 17-01-2019
DOI: 10.1007/S12094-018-02023-5
Abstract: Drug repurposing offers advantages over traditional drug development in terms of cost, speed and improved patient outcomes. The receptor activator of nuclear factor kappa B (RANK) ligand (RANKL) inhibitor denosumab is approved for the prevention of skeletal-related events in patients with advanced malignancies involving bone, including solid tumours and multiple myeloma. Following improved understanding of the role of RANK/RANKL in cancer biology, denosumab has already been repurposed as a treatment for giant cell tumour of bone. Here, we review the role of RANK/RANKL in tumourigenesis, including effects on tumour initiation, progression and metastasis and consider the impact of RANK/RANKL on tumour immunology and immune evasion. Finally, we look briefly at ongoing trials and future opportunities for therapeutic synergy when combining denosumab with anti-cancer agents such as immune checkpoint inhibitors.
Publisher: Wiley
Date: 13-03-2023
Abstract: Glioblastoma (GBM) is the most frequent and deadly primary brain tumor in adults. Temozolomide (TMZ) is the standard systemic therapy in GBM but has limited and restricted efficacy. Better treatments are urgently needed. The role of endoplasmic reticulum stress (ER stress) is increasingly described in GBM pathophysiology. A key molecular mediator of ER stress, the spliced form of the transcription factor x‐box binding protein 1 (XBP1s) may constitute a novel therapeutic target here we report XBP1s expression and biological activity in GBM. Tumor s les from patients with GBM ( n = 85) and low‐grade glioma ( n = 20) were analyzed by immunohistochemistry for XBP1s with digital quantification. XBP1s expression was significantly increased in GBM compared to low‐grade gliomas. XBP1s mRNA showed upregulation by qPCR analysis in a panel of patient‐derived GBM cell lines. Inhibition of XBP1 splicing using the small molecular inhibitor MKC‐3946 significantly reduced GBM cell viability and potentiated the effect of TMZ in GBM cells, particularly in those with methylated O 6 ‐methylguanine‐DNA methyl transferase gene promoter. GBM cells resistant to TMZ were also responsive to MKC‐3946 and the long‐term inhibitory effect of MKC‐3946 was confirmed by colony formation assay. In conclusion, this data reveals that XBP1s is overexpressed in GBM and contributes to cancer cell growth. XBP1s warrants further investigation as a clinical biomarker and therapeutic target in GBM.
Publisher: AMPCo
Date: 05-2016
DOI: 10.5694/MJA15.00961
Publisher: Elsevier BV
Date: 2018
DOI: 10.1016/J.EJCA.2017.10.025
Abstract: Biobanking consent processes should accord with patients' preferences and be offered in a consistent and systematic manner. However, these aims can be difficult to achieve under healthcare professionals' (HCPs) time-constrained workflows, resulting in low participation rates. This current perspective provides a brief overview of HCP involvement in consent and reports new data on participant attrition at each step of the biobanking consent process as experienced by 113 patients at an Australian tertiary cancer centre. To determine attrition in this HCP-driven consent process, we reviewed medical records for the following events: inclusion of biobanking consent forms visible patient and HCP signatures consent status selected (decline or accept) and specimen registration with local biobank. Accessible medical records revealed the following data: 75 of 85 records included viewable forms 22 of 85 records included patient and 19 of 85 included HCP signatures 15 of 85 records included signed and completed forms and 3 of 85 had s les banked with annotated clinical data. We compared these data with self-reported experiences of being approached to participate by HCPs. Of the 15 participants (17.6%) who successfully completed consent, only five could recall being asked and providing consent. The low enrolment rate is a considerable lost opportunity because most patients (59%) who were not asked to participate indicated they would have consented if asked. Furthermore, in comparing self-reported experiences with medical records, we believe cancer patients' preferences for participation are mismatched with actual biobanking enrolment, which has considerable attrition at each step in the consent process.
Publisher: Society of Nuclear Medicine
Date: 29-11-8022
No related grants have been discovered for Craig Gedye.