224 results on '"C, Underhill"'
Search Results
102. Fishes of the Minnesota Region
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Gary L. Phillips, William D. Schmid, James C. Underhill, Gary L. Phillips, William D. Schmid, and James C. Underhill
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- Fishes--Minnesota
- Abstract
Fishes of the Minnesota Region was first published in 1982. Minnesota Archive Editions uses digital technology to make long-unavailable books once again accessible, and are published unaltered from the original University of Minnesota Press editions.From Northern Pike to the Walleye, this is the definitive guide to all of Minnesota's 149 kinds of fishes. Illustrated with over 80 color photographs, this book will appeal to enthusiastic anglers as well as curious naturalists.Along with a guide to identification, the authors cover habitat, distribution, conservation, and even some recipes. If you catch a fish from one of Minnesota's 10,000 lakes you'll find a description of it in this book.
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- 1982
103. Real-world impact of pembrolizumab availability for deficient mismatch repair metastatic colorectal cancer.
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Loft M, Wong V, Kosmider S, Wong R, Shapiro J, Hong W, Jennens R, Tie J, Caird S, Steel S, Lee B, Nott L, Khattak MA, Lim S, Chong G, Hayes T, Underhill C, McLachlan SA, Rainey N, Dunn C, and Gibbs P
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- Humans, Aged, Female, Male, Middle Aged, Australia, Aged, 80 and over, Adult, Registries, Neoplasm Metastasis, Antibodies, Monoclonal, Humanized therapeutic use, Colorectal Neoplasms drug therapy, Colorectal Neoplasms pathology, DNA Mismatch Repair, Antineoplastic Agents, Immunological therapeutic use
- Abstract
Background: Immunotherapy has emerged as a standard treatment for deficient mismatch repair (dMMR) metastatic colorectal cancer (mCRC). Pembrolizumab became widely available as a first-line (1L) option in Australia following the Pharmaceutical Benefits Scheme (PBS) listing in August 2021. The uptake of new treatment options can be lengthy., Methods: The Treatment of Recurrent and Advanced Colorectal Cancer mCRC registry data at participating Australian sites was analysed from January 2015 (when MMR testing became routine). 1L treatment of dMMR cancers was compared with pre- and post-PBS funding., Results: Out of 2819 patients, 2344 (83%) had known MMR status. Of these, 162 (7%) were dMMR, which was associated with older age (median age 69 vs 63 years, P = 0.001), a right-side primary (68% vs 31%, P < 0.001) and a BRAF V600E mutation (49% vs 11%, P < 0.001). Prior to August 2021, 85 out of 117 (73%) patients with dMMR received 1L treatment: 63 out of 85 (74%) chemotherapy and 20 out of 85 (24%) immunotherapy. Following approval, 39 out of 45 (87%) received 1L treatment and 39 out of 39 (100%) pembrolizumab. Of the patients 75 years and older, a significantly higher proportion of patients were treated with any 1L therapy post-PBS listing (89% vs 60%, P = 0.036)., Conclusion: Previously reported associations of dMMR were observed. The higher-than-expected proportion of patients with dMMR is likely driven by the inclusion of older patients in this real-world study. Many patients were able to access immunotherapy prior to PBS listing, potentially through trials or access programs. Early uptake of pembrolizumab following PBS listing has been high, and this effective and well-tolerated option has increased the proportion of elderly patients receiving active therapy., (© 2024 Royal Australasian College of Physicians.)
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- 2025
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104. Stage-Specific Guideline Concordant Treatment Impacts on Survival in Nonsmall Cell Lung Cancer: A Novel Quality Indicator.
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Tissera S, Billah B, Brand M, Karim MN, Antippa P, Blum R, Caldecott M, Conron M, Faisal W, Harden S, Olesen I, Parente P, Richardson G, Samuel E, See K, Underhill C, Wright G, Zalcberg J, and Stirling RG
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- Humans, Female, Male, Aged, Middle Aged, Neoplasm Staging, Quality Indicators, Health Care, Registries, Survival Rate, Guideline Adherence statistics & numerical data, Australia epidemiology, Aged, 80 and over, Lung Neoplasms mortality, Lung Neoplasms drug therapy, Lung Neoplasms therapy, Lung Neoplasms pathology, Carcinoma, Non-Small-Cell Lung mortality, Carcinoma, Non-Small-Cell Lung drug therapy, Carcinoma, Non-Small-Cell Lung pathology, Practice Guidelines as Topic
- Abstract
Background: Lung cancer in Australia contributes 9% of all new cancer diagnoses and is the leading cause of cancer death and burden. Clinical practice guidelines provide evidence-based treatment recommendations for best practice management. We aimed to determine the extent of delivery of guideline-concordant treatment (GCT) and to identify modifiable variables influencing receipt of GCT and survival., Methods: Data was sourced from the Victorian Lung Cancer Registry (VLCR) in Victoria, Australia. Descriptive statistics were used to summarize patient and disease characteristics according to treatment type: GCT versus non-GCT versus no/declined treatment. Statistical analyses included multiple logistic regression, multiple COX regression and Kaplan-Meier survival estimates., Results: 52% of patients were treated with GCT, 32.8% non-GCT and 15.2% declined or received no treatment. GCT treated patients were younger, never smoked, had no comorbidities, had better performance status, had early stage cancer, were discussed at a multidisciplinary meeting or had treatment at a higher volume hospital. Overall, patients that received GCT had a 24% lower risk of mortality compared to patients that received non-GCT., Conclusion: Modifiable variables impacting likelihood of receiving GCT included age, smoking status and treating hospital characteristics. Several modifiable variables were identified with positive impacts on survival including increased treatment of the elderly, smoking cessation, delivery of GCT, and treatment in higher volume hospitals. The measurement and reporting of delivery of GCT has positive impacts on survival and therefore merits consideration as an evidence-based quality indicator in the reporting of lung cancer quality and safety outcomes., Competing Interests: Disclosure All other authors state that they have no conflicts of interest., (Copyright © 2024. Published by Elsevier Inc.)
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- 2024
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105. Pharmacogenetic-guided dosing for fluoropyrimidine (DPYD) and irinotecan (UGT1A1*28) chemotherapies for patients with cancer (PACIFIC-PGx): A multicenter clinical trial.
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Glewis S, Lingaratnam S, Lee B, Campbell I, IJzerman M, Fagery M, Harris S, Georgiou C, Underhill C, Warren M, Campbell R, Jayawardana M, Silva SSM, Martin JH, Tie J, Alexander M, and Michael M
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- Humans, Male, Middle Aged, Female, Aged, Adult, Prospective Studies, Pharmacogenomic Variants, Feasibility Studies, Genotype, Australia, Fluorouracil administration & dosage, Fluorouracil adverse effects, Aged, 80 and over, Young Adult, Glucuronosyltransferase genetics, Irinotecan administration & dosage, Irinotecan adverse effects, Neoplasms drug therapy, Neoplasms genetics, Dihydrouracil Dehydrogenase (NADP) genetics, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Antineoplastic Combined Chemotherapy Protocols adverse effects, Pharmacogenomic Testing
- Abstract
PACIFIC-PGx evaluated the feasibility of implementing pharmacogenetics (PGx) screening in Australia and the impact of DPYD/UGT1A1 genotype-guided dosing on severe fluoropyrimidine (FP) and irinotecan-related toxicities and hospitalizations, compared to historical controls. This prospective single arm trial enrolled patients starting FP/irinotecan for any cancer between 7 January 2021 and 25 February 2022 from four Australian hospitals (one metropolitan, three regional). During the accrual period, 462/487 (95%) consecutive patients screened for eligibility for DPYD and 50/109 (46%) for UGT1A1 were enrolled and genotyped (feasibility analysis), with 276/462 (60%) for DPYD and 30/50 (60%) for UGT1A1 received FP/irinotecan (safety analysis). DPYD genotyping identified 96% (n = 443/462) Wild-Type, 4% (n = 19/462) Intermediate Metabolizers (50% dose reduction), and 0% Poor Metabolizers. UGT1A1 genotyping identified 52% (n = 26/50) Wild-Type, 40% (n = 20/50) heterozygous, and 8% (n = 4/50) homozygous (30% dose reduction). Key demographics for the FP/irinotecan safety cohorts included: age range 23-89/34-74 years, male 56%/73%, Caucasian 83%/73%, lower gastrointestinal cancer 50%/57%. Genotype results were reported prior to cycle-1 (96%), average 5-7 days from sample collection. PGx-dosing for DPYD variant allele carriers reduced high-grade toxicities compared to historic controls (7% vs. 39%; OR = 0.11, 95% CI 0.01-0.97, p = 0.024). High-grade toxicities among Wild-Type were similar (14% vs. 14%; OR = 0.99, 95% CI 0.64-1.54, p = 0.490). PGx-dosing reduced FP-related hospitalizations (-22%) and deaths (-3.7%) compared to controls. There were no high-grade toxicities or hospitalizations for UGT1A1*28 homozygotes. PGx screening and prescribing were feasible in routine oncology care and improved patient outcomes. Findings may inform expanded PGx programs within cancer and other disease settings., (© 2024 The Author(s). Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)
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- 2024
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106. Decentralised clinical trials: a game changer for improved access to clinical trials.
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Underhill C, Sabesan S, and Wilson E
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Competing Interests: We declare no competing interests.
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- 2024
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107. Telehealth in cancer care during the COVID-19 pandemic.
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Burbury K, Brooks P, Gilham L, Solo I, Piper A, Underhill C, Campbell P, Blum R, Brown S, Barnett F, Torres J, Wang X, Poole W, Grobler A, Johnston G, Beer C, Cross H, and Wong ZW
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- Adult, Aged, Female, Humans, Male, Middle Aged, Caregivers psychology, Cross-Sectional Studies, Patient Acceptance of Health Care statistics & numerical data, Patient Satisfaction, Prospective Studies, SARS-CoV-2, Victoria, COVID-19 epidemiology, Neoplasms therapy, Pandemics, Telemedicine organization & administration, Cancer Care Facilities
- Abstract
Introduction: The Victorian COVID-19 Cancer Network (VCCN) Telehealth Expert Working Group aimed to evaluate the telehealth (TH) experience for cancer patients, carers and clinicians with the rapid uptake of TH in early 2020 during the COVID-19 pandemic., Methods: We conducted a prospective multi-centre cross-sectional survey involving eight Victorian regional and metropolitan cancer services and three consumer advocacy groups. Patients or their carers and clinicians who had TH consultations between 1 July 2020 and 31 December 2020 were invited to participate in patient and clinician surveys, respectively. These surveys were opened from September to December 2020., Results: The acceptability of TH via both video (82.9%) and phone (70.4%) were high though acceptability appeared to decrease in older phone TH users. Video was associated with higher satisfaction compared to phone (87.1% vs 79.7%) even though phone was more commonly used. Various themes from the qualitative surveys highlighted barriers and enablers to rapid TH implementation., Discussion: The high TH acceptability supports this as a safe and effective strategy for continued care and should persist beyond the pandemic environment, where patient preferences are considered and clinically appropriate. Ongoing support to health services for infrastructure and resources, as well as expansion of reimbursement eligibility criteria for patients and health professionals, including allied health and nursing, are crucial for sustainability., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article.
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- 2024
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108. Exploring management and outcomes of elderly patients with glioblastoma using data from two randomised trials (GEINO1401/EX-TEM).
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Gately L, Mesía C, Sepúlveda JM, Del Barco S, Pineda E, Gironés R, Fuster J, Dumas M, Gill S, Navarro LM, Herrero A, Dowling A, de Las Peñas R, Vaz MA, Alonso M, Lwin Z, Harrup R, Peralta S, Long A, Perez-Segura P, Ahern E, Garate CO, Wong M, Campbell R, Cuff K, Jennens R, Gallego O, Underhill C, Martinez-Garcia M, Covela M, Cooper A, Brown S, Rosenthal M, Torres J, Collins IM, Gibbs P, and Balana C
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- Humans, Aged, Male, Female, Middle Aged, Aged, 80 and over, Temozolomide therapeutic use, Adult, Antineoplastic Agents, Alkylating therapeutic use, Age Factors, Combined Modality Therapy, Treatment Outcome, Disease Management, Glioblastoma therapy, Glioblastoma mortality, Brain Neoplasms therapy, Brain Neoplasms mortality
- Abstract
Purpose: The impact of age on optimal management of glioblastoma remains unclear. A recent combined analysis of two randomised trials, GEINO14-01 and EX-TEM, found no benefit from extending post-radiation temozolomide in newly diagnosed glioblastoma. Here, we explore the impact of age., Methods: Relevant intergroup statistics were used to identify differences in tumour, treatment and outcome characteristics based on age with elderly patients (EP) defined as age 65 years and over. Survival was estimated using the Kaplan Meier method., Results: Of the combined 205 patients, 57 (28%) were EP. Of these, 95% were ECOG 0-1 and 65% underwent macroscopic resection compared with 97% and 61% of younger patients (YP) respectively. There were numerically less MGMT-methylated (56% vs. 63%, p = 0.4) and IDH-mutated (4% vs. 13%, p = 0.1) tumours in EP vs. YP. Following surgery, EP were more likely to receive short course chemoradiation (17.5% vs. 6%, p = 0.017). At recurrence, EP tended to receive or best supportive care (28.3% vs. 15.4%, p = 0.09) or non-surgical options (96.2% vs. 84.6%, p = 0.06), but were less likely to receive bevacizumab (23.1% vs. 49.5%, p < 0.01). Median PFS was similar at 9.3months in EP and 8.5months in YP, with similar median OS at 20months., Conclusion: In this trial population of predominantly fit EP, survival was similar to YP despite a proportion receiving less aggressive therapy at diagnosis and recurrence. Advancing age does not appear to be an adverse prognostic factor for glioblastoma when patients are fit for treatment, and a less aggressive approach in selected patients may not compromise outcomes., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)
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- 2024
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109. Phase 1a dose escalation study of ivonescimab (AK112/SMT112), an anti-PD-1/VEGF-A bispecific antibody, in patients with advanced solid tumors.
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Frentzas S, Austria Mislang AR, Lemech C, Nagrial A, Underhill C, Wang W, Wang ZM, Li B, Xia Y, and Coward JIG
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- Humans, Antibodies, Monoclonal, Humanized adverse effects, Carcinoma, Non-Small-Cell Lung drug therapy, Hypertension chemically induced, Immune Checkpoint Inhibitors therapeutic use, Lung Neoplasms drug therapy, Programmed Cell Death 1 Receptor therapeutic use, Tumor Microenvironment, Vascular Endothelial Growth Factor A, Antibodies, Bispecific adverse effects, Neoplasms drug therapy
- Abstract
Background: Studies showed that vascular endothelial growth factor (VEGF) inhibitors could improve therapeutic efficacy of PD-1/PD-L1 antibodies by transforming the immunosuppressive tumor microenvironment (TME) into an immunoresponsive TME. Ivonescimab is a first-in-class, humanized tetravalent bispecific antibody targeting PD-1 and VEGF-A simultaneously. Here, we report the first-in-human, phase 1a study of ivonescimab in patients with advanced solid tumors., Methods: Patients with advanced solid tumors were treated with ivonescimab 0.3, 1, 3, 10, 20 or 30 mg/kg intravenously every 2 weeks using a 3+3+3 dose escalation design. Dose expansion occurred at 10 and 20 mg/kg in selected tumor types. The primary objective was to assess the safety and tolerability, and to determine the maximum tolerated dose (MTD). The secondary objectives included pharmacokinetics, pharmacodynamics and preliminary antitumor activity based on Response Evaluation Criteria in Solid Tumors V.1.1., Results: Between October 2, 2019 and January 14, 2021, a total of 51 patients were enrolled and received ivonescimab. Two dose-limiting toxicities were reported at 30 mg/kg. The MTD of ivonescimab was 20 mg/kg every 2 weeks. Grade≥3 treatment-related adverse events (TRAEs) occurred in 14 patients (27.5%). The most common TRAEs of any grade were rash (29.4%), arthralgia (19.6%), hypertension (19.6%), fatigue (17.6%), diarrhea (15.7%) and pruritus (11.8%). The most common grade≥3 TRAEs were hypertension (7/51, 13.7%), alanine aminotransferase increased (3/51, 5.2%), aspartate aminotransferase increased (2/51, 3.9%) and colitis (2/51, 3.9%). Of 47 patients who had at least one postbaseline assessment, the confirmed objective response rate was 25.5% (12/47) and disease control rate was 63.8% (30/47). Among 19 patients with platinum-resistant ovarian cancer, 5 patients (26.3%) achieved partial response (PR). Efficacy signals were also observed in patients with mismatch repair proficient (pMMR) colorectal cancer, non-small cell lung cancer, and both MMR deficient and pMMR endometrial cancer., Conclusions: Ivonescimab demonstrated manageable safety profiles and promising efficacy signals in multiple solid tumors. Exploration of alternative dosing regimens of ivonescimab monotherapy and combination therapies is warranted., Trial Registration Number: NCT04047290., Competing Interests: Competing interests: WW, ZMW, BL, and YX are all employees of Akeso Biopharma, Zhongshan, China. JIGC provided consultancy work for Akeso since 2022. The other authors declare no potential conflicts of interest., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
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- 2024
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110. Changing high-risk asthma in Memphis through partnership: Results from the CHAMP program.
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Steppe S, Stokes DC, Underhill C, Winders TA, Gardner DD, and Michael CF
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- United States, Child, Humans, Male, Female, Tennessee epidemiology, Managed Care Programs, Ohio, Medicaid, Asthma epidemiology, Asthma therapy
- Abstract
Background: Children in metro Shelby County, Tennessee, have disproportionally high asthma-related health care resource use (HRU) compared with those in other regions in Tennessee., Objective: To describe the goals, logistics, and outcomes of the Changing High-Risk Asthma in Memphis through Partnership (CHAMP) program implemented to improve pediatric asthma care in Shelby County., Methods: CHAMP established a multidisciplinary team with dedicated medical staff and community health workers, implemented a 24/7 call line to improve access to care, established a patient data registry to address fragmented care, assigned community health educators to improve asthma education and social needs, and partnered with services to address environmental triggers and social determinants of health. Patients eligible for CHAMP are Shelby County residents aged 2 to 18 years with high-risk asthma enrolled in Tennessee's Medicaid managed care program. Health care resource use outcomes 1-year pre- and post-CHAMP enrollment were analyzed for patients who had completed 1 year of CHAMP between January 2013 and December 2022. The 24/7 call line data between November 2013 and December 2022 were analyzed., Results: CHAMP has enrolled 1348 children; 945 have completed 1 year (63% male; 90% identified as Black). At 1-year post-CHAMP enrollment, patients had 58%, 68%, 42%, and 53% reductions in emergency department visits, inpatient and observation visits, urgent care visits, and total asthma exacerbations, respectively. The number of asthma exacerbations per patient significantly decreased from 2.97 to 1.40 at 1-year post-CHAMP enrollment. Of the calls made to the 24/7 call line, 58% occurred after hours and 52% led to issue resolution without a medical facility visit., Conclusion: CHAMP successfully decreased asthma HRU in children with high-risk asthma in Shelby County by implementing initiatives that targeted barriers to asthma care., Competing Interests: Disclosures The authors have no conflicts of interest to report., (Copyright © 2023 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)
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- 2024
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111. Decentralized Clinical Trials as a New Paradigm of Trial Delivery to Improve Equity of Access.
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Underhill C, Freeman J, Dixon J, Buzza M, Long D, Burbury K, Sabesan S, McBurnie J, and Woollett A
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- Humans, Health Services Accessibility, Australia, Pandemics, COVID-19
- Abstract
Importance: The need to maintain clinical trial recruitment during the COVID-19 pandemic has precipitated the rapid uptake of digital health for the conduct of clinical trials. Different terms are used in different jurisdictions and clinical contexts, including digital trials, networked trials, teletrials (TT), and decentralized clinical trials (DCT) with a need to agree to terms., Observations: This clinical care review summarized publications and gray literature, including government policies for the safe conduct of clinical trials using digital health. It compares 2 frequently used methodologies, DCT and TT, first developed before the COVID-19 pandemic by trialists and stakeholders in Australia to improve access to cancer clinical trials for geographically dispersed populations. TT uses a networked approach to implement clinical trials to share care between facilities and uses an agreement between sites or a supervision plan to improve governance and safety. Government regulators have adapted existing regulations and invested in the rollout of the TT model. The term DCT emerged in the northern hemisphere and has been the subject of guidance from regulatory agencies. DCT uses digital health to deliver care in nontraditional sites, such as participants' homes, but does not mandate a networked approach between health facilities or require a supervision plan to be in place., Conclusions and Relevance: TT can be considered as a specific type of DCT with several potential advantages, including upskilling across a network. DCT is a new paradigm for the use of digital health in the safe conduct of clinical trials and is a transformative issue in cancer care, addressing disparities in access to clinical trials and improving clinical outcomes.
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- 2024
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112. A gut microbial signature for combination immune checkpoint blockade across cancer types.
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Gunjur A, Shao Y, Rozday T, Klein O, Mu A, Haak BW, Markman B, Kee D, Carlino MS, Underhill C, Frentzas S, Michael M, Gao B, Palmer J, Cebon J, Behren A, Adams DJ, and Lawley TD
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- Humans, Immune Checkpoint Inhibitors therapeutic use, Gastrointestinal Microbiome genetics, Neoplasms drug therapy, Neoplasms genetics
- Abstract
Immune checkpoint blockade (ICB) targeting programmed cell death protein 1 (PD-1) and cytotoxic T lymphocyte protein 4 (CTLA-4) can induce remarkable, yet unpredictable, responses across a variety of cancers. Studies suggest that there is a relationship between a cancer patient's gut microbiota composition and clinical response to ICB; however, defining microbiome-based biomarkers that generalize across cohorts has been challenging. This may relate to previous efforts quantifying microbiota to species (or higher taxonomic rank) abundances, whereas microbial functions are often strain specific. Here, we performed deep shotgun metagenomic sequencing of baseline fecal samples from a unique, richly annotated phase 2 trial cohort of patients with diverse rare cancers treated with combination ICB (n = 106 discovery cohort). We demonstrate that strain-resolved microbial abundances improve machine learning predictions of ICB response and 12-month progression-free survival relative to models built using species-rank quantifications or comprehensive pretreatment clinical factors. Through a meta-analysis of gut metagenomes from a further six comparable studies (n = 364 validation cohort), we found cross-cancer (and cross-country) validity of strain-response signatures, but only when the training and test cohorts used concordant ICB regimens (anti-PD-1 monotherapy or combination anti-PD-1 plus anti-CTLA-4). This suggests that future development of gut microbiome diagnostics or therapeutics should be tailored according to ICB treatment regimen rather than according to cancer type., (© 2024. The Author(s).)
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- 2024
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113. Correction to: A combined analysis of two prospective randomised studies exploring the impact of extended post-radiation temozolomide on survival outcomes in newly diagnosed glioblastoma.
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Gately L, Mesía C, Sepúlveda JM, Del Barco S, Pineda E, Gironés R, Fuster J, Hong W, Dumas M, Gill S, Navarro LM, Herrero A, Dowling A, de Las Peñas R, Vaz MA, Alonso M, Lwin Z, Harrup R, Peralta S, Long A, Perez-Segura P, Ahern E, Garate CO, Wong M, Campbell R, Cuff K, Jennens R, Gallego O, Underhill C, Martinez-Garcia M, Covela M, Cooper A, Brown S, Rosenthal M, Torres J, Collins IM, Gibbs P, and Balana C
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- 2024
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114. A phase II trial of nivolumab followed by ipilimumab and nivolumab in advanced non-clear-cell renal cell carcinoma.
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Conduit C, Davis ID, Goh JC, Kichenadasse G, Gurney H, Harris CA, Pook D, Krieger L, Parnis F, Underhill C, Adams D, Roncolato F, Joshua A, Ferguson T, Prithviraj P, Morris M, Harrison M, Begbie S, Hovey E, George M, Liow EC, Link EK, McJannett M, and Gedye C
- Subjects
- Adult, Humans, Ipilimumab adverse effects, Disease Progression, Antineoplastic Combined Chemotherapy Protocols adverse effects, Nivolumab therapeutic use, Nivolumab adverse effects, Carcinoma, Renal Cell drug therapy, Carcinoma, Renal Cell pathology
- Abstract
Objective: To evaluate the efficacy of sequential treatment with ipilimumab and nivolumab following progression on nivolumab monotherapy in individuals with advanced, non-clear-cell renal cell carcinoma (nccRCC)., Materials and Methods: UNISoN (ANZUP1602; NCT03177239) was an open-label, single-arm, phase 2 clinical trial that recruited adults with immunotherapy-naïve, advanced nccRCC. Participants received nivolumab 240 mg i.v. two-weekly for up to 12 months (Part 1), followed by sequential addition of ipilimumab 1 mg/kg three-weekly for four doses to nivolumab if disease progression occurred during treatment (Part 2). The primary endpoint was objective tumour response rate (OTRR) and secondary endpoints included duration of response (DOR), progression-free (PFS) and overall survival (OS), and toxicity (treatment-related adverse events)., Results: A total of 83 participants were eligible for Part 1, including people with papillary (37/83, 45%), chromophobe (15/83, 18%) and other nccRCC subtypes (31/83, 37%); 41 participants enrolled in Part 2. The median (range) follow-up was 22 (16-30) months. In Part 1, the OTRR was 16.9% (95% confidence interval [CI] 9.5-26.7), the median DOR was 20.7 months (95% CI 3.7-not reached) and the median PFS was 4.0 months (95% CI 3.6-7.4). Treatment-related adverse events were reported in 71% of participants; 19% were grade 3 or 4. For participants who enrolled in Part 2, the OTRR was 10%; the median DOR was 13.5 months (95% CI 4.8-19.7) and the median PFS 2.6 months (95% CI 2.2-3.8). Treatment-related adverse events occurred in 80% of these participants; 49% had grade 3, 4 or 5. The median OS was 24 months (95% CI 16-28) from time of enrolment in Part 1., Conclusions: Nivolumab monotherapy had a modest effect overall, with a few participants experiencing a long DOR. Sequential combination immunotherapy by addition of ipilimumab in the context of disease progression to nivolumab in nccRCC is not supported by this study, with only a minority of participants benefiting from this strategy., (© 2023 BJU International.)
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- 2024
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115. A combined analysis of two prospective randomised studies exploring the impact of extended post-radiation temozolomide on survival outcomes in newly diagnosed glioblastoma.
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Gately L, Mesía C, Sepúlveda JM, Del Barco S, Pineda E, Gironés R, Fuster J, Hong W, Dumas M, Gill S, Navarro LM, Herrero A, Dowling A, de Las Peñas R, Vaz MA, Alonso M, Lwin Z, Harrup R, Peralta S, Long A, Perez-Segura P, Ahern E, Garate CO, Wong M, Campbell R, Cuff K, Jennens R, Gallego O, Underhill C, Martinez-Garcia M, Covela M, Cooper A, Brown S, Rosenthal M, Torres J, Collins IM, Gibbs P, and Balana C
- Subjects
- Humans, Temozolomide therapeutic use, Prospective Studies, Dacarbazine adverse effects, Disease-Free Survival, Antineoplastic Agents, Alkylating adverse effects, Glioblastoma drug therapy, Glioblastoma radiotherapy, Brain Neoplasms drug therapy, Brain Neoplasms radiotherapy
- Abstract
Purpose: The optimal duration of post-radiation temozolomide in newly diagnosed glioblastoma remains unclear, with no published phase III randomised trials. Standard-of-care stipulates 6 months. However, in routine care, it is often extended to 12 months, despite lacking robust supporting data., Methods: GEINO14-01 (Spain) and EX-TEM (Australia) studies enrolled glioblastoma patients without progression at the end of 6 months post-radiation temozolomide. Participants were randomised 1:1 to six additional months of temozolomide or observation. Primary endpoint was 6-month progression free survival from date of randomisation (6mPFS). Secondary endpoints included overall survival (OS) and toxicity. 204 patients were required to detect an improvement in 6mPFS from 50 to 60% (80% power). Neither study recruited sufficient patients. We performed a combined analysis of individual patient data., Results: 205 patients were recruited: 159 in GEINO14-01 (2014-2018) and 46 in EX-TEM (2019-2022). Median follow-up was 20.0 and 14.5 months. Baseline characteristics were balanced. There was no significant improvement in 6mPFS (57.2% vs 64.0%, OR0.75, p = 0.4), nor across any subgroups, including MGMT methylated; PFS (HR0.92, p = 0.59, median 7.8 vs 9.7 months); or OS (HR1.03, p = 0.87, median 20.1 vs 19.4 months). During treatment extension, 64% experienced any grade adverse event, mainly fatigue and gastrointestinal (both 54%). Only a minority required treatment changes: 4.5% dose delay, 7.5% dose reduction, 1.5% temozolomide discontinuation., Conclusion: For glioblastoma patients, extending post-radiation temozolomide from 6 to 12 months is well tolerated but does not improve 6mPFS. We could not identify any subset that benefitted from extended treatment. Six months should remain standard-of-care., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)
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- 2024
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116. Telehealth in oncology: a cost analysis to evaluate the financial impact of implementing regional trial hubs within a phase 3 cancer clinical trial.
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Alexander M, Collins I, Abraham P, Underhill C, Harris S, Torres J, Sharma S, Solomon B, Tran-Duy A, and Burbury K
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- Humans, Australia epidemiology, Cost-Benefit Analysis, Costs and Cost Analysis, Medical Oncology, Randomized Controlled Trials as Topic, Clinical Trials, Phase III as Topic, Neoplasms epidemiology, Neoplasms therapy, Telemedicine
- Abstract
This cost analysis, from a societal perspective, compared the cost difference of a networked teletrial model (NTTM) with four regional hubs versus conventional trial operation at a single metropolitan specialist centre. The Australian phase 3 cancer interventional randomised controlled trial included 152 of 328 regional participants (patient enrolment 2018-2021; 6-month primary end point). The NTTM significantly reduced (AU$2155 per patient) patient travel cost and time and lost productivity., (© 2023 The Authors. Internal Medicine Journal published by John Wiley & Sons Australia, Ltd on behalf of Royal Australasian College of Physicians.)
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- 2023
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117. Patient and healthcare professional acceptability of pharmacogenetic screening for DPYD and UGT1A1: A cross sectional survey.
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Glewis S, Krishnasamy M, Lingaratnam S, Harris S, Underhill C, Georgiou C, Warren M, Campbell R, IJzerman M, Fagery M, Campbell I, Martin JH, Tie J, Alexander M, and Michael M
- Subjects
- Humans, Cross-Sectional Studies, Health Personnel, Patient Acceptance of Health Care, Pharmacogenetics, Neoplasms, Pharmacogenomic Testing, Dihydropyrimidine Dehydrogenase Deficiency diagnosis, Dihydropyrimidine Dehydrogenase Deficiency genetics
- Abstract
This study explored the acceptability of a novel pharmacist-led pharmacogenetics (PGx) screening program among patients with cancer and healthcare professionals (HCPs) taking part in a multicenter clinical trial of PGx testing (PACIFIC-PGx ANZCTR:12621000251820). Medical oncologists, oncology pharmacists, and patients with cancer from across four sites (metropolitan/regional), took part in an observational, cross-sectional survey. Participants were recruited from the multicenter trial. Two study-specific surveys were developed to inform implementation strategies for scaled and sustainable translation into routine clinical care: one consisting of 21 questions targeting HCPs and one consisting of 17 questions targeting patients. Responses were collected from 24 HCPs and 288 patients. The 5-to-7-day PGx results turnaround time was acceptable to HCP (100%) and patients (69%). Most HCPs (92%) indicated that it was appropriate for the PGx clinical pharmacist to provide results to patients. Patients reported equal preference for receiving PGx results from a doctor/pharmacist. Patients and HCPs highly rated the pharmacist-led PGx service. HCPs were overall accepting of the program, with the majority (96%) willing to offer PGx testing to their patients beyond the trial. HCPs identified that lack of financial reimbursements (62%) and lack of infrastructure (38%) were the main reasons likely to prevent/slow the implementation of PGx screening program into routine clinical care. Survey data have shown overall acceptability from patients and HCPs participating in the PGx Program. Barriers to implementation of PGx testing in routine care have been identified, providing opportunity to develop targeted implementation strategies for scaled translation into routine practice., (© 2023 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)
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- 2023
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118. Risk-Directed Ambulatory Thromboprophylaxis in Lung and Gastrointestinal Cancers: The TARGET-TP Randomized Clinical Trial.
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Alexander M, Harris S, Underhill C, Torres J, Sharma S, Lee N, Wong H, Eek R, Michael M, Tie J, Rogers J, Heriot AG, Ball D, MacManus M, Wolfe R, Solomon BJ, and Burbury K
- Subjects
- Adult, Humans, Male, Aged, Anticoagulants adverse effects, Enoxaparin adverse effects, Hemorrhage chemically induced, Lung, Biomarkers, Venous Thromboembolism prevention & control, Venous Thromboembolism chemically induced, Thrombosis drug therapy, Gastrointestinal Neoplasms drug therapy
- Abstract
Importance: Thromboprophylaxis for individuals receiving systemic anticancer therapies has proven to be effective. Potential to maximize benefits relies on improved risk-directed strategies, but existing risk models underperform in cohorts with lung and gastrointestinal cancers., Objective: To assess clinical benefits and safety of biomarker-driven thromboprophylaxis and to externally validate a biomarker thrombosis risk assessment model for individuals with lung and gastrointestinal cancers., Design, Setting, and Participants: This open-label, phase 3 randomized clinical trial (Targeted Thromboprophylaxis in Ambulatory Patients Receiving Anticancer Therapies [TARGET-TP]) conducted from June 2018 to July 2021 (with 6-month primary follow-up) included adults aged 18 years or older commencing systemic anticancer therapies for lung or gastrointestinal cancers at 1 metropolitan and 4 regional hospitals in Australia. Thromboembolism risk assessment based on fibrinogen and d-dimer levels stratified individuals into low-risk (observation) and high-risk (randomized) cohorts., Interventions: High-risk patients were randomized 1:1 to receive enoxaparin, 40 mg, subcutaneously daily for 90 days (extending up to 180 days according to ongoing risk) or no thromboprophylaxis (control)., Main Outcomes and Measures: The primary outcome was objectively confirmed thromboembolism at 180 days. Key secondary outcomes included bleeding, survival, and risk model validation., Results: Of 782 eligible adults, 328 (42%) were enrolled in the trial (median age, 65 years [range, 30-88 years]; 176 male [54%]). Of these participants, 201 (61%) had gastrointestinal cancer, 127 (39%) had lung cancer, and 132 (40%) had metastatic disease; 200 (61%) were high risk (100 in each group), and 128 (39%) were low risk. In the high-risk cohort, thromboembolism occurred in 8 individuals randomized to enoxaparin (8%) and 23 control individuals (23%) (hazard ratio [HR], 0.31; 95% CI, 0.15-0.70; P = .005; number needed to treat, 6.7). Thromboembolism occurred in 10 low-risk individuals (8%) (high-risk control vs low risk: HR, 3.33; 95% CI, 1.58-6.99; P = .002). Risk model sensitivity was 70%, and specificity was 61%. The rate of major bleeding was low, occurring in 1 participant randomized to enoxaparin (1%), 2 in the high-risk control group (2%), and 3 in the low-risk group (2%) (P = .88). Six-month mortality was 13% in the enoxaparin group vs 26% in the high-risk control group (HR, 0.48; 95% CI, 0.24-0.93; P = .03) and 7% in the low-risk group (vs high-risk control: HR, 4.71; 95% CI, 2.13-10.42; P < .001)., Conclusions and Relevance: In this randomized clinical trial of individuals with lung and gastrointestinal cancers who were stratified by risk score according to thrombosis risk, risk-directed thromboprophylaxis reduced thromboembolism with a desirable number needed to treat, without safety concerns, and with reduced mortality. Individuals at low risk avoided unnecessary intervention. The findings suggest that biomarker-driven, risk-directed primary thromboprophylaxis is an appropriate approach in this population., Trial Registration: ANZCTR Identifier: ACTRN12618000811202.
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- 2023
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119. Implementing national models utilizing telehealth for the conduct of clinical trials: A collaborative effort by the cancer sector in Victoria.
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Woollett A, Burbury K, Harris S, Dixon J, Freeman J, McBurnie J, Buzza M, Jane S, and Underhill C
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- Humans, Telemedicine, Neoplasms therapy
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- 2023
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120. Workforce challenges across Victorian medical oncology services.
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Collins IM, Blum R, Segelov E, Parente P, and Underhill C
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- Adult, Humans, Pandemics, Cross-Sectional Studies, Medical Oncology, Workforce, COVID-19 epidemiology, Neoplasms epidemiology, Neoplasms therapy
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Background: Cancer incidence is growing, with increasing treatment options and durations. This has led to an increase workload on the current oncology workforce. The global pandemic has increased this pressure further., Aims: To determine the current medical oncology workforce in Victoria, current shortfalls and future anticipated shortfalls beyond the COVID-19 pandemic., Methods: A self-reported, cross-sectional observational study of all current adult Victorian cancer services in June 2020 examining workforce, workload and early effects of the COVID-19 pandemic., Results: The current average workload of 242 new patients per full-time equivalent consultant in medical oncology across Victoria. This is higher than optimal to deliver a safe and efficient cancer service. The significant variation in workforce between sites highlights the areas in need of most urgent resource allocation. Use of safe prescribing practises such as electronic chemotherapy prescribing are not universal but urgently needed., Conclusions: The medical oncology workforce in Victoria is inadequate to meet current and future demands. This needs to be addressed urgently to avoid an adverse impact on cancer measures and quality standards. Better, standardised data collection is needed to allow for ongoing measures of workforce activity. Novel workforce solutions will also need to be implemented in the short and medium term in the face of global workforce shortages., (© 2022 The Authors. Internal Medicine Journal published by John Wiley & Sons Australia, Ltd on behalf of Royal Australasian College of Physicians.)
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- 2023
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121. Workforce challenges across Victorian oncology services: author reply.
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Collins IM, Blum R, Segelov E, Parente P, and Underhill C
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- Humans, Workforce, Health Services Needs and Demand
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- 2023
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122. Is there a role for combined anti-PD-1/CTLA-4 checkpoint blockade in the management of advanced biliary tract cancers?
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Klein O, Kee D, Nagrial A, Markman B, Underhill C, Michael M, Behren A, Palmer J, Tebbutt NC, Carlino MS, and Cebon J
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- Humans, CTLA-4 Antigen, Antibodies, Monoclonal therapeutic use, Immunotherapy, Melanoma, Bile Duct Neoplasms
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- 2023
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123. SARS-CoV-2 Seroprevalence in a Cohort of International Travellers Returning to Rural Australia: Enablers and Barriers to Containment of COVID-19.
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Jackson J, Chan C, McBurnie J, La Hera-Fuentes G, Burston J, Bridges L, Underhill C, Eek R, Hueston L, O'Sullivan M, and Dwyer DE
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- Adult, Humans, SARS-CoV-2, Seroepidemiologic Studies, Prospective Studies, Rural Population, COVID-19 diagnosis, COVID-19 epidemiology
- Abstract
Objective: To describe the effectiveness of the public health response to COVID-19 in our local region by documenting detection of SARS-CoV-2 infection by nucleic acid testing (NAT) positivity and seroprevalence., Methods: In this prospective study (ACTRN12620000487910), symptomatic adult international travellers returning to regional Australia in March 2020 underwent SARS-CoV-2 NAT and SARS-CoV-2-specific serology., Results: Ninety-nine eligible participants were included. Nine participants had laboratory confirmed SARS-CoV-2, all returning between 16-20 March 2020. Eight (89%) had a positive NAT and seven (78%) had a positive serology test. The majority returned from New Zealand. Participants most frequently presented with cough (100%), headache (66.7%) and sore throat (44.4%). No community cases were detected from 1 March to 30 June 2020., Conclusions: The study cohort of international travellers returning to regional Australia in March 2020 returned eight positive SARS-CoV-2 NAT results over a five-day window. Serology identified one additional case and was negative in two cases who were PCR positive. Longitudinal data confirmed an absence of local community transmission to 30 June 2020., Implications for Public Health: A combination of local, national and environmental factors were necessary to prevent the establishment of community transmission in our local region., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)
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- 2023
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124. Teletrials, the new norm? Expert recommendations for teletrials into the future: Findings from the Clinical Oncology Society of Australia Clinical Trial Research Professionals Group Workshop.
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Roberts NA, Cubitt A, Lindsay D, Bury K, Dixon J, Gebbie C, Hawkins CA, Major T, Jenkins-Marsh S, Morris-Smith B, Poxton M, Richmond S, Smith D, Stoneley A, Thaker DA, Wilson E, Woollett A, Underhill C, and Sabesan S
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- Humans, Australia, Medical Oncology, Pandemics, Congresses as Topic, Societies, Medical, COVID-19, Neoplasms therapy
- Abstract
Introduction: The Australasian Teletrial Model was piloted in co-funded sites across Australia. The purpose was to extend the reach of clinical trials using telemedicine to improve equity and access to this treatment pathway for oncology patients. Experts across Australia gathered to share the learnings of implementation so that future directions can be effective and sustainable., Methods: The 1-day workshop was attended in person and virtually. Attendees were invited to analyze and disseminate the results. Recordings from the presentations were coded independently by three researchers and synthesized. The results were sent to the authorship team for further review to build consensus on the findings in three drafts., Results: Four key themes were identified: "Being on the Same Page," "Building Foundations," "Key Roles in Teletrials," and "Incentives." Although there were many successes that were accelerated by the COVID-19 pandemic, there is work still to be done., Conclusion: The Australasian Teletrial Model has been identified as acceptable and feasible. Future directions need to continue to work on streamlining regulatory processes, implementation and monitoring, and build knowledge to further build networks across Australia., (© 2022 John Wiley & Sons Australia, Ltd.)
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- 2022
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125. Penpulimab, an anti-PD1 IgG1 antibody in the treatment of advanced or metastatic upper gastrointestinal cancers.
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Zheng Y, Mislang ARA, Coward J, Cosman R, Cooper A, Underhill C, Zhu J, Xiong J, Jiang O, Wang H, Xie Y, Zhou Y, Jin X, Li B, Wang ZM, Kwek KY, Xia D, Xia Y, and Xu N
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- Humans, Immunoglobulin G, Antibodies, Monoclonal adverse effects, Gastrointestinal Neoplasms drug therapy, Gastrointestinal Neoplasms pathology, Immune Checkpoint Inhibitors adverse effects
- Abstract
Background: The safety and anti-tumor activity of penpulimab in patients with advanced upper gastrointestinal (UGI) cancers were evaluated in this study., Methods: Patients with advanced UGI cancers naive to immune checkpoint inhibitors were enrolled in two trials of penpulimab. In the Phase Ia/Ib trial in Australia, patients received penpulimab intravenous infusion of 1, 3 and 10 mg/kg every 2 weeks in dose-escalation phase and 200 mg every 2 weeks in dose-expansion phase. In the phase Ib/II trial conducted in China, patients received 200 mg penpulimab every 2 weeks. Primary endpoints were safety and tolerability for the phase Ia/Ib trial and the objective response rate for the phase Ib/II trial. The safety and efficacy of penpulimab in patients with UGI cancers in these two trials were evaluated., Results: A total of 67 patients with UGI cancers from Australia and China were enrolled in these two trials and had received penpulimab with a median of 6 (1-64) doses. 44.8% of patients experienced at least one treatment-related adverse event (TRAE), and 7.5% of patients experienced a grade ≥3 TRAE. Among 60 patients evaluable for response, the confirmed objective response rates ranged between 11.1 and 26.3% across cohorts for pancreatic cancer, cholangiocarcinoma, gastric or Gastroesophageal junction carcinoma (Gastric/GEJ), and hepatocellular carcinoma. 11/13 (85.0%) responders had ongoing responses at data cutoff date., Conclusions: Penpulimab monotherapy demonstrated an acceptable safety and encouraged anti-tumor activity in patients with advanced UGI cancers. Further exploration in a large cohort of patients is warranted., Trial Registration: Phase Ia/Ib trial in Australia (NCT03352531) and phase Ib/II trial in China (NCT04172506)., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)
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- 2022
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126. Pharmacogenomics guided dosing for fluoropyrimidine and irinotecan chemotherapies for patients with cancer (PACIFIC-PGx): study protocol of a multicentre clinical trial.
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Glewis S, Alexander M, Lingaratnam S, Lee B, Campbell I, Krishnasamy M, IJzerman M, Fagery M, Harris S, Georgiou C, Underhill C, Warren M, Campbell R, Martin J, Tie J, and Michael M
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- Humans, Immunologic Factors therapeutic use, Irinotecan, Multicenter Studies as Topic, Pharmacogenetics methods, Heterocyclic Compounds therapeutic use, Neoplasms drug therapy, Neoplasms genetics
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- 2022
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127. COVID-19 Vaccine Hesitancy in Australian Patients with Solid Organ Cancers.
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Bain N, Nguyen M, Grech L, Day D, McCartney A, Webber K, Kwok A, Harris S, Chau H, Chan B, Nott L, Hamad N, Tognela A, Underhill C, Loe BS, Freeman D, Segelov E, and On Behalf Of The Canvaccs Investigators
- Abstract
Background: Vaccination is the cornerstone of the global public health response to the COVID-19 pandemic. Excess morbidity and mortality of COVID-19 infection is seen in people with cancer. COVID-19 vaccine hesitancy has been observed in this medically vulnerable population, although associated attitudes and beliefs remain poorly understood., Methods: An online cross-sectional survey of people with solid organ cancers was conducted through nine health services across Australia. Demographics, cancer-related characteristics and vaccine uptake were collected. Perceptions and beliefs regarding COVID-19 vaccination were assessed using the Oxford COVID-19 Vaccine Hesitancy Scale, the Oxford COVID-19 Vaccine Confidence and Complacency Scale and the Disease Influenced Vaccine Acceptance Scale-6., Results: Between June and October 2021, 2691 people with solid organ cancers completed the survey. The median age was 62.5 years ( SD = 11.8; range 19-95), 40.9% were male, 71.3% lived in metropolitan areas and 90.3% spoke English as their first language. The commonest cancer diagnoses were breast (36.6%), genitourinary (18.6%) and gastrointestinal (18.3%); 59.2% had localized disease and 56.0% were receiving anti-cancer therapy. Most participants (79.7%) had at least one COVID-19 vaccine dose. Vaccine uptake was higher in people who were older, male, metropolitan, spoke English as a first language and had a cancer diagnosis for more than six months. Vaccine hesitancy was higher in people who were younger, female, spoke English as a non-dominant language and lived in a regional location, and lower in people with genitourinary cancer. Vaccinated respondents were more concerned about being infected with COVID-19 and less concerned about vaccine safety and efficacy., Conclusions: People with cancer have concerns about acquiring COVID-19, which they balance against vaccine-related concerns about the potential impact on their disease progress and/or treatment. Detailed exploration of concerns in cancer patients provides valuable insights, both for discussions with individual patients and public health messaging for this vulnerable population.
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- 2022
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128. Exploring Australian regional cancer patients' experiences of clinical trial participation via telehealth.
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Lee JJ, Burbury K, Underhill C, Harris S, Shackleton K, McBurnie J, McPhee N, Osmond F, Wilkins K, Baden P, and Krishnasamy M
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- Australia, Caregivers, Clinical Trials as Topic, Humans, Palliative Care, Qualitative Research, Quality of Life, Neoplasms therapy, Telemedicine
- Abstract
Introduction: Regional cancer patients face various barriers in accessing specialist cancer services. Teletrials are a new model of care that utilise communications technologies to enable access to and participation in clinical trials close to home. The present study aimed to explore the experiences of regional cancer patients and their carers while participating in a teletrial, and those of regional patients who travelled to a metropolitan centre for trial participation., Methods: A concurrent, mixed methods study design was used to address the study aim. Patient quality of life data were gathered for both groups and an audio-recorded semi-structured interview undertaken to explore patients' and carers' experiences of the two modes of trial participation. Greater weighting was given to the qualitative data., Results: Participants described teletrials as an acceptable and valuable initiative that reduced overall burden of trial participation. Irrespective of mode of delivery, patients and carers identified access to trials and specialist cancer services as an important equity issue for regional cancer patients., Discussion: From the perspective of regional cancer patients and carers, a teletrial offers convenient, acceptable access to a clinical trial. Although not all patients may want to engage in a teletrial, patients and carers agree that it offers equity of opportunity for trial participation, irrespective of where people live.
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- 2022
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129. Serious Underlying Medical Conditions and COVID-19 Vaccine Hesitancy: A Large Cross-Sectional Analysis from Australia.
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Day D, Grech L, Nguyen M, Bain N, Kwok A, Harris S, Chau H, Chan B, Blennerhassett R, Nott L, Hamad N, Tognela A, Hoffman D, McCartney A, Webber K, Wong J, Underhill C, Sillars B, Winkel A, Savage M, Loe BS, Freeman D, Segelov E, and On Behalf Of The Canvaccs Diabvaccs And Msvaccs Investigators
- Abstract
As COVID-19 vaccinations became available and were proven effective in preventing serious infection, uptake amongst individuals varied, including in medically vulnerable populations. This cross-sectional multi-site study examined vaccine uptake, hesitancy, and explanatory factors amongst people with serious and/or chronic health conditions, including the impact of underlying disease on attitudes to vaccination. A 42-item survey was distributed to people with cancer, diabetes, or multiple sclerosis across ten Australian health services from 30 June to 5 October 2021. The survey evaluated sociodemographic and disease-related characteristics and incorporated three validated scales measuring vaccine hesitancy and vaccine-related beliefs generally and specific to their disease: the Oxford COVID-19 Vaccine Hesitancy Scale, the Oxford COVID-19 Vaccine Confidence and Complacency Scale and the Disease Influenced Vaccine Acceptance Scale-Six. Among 4683 participants (2548 [54.4%] female, 2108 [45.0%] male, 27 [0.6%] other; mean [SD] age, 60.6 [13.3] years; 3560 [76.0%] cancer, 842 [18.0%] diabetes, and 281 [6.0%] multiple sclerosis), 3813 (81.5%) self-reported having at least one COVID-19 vaccine. Unvaccinated status was associated with younger age, female sex, lower education and income, English as a second language, and residence in regional areas. Unvaccinated participants were more likely to report greater vaccine hesitancy and more negative perceptions toward vaccines. Disease-related vaccine concerns were associated with unvaccinated status and hesitancy, including greater complacency about COVID-19 infection, and concerns relating to vaccine efficacy and impact on their disease and/or treatment. This highlights the need to develop targeted strategies and education about COVID-19 vaccination to support medically vulnerable populations and health professionals.
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- 2022
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130. GUIDE: a randomised non-comparative phase II trial of biomarker-driven intermittent docetaxel versus standard-of-care docetaxel in metastatic castration-resistant prostate cancer (clinical trial protocol).
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Conduit C, Mak B, Qu W, Lulio JD, Burder R, Bressel M, Cusick T, Dhillon HM, Lourenço RA, Underhill C, Torres J, Crumbaker M, Honeyball F, Linton A, Allen R, Davis ID, Clark SJ, Horvath LG, and Mahon KL
- Abstract
Objective: To determine the efficacy and safety of intermittent docetaxel chemotherapy guided by circulating methylated glutathione S-transferase Pi-1 ( mGSTP1 ) in men with metastatic castration-resistant prostate cancer (CRPC)., Patients and Methods: GUIDE (NCT04918810) is a randomised, two-arm, non-comparative phase-2 trial recruiting 120 patients at six Australian centres. Patients with Prostate Cancer Working Group-3 defined metastatic CRPC who are commencing docetaxel 75 mg/m
2 q3w will be pre-screened for detectable mGSTP1 at baseline ± following two cycles of treatment. Those with detectable plasma mGSTP1 at baseline that becomes undetectable after two cycles of chemotherapy will be eligible for GUIDE. Prior to Cycle 4 of docetaxel, these patients are randomised 2:1 to one of two treatment arms: Arm A (cease docetaxel and reinstitute if mGSTP1 becomes detectable) or Arm B (continue docetaxel 75 mg/m2 q3w in accordance with clinician's usual practice). The primary endpoint is radiographic progression-free survival. Secondary endpoints include time on treatment holidays, safety, patient-reported outcomes, overall survival, health resource use, and cost associated with treatment. Enrolment commenced November 2021., Results and Conclusion: The results of this trial will generate data on the clinical utility of mGSTP1 as a novel biomarker to guide treatment de-escalation in metastatic CRPC., Competing Interests: Conflict of interest statement: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s), 2022.)- Published
- 2022
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131. CCTG BR34: A Randomized Phase 2 Trial of Durvalumab and Tremelimumab With or Without Platinum-Based Chemotherapy in Patients With Metastatic NSCLC.
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Leighl NB, Laurie SA, Goss GD, Hughes BGM, Stockler M, Tsao MS, Hwang DM, Joubert P, Kulkarni S, Blais N, Joy AA, Mates M, Rana P, Yadav SK, Underhill C, Lee C, Bradbury PA, Hiltz A, Dancey J, Ding K, and Vera-Badillo F
- Subjects
- Antibodies, Monoclonal, Antibodies, Monoclonal, Humanized, Antineoplastic Combined Chemotherapy Protocols adverse effects, Humans, Platinum therapeutic use, Carcinoma, Non-Small-Cell Lung pathology, Lung Neoplasms pathology
- Abstract
Introduction: 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., Methods: 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., Results: 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., Conclusions: 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., (Copyright © 2021 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)
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- 2022
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132. Psychosocial well-being and supportive care needs of cancer patients and survivors living in rural or regional areas: a systematic review from 2010 to 2021.
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van der Kruk SR, Butow P, Mesters I, Boyle T, Olver I, White K, Sabesan S, Zielinski R, Chan BA, Spronk K, Grimison P, Underhill C, Kirsten L, and Gunn KM
- Subjects
- Caregivers, Humans, Rural Population, Survivors, Neoplasms therapy, Quality of Life
- Abstract
Purpose: To summarise what is currently known about the psychosocial morbidity, experiences, and needs of people with cancer and their informal caregivers, who live in rural or regional areas of developed countries., Methods: Eligible studies dating from August 2010 until May 2021 were identified through several online databases, including MEDLINE, EMBASE, PsychINFO, and RURAL (Rural and Remote Health Database). Results were reported according to the PRISMA guidelines and the protocol was registered on PROSPERO (CRD42020171764)., Results: Sixty-five studies were included in this review, including 20 qualitative studies, 41 quantitative studies, and 4 mixed methods studies. Qualitative research demonstrated that many unique psychosocial needs of rural people remain unmet, particularly relating to finances, travel, and accessing care. However, most (9/19) quantitative studies that compared rural and urban groups reported no significant differences in psychosocial needs, morbidity, or quality of life (QOL). Five quantitative studies reported poorer psychosocial outcomes (social and emotional functioning) in urban cancer survivors, while three highlighted poorer outcomes (physical functioning, role functioning, and self-reported mental health outcomes) in the rural group., Conclusion: Recent research shows that rural people affected by cancer have unique unmet psychosocial needs relating to rurality. However, there was little evidence that rural cancer survivors report greater unmet needs than their urban counterparts. This contrasts to the findings from a 2011 systematic review that found rural survivors consistently reported worse psychosocial outcomes. More population-based research is needed to establish whether uniquely rural unmet needs are due to general or cancer-specific factors., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)
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- 2022
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133. Victorian Lung Cancer Service Redesign Project: impacts of a quality improvement collaborative on timeliness and management in lung cancer.
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Largey G, Briggs P, Davies H, Underhill C, Ross C, Harvey K, Blum R, Parker C, Guthrie C, Parente P, Trevorah B, Torres J, Mott C, Lancaster C, Brand M, Earnest A, Pellegrini B, Reed M, Zalcberg J, and Stirling R
- Subjects
- Humans, Prospective Studies, Referral and Consultation, Lung Neoplasms diagnosis, Lung Neoplasms epidemiology, Lung Neoplasms therapy, Quality Improvement
- Abstract
Background: Lung cancer management is characterised by a high disease burden, poor survival and substantial variation in management and outcomes. Service redesign provides opportunities for quality improvement (QI) and this improvement may be leveraged across multiple sites using QI collaboration., Aim: This initiative targeted Quality Improvement (QI) in lung cancer management, engaging a QI collaborative using service redesign methodologies in five Victorian hospitals. QI targets included timeliness from referral and diagnosis to treatment, multi-disciplinary meeting (MDM) presentation and supportive care screening. Redesign strategies targeted process sustainability through enhanced team capability., Methods: This study engaged a prospective quality improvement cohort design targeting newly diagnosed tissue confirmed lung cancer with 6-month pre-intervention period and 6-month redesign implementation period, between September 2016 and August 2017, evaluated using Interrupted Time Series Analysis. Hospital sites included three regional and two metropolitan hospitals in Victoria. QI redesign targeted time intervals from referral to first specialist appointment (FSA), referral to diagnosis, diagnosis to first treatment (any intent), MDM documented in medical records and Supportive Care Screening Tool documented in medical records., Results: There was a marked reduction in referral to FSA interval across all sites, with median (interquartile range) falling from 6 (0-15) to 4 (1-10) days, and proportion seen by a specialist within 14 days increased from 74.3% to 84.2%. The interval between diagnosis and treatment was not substantively changed in the 6-month implementation period. The proportion of subjects with documented presentation to the MDM increased from 61% to 67%. The proportion for which Supportive Care Screening documentation remained low at 26.3% post-intervention., Conclusions: Data-driven redesign initiatives enable identification and analysis of clinical practice variation and may be utilised to enhance timeliness of cancer care and improve local data service capabilities., (© 2020 Royal Australasian College of Physicians.)
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- 2021
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134. Medical Oncology Group of Australia position statement: COVID-19 vaccination in patients with solid tumours.
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Kanjanapan Y, Blinman P, Underhill C, Karikios D, Segelov E, and Yip D
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- Australia epidemiology, COVID-19 Vaccines, Humans, Medical Oncology, SARS-CoV-2, Vaccination, COVID-19, Neoplasms epidemiology, Neoplasms therapy
- Abstract
People with cancer are vulnerable to increased morbidity and mortality from the coronavirus disease 2019 (COVID-19). COVID-19 vaccination is key to protecting the population of people with cancer from adverse outcomes of SARS-CoV-2 infection. The Medical Oncology Group of Australia aimed to address the considerations around COVID-19 vaccination in people with cancer, in particular, safety and efficacy of vaccination. The assessment of patients with generalised allergic reaction to anti-cancer therapy containing vaccine components and practical implementation of vaccination of people on active anti-cancer therapy are also discussed., (© 2021 Royal Australasian College of Physicians.)
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- 2021
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135. Evaluation of TMB as a predictive biomarker in patients with solid cancers treated with anti-PD-1/CTLA-4 combination immunotherapy.
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Klein O, Kee D, Markman B, Carlino MS, Underhill C, Palmer J, Power D, Cebon J, and Behren A
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- Biomarkers, Tumor immunology, CTLA-4 Antigen metabolism, Carcinoma, Non-Small-Cell Lung immunology, Humans, Lung Neoplasms immunology, CTLA-4 Antigen immunology, Carcinoma, Non-Small-Cell Lung therapy, Immunotherapy methods, Lung Neoplasms therapy
- Abstract
Competing Interests: Declaration of interests J.C. reports honoraria/advisory board fees from Bristol-Myers Squibb, Amgen, Novartis, and MSD and speaker fees from Roche. O.K. reports speaker fees from Bristol-Myers Squibb and MSD, as well as travel support from Bristol-Myers Squibb. D.K. reports honoraria/advisory board fees from Novartis and travel support from Bristol-Myers Squibb. M.S.C. reports honoraria/advisory board fees from Bristol-Myers Squibb, Amgen, Novartis, MSD, Roche, Pierre Fabre, Ideaya, Sanofi, Merck, and Nektar. B.M. reports honoraria/advisory board fees from Novartis and Amgen. D.P. is an employee of Thermo Fisher Scientific Ltd. The other authors report no competing interests to disclose.
- Published
- 2021
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136. Circulating tumor DNA dynamics and recurrence risk in patients undergoing curative intent resection of colorectal cancer liver metastases: A prospective cohort study.
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Tie J, Wang Y, Cohen J, Li L, Hong W, Christie M, Wong HL, Kosmider S, Wong R, Thomson B, Choi J, Fox A, Field K, Burge M, Shannon J, Kotasek D, Tebbutt NC, Karapetis C, Underhill C, Haydon A, Schaeffer J, Ptak J, Tomasetti C, Papadopoulos N, Kinzler KW, Vogelstein B, and Gibbs P
- Subjects
- Adult, Aged, Aged, 80 and over, Chemotherapy, Adjuvant statistics & numerical data, Colorectal Neoplasms diagnosis, Female, Humans, Liver Neoplasms diagnosis, Liver Neoplasms secondary, Male, Middle Aged, Neoplasm Recurrence, Local surgery, Prognosis, Prospective Studies, Risk, Treatment Outcome, Circulating Tumor DNA blood, Colorectal Neoplasms pathology, Liver Neoplasms surgery, Neoplasm Recurrence, Local epidemiology
- Abstract
Background: In patients with resectable colorectal liver metastases (CRLM), the role of pre- and postoperative systemic therapy continues to be debated. Previous studies have shown that circulating tumor DNA (ctDNA) analysis, as a marker of minimal residual disease, is a powerful prognostic factor in patients with nonmetastatic colorectal cancer (CRC). Serial analysis of ctDNA in patients with resectable CRLM could inform the optimal use of perioperative chemotherapy. Here, we performed a validation study to confirm the prognostic impact of postoperative ctDNA in resectable CRLM observed in a previous discovery study., Methods and Findings: We prospectively collected plasma samples from patients with resectable CRLM, including presurgical and postsurgical samples, serial samples during any pre- or postoperative chemotherapy, and serial samples in follow-up. Via targeted sequencing of 15 genes commonly mutated in CRC, we identified at least 1 somatic mutation in each patient's tumor. We then designed a personalized assay to assess 1 mutation in plasma samples using the Safe-SeqS assay. A total of 380 plasma samples from 54 patients recruited from July 2011 to Dec 2014 were included in our analysis. Twenty-three (43%) patients received neoadjuvant chemotherapy, and 42 patients (78%) received adjuvant chemotherapy after surgery. Median follow-up was 51 months (interquartile range, 31 to 60 months). At least 1 somatic mutation was identified in all patients' tumor tissue. ctDNA was detectable in 46/54 (85%) patients prior to any treatment and 12/49 (24%) patients after surgery. There was a median 40.93-fold (19.10 to 87.73, P < 0.001) decrease in ctDNA mutant allele fraction with neoadjuvant chemotherapy, but ctDNA clearance during neoadjuvant chemotherapy was not associated with a better recurrence-free survival (RFS). Patients with detectable postoperative ctDNA experienced a significantly lower RFS (HR 6.3; 95% CI 2.58 to 15.2; P < 0.001) and overall survival (HR 4.2; 95% CI 1.5 to 11.8; P < 0.001) compared to patients with undetectable ctDNA. For the 11 patients with detectable postoperative ctDNA who had serial ctDNA sampling during adjuvant chemotherapy, ctDNA clearance was observed in 3 patients, 2 of whom remained disease-free. All 8 patients with persistently detectable ctDNA after adjuvant chemotherapy have recurred. End-of-treatment (surgery +/- adjuvant chemotherapy) ctDNA detection was associated with a 5-year RFS of 0% compared to 75.6% for patients with an undetectable end-of-treatment ctDNA (HR 14.9; 95% CI 4.94 to 44.7; P < 0.001). Key limitations of the study include the small sample size and the potential for false-positive findings with multiple hypothesis testing., Conclusions: We confirmed the prognostic impact of postsurgery and posttreatment ctDNA in patients with resected CRLM. The potential utility of serial ctDNA analysis during adjuvant chemotherapy as an early marker of treatment efficacy was also demonstrated. Further studies are required to define how to optimally integrate ctDNA analyses into decision-making regarding the use and timing of adjuvant therapy for resectable CRLM., Trial Registration: ACTRN12612000345886., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: BV, KWK, & NP are founders of, and hold equity in Thrive Earlier Detection and Personal Genome Diagnostics. KWK & NP are on the Board of Directors of, and consultants to, Thrive Earlier Detection. KWK & BV are consultants to Sysmex, Eisai, Personal Genome Diagnostics and CAGE Pharma and hold equity in CAGE Pharma. KWK, BV, and NP are consultants to and hold equity in NeoPhore. BV is a consultant to and holds equity in Catalio Capital Management. NP is an advisor to and holds equity in CAGE Pharma. The companies named above, as well as other companies, have licensed previously described technologies related to the work described in this paper from Johns Hopkins University. BV, KWK, and NP are inventors on some of these technologies. Licenses to these technologies are or will be associated with equity or royalty payments to the inventors as well as to Johns Hopkins University. CT and the University are entitled to royalty distributions related to technology licensed to Thrive Earlier Detection. CT is a consultant to Thrive. The terms of all these arrangements are being managed by Johns Hopkins University in accordance with its conflict of interest policies. All other authors declare no competing interests.
- Published
- 2021
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137. Developing a Congregational Health Needs Assessment: Lessons Learned from Using a Participatory Research Approach.
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Harmon BE, San Diego ER, Pichon LC, Powell TW, Rugless F, McCann L, Minor LL, Davis R, Underhill C, Campbell B, Smith JB, McNeal S, Evans J, and Calvin V
- Subjects
- Humans, Leadership, Community-Based Participatory Research, Delivery of Health Care
- Abstract
Background: Health needs assessments help congregations identify issues of importance to them and the communities they serve. Few tools exist, with little known about the processes needed to develop such tools., Objective: Develop a congregational health needs assessment tool and implementation protocol with community, health-care, and academic partners., Methods: Meetings began in August 2018 to develop the Mid-South Congregational Health Needs Survey (MSCHS) and implementation protocol. Pilot testing occurred in December 2018 and feedback from 95 churches was used in modifications., Results: The MSCHS includes: demographics section, a 36-item health index, and the congregation's top five needs.The implementation protocol includes steps for working with congregation leadership to identify members to complete the survey., Conclusions: Cross-disciplinary partnerships made the creation of the MSCHS and implementation protocol possible. Successes include long-term engagement across partnership sectors, organizational "buy-in," and development of a common language. These lessons can help others wanting to develop successful multi-sector partnerships.
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- 2021
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138. Telehealth in cancer care: during and beyond the COVID-19 pandemic.
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Burbury K, Wong ZW, Yip D, Thomas H, Brooks P, Gilham L, Piper A, Solo I, and Underhill C
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- Humans, COVID-19, Medical Oncology trends, Neoplasms therapy, Pandemics, Telemedicine trends
- Abstract
The COVID-19 pandemic has precipitated the rapid uptake of telehealth in cancer care and in other fields. Many of the changes made in routine clinical practice could be embedded beyond the duration of the pandemic. This is intended as a practical guide to cancer clinicians and others in establishing and improving the quality of consultations performed by telehealth., (© 2021 Royal Australasian College of Physicians.)
- Published
- 2021
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139. Towards new models of cancer care in Australia: lessons from Victoria's response to the COVID-19 pandemic.
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Underhill C, Parente P, McArthur G, Haydon A, McLachlan SA, Wong ZW, and Segelov E
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- Betacoronavirus, COVID-19, Communication, Cooperative Behavior, Humans, Pandemics, Patient Care Team organization & administration, Referral and Consultation, SARS-CoV-2, Telemedicine organization & administration, Victoria epidemiology, Coronavirus Infections epidemiology, Home Care Services organization & administration, Neoplasms epidemiology, Neoplasms therapy, Pneumonia, Viral epidemiology
- Abstract
In response to the COVID-19 pandemic, the Department of Health and Human Services Victoria (DHHS), the Monash Partners Comprehensive Cancer Consortium (MPCCC) and Victorian Comprehensive Cancer Centre (VCCC) pooled their combined infrastructure to establish the Victorian COVID-19 Cancer Network (VCCN) backed by a Taskforce of expert members. In a few short months, this state-wide clinical network implemented a number of new models of care including clinics to manage acutely presenting cancer patients away from emergency departments, chemotherapy in the home, telehealth models and addressing sustainability of clinical trials., (© 2020 Royal Australasian College of Physicians.)
- Published
- 2020
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140. Immunotherapy of Ipilimumab and Nivolumab in Patients with Advanced Neuroendocrine Tumors: A Subgroup Analysis of the CA209-538 Clinical Trial for Rare Cancers.
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Klein O, Kee D, Markman B, Michael M, Underhill C, Carlino MS, Jackett L, Lum C, Scott C, Nagrial A, Behren A, So JY, Palmer J, and Cebon J
- Subjects
- Adult, Aged, Aged, 80 and over, Antineoplastic Combined Chemotherapy Protocols adverse effects, CTLA-4 Antigen antagonists & inhibitors, Female, Humans, Ipilimumab adverse effects, Male, Middle Aged, Neoplasm Staging, Neuroendocrine Tumors diagnosis, Neuroendocrine Tumors mortality, Neuroendocrine Tumors pathology, Nivolumab adverse effects, Programmed Cell Death 1 Receptor antagonists & inhibitors, Progression-Free Survival, Prospective Studies, Response Evaluation Criteria in Solid Tumors, Young Adult, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Ipilimumab administration & dosage, Neuroendocrine Tumors drug therapy, Nivolumab administration & dosage
- Abstract
Purpose: Combination immunotherapy with anti-CTLA-4 and anti-PD-1 blockade has demonstrated significant clinical activity across several tumor types. Neuroendocrine tumors (NET) are a heterogeneous group of rare tumors with limited treatment options. CA209-538 is a clinical trial of combination immunotherapy with ipilimumab and nivolumab in rare cancers, including advanced NETs., Patients and Methods: CA209-538 is a prospective multicenter clinical trial in patients with advanced rare cancers. Patients received treatment with nivolumab at a dose of 3 mg/kg and ipilimumab at 1 mg/kg every three weeks for four doses, followed by nivolumab 3 mg/kg every two weeks and continued for up to 96 weeks, until disease progression or the development of unacceptable toxicity. Response was assessed every 12 weeks by RECIST 1.1. The primary endpoint was clinical benefit rate (CBR; complete remission + partial remission + stable disease)., Results: Twenty-nine patients with advanced NETs received treatment. Three (10%) patients had low-, 13 (45%) had intermediate-, and 13 (45%) had high-grade tumors; lung was the most common primary site (39%). The objective response rate was 24% with a CBR of 72%; 43% of patients with pancreatic neuroendocrine neoplasms (NEN), and 33% of patients with atypical bronchial carcinoid achieved an objective response. The median progression-free survival was 4.8 months [95% confidence interval (CI): 2.7-10.5] and overall survival was 14.8 months (95% CI: 4.1-21.3). Immune-related toxicity was reported in 66% of patients with 34% experiencing grade 3/4 events., Conclusions: Combination immunotherapy with ipilimumab and nivolumab demonstrated significant clinical activity in subgroups of patients with advanced NETs including patients with atypical bronchial carcinoid and high-grade pancreatic NENs., (©2020 American Association for Cancer Research.)
- Published
- 2020
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141. Evaluation of Combination Nivolumab and Ipilimumab Immunotherapy in Patients With Advanced Biliary Tract Cancers: Subgroup Analysis of a Phase 2 Nonrandomized Clinical Trial.
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Klein O, Kee D, Nagrial A, Markman B, Underhill C, Michael M, Jackett L, Lum C, Behren A, Palmer J, Tebbutt NC, Carlino MS, and Cebon J
- Subjects
- Adult, Aged, Aged, 80 and over, Antibodies, Monoclonal adverse effects, Biliary Tract Neoplasms pathology, Disease Progression, Female, Humans, Immunotherapy adverse effects, Ipilimumab adverse effects, Male, Microsatellite Instability drug effects, Middle Aged, Nivolumab adverse effects, Programmed Cell Death 1 Receptor antagonists & inhibitors, Programmed Cell Death 1 Receptor immunology, Progression-Free Survival, Antibodies, Monoclonal administration & dosage, Biliary Tract Neoplasms drug therapy, Ipilimumab administration & dosage, Nivolumab administration & dosage
- Abstract
Importance: Biliary tract cancers represent a rare group of malignant conditions with very limited treatment options. Patients with advanced disease have a poor outcome with current therapies., Objective: To evaluate the efficacy and safety of combination immunotherapy with nivolumab and ipilimumab in patients with advanced biliary tract cancers., Design, Setting, and Participants: The CA209-538 prospective multicenter phase 2 nonrandomized clinical trial included patients with advanced rare cancers including patients with biliary tract cancers. This subgroup analysis evaluated 39 patients from CA209-538 with biliary tract cancers who were enrolled from December 2017 to December 2019. Most of the patients (n = 33) had experienced disease progression after 1 or more lines of therapy and had tumor tissue available for biomarker research., Interventions: Patients received treatment with nivolumab at a dose of 3 mg/kg and ipilimumab at 1 mg/kg every 3 weeks for 4 doses, followed by nivolumab 3 mg/kg every 2 weeks and continued for up to 96 weeks until disease progression or the development of unacceptable toxic events., Main Outcomes and Measures: The primary end point was disease control rate (complete remission, partial remission, or stable disease) as assessed by RECIST 1.1., Results: Among the 39 patients included in this subgroup analysis of a phase 2 clinical trial (20 men, 19 women; mean [range] age, 65 [37-81] years), the objective response rate was 23% (n = 9) with a disease control rate of 44% (n = 17); all responders had received prior chemotherapy, and none had a microsatellite unstable tumor. Responses were exclusively observed in patients with intrahepatic cholangiocarcinoma and gallbladder carcinoma. The median duration of response was not reached (range, 2.5 to ≥23 months). The median progression-free survival was 2.9 months (95% CI, 2.2-4.6 months), and overall survival was 5.7 months (95% CI, 2.7-11.9 months). Immune-related toxic events were reported in 49% of patients (n = 19), with 15% (n = 6) experiencing grade 3 or 4 events., Conclusions and Relevance: This subgroup analysis of a phase 2 clinical trial found that combination immunotherapy with nivolumab and ipilimumab was associated with substantial positive outcomes patients with advanced biliary tract cancers. This treatment compares favorably to single-agent anti-programmed cell death protein 1 (anti-PD-1) therapy and warrants further investigation. Ongoing translational research is focused on identifying biomarkers that can predict treatment response., Trial Registration: ClinicalTrials.gov Identifier: NCT02923934.
- Published
- 2020
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142. Practical Considerations for Treating Patients With Cancer in the COVID-19 Pandemic.
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Segelov E, Underhill C, Prenen H, Karapetis C, Jackson C, Nott L, Clay T, Pavlakis N, Sabesan S, Heywood E, Steer C, Lethborg C, Gan HK, Yip D, Karanth N, Karikios D, and MacIntyre CR
- Subjects
- COVID-19, Coronavirus Infections complications, Coronavirus Infections therapy, Coronavirus Infections virology, Delivery of Health Care, Humans, Neoplasms complications, Neoplasms therapy, Neoplasms virology, Pandemics, Pneumonia, Viral complications, Pneumonia, Viral therapy, Pneumonia, Viral virology, Risk Factors, SARS-CoV-2, Telemedicine, Betacoronavirus pathogenicity, Coronavirus Infections mortality, Medical Oncology, Neoplasms mortality, Pneumonia, Viral mortality
- Abstract
Cancer has become a prevalent disease, affecting millions of new patients globally each year. The COVID-19 pandemic is having far-reaching impacts around the world, causing substantial disruptions to health and health care systems that are likely to last for a prolonged period. Early data have suggested that having cancer is a significant risk factor for mortality from severe COVID-19. A diverse group of medical oncologists met to formulate detailed practical advice on systemic anticancer treatments during this crisis. In the context of broad principles, issues including risks of treatment, principles of prioritizing resources, treatment of elderly patients, and psychosocial impact are discussed. Detailed treatment advice and options are given at a tumor stream level. We must maintain care for patients with cancer as best we can and recognize that COVID-19 poses a significant competing risk for death that changes conventional treatment paradigms.
- Published
- 2020
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143. Outpatient rituximab, ifosfamide, etoposide (R-IE) in patients older than 60 years with relapsed or refractory diffuse large B-cell lymphoma who are not candidates for stem cell transplantation.
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Joshi M, Taper J, Forsyth C, Rowlings P, Campbell P, Crispin P, Harvey M, Underhill C, Bayley A, Byth K, Huang G, and Hertzberg M
- Subjects
- Antineoplastic Combined Chemotherapy Protocols therapeutic use, Humans, Middle Aged, Neoplasm Recurrence, Local, Outpatients, Transplantation, Autologous, Etoposide therapeutic use, Hematopoietic Stem Cell Transplantation, Ifosfamide therapeutic use, Lymphoma, Large B-Cell, Diffuse drug therapy, Rituximab therapeutic use
- Abstract
Patients with relapsed-refractory diffuse large B-cell lymphoma (RR-DLBCL) ineligible for autologous stem cell transplantation (autoSCT) have poor survival. Thirty transplant-ineligible patients older than 60 years were administered rituximab 375 mg/m2 day 1, ifosfamide 1333 mg/m
2 days 1 to 3, and etoposide 80 mg/m2 days 1 to 3 (R-IE) every 21 days for 6 cycles plus 2 doses of rituximab. Revised international prognostic index 3-4 was seen in 53% and prior rituximab exposure in 60%. The complete and overall response rates were 55% and 76%, respectively. Median progression free survival (PFS) and overall survival were 23 and 24 months, respectively. Patients relapsing within 12 months of prior treatment had a median PFS of 2.5 months compared to 23 months for those relapsing beyond 12 months. Grade 3-4 thrombocytopenia and neutropenia occurred in one and eight patients, respectively. R-IE is an effective, well tolerated regimen in RR-DLBCL patients not fit for autoSCT.- Published
- 2020
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144. Gender differences in doxorubicin pharmacology for subjects with chemosensitive cancers of young adulthood.
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Liu Z, Martin J, Orme L, Seddon B, Desai J, Nicholls W, Thomson D, Porter D, McCowage G, Underhill C, Cranswick N, Michael M, Zacharin M, Herschtal A, Sivasuthan J, and Thomas DM
- Subjects
- Adolescent, Adult, Age Factors, Antibiotics, Antineoplastic administration & dosage, Antibiotics, Antineoplastic therapeutic use, Bone Neoplasms drug therapy, Bone Neoplasms metabolism, Doxorubicin administration & dosage, Doxorubicin pharmacokinetics, Doxorubicin therapeutic use, Female, Hodgkin Disease drug therapy, Hodgkin Disease metabolism, Humans, Neoplasms metabolism, Pregnancy, Prospective Studies, Sarcoma, Ewing drug therapy, Sarcoma, Ewing metabolism, Young Adult, Antibiotics, Antineoplastic pharmacokinetics, Doxorubicin analogs & derivatives, Models, Biological, Neoplasms drug therapy, Sex Characteristics
- Abstract
Purpose: For many cancers, adolescents and young adults (AYA) have worse outcomes than for children and adults. Many factors may contribute to the AYA survival gap, including differences in biology, therapeutic intent, and adherence to therapy. It has been observed that male AYAs have poorer outcomes than females. The purpose of this work was to test the proposition that gender-related pharmacologic factors may account for a component of the AYA survival gap., Patients and Methods: A prospective, multi-institutional pharmacologic study of 79 patients in total with chemosensitive cancers (Ewing sarcoma, osteosarcoma and Hodgkin lymphoma) was conducted, with conventional doxorubicin treatment. Pharmacokinetic data of 13 children, 40 AYAs and 13 adults were valid for analysis. Population pharmacokinetics models were developed for doxorubicin and its metabolite doxorubicinol based on the data created in this study. Consequently, model-based analysis was conducted to investigate the relevant topics., Results: The clearance of doxorubicinol (normalized to body surface area), the main active metabolite of doxorubicin, appears faster in male AYAs than female (p = 0.04, 95% CI 0.1-3.9 L/h). The exposure of doxorubicinol (normalized to dose) is lower in male AYA than female (p = 0.03, 95% CI - 0.005 to - 0.0002 h/L). These might be correlated to the observed difference on nadir neutrophil count between male AYA and female (p = 0.027, 95% CI 0.09-1.4)., Conclusion: Gender-related differences in doxorubicin pharmacology may account for worse outcomes for male AYAs with chemosensitive cancers compared to females. These findings may reduce the AYA survival gap compared to other age groups.
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- 2018
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145. Functional implications of corticosteroid-binding globulin N -glycosylation.
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Simard M, Underhill C, and Hammond GL
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- Animals, CHO Cells, Cricetinae, Cricetulus, Glycosylation, Humans, Polysaccharides chemistry, Polysaccharides metabolism, Proteolysis, Rats, Steroids metabolism, Transcortin chemistry, Transcortin metabolism
- Abstract
Corticosteroid-binding globulin (CBG) is a plasma carrier of glucocorticoids. Human and rat CBGs have six N -glycosylation sites. Glycosylation of human CBG influences its steroid-binding activity, and there are N -glycosylation sites in the reactive center loops (RCLs) of human and rat CBGs. Proteolysis of the RCL of human CBG causes a structural change that disrupts steroid binding. We now show that mutations of conserved N -glycosylation sites at N238 in human CBG and N230 in rat CBG disrupt steroid binding. Inhibiting glycosylation by tunicamycin also markedly reduced human and rat CBG steroid-binding activities. Deglycosylation of fully glycosylated human CBG or human CBG with only one N -glycan at N238 with Endo H-reduced steroid-binding affinity, while PNGase F-mediated deglycosylation does not, indicating that steroid binding is preserved by deamidation of N238 when its N -glycan is removed. When expressed in N -acetylglucosaminyltransferase-I-deficient Lec1 cells, human and rat CBGs, and a human CBG mutant with only one glycosylation site at N238, have higher (2-4 fold) steroid-binding affinities than when produced by sialylation-deficient Lec2 cells or glycosylation-competent CHO-S cells. Thus, the presence and composition of an N -glycan in this conserved position both appear to influence the steroid binding of CBG. We also demonstrate that neutrophil elastase cleaves the RCL of human CBG and reduces its steroid-binding capacity more efficiently than does chymotrypsin or the Pseudomonas aeruginosa protease LasB. Moreover, while glycosylation of N347 in the RCL limits these activities, N -glycans at other sites also appear to protect CBG from neutrophil elastase or chymotrypsin., (© 2018 The authors.)
- Published
- 2018
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146. Switching to biosimilar infliximab: real world data in patients with severe inflammatory arthritis.
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Holroyd CR, Parker L, Bennett S, Zarroug J, Underhill C, Davidson B, Armstrong R, Harvey NC, Dennison E, Cooper C, and Edwards CJ
- Subjects
- Aged, Antirheumatic Agents adverse effects, Arthritis diagnosis, Arthritis immunology, Biological Products adverse effects, Biosimilar Pharmaceuticals adverse effects, Databases, Factual, Female, Humans, Infliximab adverse effects, Male, Middle Aged, Retrospective Studies, Time Factors, Treatment Outcome, Antirheumatic Agents administration & dosage, Arthritis drug therapy, Biological Products administration & dosage, Biosimilar Pharmaceuticals administration & dosage, Drug Substitution, Infliximab administration & dosage
- Published
- 2018
147. Biosimilar Infliximab in Inflammatory Bowel Disease: Outcomes of a Managed Switching Programme.
- Author
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Razanskaite V, Bettey M, Downey L, Wright J, Callaghan J, Rush M, Whiteoak S, Ker S, Perry K, Underhill C, Efrem E, Ahmed I, and Cummings F
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Antibodies blood, Antibodies, Monoclonal blood, Antibodies, Monoclonal economics, Antibodies, Monoclonal immunology, Biosimilar Pharmaceuticals blood, Biosimilar Pharmaceuticals economics, C-Reactive Protein drug effects, Drug Costs, Female, Gastrointestinal Agents blood, Gastrointestinal Agents economics, Gastrointestinal Agents immunology, Hemoglobins drug effects, Humans, Infliximab economics, Leukocyte Count, Male, Middle Aged, Patient Reported Outcome Measures, Platelet Count, Serum Albumin drug effects, Young Adult, Antibodies, Monoclonal therapeutic use, Biosimilar Pharmaceuticals therapeutic use, Drug Substitution, Gastrointestinal Agents therapeutic use, Inflammatory Bowel Diseases drug therapy, Infliximab therapeutic use
- Abstract
Background and Aims: Biosimilar infliximab CT-P13 offers the potential for large drug acquisition cost savings. However, there are limited published data regarding its efficacy, safety, and immunogenicity in inflammatory bowel disease [IBD], particularly in switching IBD patients from originator to biosimilar infliximab. We present the outcomes of a service evaluation of switching IBD patients established on originator infliximab to biosimilar, using a managed switching programme funded via a gain share agreement in a UK teaching hospital., Methods: Evaluation outcomes included drug persistence, changes in drug acquisition costs, patient-reported side effects, adverse events, patient outcomes assessed using the IBD-control Patient-Reported Outcome Measures [PROM] questionnaire, serum drug and antibody levels, and routinely collected biochemical markers., Results: A total of 143 patients with IBD [118 Crohn's disease, 23 ulcerative colitis, 2 IBD unclassified] were switched from originator infliximab to CT-P13. Patients reported a similar incidence of side effects before and after switch. No clinically significant differences were observed in mean C-reactive protein [CRP], albumin, haemoglobin levels, or platelet and white cell counts after the switch to CT-P13, whereas mean IBD-control-8 score improved from 10.4 to 11.2 [p = 0.041]. There was no significant difference in drug persistence between biosimilar and originator infliximab [p = 0.94] and no increase in immunogenicity was found. Drug acquisition costs decreased by £40,000-60,000 per month., Conclusions: A managed switching programme from originator infliximab to biosimilar CT-P13 in IBD, using a gain-share agreement, delivers significant cost savings and investment in clinical services while maintaining similar patient-reported outcomes, biochemical response, drug persistence, and adverse event profile., (Copyright © 2017 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com)
- Published
- 2017
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148. Upfront lower dose lenalidomide is less toxic and does not compromise efficacy for vulnerable patients with relapsed refractory multiple myeloma: final analysis of the phase II RevLite study.
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Quach H, Fernyhough L, Henderson R, Corbett G, Baker B, Browett P, Blacklock H, Forsyth C, Underhill C, Cannell P, Trotman J, Neylon A, Harrison S, Link E, Swern A, Cowan L, Dimopoulos MA, and Miles Prince H
- Subjects
- Adult, Aged, Aged, 80 and over, Angiogenesis Inhibitors adverse effects, Antineoplastic Combined Chemotherapy Protocols adverse effects, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Dexamethasone administration & dosage, Disease Progression, Dose-Response Relationship, Drug, Drug Administration Schedule, Female, Humans, Lenalidomide, Male, Middle Aged, Prognosis, Prospective Studies, Recurrence, Thalidomide administration & dosage, Thalidomide adverse effects, Angiogenesis Inhibitors administration & dosage, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Multiple Myeloma drug therapy, Thalidomide analogs & derivatives
- Abstract
The combination of lenalidomide and dexamethasone is an established treatment for patients with multiple myeloma (MM). Increasingly, treatment attenuation is advocated for frail/elderly patients to minimize toxicity even though there have been no prospective studies to demonstrate whether lenalidomide dose attenuation impacts on response and survival outcome. This prospective multicentre phase II study assessed the efficacy and tolerability of lower dose lenalidomide (15 mg) and dexamethasone (20 mg) in 149 eligible patients with relapsed/refractory MM aged over 59 years and/or with renal impairment. The overall response rate was 71% (complete response 15%). Median (range) progression-free survival (PFS) and overall survival (OS) were 8·9 (6·9-11·5) and 30·5 (20·0-36·2) months, respectively. Upon formal statistical comparison of these endpoints to that of a matched cohort of patients from the pivotal phase III MM009/MM010 studies who received standard-dose lenalidomide (25 mg) and high-dose dexamethasone (40 mg) no difference was seen in PFS (P = 0·34) and OS (P = 0·21). Importantly, grade 3-4 toxicities were reduced with low-dose lenalidomide, mainly lower neutropenia (29% vs. 41%), infections (23% vs. 31%) and venous thromboembolism (3% vs. 13%). This study supports a strategy of lenalidomide dose reduction at the outset for at-risk patients, and prospectively confirms that such an approach reduces adverse events while not compromising patient response or survival outcomes., (© 2017 John Wiley & Sons Ltd.)
- Published
- 2017
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149. The impact of an inflammatory bowel disease nurse-led biologics service.
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Taylor NS, Bettey M, Wright J, Underhill C, Kerr S, Perry K, and Cummings JF
- Abstract
Introduction: Southampton General Hospital provides inflammatory bowel disease (IBD) services for a population of 650 000. Biological agents have impacted hugely on IBD but are costly drugs requiring careful supervision. These challenges led us to develop a specialist nurse-led biologics service to improve patient care., Method: A 2010 case note audit highlighted areas for improvement in monitoring biologics and follow-up. A business case was developed to establish an IBD nurse to ensure identification and appropriate screening, education and review of biologics patients. A gain share was agreed with the local Care Commissioning Group (CCG) and £60 000 invested. Outcomes were reaudited in 2014., Results: Biologic use has grown rapidly from 90 patients in 2011 to 330 in 2014. All records are now kept in a centralised database. Infection screening improved from 79% to 100%. In 2014, 96% of patients had follow-up ≤4 months post-induction to assess response, but two patients were seen at 7 months. 80% were followed up again at 9-12 months (100% at 9-14 months), all with treatment decisions. The initial investment was recouped via commissioners funding 368 additional outpatient appointments and 35 colonoscopies. Savings represented 15% total yearly biologic costs., Conclusions: The introduction of the IBD biologics nurse-led service resulted in significant gains in care quality and costs. The need for improved follow-up of patients on biologics reflects increased pressures on clinic resources across the country. With continued biologics expansion, the introduction of a biologics nurse has provided invaluable support to patients and the IBD team at Southampton General Hospital.
- Published
- 2016
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150. Guidelines for timely initiation of chemotherapy: a proposed framework for access to medical oncology and haematology cancer clinics and chemotherapy services.
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Alexander M, Beattie-Manning R, Blum R, Byrne J, Hornby C, Kearny C, Love N, McGlashan J, McKiernan S, Milar JL, Murray D, Opat S, Parente P, Thomas J, Tweddle N, Underhill C, Whitfield K, Kirsa S, and Rischin D
- Subjects
- Australia, Disease Management, Humans, Practice Guidelines as Topic, Quality Indicators, Health Care, Drug Therapy methods, Hematology, Medical Oncology, Neoplasms drug therapy, Time-to-Treatment
- Abstract
These guidelines, informed by the best available evidence and consensus expert opinion, provide a framework to guide the timely initiation of chemotherapy for treating cancer. They sit at the intersection of patient experience, state-of-the-art disease management and rational efficient service provision for these patients at a system level. Internationally, cancer waiting times are routinely measured and publicly reported. In Australia, there are existing policies and guidelines relating to the timeliness of cancer care for surgery and radiation therapy; however, until now, equivalent guidance for chemotherapy was lacking. Timeliness of care should be informed, where available, by evidence for improved patient outcomes. Independent of this, it should be recognised that shorter waiting periods are likely to reduce patient anxiety. While these guidelines were developed as part of a proposed framework for consideration by the Victorian Department of Health, they are clinically relevant to national and international cancer services. They are intended to be used by clinical and administrative staff within cancer services. Adoption of these guidelines, which are for the timely triage, review and treatment of cancer patients receiving systemic chemotherapy, aims to ensure that patients receive care within a timeframe that will maximise health outcomes, and that access to care is consistent and equitable across cancer services. Local monitoring of performance against this guideline will enable cancer service providers to manage proactively future service demand., (© 2016 Royal Australasian College of Physicians.)
- Published
- 2016
- Full Text
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