ORCID Profile
0000-0002-1811-0537
Current Organisations
Prince Charles Hospital
,
Royal Brisbane and Women's Hospital
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Publisher: Springer Science and Business Media LLC
Date: 12-2019
DOI: 10.1186/S13063-019-3951-X
Abstract: Neoadjuvant immunotherapy targeting immune checkpoint programmed death-1 (PD-1) is under investigation in various tumour settings including non-small-cell lung cancer (NSCLC). Preclinical models demonstrate the superior power of the immunotherapy provided in a neoadjuvant (pre-operative) compared with an adjuvant (post-operative) setting to eradicate metastatic disease and induce long-lasting antigen-specific immunity. Novel effective immunotherapy combinations are widely sought in the oncology field, targeting non-redundant mechanisms of immune evasion. A promising combination partner with anti-PD1 in NSCLC is denosumab, a monoclonal antibody blocking receptor activator of NF-κB ligand (RANKL). In preclinical cancer models and in a large retrospective case series in NSCLC, anti-cancer activity has been reported for the combination of immune checkpoint inhibition (ICI) and denosumab. Furthermore, clinical trials of ICI and denosumab are underway in advanced melanoma and clear-cell renal cell carcinoma. However, the mechanism of action of combination anti-PD1 and anti-RANKL is poorly defined. This open-label multicentre trial will randomise by minimisation 30 patients with resectable stage IA (primary 2 cm) to IIIA NSCLC to a neoadjuvant treatment regime of either two doses of nivolumab (3 mg/kg every 2 weeks) or two doses of nivolumab (same regimen) plus denosumab (120 mg every 2 weeks, following nivolumab). Each treatment arm is of equal size and will be approximately balanced with respect to histology (squamous vs. non-squamous) and clinical stage (I-II vs. IIIA). All patients will receive surgery for their tumour 2 weeks after the final dose of neoadjuvant therapy. The primary outcome will be translational research to define the tumour-immune correlates of combination therapy compared with monotherapy. Key secondary outcomes will include a comparison of rates of the following between each arm: toxicity, response (pathological and radiological), and microscopically complete resection. The POPCORN study provides a unique platform for translational research to determine the mechanism of action of a novel proposed combination immunotherapy for cancer. Prospectively registered on Australian New Zealand Clinical Trials Registry ( ACTRN12618001121257 ) on 06/07/2018.
Publisher: Wiley
Date: 09-06-2020
DOI: 10.1111/AJCO.13350
Publisher: Frontiers Media SA
Date: 31-03-2020
Publisher: BMJ
Date: 12-2022
Abstract: CD73 is widely expressed on immune cells playing a critical role in immunomodulatory functions including cell adhesion and migration, as a costimulatory molecule for T cells and in production of adenosine. The function of CD73 expressed on B cells has not been fully characterized. Mupadolimab is an anti-human CD73 antibody that activates B cells. We evaluated the characteristics of this antibody and its effects on immune cells in vitro and in vivo. Mupadolimab binding to CD73, inhibition of CD73 enzymatic activity, and effects on lymphocyte activation were evaluated in vitro by measuring changes in immunophenotype by flow cytometry. Cryogenic-transmission electron microscopy was used to determine epitope binding. Effects on human B cells in vivo were evaluated in immunodeficient NSG-SGM3 mice immunized with SARS-CoV-2 and influenza viral antigens. Safety and immune effects were evaluated in the completed dose escalation portion of a phase 1 trial conducted in patients with cancer. Mupadolimab binds to a unique epitope on CD73 POS B cells resulting in their activation and differentiation through B cell receptor signaling pathways. Mupadolimab induces expression of CD69, CD83, CD86 and MHC class II on B cells along with morphological transformation into plasmablasts and expression of CD27, CD38 and CD138. These effects are independent of adenosine. Mupadolimab binds to the N-terminal of CD73 in the closed position and competitively inhibits substrate binding. Mupadolimab enhanced antigen specific antibody response to SARS-CoV-2 spike protein and influenza hemagglutinin in humanized mouse models. Mupadolimab was evaluated as a monotherapy in a phase 1 trial ( NCT03454451 ) in 34 patients with advanced cancer and demonstrated binding to CD73 POS circulating cells and transient reduction in the number of B cells, with return of CD73 NEG B cells with memory phenotype. No dose-limiting toxicities or changes in serum immunoglobulins were seen. Mupadolimab activates B cells and stimulates the production of antigen specific antibodies. The effects in patients with cancer suggest that activated, CD69 POS B cells redistribute to lymphoid tissues. Minor tumor regression was observed in several patients. These results support further investigation of mupadolimab as an immunotherapy for cancer and its potential use as a vaccine adjuvant. NCT03454451 .
Publisher: Mary Ann Liebert Inc
Date: 05-2022
Publisher: Elsevier BV
Date: 03-2018
DOI: 10.1016/J.JAD.2017.12.081
Abstract: Evidence that repetitive negative thinking (RNT) is a shared feature of a number of disorders has prompted the need for transdiagnostic self-report instruments that is, measures of RNT that can be administered to in iduals irrespective of their diagnosis. The Repetitive Thinking Questionnaire (RTQ McEvoy et al., 2010) was developed to meet this need, and its psychometric properties and capacity to predict psychopathology have been tested in undergraduate and clinically anxious s les. We administered the RTQ to currently depressed (n = 29), formerly depressed (n = 61) and never-depressed (n = 93) community participants. The RTQ demonstrated good psychometric properties, with excellent internal consistency for the RNT subscale (α=.93) and good convergent validity with measures of negative affect and psychopathology symptoms (rs= .47-.61). In addition, and in accord with our predictions, currently depressed and recovered depressed participants reported more RNT than never-depressed participants, but currently and recovered depressed participants did not differ. In addition, RNT scores explained additional variance in depression and anxiety symptoms, after controlling for gender, age, neuroticism, state negative affect, and intolerance of uncertainty. Our s le was drawn from the community but participants were not treatment-seeking, and we employed a cross-sectional design. Taken together with previous experimental and longitudinal studies, our results support the utility of addressing RNT in the treatment and prevention of relapse in depression. Moreover, these data confirm the utility of the RTQ as a brief, transdiagnostic self-report measure of RNT.
Publisher: Elsevier BV
Date: 07-2022
Publisher: Springer Science and Business Media LLC
Date: 23-06-2022
DOI: 10.1007/S13402-022-00681-W
Abstract: Local recurrence and metastasis remain the major causes of death in head and neck cancer (HNC) patients. Circulating tumour cells (CTCs) are shed from primary and metastatic sites into the circulation system and have been reported to play critical roles in the metastasis and recurrence of HNC. Here, we explored the use of CTCs to predict the response to treatment and disease progression in HNC patients. Blood s les were collected at diagnosis from HNC patients (n = 119). CTCs were isolated using a spiral microfluidic device and were identified using immunofluorescence staining. Correlation of baseline CTC numbers to 13-week PET-CT data and multidisciplinary team consensus data were conducted. CTCs were detected in 60/119 (50.4%) of treatment naïve HNC patients at diagnosis. Baseline CTC numbers were higher in stage III vs. stage I-II p16-positive oropharyngeal cancers (OPCs) and other HNCs ( p = 0.0143 and 0.032, respectively). In addition, we found that baseline CTC numbers may serve as independent predictors of treatment response, even after adjusting for other conventional prognostic factors. CTCs were detected in 10 out of 11 patients exhibiting incomplete treatment responses. We found that baseline CTC numbers are correlated with treatment response in patients with HNC. The expression level of cell-surface vimentin (CSV) on CTCs was significantly higher in patients with persistent or progressive disease, thus providing additional prognostic information for stratifying the risk at diagnosis in HNC patients. The ability to detect CTCs at diagnosis allows more accurate risk stratification, which in the future may be translated into better patient selection for treatment intensification and/or de-intensification strategies.
Publisher: Wiley
Date: 11-2004
DOI: 10.1111/J.1445-1433.2004.03218.X
Abstract: Improved disease free and overall survivals were seen in curatively resected patients with gastric and gastroesophageal adenocarcinoma treated with the Intergroup 0116 (INT 0116) protocol of postoperative adjuvant chemoradiotherapy compared to surgery alone. This protocol has not been widely adopted in Australian centres because of perceived risks of toxicity. We reviewed the case records from 45 consecutive patients treated between May 1998 and August 2003 with the INT 0116 protocol and variations at five Australian institutions. The median age was 61.5 years (range 38-79). Twenty-nine patients had gastric and 12 had gastroesophageal junction primaries. All patients had attempted curative resection, however, seven had involved microscopic margins (R1 resection). Thirty-five had regional node involvement and none had evidence of distant metastasis. The overall National Cancer Institute-Common Toxicity Criteria (NCI-CTC) version 2.0 grade 3 and grade 4 toxicity rates for all patients were 37.8% and 4.4%, respectively. There were no treatment related deaths. Gastrointestinal grade 3 toxicity was observed in 20% of patients, while haematologic grade 3 and 4 toxicity was observed in 17.8%. Toxicities experienced led to chemotherapy dose reductions in 22 patients and dose delay in 11 patients. Seven patients had a delay in radiotherapy and two did not proceed with radiotherapy. At a median follow up of 16 months (range 5-35) from surgery, 28 patients have relapsed (six with local recurrence alone) with 22 deaths occurring, all but one caused by cancer. The INT 0116 protocol is a safe and feasible schedule in a multicentre setting with an acceptable rate of toxicity and is an appropriate adjuvant treatment option for high-risk resected gastroesophageal adenocarcinoma.
Publisher: Frontiers Media SA
Date: 19-01-2021
Abstract: Immune checkpoint inhibitors (ICI) have shown durable and long-term benefits in a subset of head and neck squamous cell carcinoma (HNSCC) patients. To identify patient-responders from non-responders, biomarkers are needed which are predictive of outcome to ICI therapy. Cues in the tumor microenvironment (TME) have been informative in understanding the tumor-immune contexture. In this preliminary study, the NanoString GeoMx™ Digital Spatial Profiling (DSP) technology was used to determine the immune marker and compartment specific measurements in a cohort of HNSCC tumors from patients receiving ICI therapy. Our data revealed that markers involved with immune cell infiltration (CD8 T-cells) were not predictive of outcome to ICI therapy. Rather, a number of immune cell types and protein markers (CD4, CD68, CD45, CD44, CD66b) were found to correlate with progressive disease. Cross platform comparison with the Opal Vectra (Perkin Elmer) for a number of markers across similar regions of interest demonstrated concordance for pan-cytokeratin, CD8, and PD-L1. This study, to our knowledge, represents the first digital spatial analysis of HNSCC tumors. A larger cohort of HNSCC will be required to orthogonally validate the findings.
Publisher: Wiley
Date: 07-08-2020
DOI: 10.1111/CAS.14585
Publisher: Cambridge University Press (CUP)
Date: 14-02-2022
DOI: 10.1017/S0007114522000435
Abstract: Malnutrition and sarcopenia are prevalent in patients with head and neck squamous cell carcinoma (HNSCC). Pre-treatment sarcopenia and adverse oncological outcomes in this population are well described. The impact of myosteatosis and post-treatment sarcopenia is less well known. Patients with HNSCC ( n = 125) undergoing chemoradiotherapy, radiotherapy alone and/or surgery were assessed for sarcopenia and myosteatosis, using cross-sectional computed tomography (CT) imaging at the third lumbar (L3) vertebra, at baseline and 3 months post-treatment. Outcomes were overall survival (OS) at 12 months and 5 years post-treatment. One hundred and one participants had a CT scan evaluable at one or two time points, of which sixty-seven (66 %) participants were sarcopenic on at least one time point. Reduced muscle attenuation affected 93 % ( n = 92) pre-treatment compared with 97 % ( n = 90) post-treatment. Five-year OS favoured those without post-treatment sarcopenia (hazard ratio, HR 0·37, 95 % CI 0·16, 0·88, P = 0·06) and those without both post-treatment myosteatosis and sarcopenia (HR 0·33, 95 % CI 0·13, 0·83, P = 0·06). Overall, rates of myosteatosis were high at both pre- and post-treatment time points. Post-treatment sarcopenia was associated with worse 5-year OS, as was post-treatment sarcopenia in those who had myosteatosis. Post-treatment sarcopenia should be evaluated as an independent risk factor for decreased long-term survival post-treatment containing radiotherapy (RT) for HNSCC.
Publisher: Wiley
Date: 13-08-2015
DOI: 10.1002/HED.24184
Abstract: Swallowing and nutrition guidelines for patients with head and neck cancer are available for identification of proactive gastrostomy placement in patients with high nutritional risk. The purpose of this study was to investigate improvements to the validity of these guidelines. A multivariate analysis was fitted to the original dataset (n = 501) to examine the variables that may predict gastrostomy placement (eg, tumor site, treatment, sex, and age). Using these factors, the high risk category was modified and retrospectively validated in the same cohort to provide new measures of sensitivity and specificity. The following were positive predictors of gastrostomy placement: T3 (p = .01), T4 (p < .001), and chemoradiotherapy (p < .001). Laryngeal (p = .02) and skin cancer (p < .001) were negative predictors. Modification of the high risk definition improved sensitivity to 58% and maintained specificity at 92%. Minor modifications to the high risk definition in the guidelines have improved the guideline sensitivity for future use. © 2015 Wiley Periodicals, Inc. Head Neck 38: E1163-E1171, 2016.
Publisher: American Society of Clinical Oncology (ASCO)
Date: 09-2020
DOI: 10.1200/JCO.19.03054
Abstract: Treatment options are limited for patients with recurrent and/or metastatic (R/M) cutaneous squamous cell carcinoma (cSCC) mortality rates exceed 70% in patients with distant metastases. Here, we present the first interim analysis of the R/M cSCC cohort from the 2-cohort—locally advanced and R/M—phase II KEYNOTE-629 study. Patients with R/M cSCC not amenable to surgery or radiation received pembrolizumab 200 mg every 3 weeks. The primary end point was objective response rate per RECIST v1.1. Secondary end points were duration of response, disease control rate, progression-free survival, overall survival, and safety. At data cutoff (April 8, 2019), median follow-up of 105 enrolled patients in the R/M cohort was 11.4 months (range, 0.4 to 16.3 months). Objective response rate was 34.3% (95% CI, 25.3% to 44.2% 4 complete responses, 32 partial responses), and disease control rate was 52.4% (95% CI, 42.4% to 62.2%). Median duration of response was not reached (range, 2.7 to 13.1+ months ‘+’ refers to ongoing response at data cutoff). Median progression-free survival was 6.9 months (95% CI, 3.1 months to 8.5 months). Median overall survival was not reached (95% CI, 10.7 months to not reached). Treatment-related adverse events occurred in 66.7% of patients (n = 70), the most common of which were pruritus (n = 15 14.3%), asthenia (n = 14 13.3%), and fatigue (n = 13 12.4%). Grade 3 to 5 treatment-related adverse events occurred in 5.7% (n = 6) of patients. One patient died of treatment-related cranial nerve neuropathy. Pembrolizumab demonstrated effective antitumor activity clinically meaningful, durable responses and acceptable safety in primarily elderly patients with R/M cSCC, supporting its use in clinical practice. Pembrolizumab adverse events in this study were consistent with its established safety profile.
Publisher: Elsevier BV
Date: 11-2015
Abstract: We sought to determine whether the substantial benefits of topical nitroglycerin with first-line, platinum-based, doublet chemotherapy in advanced nonsmall-cell lung cancer (NSCLC) seen in a phase II trial could be corroborated in a rigorous, multicenter, phase III trial. Patients starting one of five, prespecified, platinum-based doublets as first-line chemotherapy for advanced NSCLC were randomly allocated treatment with or without nitroglycerin 25 mg patches for 2 days before, the day of, and 2 days after, each chemotherapy infusion. Progression-free survival (PFS) was the primary end point. Accrual was stopped after the first interim analysis of 270 events. Chemotherapy was predominantly with carboplatin and gemcitabine (79%) or carboplatin and paclitaxel (18%). The final analysis included 345 events in 372 participants with a median follow-up of 33 months. Topical nitroglycerin had no demonstrable effect on PFS [median 5.0 versus 4.8 months, hazard ratio (HR) = 1.07, 95% confidence interval (CI) 0.86-1.32, P = 0.55], overall survival (median 11.0 versus 10.3 months, HR = 0.99, 95% CI 0.79-1.24, P = 0.94), or objective tumor response (31% versus 30%, relative risk = 1.03, 95% CI 0.82-1.29, P = 0.81). Headache, hypotension, syncope, diarrhea, dizziness, and anorexia were more frequent in those allocated nitroglycerin. The addition of topical nitroglycerin to carboplatin-based, doublet chemotherapy in NSCLC had no demonstrable benefit and should not be used or pursued further. Australian New Zealand Clinical Trials Registry Number ACTRN12608000588392.
Publisher: Springer Science and Business Media LLC
Date: 27-04-2022
DOI: 10.1007/S00520-022-07056-9
Abstract: Human papillomavirus (HPV) is now the primary cause of oropharyngeal head and neck cancer (OPC) worldwide yet limited research has examined the effect of HPV-positive status (OPC+) on nutrition outcomes. This study aims to determine the impact of HPV status on nutritional outcomes for adult patients with OPC undergoing any treatment modality. A systematic literature review was conducted up to and including July 2021 of PubMed, Embase, CENTRAL, CINAHL, and Web of Science to identify studies conducted in adults ( years) with known OPC reporting on any outcome(s) related to nutrition, according to HPV status (OPC+ versus OPC−). Bias was assessed using QUIPS tool, with certainty of evidence assessed using GRADE system. Six studies (total n = 635) all at moderate-high risk of bias were included. Three studies reported on weight change ( n = 255), three feeding tube dependency ( n = 380), three feeding tube timing of placement (prophylactic or reactive) and/or utilisation ( n = 255), two nutritional (energy and/or protein) intake ( n = 230), and one nutritional status ( n = 83). Patients with OPC+ may experience greater weight loss, may have higher utilisation of reactive feeding tubes (both GRADE low certainty, downgraded due to serious bias and imprecision), and may have lower feeding tube dependency rates (GRADE low certainty, downgraded due to serious bias and inconsistency) versus OPC− . It is uncertain whether nutritional intake and nutritional status differed between populations (GRADE very low certainty, downgraded due to serious bias and very serious imprecision). Further, high-quality research is needed to understand optimal nutritional care practices for patients with OPC + to achieve positive health outcomes into survivorship.
Publisher: Elsevier BV
Date: 10-2021
DOI: 10.1016/J.ANNONC.2021.07.008
Abstract: Pembrolizumab demonstrated clinically meaningful and durable antitumor activity with a manageable safety profile in recurrent/metastatic (R/M) cutaneous squamous cell carcinoma (cSCC). KEYNOTE-629 was a global, open-label, nonrandomized, phase II trial of patients with locally advanced (LA) or R/M cSCC conducted at 59 centers. Eligible patients received intravenous pembrolizumab 200 mg every 3 weeks for up to 35 cycles. Primary endpoint was objective response rate (ORR), defined as the percentage of patients with a complete (CR) or partial response (PR), by blinded independent central review as per Response Evaluation Criteria in Solid Tumors 1.1. Secondary endpoints included duration of response (DOR), disease control rate, progression-free survival, overall survival, and safety and tolerability. Efficacy and safety were analyzed in patients who were treated with at least one dose of pembrolizumab. Between 29 November 2017 and 25 September 2019, 159 patients were enrolled and treated with pembrolizumab (LA cohort, n = 54 R/M cohort, n = 105). The median time from the first dose to data cut-off date (29 July 2020) was 14.9 [interquartile range (IQR), 12.6-17.2] months for the LA cohort and 27.2 (IQR, 25.6-29.2) months for the R/M cohort. In the LA cohort, ORR was 50.0% [95% confidence interval (CI), 36.1% to 63.9%], including 16.7% of patients with a CR and 33.3% with a PR. In the R/M cohort, ORR was 35.2% (95% CI, 26.2% to 45.2%), including 10.5% of patients with a CR and 24.8% with a PR. Median DOR was not reached in either cohort. Grade 3-5 treatment-related adverse events occurred in 11.9% of patients. The robust antitumor activity of pembrolizumab in both LA and R/M cSCC was confirmed and demonstrated to be durable without unexpected safety signals. Our findings establish pembrolizumab as a promising treatment option for cSCC.
Publisher: Frontiers Media SA
Date: 16-05-2022
DOI: 10.3389/FIMMU.2022.895513
Abstract: Head and neck squamous cell carcinoma (HNSCC) often presents with locoregional or distant disease, despite multimodal therapeutic approaches, which include surgical resection, chemoradiotherapy, and more recently, immunotherapy for metastatic or recurrent HNSCC. Therapies often target the primary and nodal regional HNSCC sites, and their efficacy at controlling occult distant sites remains poor. While our understanding of the tumor microenvironment conducive to effective therapies is increasing, the biology underpinning locoregional sites remains unclear. Here, we applied targeted spatial proteomic approaches to primary and lymph node metastasis from an oropharyngeal SCC (OPSCC) cohort to understand the expression of proteins within tumors, and stromal compartments of the respective sites in s les of both matched and unmatched patients. In unmatched analyses of n = 43 primary and 11 nodal metastases, our data indicated that tumor cells in nodal metastases had higher levels of Ki-67, PARP, BAD, and cleaved caspase 9, suggesting a role for increased proliferation, DNA repair, and apoptosis within these metastatic cells. Conversely, in matched analyses (n = 7), pro-apoptotic markers BIM and BAD were enriched in the stroma of primary tumors. Univariate, overall survival (OS) analysis indicated CD25 in tumor regions of primary tumors to be associated with reduced survival (HR = 3.3, p = 0.003), while progesterone receptor (PR) was associated with an improved OS (HR = 0.33, p = 0.015). This study highlights the utility of spatial proteomics for delineating the tumor and stromal compartment composition, and utility toward understanding these properties in locoregional metastasis. These findings indicate unique biological properties of lymph node metastases that may elucidate further understanding of distant metastatic in OPSCC.
Publisher: AME Publishing Company
Date: 12-2019
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 05-2009
Publisher: Elsevier BV
Date: 04-2023
Publisher: Elsevier BV
Date: 09-2022
DOI: 10.1016/J.JVAL.2022.01.017
Abstract: The EuroQoL 3-level version of EQ-5D and 5-level version of EQ-5D questionnaires are often used to quantify health states. They include ordinal responses across 5 health dimensions (EQ-5D index) and an EQ-visual analog scale (EQ-VAS) overall health rating. We investigated the value of incorporating the EQ-VAS to update health utility estimates using a Bayesian framework. We created a joint bivariate normal EQ-VAS and EQ-5D index utility model and compared this to a univariate normal EQ-5D index utility model. We tested these models for 1026 Sri Lankan patients with chronic kidney disease and 94 Australian patients with wounds. We validated our approach by simulating EQ-VAS and EQ-5D index responses and applying our Bayesian model and then comparing the modeled estimates to our observed data. The combined model showed a reduction in estimate uncertainty for all respondents. Compared with the EQ-5D index-only model, the mean utility for Sri Lankan respondents dropped from 0.556 (0.534-0.579) to 0.540 (0.521-0.559) in men and increased from 0.489 (0.461-0.518) to 0.528 (0.506-0.550) in women, with reduced credible interval width by 13% and 23%, respectively. The mean utility in Australian respondents moved from 0.715 (0.633-0.800) to 0.716 (0.652-0.782) in men, and 0.652 (0.581-0.723) to 0.652 (0.593-0.711) in women, with reduced credible interval width by 23% and 17%, respectively. The credible interval width for simulated data also narrowed, ranging from 8.3 to 8.5%. Including the EQ-VAS through Bayesian methods can add value by reducing requisite s le sizes and decision uncertainty using small amounts of additional data that is often collected but rarely used.
Publisher: BMJ
Date: 06-2021
Abstract: Standard curative treatment of early-stage non-small cell lung cancer (NSCLC) involves surgery in combination with postoperative (adjuvant) platinum-based chemotherapy where indicated. Preoperative (neoadjuvant) therapies offer certain theoretical benefits compared with adjuvant approaches, including the ability to assess on-treatment response, reduce the tumor bulk prior to surgery, and enhance tolerability in the preoperative setting. Indeed, the use of neoadjuvant therapies are well established in other cancers such as breast and rectal cancers to debulk the tumor and guide ongoing therapy, and neoadjuvant chemotherapy has similar efficacy but less toxicity in NSCLC. More recently, immune checkpoint inhibitors (ICI) targeting programmed death-1 (PD1)/PD1-ligand 1 (PD-L1) have transformed the treatment of advanced NSCLC the unique mechanisms of action of ICI offer additional rationale for assessment in the neoadjuvant setting. Preclinical studies in mouse cancer models support the proof of concept of neoadjuvant ICI (NAICI) through improvement of T-cell effector function and long-term memory induction. Preliminary early-phase human trial data support the proposition that NAICI in NSCLC may provide an feasible and potentially efficacious future treatment strategy and large, randomized phase III trials are currently recruiting to assess this approach. However, outstanding issues include defining optimal treatment combinations which balance high efficacy with acceptable toxicity, validating biomarkers to aid in patient selection, and avoiding potential pitfalls such as missing a window for successful surgery, that is, choosing the right drugs, for the right patient, at the right time. Predictive biomarkers to direct selection of therapy are required, and the validation of major pathological response (MPR) as a surrogate for survival will be important in the uptake of the neoadjuvant approach.
Publisher: Springer Science and Business Media LLC
Date: 15-05-2012
DOI: 10.1038/BJC.2012.194
Publisher: Elsevier BV
Date: 04-2018
DOI: 10.1016/J.JAND.2016.10.013
Abstract: The optimal method of tube feeding for patients with head and neck cancer remains unclear. A validated protocol is available that identifies high-nutritional-risk patients who would benefit from prophylactic gastrostomy tube placement. Adherence to this protocol is ultimately determined by clinical team discretion or patient decision. The study aim was to compare outcomes after adherence and nonadherence to this validated protocol, thus comparing a prophylactic and reactive approach to nutrition support in this patient population. We conducted a prospective comparative cohort study. Patients were observed during routine clinical practice over 2 years. Patients with head and neck cancer having curative-intent treatment between August 2012 and July 2014 at a tertiary hospital in Queensland, Australia, were included if assessed as high nutrition risk according to the validated protocol (n=130). Patients were grouped according to protocol adherence as to whether they received prophylactic gastrostomy (PEG) per protocol recommendation (prophylactic PEG group, n=69) or not (no PEG group, n=61). Primary outcome was percentage weight change during treatment. Secondary outcomes were feeding tube use and hospital admissions. Fisher's exact, χ Patients were 88% male, median age was 59 years, with predominantly stage IV oropharyngeal cancer receiving definitive chemoradiotherapy. Statistically significantly less weight loss in the prophylactic PEG group (7.0% vs 9.0% P=0.048) and more unplanned admissions in the no PEG group (82% vs 75% P=0.029). In the no PEG group, 26 patients (43%) required a feeding tube or had ≥10% weight loss. Prophylactic gastrostomy improved nutrition outcomes and reduced unplanned hospital admissions. Additional investigation of characteristics of patients with minimal weight loss or feeding tube use could help refine and improve the protocol.
Publisher: CSIRO Publishing
Date: 2018
DOI: 10.1071/AH17276
Abstract: Objective The HealthPathways program is an online information portal that helps clinicians provide consistent and integrated patient care within a local health system through localised pathways for diagnosis, treatment and management of various health conditions. These pathways are consistent with the definition of clinical pathways. Evaluations of HealthPathways programs have thus far focused primarily on website utilisation and clinical users’ experience and satisfaction, with limited evidence on changes to patient outcomes. This lack motivated a literature review of the effects of clinical pathways on patient and economic outcomes to inform a subsequent HealthPathways evaluation. Methods A systematic review was performed to summarise the analytical methods, study designs and results of studies evaluating clinical pathways with an economic outcome component published between 1 January 2000 and 31 August 2017 in four academic literature databases. Results Fifty-five relevant articles were identified for inclusion in this review. The practical pre-post study design with retrospective baseline data extraction and prospective intervention data collection was most commonly used in the evaluations identified. Straightforward statistical methods for comparing outcomes, such as the t-test or χ2 test, were frequently used. Only four of the 55 articles performed a cost-effectiveness analysis. Clinical pathways were generally associated with improved patient outcomes and positive economic outcomes in hospital settings. Conclusions Clinical pathways evaluations commonly use pragmatic study designs, straightforward statistical tests and cost–consequence analyses. More HealthPathways program evaluations focused on patient and economic outcomes, clinical pathway evaluations in a primary care setting and cost-effectiveness analyses of clinical pathways are needed. What is known about the topic? HealthPathways is a web-based program that originated from Canterbury, New Zealand, and has seen uptake elsewhere in New Zealand, Australia and the UK. The HealthPathways program aims to assist the provision of consistent and integrated health services through dedicated, localised pathways for various health conditions specific to the health region. Evaluations of HealthPathways program focused on patient and economic outcomes have been limited. What does this paper add? This review synthesises the academic literature of clinical pathways evaluations in order to inform a subsequent HealthPathways evaluation. The focus of the synthesis was on the analytical methods and study designs used in the previous evaluations. The previous clinical pathway evaluations have been pragmatic in nature with relatively straightforward study designs and analysis. What are the implications for practitioners? There is a need for more economic and patient outcome evaluations for HealthPathways programs. More sophisticated statistical analyses and economic evaluations could add value to these evaluations, where appropriate and taking into consideration the data limitations.
Publisher: Wiley
Date: 14-12-2016
DOI: 10.1111/AJCO.12650
Abstract: To determine the incidence of symptomatic versus incidental pulmonary embolism (PE) in oncology patients, characterize the nature and extent of incidental PE and the factors contributing to diagnosis. Specialized web search engine was used to identify oncology patients with positive imaging studies for PE. PE identified at staging CT scans were classified as incidental PEs, whereas PE diagnosed by CTPA/VQ scan were classified as symptomatic PEs. A total of 111 patients with PE were identified over the period of three years. Of these, 67 (60%) patients had symptomatic whereas 44 (40%) patients had incidental PE. Most PEs were segmental and non-occlusive irrespective of the type of PE or stage of the disease. Incidence of PE was equal with/without chemotherapy. Platinum-based chemotherapy was more commonly associated with PE. Most patients received anticoagulation irrespective of type of PE. Forty percent of the diagnosed PEs were incidental, more common in the metastatic group. This may be due to the increased frequency of staging scans performed in patients with metastatic disease, as well as the inherent disease biology of metastatic compared with localized disease. Further prospective analysis of survival by PE subtype and optimal length of anticoagulation in incidental PE is warranted.
Publisher: Springer Science and Business Media LLC
Date: 11-06-2013
DOI: 10.1038/BJC.2013.279
Publisher: Elsevier BV
Date: 2015
Publisher: BMJ
Date: 12-2019
Abstract: Erlotinib used in the treatment of advanced non-small cell lung cancer (NSCLC) is a first-generation small-molecule tyrosine kinase inhibitor which reversibly inhibits the kinase domain of epithelial growth factor receptor (EGFR). The incidence of ocular toxicities as adverse effects (AE) of erlotinib is relatively common. However, post-marketing, acute anterior uveitis (AAU) has been reported in a small number of cases as a putative AE resulting from erlotinib therapy. We present a case of a 67-year-old, Caucasian woman, lifelong non-smoker with stage IV NSCLC who presents with decreased visual acuity and ‘floaters’ 6 weeks after commencing erlotinib. She was later diagnosed with erlotinib-associated bilateral AAU. This is the fifth documented case of erlotinib-associated bilateral AAU since 2010, highlighting the rarity of this AE. Thus, the possibility of AAU should always be considered in patients on EGFR-blocking therapies as significant ocular damage can occur if ophthalmic complaints are not triaged and assessed quickly.
Publisher: American Society of Clinical Oncology (ASCO)
Date: 20-07-2022
DOI: 10.1200/JCO.21.02198
Abstract: The phase III KEYNOTE-048 (ClinicalTrials.gov identifier: NCT02358031 ) trial of pembrolizumab in recurrent or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) included planned efficacy analyses in the total population and in participants with programmed death ligand-1 (PD-L1) combined positive score (CPS) ≥ 1 and CPS ≥ 20. To further characterize the predictive value of PD-L1 expression on outcome, we conducted efficacy analyses in the PD-L1 CPS 1 and CPS 1-19 subgroups in KEYNOTE-048. Participants with R/M HNSCC and no prior systemic therapy for R/M disease were randomly assigned 1:1:1 to pembrolizumab, pembrolizumab-chemotherapy, or cetuximab-chemotherapy. Post hoc efficacy analyses of the PD-L1 CPS 1 and CPS 1-19 subgroups were performed. Of 882 participants enrolled, 128 had PD-L1 CPS 1 and 373 had CPS 1-19. For pembrolizumab versus cetuximab-chemotherapy, the median overall survival was 7.9 versus 11.3 months in the PD-L1 CPS 1 subgroup (hazard ratio [HR], 1.51 [95% CI, 0.96 to 2.37]) and 10.8 versus 10.1 months in the CPS 1-19 subgroup (HR, 0.86 [95% CI, 0.66 to 1.12]). For pembrolizumab-chemotherapy versus cetuximab-chemotherapy, the median overall survival was 11.3 versus 10.7 months in the PD-L1 CPS 1 subgroup (HR, 1.21 [95% CI, 0.76 to 1.94]) and 12.7 versus 9.9 months in the CPS 1-19 subgroup (HR, 0.71 [95% CI, 0.54 to 0.94]). Increased efficacy of pembrolizumab or pembrolizumab-chemotherapy was observed with increasing PD-L1 expression. PD-L1 CPS 1 subgroup analysis was limited by small participant numbers. Results from the PD-L1 CPS 1-19 subgroup support previous findings of treatment benefit with pembrolizumab monotherapy and pembrolizumab-chemotherapy in patients with PD-L1 CPS ≥ 1 tumors. Although PD-L1 expression is informative, exploration of additional predictive biomarkers is needed for low PD-L1–expressing HNSCC.
Publisher: Ubiquity Press, Ltd.
Date: 2022
DOI: 10.5334/IJIC.5997
Publisher: Elsevier BV
Date: 10-2020
DOI: 10.1016/J.IMMUNI.2020.09.010
Abstract: The activating receptor CD226 is expressed on lymphocytes, monocytes, and platelets and promotes anti-tumor immunity in pre-clinical models. Here, we examined the role of CD226 in the function of tumor-infiltrating lymphocytes (TILs) and resistance to immunotherapy. In murine tumors, a large proportion of CD8
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 09-2012
Publisher: Elsevier BV
Date: 03-2022
DOI: 10.1016/J.JTHO.2021.10.023
Abstract: First-line therapy for patients with metastatic NSCLC includes checkpoint inhibitor monotherapy, dual checkpoint inhibition, or combination with chemotherapy. We compared outcomes with combination chemoimmunotherapy versus dual checkpoint inhibition as first-line treatment for patients with metastatic NSCLC. This open-label, randomized clinical trial was conducted at 44 sites in Canada and Australia. Patients with treatment-naive, metastatic NSCLC without sensitizing EGFR or ALK alterations were randomized (1:1) to receive treatment with durvalumab plus tremelimumab with or without platinum-doublet chemotherapy. The primary end point was overall survival (OS). Secondary end points were progression-free survival, overall response rate, and safety. A total of 301 patients were randomized. Median OS was 16.6 months (95% confidence interval [CI]: 12.6-19.1) with chemotherapy plus immunotherapy and 14.1 months (95% CI: 10.6-18.3) with immunotherapy (hazard ratio = 0.88, 90% CI: 0.67-1.16, p = 0.46). Median progression-free survival with chemotherapy plus immunotherapy was 7.7 months (95% CI: 5.5-8.5) and 3.2 months (95% CI: 2.7-5.1) with immunotherapy (hazard ratio = 0.67, 95% CI: 0.52-0.88). The overall response rate with chemoimmunotherapy was 42.4% and 29.3% with immunotherapy (adjusted OR = 1.69, 95% CI: 1.04-2.76). The percentage of patients with grade 3 or higher adverse events was 82% in the chemotherapy plus immunotherapy group and 70% in the immunotherapy group. Exploratory analyses of programmed death-ligand 1 expression and blood-based tumor mutation burden revealed no differential treatment effect on OS. The addition of chemotherapy to durvalumab plus tremelimumab in the first-line treatment of stage IV NSCLC did not improve survival compared with durvalumab plus tremelimumab alone. Further study is warranted to identify patients that benefit from initial immunotherapy alone versus combination chemotherapy plus immunotherapy as first-line treatment.
Publisher: Wiley
Date: 09-02-2017
DOI: 10.1111/AJCO.12649
Abstract: Despite recent advances, outcomes for patients with stage III non-small cell lung cancer (NSCLC) with concurrent chemoradiotherapy (CRT) remain poor. We evaluated the combination of ciplatin/vinorelbine and concurrent thoracic radiotherapy followed by consolidation oral vinorelbine in this phase II study. Eligible patients with unresectable stage III NSCLC received cisplatin intravenous (IV) 40 mg/m Twenty-seven eligible patients were enrolled from December 2007 to June 2010 before the trial was prematurely closed due to toxicity concerns. The median age was 63 years (range, 42-71), 56% were male, 52% ECOG 0 and 52% stage IIIa. The ORR was 81% (including 37% complete response rate) and disease control rate of 93%. The median PFS was 11 months and median OS was 26 months. Consolidation vinorelbine was associated with significant grade 3/4 toxicity (68%) including grade 3-5 febrile neutropenia (27%) and respiratory infections (36%) including two deaths in the consolidation phase (9%). Consolidation oral vinorelbine after CRT was associated with significant toxicity. Overall, this regimen achieved a high ORR and survival results comparable to other CRT protocols but the significant toxicity precludes further evaluation of this approach.
Publisher: Springer Science and Business Media LLC
Date: 10-02-2016
Abstract: Evidence-based practice guidelines are available to assist in the decision making for nutrition interventions in patients with head and neck cancer. Re-assessment of guideline recommendations is important with changing demographics, new treatment regimens, advancing radiotherapy techniques, such as helical intensity-modulated radiotherapy, and the emergence of new literature. The aim of this study was to validate the updated high-risk category definition in our local hospital protocol for the swallowing and nutrition management of patients with head and neck cancer to determine the ongoing predictive ability for identifying proactive gastrostomy requirement in a new cohort. Patients attending a major tertiary hospital for head and neck cancer treatment from 2010 to 2011 were included (n=270). Data were collected on patient demographics (age and gender), clinical factors (tumour site, staging and treatment), nutrition outcome measures (weight, enteral feeding) and protocol adherence. Sensitivity and specificity were calculated and compared with the original validation study. Proactive gastrostomy tubes were inserted in 86 patients. Overall protocol adherence was 93%. Sensitivity improved to 72% (increase of 18%) and specificity improved to 96% (increase of 3%) compared with the original validation study where patients received three-dimensional (3-D) conformal radiotherapy. The results of this study confirm that the updated high-risk category in the protocol for the swallowing and nutrition management of patients with head and neck cancer remains valid to predict proactive gastrostomy in a mixed population receiving helical intensity-modulated radiotherapy and 3-D conformal radiotherapy. The protocol has an improved sensitivity and specificity and hence remains just as relevant for advanced techniques of radiation treatment delivery.
Publisher: Elsevier BV
Date: 11-2019
Publisher: American Society of Clinical Oncology (ASCO)
Date: 02-2023
DOI: 10.1200/JCO.21.02508
Abstract: Pembrolizumab and pembrolizumab-chemotherapy demonstrated efficacy in recurrent/metastatic head and neck squamous cell carcinoma in KEYNOTE-048. Post hoc analysis of long-term efficacy and progression-free survival on next-line therapy (PFS2) is presented. Patients were randomly assigned (1:1:1) to pembrolizumab, pembrolizumab-chemotherapy, or cetuximab-chemotherapy. Efficacy was evaluated in programmed death ligand 1 (PD-L1) combined positive score (CPS) ≥ 20, CPS ≥ 1, and total populations, with no multiplicity or alpha adjustment. The median study follow-up was 45.0 months (interquartile range, 41.0-49.2 n = 882). At data cutoff (February 18, 2020), overall survival improved with pembrolizumab in the PD-L1 CPS ≥ 20 (hazard ratio [HR], 0.61 95% CI, 0.46 to 0.81) and CPS ≥ 1 populations (HR, 0.74 95% CI, 0.61 to 0.89) and was noninferior in the total population (HR, 0.81 95% CI, 0.68 to 0.97). Overall survival improved with pembrolizumab-chemotherapy in the PD-L1 CPS ≥ 20 (HR, 0.62 95% CI, 0.46 to 0.84), CPS ≥ 1 (HR, 0.64 95% CI, 0.53 to 0.78), and total (HR, 0.71 95% CI, 0.59 to 0.85) populations. The objective response rate on second-course pembrolizumab was 27.3% (3 of 11). PFS2 improved with pembrolizumab in the PD-L1 CPS ≥ 20 (HR, 0.64 95% CI, 0.48 to 0.84) and CPS ≥ 1 (HR, 0.79 95% CI, 0.66 to 0.95) populations and with pembrolizumab-chemotherapy in the PD-L1 CPS ≥ 20 (HR, 0.64 95% CI, 0.48 to 0.86), CPS ≥ 1 (HR, 0.66 95% CI, 0.55 to 0.81), and total (HR, 0.73 95% CI, 0.61 to 0.88) populations. PFS2 was similar after pembrolizumab and longer after pembrolizumab-chemotherapy on next-line taxanes and shorter after pembrolizumab and similar after pembrolizumab-chemotherapy on next-line nontaxanes. With a 4-year follow-up, first-line pembrolizumab and pembrolizumab-chemotherapy continued to demonstrate survival benefit versus cetuximab-chemotherapy in recurrent/metastatic head and neck squamous cell carcinoma. Patients responded well to subsequent treatment after pembrolizumab-based therapy.
Publisher: Elsevier BV
Date: 09-2017
DOI: 10.1016/J.EJCA.2017.05.019
Abstract: Central nervous system (CNS) progression is common in patients with anaplastic lymphoma kinase-positive (ALK+) non-small-cell lung cancer (NSCLC) receiving crizotinib. Next-generation ALK inhibitors have shown activity against CNS metastases, but accurate assessment of response and progression is vital. Data from two phase II studies in crizotinib-refractory ALK+ NSCLC were pooled to examine the CNS efficacy of alectinib, a CNS-active ALK inhibitor, using Response Evaluation Criteria in Solid Tumours (RECIST version 1.1) and Response Assessment in Neuro-Oncology high-grade glioma (RANO-HGG) criteria. Both studies enrolled patients aged ≥18 years who had previously received crizotinib. NP28761 was conducted in North America and NP28673 was a global study. All patients received 600 mg oral alectinib twice daily and had baseline CNS imaging. CNS response for those with baseline CNS metastases was determined by an independent review committee. Baseline measurable CNS disease was identified in 50 patients by RECIST and 43 by RANO-HGG. CNS objective response rate was 64.0% by RECIST (95% confidence interval [CI]: 49.2-77.1 11 CNS complete responses [CCRs]) and 53.5% by RANO-HGG (95% CI: 37.7-68.8 eight CCRs). CNS responses were durable, with consistent estimates of median duration of 10.8 months with RECIST and 11.1 months with RANO-HGG. Of the 39 patients with measurable CNS disease by both RECIST and RANO-HGG, only three (8%) had CNS progression according to one criteria but not the other (92% concordance rate). Alectinib demonstrated promising efficacy in the CNS for ALK+ NSCLC patients pretreated with crizotinib, regardless of the assessment criteria used.
Publisher: Elsevier BV
Date: 03-2018
Publisher: BMJ
Date: 08-2021
Abstract: To provide pooled longer term data from three groups of a phase 2 study of cemiplimab in patients with advanced cutaneous squamous cell carcinoma (CSCC), and to determine duration of response (DOR) and impact on quality of life (QoL). Patients received cemiplimab 3 mg/kg every 2 weeks (group 1, metastatic CSCC [mCSCC], n=59 group 2, locally advanced CSCC, n=78) or cemiplimab 350 mg every 3 weeks (group 3, mCSCC, n=56). Primary endpoint was objective response rate (ORR) per independent central review (ICR). QoL was repeatedly measured at day 1 of each treatment cycle (groups 1 and 2: 8 weeks group 3: 9 weeks). Median duration of follow-up was 15.7 months. Overall, ORR per ICR was 46.1% (95% CI: 38.9% to 53.4%). Complete response (CR) rates were 20.3%, 12.8%, and 16.1% for groups 1, 2, and 3, respectively. Median time to CR was 11.2 months. Among patients with partial response or CR, the estimated proportion of patients with ongoing response at 12 months from the first objective response was 87.8% (95% CI: 78.5% to 93.3%), with median DOR not reached. Kaplan-Meier estimated probability of overall survival (OS) was 73.3% (95% CI: 66.1% to 79.2%) at 24 months, with median OS not reached. Global Health Status (GHS)/QoL improvements were observed as early as cycle 2 and were significantly improved and durable until last assessment. Kaplan-Meier estimate of median time to first clinically meaningful improvement for pain was 2.1 (95% CI: 2.0 to 3.7) months and was significantly improved in responders versus non-responders (p .0001). This is the largest (n=193) clinical dataset for a programmed cell death-1 inhibitor against advanced CSCC, confirming the sustained substantial clinical activity of cemiplimab in these patients, including new findings of improved CR rates over time, increasing DOR, and durable pain control and GHS/QoL improvement. ClinicalTrials.gov Registry ( NCT02760498 ), clinicaltrialsgov/ct2/show/NCT02760498 .
Publisher: Frontiers Media SA
Date: 03-04-2023
DOI: 10.3389/FIMMU.2023.1135489
Abstract: Mucosal head and neck squamous cell carcinoma (HNSCC) are the seventh most common cancer, with approximately 50% of patients living beyond 5 years. Immune checkpoint inhibitors (ICIs) have shown promising results in patients with recurrent or metastatic (R/M) disease, however, only a subset of patients benefit from immunotherapy. Studies have implicated the tumor microenvironment (TME) of HNSCC as a major factor in therapy response, highlighting the need to better understand the TME, particularly by spatially resolved means to determine cellular and molecular components. Here, we employed targeted spatial profiling of proteins on a cohort of pre-treatment tissues from patients with R/M disease to identify novel biomarkers of response within the tumor and stromal margins. By grouping patient outcome categories into response or non-response, based on Response Evaluation Criteria in Solid Tumors (RECIST) we show that immune checkpoint molecules, including PD-L1, B7-H3, and VISTA, were differentially expressed. Patient responders possessed significantly higher tumor expression of PD-L1 and B7-H3, but lower expression of VISTA. Analysis of response subgroups indicated that tumor necrosis factor receptor (TNFR) superfamily members including OX40L, CD27, 4-1BB, CD40, and CD95/Fas, were associated with immunotherapy outcome. CD40 expression was higher in patient-responders than non responders, while CD95/Fas expression was lower in patients with partial response (PR) relative to those with stable disease (SD) and progressive disease (PD). Furthermore, we found that high 4-1BB expression in the tumor compartment, but not in the stroma, was associated with better overall survival (OS) (HR= 0.28, p-adjusted= 0.040). Moreover, high CD40 expression in tumor regions (HR= 0.27, p-adjusted= 0.035), and high CD27 expression in the stroma (HR= 0.2, p-adjusted=0.032) were associated with better survival outcomes. Taken together, this study supports the role of immune checkpoint molecules and implicates the TNFR superfamily as key players in immunotherapy response in our cohort of HNSCC. Validation of these findings in a prospective study is required to determine the robustness of these tissue signatures.
Publisher: Wiley
Date: 20-02-2014
DOI: 10.1111/AJCO.12167
Abstract: Perioperative chemotherapy has improved the prognosis for patients with operable osteosarcoma. The literature is conflicting about which regimen is optimal. The aim of this study was to evaluate the survival outcomes of two cohorts of patients with operable osteosarcoma treated with different perioperative chemotherapy regimens. This was a retrospective review of patients diagnosed with operable osteosarcoma treated at the Princess Alexandra Hospital from 1986 to 2009. The standard perioperative chemotherapy regimen changed from the modified T10 Rosen protocol to cisplatin/doxorubicin in 1997. Using the Kaplan-Meier method, overall survival (OS) and disease-free survival (DFS) curves were generated for the cisplatin/doxorubicin and the modified T10 Rosen cohorts. Seventy-one patients were identified of whom 63 had potentially curable disease. Of these, 24 received the modified T10 Rosen regimen and 39 received cisplatin/doxorubicin. There was a non-significant trend toward better OS and DFS in the patients who received the modified T10 Rosen protocol. The trend toward poorer survival in the cisplatin/doxorubicin cohort, in combination with current evidence, has prompted our institution to change its practice.
Publisher: Massachusetts Medical Society
Date: 27-10-2022
Publisher: Wiley
Date: 03-11-2010
DOI: 10.1111/J.1743-7563.2010.01332.X
Abstract: Bilateral uveal metastases from papillary thyroid carcinoma are extremely rare. A 36-year-old woman with a 12-month history of papillary thyroid carcinoma presented with sudden loss of visual acuity and fields in the left eye. An examination and B-scan revealed a large, solid choroidal lesion in the left eye causing exudative retinal detachment. A small solid mass was also observed in the right eye fundus. Following left eye enucleation, immunohistopathology confirmed metastatic papillary thyroid carcinoma. The authors report the third known case of bilateral choroidal metastases.
Publisher: Elsevier BV
Date: 2017
DOI: 10.1016/J.ORALONCOLOGY.2016.11.009
Abstract: There is limited prospective data reporting the extent of treatment related toxicities associated with helical Intensity Modulated Radiotherapy (H-IMRT) for head and neck cancer (HNC). The study aim was to investigate severity, peak incidence and recovery patterns of dysphagia and related toxicities in patients undergoing H-IMRT±chemotherapy to examine when patients are experiencing symptoms requiring supportive clinical care. Prospective study of 212 patients undergoing H-IMRT. Dysphagia and associated acute toxicities were monitored weekly during treatment and at weeks 2, 4 and 12 post treatment using the CTCAE v4, Functional Oral Intake Score and National Dysphagia Diet Descriptors. 75% experienced Grade 2-3 dysphagia. Over 70% had grade 2-3 dysguesia, xerostomia, and thick saliva, and >50% experienced grade 2-3 pharyngeal mucositis, oral mucositis, and nausea. 13% patients declined to NBM requiring complete enteral nutrition, 25% required enteral nutrition but maintained some form of oral intake. Symptoms peaked in final week of treatment, consistently improving thereafter, with the majority better than baseline by 12 weeks post-treatment. Concurrent chemotherapy at least doubles the odds of experiencing most symptoms excepting xerostomia, taste and fluid level. Despite advancements in radiation techniques, results confirm a high proportion of HNC patients experience dysphagia and related toxicities requiring supportive care during H-IMRT. Patients receiving H-IMRT alone experience a lower incidence of symptoms compared with those receiving concurrent chemotherapy. The data confirms the ongoing need for active on treatment monitoring with implications for the timing and intensity of patient support services.
Publisher: Elsevier BV
Date: 10-2021
Publisher: Springer Science and Business Media LLC
Date: 26-08-2015
Abstract: Since 2007, our institution has used validated guidelines for the insertion of proactive gastrostomy feeding tubes in patients with head and neck cancer. Helical intensity-modulated radiotherapy (H-IMRT) delivered by Tomotherapy, is an advanced radiotherapy technique introduced at our centre in 2010. This form of therapy reduces long-term treatment-related toxicity to normal tissues. The aim of this study is to compare weight change and need for tube feeding following H-IMRT (n=53) with patients that would have previously been treated with three-dimensional conformal radiotherapy (n=134). Patients with head and neck cancer assessed as high nutritional risk with recommendation for proactive gastrostomy were identified from cohorts from 2007 to 2008 and 2010 to 2011. Retrospective data were collected on clinical factors, weight change from baseline to completion of treatment, incidence of severe weight loss (⩾ 10%) and tube feeding. Statistical analyses to compare outcomes between the two treatments included χ(2)-test, Fisher's exact and two-s le Wilcoxon tests (P<0.05). The H-IMRT cohort had higher proportions of patients with definitive chemoradiotherapy (P=0.032) and more advanced N stage (P 5% and high incidences of tube feeding and severe weight loss. Nutrition intervention remains critical in this patient population, despite advances in radiotherapy techniques, and no changes to current management are recommended.
Publisher: S. Karger AG
Date: 17-08-2022
DOI: 10.1159/000525727
Abstract: b i Introduction: /i /b The digitization of hospital systems, including integrated electronic medical records, has provided opportunities to improve the prediction performance of inpatient fall risk models and their application to computerized clinical decision support systems. This review describes the data sources and scope of methods reported in studies that developed inpatient fall prediction models, including machine learning and more traditional approaches to inpatient fall risk prediction. b i Methods: /i /b This scoping review used methods recommended by the Arksey and O’Malley framework and its recent advances. PubMed, CINAHL, IEEE Xplore, and EMBASE databases were systematically searched. Studies reporting the development of inpatient fall risk prediction approaches were included. There was no restriction on language or recency. Reference lists and manual searches were also completed. Reporting quality was assessed using adherence to Transparent Reporting of a multivariable prediction model for In idual Prognosis or Diagnosis statement (TRIPOD), where appropriate. b i Results: /i /b Database searches identified 1,396 studies, 63 were included for scoping assessment and 45 for reporting quality assessment. There was considerable overlap in data sources and methods used for model development. Fall prediction models typically relied on features from patient assessments, including indicators of physical function or impairment, or cognitive function or impairment. All but two studies used patient information at or soon after admission and predicted fall risk over the entire admission, without consideration of post-admission interventions, acuity changes or length of stay. Overall, reporting quality was poor, but improved in the past decade. b i Conclusion: /i /b There was substantial homogeneity in data sources and prediction model development methods. Use of artificial intelligence, including machine learning with high-dimensional data, remains underexplored in the context of hospital falls. Future research should consider approaches with the potential to utilize high-dimensional data from digital hospital systems, which may contribute to greater performance and clinical usefulness.
Publisher: Wiley
Date: 2022
DOI: 10.1002/CTI2.1397
Abstract: Head and neck squamous cell carcinoma (HNSCC) represents a heterogeneous group of tumors. While significant progress has been made using multimodal treatment, the 5‐year survival remains at 50%. Developing effective therapies, such as immunotherapy, will likely lead to better treatment of primary and metastatic disease. However, not all HNSCC tumors respond to immune checkpoint blockade therapy. Understanding the complex cellular composition and interactions of the tumor microenvironment is likely to lead to new knowledge for effective therapies and treatment resistance. In this review, we discuss HNSCC characteristics, predictive biomarkers, factors influencing immunotherapy response, with a focus on the tumor microenvironment.
Publisher: Elsevier BV
Date: 06-2015
DOI: 10.1016/J.ORALONCOLOGY.2015.03.006
Abstract: This study examined long term swallowing outcomes of a cohort of head and neck cancer (HNC) patients identified at high risk of experiencing significant side effects from cancer treatment and were provided with a proactive PEG. Ninety-five HNC patients receiving definitive or adjuvant radiotherapy +/- chemotherapy were identified for proactive PEG placement using validated guidelines and followed for up to 3years. Functional swallowing status was recorded at regular time points and data were collected on PEG use and duration in situ. Mean duration of enteral feeding was 125days. PEGs remained in situ for approximately 7months. PEG removal was achieved by 52% by 6months and 86% by 1year. Only 3 (3%) remained PEG dependent at 3years. Over half (55%) had resumed a full non-texture modified diet by PEG removal. Proactive PEG placement did not lead to high proportion of long term tube dependence in this high risk group and the majority achieved good swallowing outcomes.
Publisher: SAGE Publications
Date: 09-2005
DOI: 10.1345/APH.1E634
Abstract: To describe a case of severe accidental cyanide poisoning following a single ingestion of amygdalin with therapeutic intent. A 68-year-old patient with cancer presented to the emergency department shortly after her first dose (3 g) of amygdalin with a reduced Glasgow Coma Score, seizures, and severe lactic acidosis requiring intubation and ventilation. The patient also ingested 4800 mg of vitamin C per day. She responded rapidly to hydroxocobalamin treatment. The adverse drug reaction was rated probable on the Naranjo probability scale. Amygdalin and laetrile (a synthetic form of amygdalin) are commonly used as complementary or alternative medicine (CAM) for the treatment of cancer. Vitamin C is known to increase the in vitro conversion of amygdalin to cyanide and reduce body stores of cysteine, which is used to detoxify cyanide. Amygdalin has been used for decades by patients with cancer who are seeking alternative therapies, and severe reactions have not been reported with this dose. An interaction with vitamin C is a plausible explanation for this life-threatening response. This case highlights the fact that CAMs can produce life-threatening toxicity. This case also adds a further note of caution, namely, the potential for serious interactions between CAMs, particularly where there is no tradition of concomitant use.
Publisher: Wiley
Date: 12-11-2019
DOI: 10.1111/AJCO.13242
Abstract: Studies suggest that combining radiotherapy (RT) with programmed cell death protein 1 (PD-1) blockade may elicit a synergistic antitumor response. We aimed to assess whether prior or concurrent RT was associated with improved disease control in patients with metastatic non-small cell lung cancer (NSCLC) treated with nivolumab. We conducted a retrospective study of patients receiving nivolumab as second or subsequent line therapy for metastatic NSCLC. Patients were categorized into those who received any RT for NSCLC prior to or during nivolumab therapy, and those with no history of RT for NSCLC. A total of 85 patients received nivolumab between July 2015 and December 2016 and were followed up for a median of 15 months. Sixty-five patients (76.4%) received RT prior to or during nivolumab and 20 patients (23.6%) received nivolumab alone. Baseline characteristics of age, performance status, histology, smoking status and previous therapy were similar between the two groups. Prior or concurrent RT was associated with a superior PFS, median 2.8 months with RT versus 1.3 months without RT (Hazard Ratio (HR) = 0.494 95% Confidence Interval (CI), 0.279-0.873 P = 0.02). The median OS of the group receiving RT was 6.4 months versus 4.2 months for the no RT group (P = 0.20). RT was not associated with an increase in toxicity. RT prior to or concurrent with nivolumab for metastatic NSCLC was associated with a modest improvement in PFS over nivolumab alone with no evidence of increase in adverse effects. RT may potentiate the effect of anti-PD-1 immunotherapy in NSCLC.
Publisher: Massachusetts Medical Society
Date: 26-07-2018
Publisher: Wiley
Date: 11-04-2021
DOI: 10.1111/AJO.13347
Abstract: Surgical site infection (SSI) following caesarean section is a serious but underreported problem with an estimated incidence of 5–9%. It is essential to identify adherence to established prevention strategies to reduce the incidence rate. The aims of this study were to quantify unwarranted variation from evidence‐based practice on the prevention of SSI at caesarean section in Australia and to identify predictors of not implementing an existing infection prevention bundle: pre‐incision antibiotic prophylaxis, vaginal preparation and spontaneous placenta removal. An online cross‐sectional survey of obstetricians and obstetric Diplomates was conducted in 2016. The primary outcome was adherence to an existing infection prevention bundle, with demographic and clinical variables predicting adherence through multivariable binary logistic regression. Forty‐nine percent of respondents (response rate 39.6%) reported implementing zero or only one element of the infection prevention bundle. The types of respondents most likely to have poor adherence were Diplomates (adjusted odds ratio (aOR) 2.58), obstetricians practising in private hospitals (aOR 3.34), those usually practising in public and private hospitals (aOR 2.23), and those not usually implementing a surgical safety checklist (aOR 3.77). Adherence to best practice at caesarean section is low among many Australian obstetricians. Infection control practitioners and obstetricians need to collaboratively implement surgical safety checklists at caesarean section, and monitor implementation using process key performance indicators, and audit and feedback. These strategies will reduce unwarranted variation from evidence‐based infection control practice.
Publisher: Elsevier BV
Date: 11-2021
DOI: 10.1016/J.IJROBP.2021.04.015
Abstract: The excellent prognosis of patients with low-risk human papillomavirus (HPV)- associated oropharyngeal squamous cell carcinoma has led to concerns about overtreatment and excessive toxicity with radiation therapy and cisplatin, leading to interest in de-intensification trials. We investigated whether cetuximab, an epidermal growth factor receptor targeting antibody, when combined with radiation therapy would result in a decrease in symptom burden and toxicity with similar efficacy compared with weekly cisplatin. TROG12.01, a randomized, multicenter trial involving 15 sites in Australia and New Zealand enrolled patients with HPV-associated oropharyngeal squamous cell carcinoma, American Joint Committee on Cancer 7th edition stage III (excluding T1-2N1) or stage IV (excluding T4 and/or N3 and/or N2b-c if smoking history >10 pack years and/or distant metastases). Patients were randomized (1:1) to receive radiation therapy (70 Gy in 35 fractions) with either weekly cisplatin, 7 doses of 40 mg/m Between June 17, 2013, and June 7, 2018, 189 patients were enrolled, with 92 in cisplatin arm and 90 in cetuximab included in the main analysis. There was no difference in the primary endpoint of symptom severity difference in area under the curve cetuximab-cisplatin was 0.05 (95% confidence interval [CI], -0.19, 0.30), P = .66. The T-score (mean number of ≥grade 3 acute adverse events) was 4.35 (standard deviation 2.48) in the cisplatin arm and 3.82 (standard deviation 1.8) in the cetuximab arm, P = .108. The 3-year failure-free survival rates were 93% (95% CI, 86%-97%) in the cisplatin arm and 80% (95% CI, 70%-87%) in the cetuximab arm (hazard ratio = 3.0 [95% CI, 1.2-7.7]) P = .015. For patients with low-risk HPV-associated oropharyngeal cancer, radiation therapy and cetuximab had inferior failure-free survival without improvement in symptom burden or toxicity compared with radiation therapy and weekly cisplatin. Radiation therapy and cisplatin remain the standard of care.
Publisher: American Society of Clinical Oncology (ASCO)
Date: 12-2019
DOI: 10.1200/JGO.19.00029
Abstract: Travel for patients with cancer has become more achievable because of gains in quality of life and overall survival. The risk assessment of these patients is complex, and there is a paucity of data to which clinicians can refer. We present the challenges of traveling with cancer and a review of the literature. A review using Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines was performed. A search using the terms ”cancer,” “advanced cancer,” ”metastases,” “brain edema,” “lymphoedema,” “pneumothorax,” ”pleural effusion,” “pericardial effusion,” pneumonitis,” “hypoxia,” “end-of-life,” and “shunt,” combined with “flying” and “air travel,” was conducted. The PubMed and Cochrane databases were searched for English-language studies up to December 2018. Studies, case reports, or guidelines referring to travel in the context of adult patients with malignancies were included. A total of 745 published articles were identified 16 studies were included. An inclusive approach to data extraction was used. There were no specific criteria to deem a patient with cancer fit to travel. Neurologic, respiratory, and cardiac implications, and time from recent surgery or procedure need to be considered There was a lack of high-quality studies to inform decisions, but the British Thoracic Society and Aerospace Medical Association Medical Guidelines included recommendations for fitness to fly for patients with cancer. In the absence of large prospective studies, in idual fitness to travel should be assessed on a case-by-case basis, bearing in mind that maximizing a patient’s ability to safely travel is an important goal for many in iduals with cancer.
Publisher: Springer Science and Business Media LLC
Date: 16-06-2022
DOI: 10.1038/S41598-022-14226-6
Abstract: We examined systems-level costs before and after the implementation of an emergency department paediatric sepsis screening, recognition and treatment pathway. Aggregated hospital admissions for all children aged 18y with a diagnosis code of sepsis upon admission in Queensland, Australia were compared for 16 participating and 32 non-participating hospitals before and after pathway implementation. Monte Carlo simulation was used to generate uncertainty intervals. Policy impacts were estimated using difference-in-difference analysis comparing observed and expected results. We compared 1055 patient episodes before (77.6% in-pathway) and 1504 after (80.5% in-pathway) implementation. Reductions were likely for non-intensive length of stay (− 20.8 h [− 36.1, − 8.0]) but not intensive care (–9.4 h [− 24.4, 5.0]). Non-pathway utilisation was likely unchanged for interhospital transfers (+ 3.2% [− 5.0%, 11.4%]), non-intensive (− 4.5 h [− 19.0, 9.8]) and intensive (+ 7.7 h, [− 20.9, 37.7]) care length of stay. After difference-in-difference adjustment, estimated savings were 596 [277, 942] non-intensive and 172 [148, 222] intensive care days. The program was cost-saving in 63.4% of simulations, with a mean value of $97,019 [− $857,273, $1,654,925] over 24 months. A paediatric sepsis pathway in Queensland emergency departments was associated with potential reductions in hospital utilisation and costs.
Publisher: Medknow
Date: 2020
Publisher: BMJ
Date: 05-2021
DOI: 10.1136/BMJOPEN-2020-044655
Abstract: Sars-CoV-2 is a novel coronavirus responsible for COVID-19 officially declared pandemic in March 2020. Health systems worldwide responded with swift changes to increase workflow capacity while protecting the vulnerable, including those with cancer. This led to unprecedented and rapid restructuring of health service provision. Published data from the 2003 SARS pandemic focuses on medical and nursing staff, overlooking other departmental employees such as administration officers or food service workers. Our protocol aims to document directives and adjustments communicated to staff in two cancer care departments and correlate this with measures of distress and perceived preparedness across the spectrum of all staff involved in cancer care. We use a semiqualitative approach comprising weekly diarising of events and simultaneous staff surveys. Principal investigators will document changes at a metropolitan quaternary cancer centre and a regional cancer centre. Communications, directives and changes will be diarised in real time in four executional domains. Simultaneously, prospective voluntary self-administered online surveys will be conducted at regular intervals by staff. The survey assesses the perceived institutional preparedness and personal well-being, with a combination of Likert scaled and open response questions. A semiquantitative self-assessment of distress adapted from National Comprehensive Cancer Network distress thermometer is incorporated. Additionally, open-text personal reflections on themes including difficult decisions will be invited. Survey participants will be drawn from various work areas of the cancer care departments: administrative staff, health professionals, for ex le, allied health, ancillary workers, nursing and medical. The study has been reviewed and approved by the Human Research Ethics Committee (LNR/2020/QRBW/62982). Published literature on domains of distress neglects categories of healthcare worker who form an essential part of the care delivery team. Our study hopes to gather insights about psychosocial impact and adjustment which could direct responses in future emergencies.
Publisher: Wiley
Date: 13-09-2013
DOI: 10.1002/HED.23146
Abstract: The "Swallowing and Nutrition Guidelines for Patients with Head and Neck Cancer" were developed to guide early identification and management of dysphagia and nutritional risk before, during, and after cancer treatment. The purpose of this study was to validate these guidelines. Patients attending a Combined Head and Neck Clinic at a major tertiary hospital in 2007 to 2008 were assessed using the guidelines, with high-risk category patients recommended for proactive gastrostomy. Data were collected on guideline adherence, gastrostomy tube insertion, and weight. Sensitivity, specificity, and positive predictive value were calculated for validation. Proactive gastrostomy tubes were inserted in 173 of 501 patients (25%). Overall guideline adherence was 87%. High-risk category adherence was 75%. Validation outcomes were sensitivity 54%, specificity 93%, and positive predictive value 82%. The risk categories in the guidelines are valid to assist early identification of swallowing and nutritional risk and guide decision-making on proactive gastrostomy tube insertion.
Publisher: American Association for Cancer Research (AACR)
Date: 2020
DOI: 10.1158/2159-8290.CD-19-0980
Abstract: This first-in-human study of an A2AR antagonist for cancer treatment establishes the safety and feasibility of targeting this pathway by demonstrating antitumor activity with single-agent and anti–PD-L1 combination therapy in patients with refractory RCC. Responding patients possess an adenosine-regulated gene-expression signature in pretreatment tumor biopsies. See related commentary by Sitkovsky, p. 16. This article is highlighted in the In This Issue feature, p. 1
Publisher: Elsevier BV
Date: 09-2017
DOI: 10.1016/J.ORALONCOLOGY.2017.07.017
Abstract: The main aim was to investigate the incidence of patient adherence to nutritional tube feeding recommendations in patients with head and neck cancer and to determine patient barriers to meeting tube feeding prescription. This was an observational study from a randomised controlled trial in patients with head and neck cancer deemed at high nutritional risk with prophylactic gastrostomy (n=125). Patients were randomised to receive early tube feeding prior to treatment (intervention group) or standard care. All patients in the intervention and standard care groups then commenced clinical tube feeding as required during treatment. Patients maintained a daily record of gastrostomy intake, main nutrition impact symptom necessitating gastrostomy use, and reasons for not meeting nutrition prescription. Adherence was defined as meeting ≥75% of total prescribed intake. Patients were predominantly male (89%), median age 60, with oropharyngeal tumours (78%), stage IV disease (87%) treated with chemoradiotherapy (87%). Primary reasons for gastrostomy use were poor appetite/dysgeusia (week 2-3) and odynophagia/mucositis (week 4-7). Early tube feeding adherence was 51%. Clinical tube feeding adherence was significantly higher in the intervention group (58% vs 38%, p=0.037). Key barriers to both phases of tube feeding were nausea, early satiety and treatment factors (related to hospital healthcare processes). Early tube feeding can improve patient adherence to clinically indicated tube feeding during treatment. Low adherence overall is a likely explanation for clinically significant weight loss despite intensive nutrition interventions. Optimising symptom management and strategies to overcome other barriers are key to improving adherence. This trial has been registered in the Australian New Zealand Clinical Trials registry as ACTRN12612000579897.
Publisher: Springer Science and Business Media LLC
Date: 27-07-2019
DOI: 10.1007/S00520-019-04992-X
Abstract: There are no evidence-based guidelines informing which patients with head and neck cancer (HNC) require regular speech pathology (SP) support during radiation treatment (RT). Hence, some services use a "one-size-fits-all" model, potentially over-servicing those patients at low risk for dysphagia. This study evaluated the clinical safety and efficiency of an interdisciplinary service model for patients identified prospectively as "low risk" for dysphagia during RT. A prospective cohort of 65 patients with HNCs of the skin, thyroid, parotid, nose, and salivary glands, receiving curative RT, were managed on a low-risk pathway. Patients with baseline dysphagia (functional oral intake score ≤ 5) were excluded. The model involved dietitians conducting dysphagia screening at weeks 3, 5, and 6/7 within scheduled appointments. Patients at risk of dysphagia were referred to SP for assessment, then management if required. To validate the model, SP assessed swallow status/toxicities at week 5/6/7 during RT and confirmed dysphagia status at weeks 2 and 6 post RT. Most (89.3%) patients did not require dysphagia support from SP services. Of the 18 patients identified on screening, only 7 (10.7%) had sufficient issues to return to SP care. Week 5/6/7 SP review confirmed low levels of toxicity. No post-treatment dysphagia was observed. There was an incremental benefit of A$15.02 for SP staff costs and a recovery of 5.31 appointments per patient. The pathway is a safe and effective service model to manage patients with HNC at low risk for dysphagia during RT, avoiding unnecessary SP appointments for the patient and service.
Publisher: Springer Science and Business Media LLC
Date: 09-10-2004
Publisher: Wiley
Date: 23-02-2017
DOI: 10.1002/HED.24630
Abstract: The purpose of this study was to determine if p16 status, chemotherapy regimen, or other nutrition markers could improve protocol accuracy in predicting proactive gastrostomy in patients with head and neck cancer. Patients who received curative treatment from July 2010 to June 2011 were included (n = 269). Associations among dependent variables (age, sex, tumor site, staging, treatment, p16 status, albumin, and Malnutrition Screening Tool [MST] score), the protocol risk rating, and requirement for proactive gastrostomy were examined. Current protocol correctly identified 81 of 88 high-risk patients (92%) for gastrostomy, but incorrectly classified 32 of 181 low-risk patients (18%). Analysis of low-risk patients with oral or oropharyngeal cancers, found p16-positive disease had 4.4 times greater odds (p = .049), and those at risk of malnutrition had 4.5 times greater odds (p = .019) of requiring gastrostomy. Malnutrition risk and p16 status could be used to identify further patients who may benefit from proactive gastrostomy. © 2017 Wiley Periodicals, Inc. Head Neck 39: 868-875, 2017.
Publisher: Oxford University Press (OUP)
Date: 27-03-2023
Abstract: Sustainable investment in computerized decision support systems (CDSS) requires robust evaluation of their economic impacts compared with current clinical workflows. We reviewed current approaches used to evaluate the costs and consequences of CDSS in hospital settings and presented recommendations to improve the generalizability of future evaluations. A scoping review of peer-reviewed research articles published since 2010. Searches were completed in the PubMed, Ovid Medline, Embase, and Scopus databases (last searched February 14, 2023). All studies reported the costs and consequences of a CDSS-based intervention compared with current hospital workflows. Findings were summarized using narrative synthesis. In idual studies were further appraised against the Consolidated Health Economic Evaluation and Reporting (CHEERS) 2022 checklist. Twenty-nine studies published since 2010 were included. Studies evaluated CDSS for adverse event surveillance (5 studies), antimicrobial stewardship (4 studies), blood product management (8 studies), laboratory testing (7 studies), and medication safety (5 studies). All studies evaluated costs from a hospital perspective but varied based on the valuation of resources affected by CDSS implementation, and the measurement of consequences. We recommend future studies follow guidance from the CHEERS checklist use study designs that adjust for confounders consider both the costs of CDSS implementation and adherence evaluate consequences that are directly or indirectly affected by CDSS-initiated behavior change examine the impacts of uncertainty and differences in outcomes across patient subgroups. Improving consistency in the conduct and reporting of evaluations will enable detailed comparisons between promising initiatives, and their subsequent uptake by decision-makers.
Publisher: Springer Science and Business Media LLC
Date: 23-09-2021
Publisher: Oxford University Press (OUP)
Date: 25-03-2023
Abstract: Clinical prediction models providing binary categorizations for clinical decision support require the selection of a probability threshold, or “cutpoint,” to classify in iduals. Existing cutpoint selection approaches typically optimize test-specific metrics, including sensitivity and specificity, but overlook the consequences of correct or incorrect classification. We introduce a new cutpoint selection approach considering downstream consequences using net monetary benefit (NMB) and through simulations compared it with alternative approaches in 2 use-cases: (i) preventing intensive care unit readmission and (ii) preventing inpatient falls. Parameter estimates for costs and effectiveness from prior studies were included in Monte Carlo simulations. For each use-case, we simulated the expected NMB resulting from the model-guided decision using a range of cutpoint selection approaches, including our new value-optimizing approach. Sensitivity analyses applied alternative event rates, model discrimination, and calibration performance. The proposed approach that considered expected downstream consequences was frequently NMB-maximizing compared with other methods. Sensitivity analysis demonstrated that it was or closely tracked the optimal strategy under a range of scenarios. Under scenarios of relatively low event rates and discrimination that may be considered realistic for intensive care (prevalence = 0.025, area under the receiver operating characteristic curve [AUC] = 0.70) and falls (prevalence = 0.036, AUC = 0.70), our proposed cutpoint method was either the best or similar to the best of the compared methods regarding NMB, and was robust to model miscalibration. Our results highlight the potential value of conditioning cutpoints on the implementation setting, particularly for rare and costly events, which are often the target of prediction model development research. This study proposes a cutpoint selection method that may optimize clinical decision support systems toward value-based care.
Publisher: Elsevier BV
Date: 08-2018
DOI: 10.1016/J.SCITOTENV.2018.03.106
Abstract: Anthropogenic effects of urban density have altered natural ecosystems. Such changes include eutrophication of freshwater and adjoining coastal habitats, and increased levels of inorganic nutrients and pollutants into waterways. In Australia, these changes are intensified by large-scale ocean-atmospheric events, leading to considerable abiotic stress on the natural flora and fauna. Bacterial communities in marine sediments from Moreton Bay (South East Queensland, Australia) were examined in order to assess the impact of rainfall changes, chemical pollution, and subsequent abiotic stress on living organisms within a marine ecosystem. Sediments were collected during the wet and dry seasons and analyzed using bacterial metagenomics and community metabolomics techniques. Physicochemical data were also analyzed to account for biological variance that may be due to non-rainfall-based abiotic stresses. Wet-dry seasonality was the dominant control on bacterial community structure and metabolic function. Changes in the availability of nutrients, organic matter and light appeared to be the major seasonal stressors. In contrast, urban and industrial pollutants appeared to be minor stressors at the sites s led. During the wet season, the bacterial community composition reflected organisms that utilize biogeochemical pathways with fast kinetics, such as aerobic metabolism, direct assimilation of inorganic compounds, and primary production. The transition to the dry season saw the bacterial community composition shift towards organisms that utilize more complex organic energy sources, such as carbohydrates and fatty acids, and anaerobic redox processes.
Publisher: The Open Journal
Date: 05-04-2023
DOI: 10.21105/JOSS.05328
Publisher: Wiley
Date: 04-2020
DOI: 10.1111/IMJ.14373
Abstract: Activity-based funding (ABF) is a means of healthcare reimbursement, where hospitals are allocated funding based on the number and mix of clinical activity. The ABF model is based solely on Australian refined diagnosis-related group (AR-DRG) classifications of hospital encounters. Each AR-DRG is allocated a weighted activity unit (WAU) translating to cost value to determine ongoing funding allocations for each hospital annually. We explored cost consequences of AR-DRG coding variances within our Medical Oncology department over a 6-month period. All inpatient encounters for medical oncology from 1 January to 30 June 2014 were identified and paired with actual AR-DRG coding sheets submitted by the hospital coders. Inpatient charts were manually reviewed by a Medical Oncology Registrar to capture any changes or additional AR-DRGs, which were subsequently evaluated for total WAU value variance. Applying 1 WAU = $4676 as per the 2014 Queensland model, cost consequences were calculated. A total of 116 encounters was identified for 72 patients. Of 116 patients, 95 (81%) had additional diagnoses captured, leading to an AR-DRG and WAU change in 26 encounters. The total reimbursement variance for this period was $143 404.07. Cost consequences resulted from: (i) use of abbreviations in clinical notes unable to be coded and (ii) diagnoses not documented despite treatment delivered as per medication charts. Clinical note documentation ultimately determines the future funding of our healthcare system. Appropriate communication and education of medical staff and hospital coders are vital to ensure precise documentation and accurate AR-DRG coding for optimal and appropriate reimbursement in this funding model.
Publisher: Oxford University Press (OUP)
Date: 11-01-2021
DOI: 10.1111/BJD.19693
Publisher: Elsevier BV
Date: 09-2020
Publisher: Elsevier BV
Date: 09-2013
DOI: 10.1016/J.LUNGCAN.2013.05.006
Abstract: BNC105P is a tubulin polymerisation inhibitor that selectively disrupts tumour vasculature and suppresses cancer cell proliferation. This agent has exhibited preclinical and phase I activity in Malignant Pleural Mesothelioma (MPM). This phase II, single arm trial investigated the efficacy and safety of BNC105P as second line therapy in MPM. Participants had progressive MPM after first line pemetrexed latinum chemotherapy, ECOG PS 0-1, adequate organ function, and measurable disease. BNC105P 16 mg/m(2) was administered intravenously on day 1 and 8 every 21 days until progression or undue toxicity. The primary endpoint was centrally reviewed objective response rate (RR). Tumour response was assessed every two cycles using modified RECIST. 30 patients were enrolled in 10 months, predominantly male (90%), ECOG PS 1 (77%), epithelioid histology (67%), and non-metastatic disease (67%). All patients received at least one dose of study drug, with a median of 2 cycles. No significant haematologic, biochemical, or cardiac adverse events (AEs) were observed. Grade 3 or 4 AEs occurred in 10 patients (33%). There were 2 deaths on study: 1 cardiorespiratory, the other to pneumonia. We observed 1 partial response (3%) 13 patients had stable disease (43%). Median progression free survival was 1.5 months (95% CI 1.4-2.4) median overall survival was 8.2 months (95% CI 3.8-11.9). BNC105P was safe and tolerable. The sole response was insufficient to warrant further research as a single agent.
Publisher: Elsevier BV
Date: 11-2018
DOI: 10.1016/J.JTHO.2018.08.007
Abstract: There is no approved second-line treatment for malignant pleural mesothelioma (MPM). On the basis of promising early results, pembrolizumab was used off-label in Switzerland and Australia. We investigated outcomes in association with clinicopathological features and expression of programmed death ligand 1 (PD-L1). Registry data in Australia and Switzerland were pooled. Patient characteristics, including age, sex, histological subtype, and previous treatments were captured. Outcomes were assessed locally. PD-L1 expression was categorized as negative (<5%), intermediate (5%-49%), and high (≥50%). A total of 93 patients (48 from Switzerland and 45 from Australia) were treated 68 patients (73%) had epithelioid MPM, and 67 (72%) had an Eastern Cooperative Oncology Group performance status of 0 or 1. Pembrolizumab was the second-line treatment in 48 of 93 patients (52%). PD-L1 expression results were available for 66 patients (71%). Most (68%) were negative, 18% were intermediate, and 14% were high for PD-L1 expression. In the full cohort, the overall response rate (ORR) was 18%, the median progression-free survival (mPFS) was 3.1 months, and the median overall survival was 7.2 months. In patients with an Eastern Cooperative Oncology Group performance status of 0 or 1 and only one previous systemic treatment (n = 35), the ORR was 37%, the mPFS was 3.7 months, and the median overall survival was 10.2 months. The nonepitheloid histological subtype showed an improved ORR (24% versus 16% [p = 0.54) and mPFS (5.6 versus 2.8 months [p = 0.02]). Compared with intermediate and negative PD-L1 expression, high PD-L1 expression was associated with an improved ORR (44% versus 42% versus 11% [p = 0.01]) and mPFS (6.2 versus 3.9 versus 2.7 months [p = 0.04]). Toxicity was as expected. These real-world data demonstrate similar response rates but inferior survival compared with those in early-phase trials. High PD-L1 expression and nonepitheloid histological subtype were associated with greater activity. Anti-PD-L1 immunotherapy is a reasonable second-line therapy in patients with MPM.
Publisher: Informa UK Limited
Date: 07-11-2019
Publisher: Elsevier BV
Date: 10-2014
Abstract: Although advanced cutaneous squamous cell carcinoma (CSCC) is quite common, there are few prospective trials regarding its optimal management. This study evaluated the efficacy and safety of single-agent panitumumab in the treatment of patients with CSCC not suitable for local therapy. Sixteen patients received single-agent panitumumab at a dose of 6 mg/kg repeated every 2 weeks for a minimum of three cycles and continued until progression, a maximum of nine cycles or dose-limiting toxicity. The primary end point was the best overall response rate (ORR) as assessed by Response Evaluation Criteria in Solid Tumours (RECIST version 1.1) criteria. Secondary end points included evaluation of safety, toxicity and progression-free survival (PFS). Between May 2010 and May 2012, 16 patients were recruited. Fourteen patients were male and the median age was 68 years. Fifteen patients had locoregionally advanced or recurrent disease with 14 patients receiving previous radiotherapy and 7 receiving previous cytotoxic chemotherapy. The best ORR [partial (PR) or complete response (CR)] was 31% (3/16 PR, 2/16 CR) with a further 6 of 16 patients achieving SD. The median PFS and overall survival were 8 and 11 months respectively. Grade 3 or 4 events were observed in five patients (four being skin toxicity) with one patient ceasing due to skin toxicity. With a median follow-up of 24 months, 10 patients died due to progressive disease, 6 are alive, one patient with no evidence of disease at the time of analysis. Single-agent panitumumab is safe and effective in the management of patients with advanced CSCC even in a previously extensively pre-treated cohort.
Publisher: AME Publishing Company
Date: 12-2022
DOI: 10.21037/TLCR-22-857
Publisher: Wiley
Date: 29-12-2017
DOI: 10.1002/HED.24662
Abstract: The purpose of this study was to present our evaluation of the outcomes of concurrent chemoradiotherapy (CRT) in patients with locally advanced cutaneous squamous cell carcinoma (SCC). This was a prospective phase II study. The primary endpoint was complete response (CR). Patients with locally/regionally advanced cutaneous SCC deemed unsuitable for surgery received definitive radiotherapy (RT 70 Gy in 35fractions) and concurrent weekly platinum-based chemotherapy (cisplatin 40 mg/m2 or carboplatin area under the curve 2). Twenty-one patients were enrolled in this study. Eighteen patients had a locally advanced primary or nodal disease in the head and neck region with 66% having stage IV nonmetastatic disease. Of 19 evaluable patients, 10 achieved a CR to definitive CRT with 2 further patients rendered disease-free by salvage surgery for an overall CR of 63%. This is the only prospective series of CRT for cutaneous SCC. A high CR rate was documented in patients with locoregional advanced disease who were unable to undergo surgery. © 2016 Wiley Periodicals, Inc. Head Neck 39: 679-683, 2017.
Publisher: Elsevier BV
Date: 03-2017
Publisher: Wiley
Date: 14-03-2019
DOI: 10.1111/AJCO.13140
Abstract: Stage III non-small cell lung cancer (NSCLC) makes up a third of all NSCLC cases and is potentially curable. Despite this 5-year survival rates remain between 15% and 20% with chemoradiation treatment alone given with curative intent. With the recent exciting breakthroughs in immunotherapy use (durvalumab) for stage III NSCLC, further improvements in patient survival can be expected. Most patients with stage III NSCLC present initially to their general practitioner (GP). The recommended time from GP referral to first specialist appointment is less than 14 days with treatment initiated within 42 days. Our review found that there is a shortfall in meeting these recommendations, however a number of initiatives have been established in Australia to improve timely and accurate diagnosis and treatment patterns. The lung cancer multidisciplinary team (MDT) is critical to consistency of evidence-based diagnosis and treatment and can improve patient survival. We aimed to review current patterns of care and clinical practice recommendations for stage III NSCLC across Australia and identify opportunities to improve practice in referral, diagnosis and treatment pathways.
Publisher: Elsevier BV
Date: 11-2022
Publisher: Wiley
Date: 12-07-2017
DOI: 10.1111/AJCO.12698
Abstract: Immune checkpoint inhibitors have recently emerged as an exciting new treatment paradigm across a broad spectrum of malignancies. This new class of agents also challenges oncologists with a unique set of immune-based toxicities. Early recognition and precise management of these toxicities can result in better outcomes, with minimization of toxicity and harm to the patient. This article provides a comprehensive review of immune-based toxicities caused by immune checkpoint inhibitors, including recommendations for their investigation and guidelines for specific management.
Publisher: Therapeutic Guidelines Limited
Date: 10-2011
Publisher: Springer Science and Business Media LLC
Date: 02-04-2014
DOI: 10.1007/S00520-014-2180-9
Abstract: Head and neck cancer patients have a high risk of malnutrition and swallowing dysfunction. This study reports on adherence and nutrition outcomes with the use of local evidence-based guidelines for the nutrition management of patients with head and neck cancer, including placement of proactive gastrostomy tubes for high risk patients. This study is a prospective observational audit in patients treated for head and neck cancer at a tertiary hospital from 2007 to 2008 (n = 539). Nutrition outcomes (weight, nutritional status and type of nutrition support) were compared for each nutrition risk category. Primary outcome was 10 % or more weight loss at 3 months post-treatment (n = 219). Overall adherence to the guideline tube feeding recommendations was 81 %. High risk patients had mean weight loss of 6 % on completion of treatment and 9 % at 3 months post-treatment, despite the majority having a proactive gastrostomy tube. Medium and low risk patients also lost weight over this time. Univariate analysis found that non-adherence to the guidelines was associated with weight loss at 3 months (p = 0.013). Multivariate analysis found overweight patients had 1.82 greater odds, and obese patients had 3.49 greater odds of losing weight (p = 0.021). Patients with significant weight loss at diagnosis had decreased odds of losing weight later (p = 0.011). Clinically significant weight loss was still prevalent in this population despite proactive interventions. Predictors of weight loss support the evidence-based guidelines' risk categories, and adherence was important to improve outcomes. Further research is required to determine the impact of significant weight loss in patients with high body mass index (BMI).
Publisher: Springer Science and Business Media LLC
Date: 23-05-2017
DOI: 10.1038/BJC.2017.138
Publisher: Springer Science and Business Media LLC
Date: 07-2014
Publisher: Elsevier BV
Date: 11-2021
DOI: 10.1016/J.CLLC.2021.04.009
Abstract: Epidermal growth factor receptor gene (EGFR) exon 20 insertion (ex20-ins) mutations are an uncommon and heterogeneous group of non-small cell lung cancers (NSCLCs), resistant to conventional EGFR tyrosine kinase inhibitors (TKIs). Characteristics and outcomes of patients with EGFR ex20-ins have not been fully established we sought to clarify them using a multinational patient database. Patients with NSCLC from six Australian institutions with EGFR exon 20 mutations (ex20-mut), excluding T790M, were retrospectively reviewed. Clinical characteristics and outcomes with systemic treatments were collected and analyzed using comparative statistics. Among 109 patients with ex20-mut, 61% were females and 75% were Caucasians. More males presented with de novo metastatic disease (84% vs. 51% P = .002). Central nervous system (48%) and liver (24%) metastases were common within metastatic patients (n = 86). Thirty-nine patients received platinum-based chemotherapy (PBC) and achieved a 43% objective response rate (ORR), median progression-free survival (mPFS) of 6.9 months, and median overall survival (mOS) of 31.0 months. Twenty-three of the patients with ex20-ins received conventional TKIs, resulting in an ORR of 13%, mPFS of 3.4 months (95% confidence interval [CI], 1.91-6.25), and mOS of 31.0 months (95% CI, 15.09-not reached). Nine patients with S786I mutations received TKIs, resulting in an ORR of 50%, mPFS of 18.2 months (2.79-not reached), and mOS of 33.4 months (95% CI, 16.14-not reached). Twenty-three patients received immune checkpoint inhibitor monotherapy (ICIm), resulting in an ORR of 4%, mPFS of 2.6 months (95% CI, 1.91-4.83), and mOS of 30.8 months (95% CI, 17.62-41.62). Although phenotypically similar to patients with common EGFR mutations, patients with EGFR ex20-mut had worse survival, perhaps due to the lack of targeted therapies. Chemotherapy was superior to conventional EGFR TKIs in patients with EGFR ex20-ins, although there was moderate activity of TKIs in S768I mutations. ICIm was ineffective.
Publisher: Wiley
Date: 13-05-2018
DOI: 10.1002/HED.25182
Abstract: Conformal radiotherapy modalities may minimize treatment toxicities. The purpose of this study was to document the extent and timing of dysphagia and related toxicities during helical intensity-modulated radiotherapy (IMRT) with chemotherapy for oropharyngeal squamous cell carcinoma (SCC). We conducted a prospective study of 76 patients with oropharyngeal SCC undergoing helical IMRT with chemotherapy. Dysphagia and acute toxicity data were collected weekly during treatment and at 2, 4, and 12 weeks posttreatment using the Functional Oral Intake Scale, diet descriptors, and Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Patients experienced maximum incidence of grade 3 dysphagia (61%), mucositis (30%), and thick saliva (38%), with grade 2 xerostomia (87%) and dysgeusia (97%). Only 14.5% were nil-by-mouth. Symptoms peaked in week 7 and improved thereafter. Grade 3 dysphagia was twice as common for T3 to T4 tumors compared with T2. Results confirm that patients with oropharyngeal SCC undergoing helical IMRT with chemotherapy continue to experience incidences of acute toxicities comparable with other conformal techniques, and need supportive cares.
Publisher: BMJ
Date: 22-06-2022
DOI: 10.1136/BMJQS-2021-014527
Abstract: Hospital patients experiencing clinical deterioration are at greater risk of adverse events. Monitoring patients through early warning systems is widespread, despite limited published evidence that they improve patient outcomes. Current limitations including infrequent or incorrect risk calculations may be mitigated by integration into electronic medical records. Our objective was to examine the impact on patient outcomes of systems for detecting and responding to real-time, automated alerts for clinical deterioration. This review was conducted according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews checklist. We searched Medline, CINAHL and Embase for articles implementing real-time, automated deterioration alerts in hospitalised adults evaluating one or more patient outcomes including intensive care unit admission, length of stay, in-hospital cardiopulmonary arrest and in-hospital death. Of 639 studies identified, 18 were included in this review. Most studies did not report statistically significant associations between alert implementation and better patient outcomes. Four studies reported statistically significant improvements in two or more patient outcomes, and were the only studies to directly involve the patient’s clinician. However, only one of these four studies was robust to existing trends in patient outcomes. Of the six studies using robust study designs, one reported a statistically significant improvement in patient outcomes the rest did not detect differences. Most studies in this review did not detect improvements in patient outcomes following the implementation of real-time deterioration alerts. Future implementation studies should consider: directly involving the patient’s physician or a dedicated surveillance nurse in structured response protocols for deteriorating patients the workflow of alert recipients and incorporating model features into the decision process to improve clinical utility.
Publisher: Oxford University Press (OUP)
Date: 23-01-2014
DOI: 10.1634/THEONCOLOGIST.2013-0026
Abstract: Combination blockade of human epidermal growth factor receptor (HER) family signaling may confer enhanced antitumor activity than single-agent blockade. We performed a single-arm study of pertuzumab, a monoclonal antibody that inhibits HER2 dimerization, and erlotinib in relapsed non-small cell lung cancer (NSCLC). Patients received pertuzumab (840-mg loading dose and 420-mg maintenance intravenously every 3 weeks) and erlotinib (150-mg or 100-mg dose orally, daily). The primary endpoint was response rate (RR) by 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) at day 56 in all patients and those with EGFR wild-type tumors. Of 41 patients, 28 (68.3%) experienced treatment-related grade ≥3 adverse events, including pneumatosis intestinalis (3 patients), resulting in early cessation of enrollment. Tissue s les from 32 patients showed mutated EGFR status in 9 of 41 (22%) and wild-type EGFR in 23 of 41 (56%). The FDG-PET RR for patients with assessments at day 56 was 19.5% in all patients (n = 41) and 8.7% in patients with wild-type EGFR NSCLC (n = 23). Investigator-assessed computed tomography RR at day 56 was 12.2%. FDG-PET suggests that pertuzumab plus erlotinib is an active combination, but combination therapy was poorly tolerated, which limits its clinical applicability. More research is warranted to identify drug combinations that disrupt HER receptor signaling but that exhibit improved tolerability profiles.
Publisher: Wiley
Date: 25-11-2022
DOI: 10.1002/HED.27249
Abstract: Enteral nutrition (EN) is often required in patients with head and neck cancer (HNSCC) however, initiation criteria is limited or inconsistent. This study aimed to describe the relationship of treatment toxicities and requirement for EN and investigate toxicity and baseline characteristics association with EN duration. Acute toxicities and baseline characteristics were collected from patients with HNSCC ( n = 110) undergoing H‐IMRT. Percentage EN contributing to estimated requirements and EN duration were measured. The threshold for patients needing ≥50% of estimated requirements via EN increased from week 3 to 4 for grade ≥2 oral haryngeal mucositis, dysgeusia, thick saliva and nausea, and for grade 3 dysphagia. Patients with grade 2–3 dysphagia had a reduced risk of ceasing EN compared to those with grade 0–1 dysphagia. Using acute toxicities in clinical practice may be a useful tool to inform prompt initiation of EN prior to decline in nutritional status and anticipate EN duration.
Publisher: Wiley
Date: 18-05-2012
DOI: 10.1002/HED.22992
Abstract: Evidence-based nutritional and swallowing guidelines were developed to identify patients at high risk of developing malnutrition during chemoradiation for head and neck cancer. These guidelines recommended a prophylactic gastrostomy and were actively implemented at our institution in January 2007. This study assesses the effect of this policy change on patient outcomes. This retrospective cohort study was carried out for the years before (2005) and after (2007) implementation of these guidelines. In all, 165 patients were treated with radical chemoradiation for head and neck cancer at our institution in the years 2005 and 2007. Gastrostomy tube complications were low. Patients in 2007 had significantly fewer hospital admissions, unexpected admissions, and a shorter mean duration of hospital stay in comparison with those in 2005. Prophylactic gastrostomy tubes in patients with high-risk head and neck cancer resulted in a significant decrease in hospital admissions and length of stay, and led to increased bed availability.
Publisher: American Association for Cancer Research (AACR)
Date: 15-05-2011
DOI: 10.1158/1078-0432.CCR-10-2763
Abstract: Purpose: Assessing clinical activity of molecularly targeted anticancer agents, especially in the absence of tumor shrinkage, is challenging. To evaluate on-treatment 18F-fluorodeoxyglucose (FDG) and/or 18F-fluorodeoxythymidine (FLT) positron emission tomography (PET) for this purpose, we conducted a prospective multicenter trial assessing PET response rates and associations with progression-free (PFS) and overall survival (OS) in 2nd/3rd-line non–small-cell lung cancer patients treated with erlotinib. Experimental Design: PET/computed tomography (CT) scans were conducted at baseline, day (d)14 and d56 after the first daily erlotinib dose, with diagnostic CT at baseline and d56 (all scans centrally reviewed). PET partial metabolic response (PMR) was defined as a mean decrease (in ≤5 lesions atient) of 15% or more maximum standardized uptake value. PFS was investigator-determined. Results: Of 74 erlotinib-treated patients, 51 completed all imaging assessments through d56 13 of 51 (26%) FDG-evaluable patients had PMR at d14, as did 9 of 50 (18%) FLT-evaluable patients. Four (7.8%) showed partial responses (PR) by d56 CT all 4 had PMR by d14 FDG-PET with 3 PMRs by d14 FLT-PET. Three of the 4 patients with CT PR had evaluable archival tumor tissue all 3 had epidermal growth factor receptor mutations. D14 and d56 PMRs by FDG or FLT were associated with improved PFS HRs for PET responders versus nonresponders were 0.3 to 0.4. D14 FDG-PET PMR was associated with improved OS (P = 0.03) compared with FDG-PET nonresponders. Conclusion: Early (d14) FDG-PET PMR is associated with improved PFS and OS, even in the absence of subsequent Response Evaluation Criteria in Solid Tumors response. These data support inclusion of FDG-PET imaging in clinical trials testing novel targeted therapies, particularly those with anticipated cytostatic effects. Clin Cancer Res 17(10) 3304–15. ©2011 AACR.
Publisher: Georg Thieme Verlag KG
Date: 14-06-2018
Abstract: Background Perineural spread (PNS) is a marker of aggressiveness and has been shown to occur in cranial nerves due to advanced mucosal and cutaneous head and neck cancer. Receptors CXC chemokine receptor 4 (CXCR4) and programmed cell death-1 (PD-1) have been shown to be overexpressed in a variety of cancers with PNS, with the inhibition of these pathways offering a potential future treatment. Methods Retrospective immunohistochemical staining for the CXCR4 and PD-1 receptors was performed on 28 head and neck specimens that demonstrated PNS from January 2017 to August 2017, at Royal Brisbane and Women's Hospital, Brisbane, Australia. Results CXCR4 staining was positive in 52 and 60% of the squamous cell carcinoma (SCC) and adenoid cystic carcinoma PNS specimens, respectively. Cutaneous SCC tumors with no PNS stained positively in 33%. No significant staining for PD-1 in peritumoral lymphocytes or tumor specimens was seen. Conclusion CXCR4 is overexpressed in advanced skin cancer and head and neck tumors that demonstrated PNS to large cranial nerves. Overall, these results provide strong support for using CXCR4 as a biomarker and further investigation of immunotherapeutic agents that could inhibit tumor progression via targeting CXCR4 expression.
Publisher: BMJ
Date: 06-2020
Abstract: Cemiplimab, a high-affinity, potent human immunoglobulin G4 monoclonal antibody to programmed cell death-1 demonstrated antitumor activity in a Phase 1 advanced cutaneous squamous cell carcinoma (CSCC) expansion cohort ( NCT02383212 ) and the pivotal Phase 2 study ( NCT02760498 ). Here we report the primary analysis of fixed dose cemiplimab 350 mg intravenously every 3 weeks (Q3W) (Group 3) and provide a longer-term update after the primary analysis of weight-based cemiplimab 3 mg/kg intravenously every 2 weeks (Q2W) (Group 1) among metastatic CSCC (mCSCC) patients in the pivotal study ( NCT02760498 ). The primary objective for each group was objective response rate (ORR) per independent central review (ICR). Secondary endpoints included ORR by investigator review (INV), duration of response (DOR) per ICR and INV, and safety and tolerability. For Group 3 (n=56) and Group 1 (n=59), median follow-up was 8.1 (range, 0.6 to 14.1) and 16.5 (range, 1.1 to 26.6) months, respectively. ORR per ICR was 41.1% (95% CI, 28.1% to 55.0%) in Group 3, 49.2% (95% CI, 35.9% to 62.5%) in Group 1, and 45.2% (95% CI, 35.9% to 54.8%) in both groups combined. Per ICR, Kaplan–Meier estimate for DOR at 8 months was 95.0% (95% CI, 69.5% to 99. 3%) in responding patients in Group 3, and at 12 months was 88.9% (95% CI, 69.3% to 96.3%) in responding patients in Group 1. Per INV, ORR was 51.8% (95% CI, 38.0% to 65.3%) in Group 3, 49.2% (95% CI, 35.9% to 62.5%) in Group 1, and 50.4% (95% CI, 41.0% to 59.9%) in both groups combined. Overall, the most common adverse events regardless of attribution were fatigue (27.0%) and diarrhea (23.5%). In patients with mCSCC, cemiplimab 350 mg intravenously Q3W produced substantial antitumor activity with durable response and an acceptable safety profile. Follow-up data of cemiplimab 3 mg/kg intravenously Q2W demonstrate ongoing durability of responses. Clinicaltrials.gov, NCT02760498 . Registered May 3, 2016, t2/show/NCT02760498
Publisher: Elsevier BV
Date: 06-2020
Publisher: Research Square Platform LLC
Date: 12-10-2023
Publisher: Springer Science and Business Media LLC
Date: 12-2018
DOI: 10.1007/S00432-018-2805-3
Abstract: Immune-checkpoint inhibitors (ICIs) represent the standard of care for platinum-pretreated advanced non-small cell lung cancer patients. Patients treated with ICIs may experience immune-related adverse events (irAEs), that might reflect antitumor responses. Here we evaluated nivolumab efficacy according to the development of irAEs. We conducted a multicenter retrospective study of patients with advanced NSCLC treated with nivolumab between October 2013 and September 2017. IrAEs were defined as AEs having immunological basis that required intensive monitoring and interventions. Among 195 patients [median (range) age, 63 (30-84) years 128 men (65.6%), 67 women (34.4%)], irAEs were observed in 85 patients (43.6%), including 15 patients (7.6%) with grade 3 or 4 events. Median PFS was 5.7 months in irAEs group compared to 2.0 months of no-irAEs group [HR: 0.41 (95% CI 0.3-0.57), P < 0.0001]. Median OS was 17.8 months compared to 4.0 months of no-irAEs group [HR: 0.33 (95% CI 0.23-0.47), P < 0.0001]. IrAEs were significantly associated with improved clinical outcome in 12- and 6-week landmark analysis. Patients who developed ≥ 2 irAEs during treatment (n: 37) had a significantly longer median PFS and OS compared to those with one (n: 48) or none AEs (n: 110) (PFS: 8.5 months vs. 4.6 vs. 2.0, P < 0.0001 OS: 26.8 months vs. 11.9 vs. 4.0, P < 0.0001). Multivariable analysis revealed that irAEs were positively associated with PFS [HR: 0.48 (95% CI 0.34-0.67), P < 0.0001] and OS [HR: 0.38 (95% CI 0.26-0.56), P < 0.0001]. In this study we confirmed that the development of irAEs was a strong predictor of survival outcomes in NSCLC patients treated with nivolumab monotherapy in landmark and multivariable models. Patients who experienced ≥ 2 irAEs had a more pronounced survival benefit compared to those with 1 irAE further suggesting a mechanistic association between irAEs and immunotherapy efficacy.
Publisher: Elsevier BV
Date: 08-2010
DOI: 10.1016/J.JOCN.2009.12.009
Abstract: Relapsed glioblastoma multiforme (GBM) responds poorly to standard therapies. Vascular endothelial growth factor (VEGF) is implicated in the development of GBM and the anti-VEGF monoclonal antibody bevacizumab has shown early clinical promise against malignant glioma. We treated six patients with recurrent GBM using bevacizumab combined with carboplatin and etoposide chemotherapy (ACE regimen). Toxicity was that expected for carboplatin and etoposide alone, except for an ischemic stroke in one patient. We observed partial responses in five patients and one responding patient developed extensive tumour necrosis after 2 cycles of treatment. Median progression-free and overall survival was 19 and 29.9weeks, respectively. Four responding patients developed recurrence, which was characterized by markedly less peri-tumoral edema, mass effect and necrosis compared with tumours at baseline. Two patients developed local extracranial extension. In conclusion, ACE was active in recurrent GBM and was mostly well tolerated.
Publisher: Elsevier BV
Date: 10-2012
DOI: 10.1016/J.EJCA.2012.04.005
Abstract: The importance of quality-of-life (QoL) research has been recognised over the past two decades in patients with head and neck (H&N) cancer. The aims of this systematic review are to evaluate the QoL status of H&N cancer survivors one year after treatment and to identify the determinants affecting their QoL. Pubmed, Medline, Scopus, Sciencedirect and CINAHL (2000-2011) were searched for relevant studies, and two of the present authors assessed their methodological quality. The characteristics and main findings of the studies were extracted and reported. Thirty-seven studies met the inclusion criteria, and the methodological quality of the majority was moderate to high. While patients of the group in question recover their global QoL by 12 months after treatment, a number of outstanding issues persist - deterioration in physical functioning, fatigue, xerostomia and sticky saliva. Age, cancer site, stage of disease, social support, smoking, feeding tube placement and alcohol consumption are the significant determinants of QoL at 12 months, while gender has little or no influence. Regular assessments should be carried out to monitor physical functioning, degree of fatigue, xerostomia and sticky saliva. Further research is required to develop appropriate and effective interventions to deal with these issues, and thus to promote the patients' QoL.
Publisher: Oxford University Press (OUP)
Date: 12-07-2019
Abstract: falls, seizures, syncope and transient ischaemic attacks (TIA) are common presentations to emergency departments sharing overlapping clinical features and diagnostic uncertainties. These transient attacks can be markers of serious adverse outcomes and are associated with high admission rates. We evaluated the effects of an integrated suite of pathways for transient attacks designed to improve adherence to best practices and reduce costs through fewer admissions. a suite of clinician-designed pathways based on initial presenting diagnosis was developed to support ambulant care in a large hospital in Queensland, Australia. We performed a set of regression analyses to identify the differences in total cost and length of stay (LOS) before and after implementation. We conducted a Monte Carlo simulation to estimate the cost savings of the freed capacity in the patient cohort. pathway implementation was associated with reduced admitted LOS and costs. Falls patients admitted LOS declined by 32.5%, and admission costs by 19.5%. Syncope, seizure, and TIA patients admitted LOS declined by 22% with no change in admitted costs. Despite a small increase in 90-day representations, total emergency department LOS was unchanged. Emergency department costs were similar between falls and non-falls patients. The Monte Carlo analysis showed that the most likely outcome was a cost savings in freed capacity of $71 per patient episode. the ATAP suite of pathways was associated with reduction in LOS, release of capacity and reduction in costs. Further study is needed to evaluate mechanisms and clinical outcomes in this vulnerable population.
Publisher: Springer Science and Business Media LLC
Date: 02-04-2019
DOI: 10.1007/S00520-019-04748-7
Abstract: A randomised controlled trial was conducted to evaluate the effectiveness of a nurse-delivered Head and Neck Cancer Survivor Self-Management Care Plan (HNCP) for patients who had completed treatment for head and neck cancer (HNC). Ten oncology nurses were trained to deliver the HNCP. The HNCP consisted of one face-to-face hour-long meeting in which the patient's treatment was recorded, as were contact details of health professionals involved in their care and follow-up schedules. Patients were guided to nominate up to three goals for their future well-being and assisted to devise an action plan to achieve these. The HNCP was given to the patient and a copy was forwarded to their primary care physician. One hundred and nine patients were randomised after definitive curative intent treatment, 36 to HNCP, 36 to receive information about survivorship, and 37 to usual care. The primary outcome, analysed by intention-to-treat, was change in quality of life measured by the FACT-H&N from baseline to 6-month follow-up. Quality of life of all groups decreased at 3 months but was close to baseline at 6 months. Compared with the usual care group, the only statistically significant mean difference at 6 months was for the information group on the physical well-being domain (mean difference 0.4, 95% - 1.8, 2.6, p < 0.05). A single-session nurse-delivered intervention is insufficient to improve the quality of life in HNC survivors compared with usual care. Provision of detailed written information about HNC survivorship is associated with improved physical well-being. ACTRN12613000542796.
Publisher: Springer Science and Business Media LLC
Date: 29-11-2017
DOI: 10.1007/S11523-017-0543-0
Abstract: Delta-like ligand 4-Notch (DLL4-Notch) signaling contributes to the maintenance of chemotherapy-resistant cancer stem cells and tumor vasculature. This phase IB trial of demcizumab, an IgG2 humanized monoclonal antibody directed against DLL4, was undertaken to determine its maximum tolerated dose, safety, immunogenicity, preliminary efficacy, pharmacokinetics, and pharmacodynamics, combined with standard chemotherapy. Forty-six treatment-naive patients with metastatic non-squamous non-small cell lung cancer (NSCLC) were enrolled in this open-label, dose-escalation study using a standard 6 + 6 design. Demcizumab (2.5, 5.0, and 7.5 mg/kg) was given once every 3 weeks with standard doses of pemetrexed and carboplatin using a continuous (six cycles followed by demcizumab maintenance) or a truncated demcizumab regimen (four cycles followed by pemetrexed maintenance). Initially, continuous demcizumab was given until progression but two patients developed grade 3 pulmonary hypertension and congestive heart failure after eight or more infusions. Thereafter, 23 patients were treated with a truncated regimen of demcizumab, which was not associated with any grade 3 or greater cardiopulmonary toxicity. Common adverse events were hypertension, raised brain natriuretic peptide, and those expected from carboplatin and pemetrexed alone. Twenty of 40 evaluable patients (50%) had objective tumor responses. In peripheral blood, demcizumab treatment modulated the expression of genes regulating Notch signaling and angiogenesis, and achieved concentrations exceeding those saturating DLL4 binding. This study has identified a truncated dosing regimen and recommended phase II dose of demcizumab (5 mg/kg q3-weekly ×4) for subsequent clinical evaluation in combination with standard carboplatin and pemetrexed chemotherapy. NCT01189968.
Publisher: SAGE Publications
Date: 2021
DOI: 10.1177/21501327211041489
Abstract: HealthPathways is a clinical information portal developed in New Zealand that enables general practitioners to manage and refer their patients in a local context. We analyzed specialist outpatient appointment costs in Mackay, Queensland before and after HealthPathways implementation. We retrospectively examined specialist outpatient costs for patients referred by Mackay general practitioners for conditions with varying levels of HealthPathways implementation. Ranked from most clinical pathways available to none, chronic diabetes, cardiology, respiratory, and urology visits from January to March 2015, pre-pathways, and January to March 2017, post-pathways, were assessed. Monte Carlo simulation was used to estimate cost changes. Per-visit costs were multiplied by visit numbers to estimate policy impact. The mean cost per visit increased from $220 to $305 for diabetes and $270 to $323 for respiratory, and decreased from $296 to $257 for cardiology and $444 to $293 for urology. The policy impact for each disease group over 3 months after accounting for visit numbers was a likely saving of $30 360 for diabetes and $10 270 for cardiology, and a likely cost increase of $24 449 for respiratory and $20 536 for urology. We observed that conditions with more comprehensive clinical pathways cost Mackay HHS substantially less following implementation. Costs for low and no pathway implementation referrals increased slightly over the same period.
Publisher: Elsevier BV
Date: 09-2017
DOI: 10.1016/J.ORALONCOLOGY.2017.06.025
Abstract: Prophylactic gastrostomy tube (PGT) is frequently used in patients with head and neck cancer (HNSCC). There are concerns this leads to tube dependency but this phenomena is not well defined. This study aimed to determine whether early feeding via PGT impacted on longer term tube feeding outcomes. Patients with HNSCC with PGT were observed monthly post-treatment regarding tube use and time to removal up to twelve months. Patients were from a randomised controlled trial comparing an early feeding intervention via the PGT (n=57) versus usual care which commenced feeding when clinically indicated (n=67). Patient characteristics male (88%), mean age 60±10.1years, oropharyngeal tumours (76%), receiving chemoradiotherapy (82%). Tubes were used by 87% (108/124) on completion of treatment and 66% (83/124) one month post. No differences in tube use between groups at any time point or tube removal rates over 12months (p=0.181). In patients free of disease (n=99), the intervention had higher tube use at 4months (p=0.003) and slower removal rates (p=0.047). Overall ten patients had their tube in-situ at 12months (8%) but five were awaiting removal (4% true dependency rate). Of the five patients legitimately using the tube, only one (<1%) was from severe dysphagia post definitive chemoradiotherapy. PGT use is high in the acute phase post-treatment. Encouraging early use may prolong time to tube removal but it does not increase long term dependency rates beyond four months post treatment. Monitoring tube use is important to prevent over-estimation of dependency rates. This trial has been registered in the Australian New Zealand Clinical Trials registry as ACTRN12612000579897. Available at www.anzctr.org.au.
Publisher: Elsevier BV
Date: 05-2022
DOI: 10.1016/J.ORALONCOLOGY.2022.105815
Abstract: To assess health-related quality of life (HRQoL) with first-line pembrolizumab, pembrolizumab-chemotherapy, or cetuximab-chemotherapy in recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) in the phase 3 KEYNOTE-048 trial (NCT02358031). HRQoL was measured using the European Organisation for Research and Treatment of Cancer 30-question quality-of-life (EORTC QLQ-C30), the EORTC 35-question quality-of-life head and neck cancer-specific module (EORTC QLQ-H&N35), and the EuroQol 5-dimension 3-level instruments (EQ-5D-3L). Secondary endpoints included mean change from baseline in EORTC QLQ-C30 global health status/quality of life (GHS/QoL) at week 15 and time to deterioration (TTD) in EORTC QLQ-C30 GHS/QoL and EORTC QLQ-H&N35 pain and swallowing. Of 882 enrolled participants, 844 received ≥ 1 dose of study treatment and completed ≥ 1 HRQoL assessment adherence was ≥ 79% at week 15 across treatment groups. At week 15, EORTC QLQ-C30 GHS/QoL scores remained stable no clinically meaningful between-group differences were observed (least squares mean difference, pembrolizumab vs cetuximab-chemotherapy, 0.24 95% CI, -3.34 to 3.82 pembrolizumab-chemotherapy vs cetuximab-chemotherapy, 0.40 95% CI, -3.46 to 4.26). Median TTD in EORTC QLQ-C30 GHS/QoL and EORTC QLQ-H&N35 pain and swallowing scores was not reached over 51 weeks across groups, showing stable HRQoL. TTD was similar between groups for EORTC QLQ-C30 GHS/QoL (pembrolizumab vs cetuximab-chemotherapy: HR, 1.38 95% CI, 0.95-2.00 pembrolizumab-chemotherapy vs cetuximab-chemotherapy: HR, 1.37 95% CI, 0.94-2.00), as was TTD in EORTC QLQ-H&N35 pain and swallowing scores. Pembrolizumab monotherapy and pembrolizumab-chemotherapy extended OS while maintaining HRQoL, further supporting first-line use for R/M HNSCC.
Publisher: BMJ
Date: 2022
DOI: 10.1136/BMJOPEN-2021-057663
Abstract: There is a strong theoretical rationale for combining checkpoint blockade with cytotoxic chemotherapy in pleural mesothelioma and other cancers. Two recent single-arm, phase 2 trials [DuRvalumab with chEmotherapy as first-line treAtment in advanced pleural Mesothelioma (DREAM) and Phase II multicenter study of anti-PD-L1, durvalumab, in combination with cisplatin and pemetrexed for the first-line treatment of unresectable malignant pleural mesothelioma (PrE0505)] combining the programmed death ligand-1 (PD-L1) inhibitor durvalumab with standard first-line chemotherapy exceeded prespecified safety and activity criteria to proceed to a phase 3 confirmatory trial to assess this combination. We present the protocol of the DREAM3R trial. This multicentre open-label randomised trial will recruit 480 treatment-naïve adults with advanced pleural mesothelioma, randomised (2:1) to either 3-weekly durvalumab 1500 mg plus 3-weekly doublet chemotherapy (cisplatin 75 mg/m 2 or carboplatin, Area Under the Curve,AUC 5 and pemetrexed 500 mg/m 2 ) 4–6 cycles, followed by 4-weekly durvalumab 1500 mg until disease progression, unacceptable toxicity or patient withdrawal OR doublet chemotherapy alone for 4–6 cycles, followed by observation. The target accrual time is 27 months, with follow-up for an additional 24 months. This provides over 85% power if the true HR for overall survival (OS) is 0.70, with two-sided alpha of 0.05, assuming a median OS of 15 months in the control group. Randomisation is stratified by age (18–70 years vs ), sex, histology (epithelioid vs non-epithelioid), platinum agent (cisplatin vs carboplatin) and region (USA vs Australia/New Zealand vs Other). The primary endpoint is OS. Secondary endpoints include progression-free survival, objective tumour response (by mRECIST V.1.1 and iRECIST), adverse events, health-related quality of life and healthcare resource use. Tertiary correlative objectives are to explore and validate potential prognostic and/or predictive biomarkers (including features identified in the DuRvalumab with chEmotherapy as first-line treAtment in advanced pleural Mesothelioma (DREAM) and PrE0505 studies, PD-L1 expression, tumour mutational burden, genomic characteristics and human leukocyte antigen subtypes) in tissue and serial blood s les. An imaging databank will be assembled for validation of radiological measures of response, and studies of possible radiomic biomarkers in mesothelioma. The protocol was approved by human research ethics review committees for all participating sites. Results will be disseminated in peer-reviewed journals and at scientific conferences. AstraZeneca. CTC 0231 / TOGA 18/001 / PrE0506 3.0, 29 July 2021. ClinicalTrials.gov Identifier: NCT04334759 ACTRN 12620001199909.
Publisher: BMJ
Date: 12-2021
DOI: 10.1136/BMJOPEN-2021-050070
Abstract: Epilepsy places a large burden on health systems, with hospitalisations for seizures alone occurring more frequently than those related to diabetes. However, the cost of epilepsy to the Australian health system is not well understood. The primary aim of this study is to quantify the health service use and cost of epilepsy in Queensland, Australia. Secondary aims are to identify differences in health service use and cost across population and disease subgroups, and to explore the associations between health service use and common comorbidities. This project will use data linkage to identify the health service utilisation and costs associated with epilepsy. A base cohort of patients will be identified from the Queensland Hospital Admitted Patient Data Collection. We will select all patients admitted between 2014 and 2018 with a diagnosis classification related to epilepsy. Two comparison cohorts will also be identified. Retrospective hospital admissions data will be linked with emergency department presentations, clinical costing data, specialist outpatient and allied health occasions of service data and mortality data. The level of health service use in Queensland, and costs associated with this, will be quantified using descriptive statistics. Difference in health service costs between groups will be explored using logistic regression. Linear regression will be used to model the associations of interest. The analysis will adjust for confounders including age, sex, comorbidities, indigenous status, and remoteness. Ethical approval has been obtained through the QUT University Human Research Ethics Committee (1900000333). Permission to waive consent has been granted under the Public Health Act 2005, with approval provided by all relevant data custodians. Findings of the proposed research will be communicated through presentations at national and international conferences, presentations to key stakeholders and decision-makers, and publications in international peer-reviewed journals.
Publisher: Elsevier BV
Date: 08-2015
DOI: 10.1016/J.EJCA.2015.05.022
Abstract: Adjuvant chemotherapy (ACT) in non-small-cell lung cancer (NSCLC) improves overall survival, but the benefits must be weighed against its harms. We sought to determine the survival benefits that patients and their doctors judged sufficient to make ACT in NSCLC worthwhile. 122 patients completed a self-administered questionnaire at baseline and 6 months (before & after ACT, if they had it) 82 doctors completed the questionnaire once only. The time trade-off method was used to determine the minimum survival benefits judged sufficient in four hypothetical scenarios. Baseline survival times were 3 years & 5 years and baseline survival rates (at 5 years) were 50% & 65%. At baseline, the median benefits judged sufficient by patients were an extra 9 months (Interquartile range (IQR) 1-12 months) beyond 3 years & 5 years and an extra 5% (IQR 0.1-10%) beyond 50% & 65%. At 6 months (n=91), patients' preferences had the same median benefit (9 months & 5%) but varied more (IQRs 0-18 months & 0-15%) than at baseline. Factors associated with judging smaller benefits sufficient were deciding to have ACT (P=0.01, 0.02) and better well-being (P=0.01, 0.006) during ACT. Doctors' preferences, compared with patients' preferences, had similar median benefits (9 months & 5%) but varied less (IQR 6-12 months versus 1-12 months, P<0.001 5%-10% versus 0.1-10%, P<0.001). Most patients and doctors judged moderate survival benefits sufficient to make ACT in NSCLC worthwhile, but the preferences of doctors varied less than those of patients. Doctors should endeavour to elicit patients' preferences during discussions about ACT in NSCLC.
Publisher: Elsevier BV
Date: 07-2023
Publisher: American Society of Clinical Oncology (ASCO)
Date: 03-2016
Abstract: Crizotinib confers improved progression-free survival compared with chemotherapy in anaplastic lymphoma kinase (ALK)-rearranged non–small-cell lung cancer (NSCLC), but progression invariably occurs. We investigated the efficacy and safety of alectinib, a potent and selective ALK inhibitor with excellent CNS penetration, in patients with crizotinib-refractory ALK-positive NSCLC. Alectinib 600 mg was administered orally twice daily. The primary end point was objective response rate (ORR) by central independent review committee (IRC). Of the 138 patients treated, 84 patients (61%) had CNS metastases at baseline, and 122 were response evaluable (RE) by IRC. ORR by IRC was 50% (95% CI, 41% to 59%), and the median duration of response (DOR) was 11.2 months (95% CI, 9.6 months to not reached). In 96 patients (79%) previously treated with chemotherapy, the ORR was 45% (95% CI, 35% to 55%). Median IRC-assessed progression-free survival for all 138 patients was 8.9 months (95% CI, 5.6 to 11.3 months). CNS disease control rate was 83% (95% CI, 74% to 91%), and the median CNS DOR was 10.3 months (95% CI, 7.6 to 11.2 months). CNS ORR in 35 patients with baseline measurable CNS lesions was 57% (95% CI, 39% to 74%). Of the 23 patients with baseline CNS metastases (measurable or nonmeasurable) and no prior radiation, 10 (43%) had a complete CNS response. At 12 months, the cumulative CNS progression rate (24.8%) was lower than the cumulative non-CNS progression rate (33.2%) for all patients. Common adverse events were constipation (33%), fatigue (26%), and peripheral edema (25%) most were grade 1 to 2. Alectinib is highly active and well tolerated in patients with advanced, crizotinib-refractory ALK-positive NSCLC, including those with CNS metastases.
Publisher: Wiley
Date: 04-12-2022
DOI: 10.1002/CAM4.5308
Abstract: In the phase 2 double‐blind Study 211, a starting dose of lenvatinib 18 mg/day was compared with the approved starting dose of 24 mg/day in patients with radioiodine‐refractory differentiated thyroid cancer (RR‐DTC). Predefined criteria for noninferiority for efficacy in the 18 mg arm were not met safety was similar in both arms. Impact of lenvatinib treatment on health‐related quality‐of‐life (HRQoL) was a secondary endpoint of Study 211. Patients with RR‐DTC were randomly assigned to a blinded starting dose of lenvatinib 18 mg/day or 24 mg/day. HRQoL was assessed at baseline, every 8 weeks until Week 24, then every 16 weeks, and at the off‐treatment visit, using the EQ‐5D‐3L and FACT‐G instruments. Completion and compliance rates, mean change from baseline, and times to first and definitive deterioration were evaluated. Baseline EQ‐5D and FACT‐G scores, and overall changes from baseline, were comparable between patients in the lenvatinib 18 mg/day ( n = 77) and 24 mg/day arms ( n = 75). For the 18 mg versus 24 mg arms, least squares mean differences were −0.42 (95% CI −4.88, 4.03) for EQ‐5D‐VAS and 0.47 (95% CI −3.45, 4.39) for FACT‐G total. Time to first deterioration did not significantly favor either arm EQ‐5D‐VAS HR [18 mg/24 mg] 0.93 (95% CI 0.61–1.40), EQ‐5D‐HUI HR [18 mg/24 mg] 0.68 (95% CI 0.44–1.05), FACT‐G total HR [18 mg/24 mg] 0.73 (95% CI 0.48–1.12). Time to definitive deterioration did not significantly favor either arm, though EQ‐5D‐VAS showed a trend in favor of the 24 mg arm (HR [18 mg/24 mg] 1.72 95% CI 0.99–3.01) EQ‐5D‐HUI HR [18 mg/24 mg] was 0.96 (95% CI 0.57–1.63), FACT‐G total HR [18 mg/24 mg] was 0.72 (95% CI 0.43–1.21). In Study 211, HRQoL for patients in the lenvatinib 18 mg/day arm was not statistically different from that of patients in the 24 mg/day arm. These data further support the use of the approved lenvatinib starting dose of 24 mg/day in patients with RR‐DTC. NCT02702388.
Publisher: Wiley
Date: 24-11-2017
DOI: 10.1111/CEN.13508
Abstract: Prognosis from differentiated thyroid cancer is worse when the disease becomes refractory to radioiodine. Until recently, treatment options have been limited to local therapies such as surgery and radiotherapy, but the recent availability of systemic therapies now provides some potential for disease control. Multitargeted kinase inhibitors (TKIs) including lenvatinib and sorafenib have been shown to improve progression-free survival in phase III clinical trials, but are also associated with a spectrum of adverse effects. Other TKIs have been utilized as "redifferentiation" agents, increasing sodium iodide symporter expression in metastases and thus restoring radioiodine avidity. Some patients whose disease progresses on initial TKI therapy will still respond to a different TKI and clinical trials currently in progress will clarify the best options for such patients. As these drugs are not inexpensive, care needs to be taken to minimize not only biological but also financial toxicity. In this review, we examine the basic biology of radioiodine refractory disease and discuss optimal treatment approaches, with specific focus on choice and timing of TKI treatment. This clinical field remains fluid, and directions for future research include exploring biomarkers and considering adjuvant TKI use in certain patient groups.
Publisher: Research Square Platform LLC
Date: 09-10-2020
DOI: 10.21203/RS.3.RS-88311/V1
Abstract: Background: Patients with unresectable advanced cutaneous squamous cell carcinoma (cSCC) are generally treated with palliative intent. Immune checkpoint blockade has significant activity in the palliative setting in patients with recurrent or metastatic cSCC. This single arm phase 2 prospective study aims to investigate the combination of curative intent chemoradiation and durvalumab (anti-PD-L1 checkpoint inhibitor) for this patient cohort. Our hypothesis is that % of patients with locally-advanced primary disease or regional metastases can be safely treated for cure using ChemoRadiation and ImmunOtherapy (CRIO) compared to the null hypothesis of ≤50%. Methods: Patients with unresectable locally and or regionally advanced pathologically confirmed cSCC deemed suitable for CRIO by consensus of the Head and Neck Multidisciplinary meeting will be eligible. We aim to accrue a total of 15 patients. The co-primary endpoints of CRIO will be the safety of treatment and the complete response rate. Secondary endpoints will include overall survival, progression free survival, and locoregional control. Translational research endpoints including biomarkers will also be explored utilising multiplex immunohistochemistry on tumour biopsy s les obtained prior to commencing treatment and during treatment (week 2). In addition, the utility of CXCR-4 PET scan will be explored. Discussion: CRIO is a novel trial evaluating the combination of curative intent chemoradiotherapy with concurrent durvalumab for patients with inoperable locally advanced cSCC. Trial registration Trial registered with the Australian New Zealand Clinical Trial Registry (ACTRN12618001573246)
Publisher: Wiley
Date: 02-12-2021
Abstract: Weight loss and malnutrition occur frequently in patients with head and neck cancer and are associated with reduced survival. This pragmatic study aimed to determine the effect of a novel pre‐treatment model of nutrition care on nutrition outcomes for patients with head and neck cancer receiving chemoradiotherapy. This health service evaluation consisted of an evaluation of the new model of care implementation (Phase 1) and an evaluation of patient outcomes (Phase 2) in pre‐ and post‐implementation cohorts ( n = 64 and n = 47, respectively). All Phase 2 patients received a prophylactic gastrostomy. The new model of care consisted of dietary counselling and commencement of proactive supplementary enteral nutrition via a prophylactic gastrostomy, in addition to normal oral intake, prior to treatment commencement. Nutrition outcomes were collected at baseline (pre‐treatment) and 3 months post‐radiotherapy completion. The new model of care was successfully incorporated into practice with high referral (96.5%) and attendance (91.5%) rates to the counselling session, and high adherence rates to proactive tube feeding (80.9%). Patients in the post‐implementation cohort had less weight‐loss (1.2% p = 0.338) and saw less of a decline in nutritional status compared to patients in the pre‐implementation cohort (23% vs. 30%, respectively p = 0.572), deemed clinically important. However, patients still experienced critical weight loss overall (mean 9.9%). Pre‐treatment nutrition care was feasible in standard clinical practice and demonstrated clinically relevant outcome improvements for patients. Future high‐quality research is warranted to investigate further multidisciplinary strategies to attenuate weight‐loss further, inclusive of patient‐reported barriers and enablers to nutrition interventions.
Publisher: Springer Science and Business Media LLC
Date: 17-07-2019
DOI: 10.1007/S00520-018-4352-5
Abstract: Reports of acute treatment-related dysphagia and toxicities for patients with parotid tumours or cutaneous head and neck cancer (HNC) are limited. This study aimed to describe the severity and timing of dysphagia and related toxicities experienced during radiotherapy for cutaneous HNC and parotid tumours, to inform the nature of future speech pathology (SP) service models required during treatment. Prospective study of 32 patients with parotid tumours and 36 with cutaneous HNC undergoing curative non-surgical management. Dysphagia and acute toxicity data was collected weekly during treatment and at 2, 4 and 12 weeks post-treatment using the Functional Oral Intake Scale, diet descriptors and CTCAE v4.0. In both groups, minimal treatment toxicities (grades 0-1) were observed. Xerostomia and dysgeusia were the most frequently reported grade 2 toxicities. Only 3% of parotid patients and 6% with cutaneous HNC experienced grade 3 dysphagia. Full or soft texture diets were maintained by > 70% of patients in both groups. Symptoms peaked in the final week of treatment and rapidly improved thereafter. Apart from xerostomia < 10% of patients had any grade 2 toxicity at 12 weeks post-treatment. Patients in these subgroups of HNC experienced minimal treatment-related toxicity during radiotherapy. As such, the need for supportive symptom management by SP is low. Models that involve interdisciplinary surveillance of symptoms with referral to SP only when required may be best suited for these in iduals to ensure issues are identified whilst minimising patient burden created by unnecessary routine SP appointments.
Publisher: Elsevier BV
Date: 04-2020
Publisher: Wiley
Date: 13-05-2005
Publisher: Ubiquity Press, Ltd.
Date: 2022
DOI: 10.5334/IJIC.6980
Publisher: Elsevier BV
Date: 02-2023
Publisher: Wiley
Date: 10-08-2005
DOI: 10.1111/J.1440-1746.2005.03868.X
Abstract: Abstract Background and Aim: Previous reports regarding the clinical significance and pathogenicity of Blastocystis hominis have been contradictory. The aim of this study was to examine the association between Blastocystis and gastrointestinal symptoms in immunocompetent in iduals. We monitored over 2800 healthy people for a period of 15 months, and took stool specimens during both asymptomatic periods and during periods of gastrointestinal symptoms. After exclusion of in iduals who had simultaneous identification of other fecal pathogens, we compared the proportions of asymptomatic versus symptomatic in iduals positive for Blastocystis and found no significant difference (P = 0.5). Symptom status did not correlate with parasite abundance. We found that some in iduals were likely to have Blastocystis detected during both asymptomatic and symptomatic periods, possibly suggesting carriage of the organism. In conclusion, we found no correlation between clinical symptoms and the presence or absence of Blastocystis among this healthy cohort.
Publisher: Future Medicine Ltd
Date: 06-2020
Abstract: Current treatment guidelines for patients with locally advanced head and neck squamous cell carcinoma (HNSCC) recommend multimodal treatment, including chemoradiation therapy (CRT) or surgery followed by radiation, with or without chemotherapy. The immune checkpoint inhibitor pembrolizumab has previously demonstrated antitumor activity in recurrent and/or metastatic HNSCC in large Phase III trials. For patients with locally advanced disease, Phase Ib data on the use of pembrolizumab in combination with chemoradiation have shown the approach to be safe and feasible. We describe here the design and rationale for KEYNOTE-412, a randomized, double-blind, Phase III trial investigating pembrolizumab or placebo administered concurrently with CRT and as maintenance treatment in patients with locally advanced HNSCC. Clinical Trial Registration: NCT03040999 ( ClinicalTrials.gov ).
Publisher: Springer Science and Business Media LLC
Date: 28-05-2014
No related grants have been discovered for Brett Hughes.