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Background: Clinical trial eligible patients with advanced non-small cell lung cancer (aNSCLC) and low programmed cell death ligand 1 (PD-L1) expression achieve greater benefit from immune checkpoint inhibitor (ICI) combination chemotherapy (ICI-Chemo) compared with Chemo alone. We examined whether patients ineligible for clinical trials may benefit from ICI-Chemo., Methods: This multicenter retrospective cohort study enrolled patients with aNSCLC, including unresectable Stage III (IIIB/IIIC) and IV disease with a PD-L1 tumor proportion score of 1-49% treated with ICI-Chemo or Chemo as first-line therapy from 2018 to 2023 in Japan. Treatment outcome and safety of ICI-Chemo versus Chemo groups in trial-eligible and trial-ineligible patients was compared based on criteria from previous phase III clinical trials., Results: Overall, 728 patients were analyzed: 333 trial-eligible and 395 ineligible patients. The median overall survival was 25.1 months in the ICI-Chemo group and 18.5 months in the Chemo group for eligible patients (HR 0.73, 95 %CI: 0.54-0.97) and was 18.2 months in the ICI-Chemo group and 14.9 months in the Chemo group for ineligible patients (HR 0.75, 95 %CI: 0.59-0.95). Median progression-free survival was longer with ICI-Chemo in both groups. For ineligible patients, performance status (PS) ≥ 2 and squamous cell carcinoma (SqCC) were clinical factors associated with worse survival prognosis, and survival outcomes with ICI-Chemo and Chemo were comparable. The ineligible group had no increase in severe adverse events compared to the eligible group., Conclusions: This study suggests a possible clinical benefit of receiving ICI-Chemo for trial-ineligible patients with low PD-L1 expression, excluding those with PS ≥ 2 or SqCC., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Tadaaki Yamada received research grants from Ono Pharmaceutical, Janssen, AstraZeneca, and Takeda Pharmaceutical, and has received speaking honoraria from Eli Lilly and Chugai-Roshe outside the purview of the submitted work. Satoshi Watanabe received grants from Boehringer Ingelheim and Nippon Kayaku, and has received honoraria for speakers bureaus from Lilly, Novartis Pharma, Chugai Pharma Bristol-Myers, Ono Pharmaceutical, Daiichi Sankyo, Taiho Pharmaceutical, Nippon Kayaku, Kyowa Kirin, Merck, Takeda Pharmaceutical, Celltrion and AstraZeneca out side the purview of the submitted work. Hirokazu Taniguchi received lecture fees from AstraZeneca and Chugai Pharma. Tomoya Fukui received personal fees from AstraZeneca K.K., Boehringer-Ingelheim Japan Inc., Chugai Pharmaceutical Co. Ltd., Eli Lilly Japan K.K., Nippon Kayaku Co. Ltd., Novartis Pharma K.K., Ono Pharmaceutical Co. Ltd., and Pfizer Japan Inc. outside the purview of the submitted work. Kyoichi Kaira has received a speaker honorarium from Ono Pharmaceutical Company, Chugai Pharmaceutical, Bristol-Myers Company, Boehringer Ingelheim, and AstraZeneca, and research grants form AstraZeneca. Asuka Okada received personal fees from Chugai-Roshe, AstraZeneca, Boehringer Ingelheim, Eli Lilly Japan, Nippon Kayaku, and Bristol-Myers Squibb outside the purview of the submitted work. Hayato Kawachi received personal fees from Bristol-Myers Squibb, Ono Pharmaceutical Co. Ltd., Chugai Pharmaceutical Co. Ltd., AstraZeneca KK, Taiho Pharmaceutical Co. Ltd., Eli Lilly Japan KK, and MSD KK outside the purview of the submitted work. Takashi Kijima received personal fees from Chugai Pharmaceutical Co. Ltd. and MSD KK outside the purview of the submitted work. Koichi Takayama received research grants from Chugai Pharmaceutical Co. Ltd. and Ono Pharmaceutical and personal fees from AstraZeneca, Chugai Pharmaceutical Co. Ltd., MSD-Merck, Eli Lilly, Boehringer Ingelheim, and Daiichi-Sankyo outside the purview of the submitted work., (Copyright © 2025 Elsevier B.V. All rights reserved.)

Polatuzumab vedotin (Pola) is an approved therapy in combination with rituximab and bendamustine for relapsed or refractory diffuse large B-cell lymphoma (RR-DLBCL) based on positive results of the landmark phase II randomised G029365 trial. However, trial results for many approved novel therapies in RR-DLBCL have not been replicated in routine care cohorts, as RR-DLBCL patient populations are heterogeneous and trial eligibility is increasingly restrictive. We evaluated outcomes from pola ± bendamustine and rituximab in patients with RR-DLBCL enrolled in a compassionate access program with no alternative treatment options identified via the Australasian Lymphoma and Related Diseases Registry according to their eligibility for the original phase II published study. Of 58 eligible patients, 74% met the criteria deeming them ineligible for the G029365 original study at the time of pola's commencement. Median progression-free survival and overall survival in our cohort were 2.3 and 3.5 months, respectively. In contrast to the landmark trial cohort, more of our patients ceased therapy prior to completion, the majority due to progressive disease and only 8/58 received any subsequent treatment. Dismal outcomes in this Australian real-world population demonstrate trial eligibility is challenging to meet, and newer treatments can be difficult to deliver in routine care. Clinically applicable results from therapeutic studies require trial cohorts to reflect representative clinical populations wherever possible, and more research is required to address the benefit of novel agents in the increasing majority who are ineligible for modern studies., Competing Interests: Briony Shaw, Eliza Chung, Edward Yoo, Rory Bennett, Callum Birks, Jock Simpson, Sumita Ratnasingam, Tasman Armytage, Denise Lee, Colm Keane, Stephanie Wallwork all declare no conflicts of interest. Anna Johnston: Consulting or advisory role, honoraria: Merck Sharpe & Dohme, Roche, Link, BeiGene, Sanofi, EUSA Pharma, Novartis, Chan Y Cheah: Consulting or advisory role, honoraria: Roche, Janssen, Gilead, AstraZenecca, Lilly, TG therapeutics, BeiGene, Novartis, Menarini, Dizal, AbbVie, Genmab, Bristol Myers Quibb; Research funding: Bristol Myers Quibb, Roche, AbbVie, Merck Sharpe & Dohme, Lilly, Nada Hamad: Honoraria: Roche, Janssen, Gilead, AstraZenecca, BeiGene, Novartis, AbbVie, Genmab, Bristol Myers Quibb, Takeda, Jazz Pharmaceuticals, Incyte, Pfizer, Mallinckrodt Pharmaceuticals, Terumo, Allison Barraclough: Honoraria: Roche, Gilead, Novartis, BeiGene, Matthew Ku: Roche, Antengene, Genor BioPharma, Nicholas Viiala: Honoraria and advisory board: Novartis, Tara Cochrane: Consulting or advisory role: Janssen; Honoraria: Celgene (in 2019); Research funding: BeiGene, Geoffrey Chong: Research funding: Bristol Myers Quibb, Merck, AstraZeneca, Pharmacyclics, Regeneron, Hutchmed, Bayer, Incyte, Amgen, Kate Manos: Advisory/honoraria: AbbVie; Research funding: Roche, Stephen Opat: Honoraria: AbbVie, BeiGene, AstraZeneca, Bristol Myers Quibb, CSL Behring, Gilead, Janssen, Merck, Roche, Takeda; Research funding: AbbVie, BeiGene, AstraZeneca, CSL Behring, Gilead, Janssen, Merck, PharmaCytics, Roche, Takeda, Eliza A. Hawkes: Consulting or advisory role: Roche, Merck Sharpe & Dohme, AstraZeneca, Gilead, Antengene, Novartis, Regeneron, Janssen, Specialised Therapeutics; Research funding: Roche, Bristol Myers Squibb, Merck KGaA, AstraZeneca, Merck, (© 2024 The Authors. eJHaem published by British Society for Haematology and John Wiley & Sons Ltd.)

Background: Juvenile-onset Huntington's disease (JHD) represents 1-5% of Huntington's disease (HD) patients, with onset before the age of 21. Pediatric HD (PHD) relates to a proportion of JHD patients that is still under 18 years of age. So far, both populations have been excluded from interventional trials., Objective: Describe the prevalence and incidence of JHD and PHD in the Netherlands and explore their ability to participate in interventional trials., Methods: The prevalence and incidence of PHD and JHD patients in the Netherlands were analyzed. In addition, we explored proportions of JHD patients diagnosed at pediatric versus adult age, their diagnostic delay, and functional and modelled (CAP100) disease stage in JHD and adult-onset HD patients at diagnosis., Results: The prevalence of JHD and PHD relative to the total manifest HD population in January 2024 was between 0.84-1.25% and 0.09-0.14% respectively. The mean incidence of JHD patients being diagnosed was between 0.85-1.28 per 1000 patient years and of PHD 0.14 per 1.000.000 under-aged person years. 55% of JHD cases received a clinical diagnosis on adult age. At diagnosis, the majority of JHD patients was functionally compromised and adolescent-onset JHD patients were significantly less independent compared to adult-onset HD patients., Conclusions: In the Netherlands, the epidemiology of JHD and PHD is lower than previously suggested. More than half of JHD cases are not eligible for trials in the PHD population. Furthermore, higher functional dependency in JHD patients influences their ability to participate in trials. Lastly, certain UHDRS functional assessments and the CAP100 score do not seem appropriate for this particular group.

Pivotal outcome trials targeting heart failure with preserved (HFpEF) and mildly-reduced ejection fraction (HFmrEF) may have excluded patients at highest risk of poor outcomes. We aimed to assess eligibility for HFpEF/HFmrEF outcome trials in an unselected heart failure cohort and its association with all-cause mortality. Among 32.028 patients presenting to a tertiary care center emergency unit for any reason between August 2018 and July 2019, we identified 407 admissions with evident HFpEF and HFmrEF. Eligibility criteria for pivotal trials CHARM-Preserved, I-PRESERVE, TOPCAT, PARAGON-HF, EMPEROR-Preserved and DELIVER were assessed by chart review. The proportions of admissions fulfilling HFpEF/HFmrEF trial eligibility criteria were 88% for CHARM-Preserved, 40% for I-PRESERVE, 35% for TOPCAT, 28% for PARAGON-HF, 51% for EMPEROR-Preserved, and 49% for DELIVER. During a median follow-up of 1.9 years, death-from-any-cause occurred in 121 cases (30%). Twenty-four-month overall survival estimates for non-eligible and eligible admissions were 53% vs. 76% for CHARM-Preserved (HR=2.32, 95% CI: 1.47-3.67, p<0.001), 62% vs. 87% for I-PRESERVE (HR=2.97, 1.85-4.77, p<0.001), 67% vs. 84% for TOPCAT (HR=2.04, 1.29-3.24, p = 0.002), 68% vs. 85% for PARAGONHF (HR=2.28, 1.33-3.90, p = 0.003), 64% vs. 81% for EMPEROR-Preserved (HR=1.90, 1.27-2.84, p = 0.002), and 65% vs. 80% for DELIVER (HR=1.71, 1.14-2.57, p = 0.010). Exclusion criteria independently predicting death were eGFR <20 ml/min/1.73 m 2 , COPD with home oxygen therapy, and severe valvular heart disease. Conclusively, in a contemporary HFpEF/HFmrEF cohort, non-eligibility for outcome trials predicted for strongly increased mortality. HFpEF/HFmrEF patients at highest mortality risk were likely underrepresented in previous outcome trials and their treatment remains an unmet medical need., Competing Interests: Declaration of Competing Interest The authors declare they have no conflict of interest, (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Participants enrolled in cardiovascular disease (CVD) randomized controlled trials are not often representative of the population living with the disease. Older adults, children, women, Black, Indigenous and People of Color, and people living in low- and middle-income countries are typically under-enrolled in trials relative to disease distribution. Treatment effect estimates of CVD therapies have been largely derived from trial evidence generated in White men without complex comorbidities, limiting the generalizability of evidence. This review highlights barriers and facilitators of trial enrollment, temporal trends, and the rationale for representativeness. It proposes strategies to increase representativeness in CVD trials, including trial designs that minimize the research burden on participants, inclusive recruitment practices and eligibility criteria, diversification of clinical trial leadership, and research capacity-building in under-represented regions. Implementation of such strategies could generate better and more generalizable evidence to reduce knowledge gaps and position the cardiovascular trial enterprise as a vehicle to counter existing healthcare inequalities., Competing Interests: Conflict of interest: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. E.L. has an American Heart Association (AHA) Strategically-Focused Research Network (SFRN) grant studying diversity in clinical trials. T.P.W. is funded by the Division of Intramural Research of the National Heart, Lung, and Blood Institute and the Intramural Research Program of the National Institute on Minority Health and Health Disparities. The views expressed in this manuscript are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute; the National Institute on Minority Health and Health Disparities; the National Institutes of Health; or the U.S. Department of Health and Human Services. J.M. has received grant support from the National Heart, Lung, and Blood Institute; Alliance for Health Policy and Systems Research; Bloomberg Philanthropies; FONDECYT; British Council, British Embassy and the Newton-Paulet Fund; DFID/MRC/Wellcome Global Health Trials; Fogarty International Center; Grand Challenges Canada; International Development Research Center Canada; Inter-American Institute for Global Change Research; National Cancer Institute; National Institute of Mental Health; Swiss National Science Foundation; Wellcome; and World Diabetes Foundation. The content in this manuscript represents the views of the authors and does not represent the views of the organizations that support J.M. L.Z. is funded by the South African Medical Research Council (SAMRC) through its Division of Research Capacity Development under the Mid-Career Scientist Programme from funding received from the South African National Treasury. The content hereof is the sole responsibility of the authors and does not necessarily represent the official views of the SAMRC. L.Z. also receives support from the National Research Foundation of South Africa (NRFSA), as well as the UK Medical Research Council (MRC) and the UK Department for International Development (DFID) under the MRC/DFID Concordat agreement, via the African Research Leader Award (MR/S005242/1)., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: The impact of prior cancer history on survival of hypopharyngeal cancer patients remains unknown. The present study assessed the impact of prior cancer history on survival of patients with hypopharyngeal cancer., Methods: Patients with primary hypopharyngeal cancer diagnosed between 2004 and 2015 were extracted from the Surveillance, Epidemiology, and End Results (SEER) database. Propensity score matching (PSM) was conducted to balance baseline characteristics. One-to-one PSM, Kaplan-Meier method, and log-rank test were performed for survival analysis., Results: We included 5017 patients with hypopharyngeal cancer. Prior cancer history had no significant impact on overall survival of hypopharyngeal cancer patients in comparison with those without prior cancer history (p = 0.845, after PSM). Subgroup analysis showed that prior cancer history had no significant effect on overall survival of hypopharyngeal cancer patients., Conclusion: More hypopharyngeal cancer patients with prior cancer history should be considered for clinical trials. However, further prospective studies are needed., (© 2022 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Objectives: We sought to evaluate the impact of baseline anxiety levels on drug placebo separation and drug and placebo response in acutely psychotic schizophrenic subjects., Methods: In this post-hoc analysis, modified intent-to-treat Positive and Negative Syndrome Scale data were obtained from a phase 2, multi-center, 5 week, randomized, double-blind, placebo-controlled trial of KarXT in hospitalized adults with DSM-5 schizophrenia experiencing an acute exacerbation or relapse of symptoms. We investigated the impact of anxiety on drug placebo separation and drug and placebo response in 2 ways. In the first set of analyses, we dichotomized the data based on the absence or presence of anxiety symptoms. In the second set of analyses, we categorized subjects by levels of anxiety. All analyses were conducted using generalized linear models with normal distribution and identity link function., Results: On average, subjects entering the trial were suffering from a moderate level of anxiety. Subjects with no baseline anxiety had a significant increase in placebo response, a decrease in drug response and did not separate drugs from placebo. With increasing levels of baseline anxiety, a larger drug placebo difference was observed., Discussion: Our analyses identified that absence of anxiety at baseline was associated with a loss of signal at end of treatment between drug and placebo driven by a differential effect on placebo and treatment response. The effect observed was not related to the overall baseline symptom severity and was not mediated by improvement in anxiety itself. Interpretation of the results is caveated by the retrospective nature of the analyses., Competing Interests: This post-hoc analysis was funded by Signant Health. Dr Kott, Dr Daniel, and MS Wang are employees of Signant Health. Dr Brannan is an employee of Karuna Therapeutics., (© The Author(s) 2023. Published by Oxford University Press on behalf of the University of Maryland's school of medicine, Maryland Psychiatric Research Center.)

Brain metastases cause significant morbidity and mortality in patients with advanced cancer. In the era of precision oncology and immunotherapy, there are rapidly evolving systemic treatment options. These novel therapies may have variable intracranial efficacy, and patients with brain metastases remain a population of special interest. Typically, only patients with stable, asymptomatic and/or treated brain metastases are enrolled in clinical trials, or may be excluded altogether, particularly in the setting of leptomeningeal carcinomatosis. Consequently, this leads to significant concerns on the external validity of clinical trial evidence to real-world clinical practice. Here we describe the current trends in cancer clinical trial eligibility for patients with brain metastases in both early and late phase trials, with a focus on targeted and immunotherapies. We evaluate recent newly FDA approved therapies and the clinical trial evidence base leading to approval. This includes analysis of inclusion and exclusion criteria, requirements for baseline screening for brain metastases, surveillance cerebral imaging and incorporation of trial endpoints for patients with brain metastases. Finally, the use of alternative sources of data such as real-world evidence with registries and collaborative studies will be discussed., Competing Interests: AT reports consultant or advisory roles for Amgen; outside of the submitted work. DB reports honoraria from Varian Medical Systems; and research funding from Varian Medical Systems and Novocure; outside of the submitted work. EL reports honoraria from MedLink, prIME Oncology, and the American Academic of Neurology (Continuum); and royalties from Wolters Kluwer Health (UpToDate); outside of the submitted work. MMK reports research funding from Blue Earth Diagnostics; outside of the submitted work. MM reports consultant or advisory roles for Zap, Mevion, Karyopharm, Tocagen and Astra-Zeneca; and Board of Directors options from Oncoceutics; outside of the submitted work. MK reports consultant or advisory roles for Janssen, AbbVie, Ipsen, Pfizer Roche, and Jackson Laboratory for Genomic Medicine; and research funding from AbbVie, Bristol-Myers Squibb, and Specialized Therapeutics; outside of the submitted work., (Copyright © 2022 Tan, Boggs, Lee, Kim, Mehta and Khasraw.)

Background: Patients with prior cancer history are commonly excluded from clinical trial. However, the impact of prior cancer on survival of patients with gastric cancer remains largely unknown. The aim of this study was to evaluate the prevalence of prior cancer and assess its impact on survival of patients diagnosed with gastric cancer., Methods: Patients with gastric cancer as the primary or second primary malignancies diagnosed from 2004 to 2010 were extracted from the Surveillance, Epidemiology, and End Results (SEER) database. Propensity score matching (PSM) was conducted to balance baseline characteristics. Kaplan-Meier method, multivariate Cox proportional hazard model, and multivariate competing risk model were performed for survival analysis., Results: A total of 28,795 eligible patients with gastric cancer were included, of whom 2695 (9.35%) had a history of prior cancer. Prostate (35%), breast (12%), colon (8%), and urinary bladder (7%) malignancies were the most common prior cancer types. Patients with prior cancer history had slightly inferior overall survival (AHR = 1.06; 95% CI [1.00-1.12]; P = 0.043) but superior gastric cancer-specific survival (AHR = 0.82; 95% CI [0.76-0.88]; P < 0.001) compared with those without prior cancer. The subgroup analysis determined that a prior cancer history did not adversely affect gastric patients' clinical outcomes, except in those with prior cancer diagnosed within one year, at distant stage, or originating from lung and bronchus., Conclusion: A substantial proportion of gastric cancer patients with a history of prior cancer had non-inferior clinical outcome to those without prior cancer. These patients should be considered in clinical trials., Competing Interests: Declaration of competing interest The authors declare that there are no conflicts of interest associated with the publication of this manuscript., (Copyright © 2021. Published by Elsevier Ltd.)

Background: Immuno-oncology (IO)-based therapies have been approved based on randomised clinical trials, yet a significant proportion of real-world patients are not represented in these trials. We sought to compare the outcomes of trial-ineligible vs. -eligible patients with advanced solid tumours treated with first-line (1L) IO therapy., Patients and Methods: Using the International Metastatic Renal Cell Carcinoma (RCC) Database Consortium and the Alberta Immunotherapy Database, patients with advanced RCC, non-small-cell lung cancer (NSCLC) or melanoma treated with 1L PD-(L)1 inhibition-based therapy were included. Trial eligibility was retrospectively determined as per commonly used exclusion criteria. The outcomes of interest were overall survival (OS), overall response rate (ORR), treatment duration (TD) and time to next treatment (TTNT)., Results: A total of 395 of 1241 (32%) patients were deemed trial-ineligible. The main reasons for ineligibility based on preselected exclusion criteria were Karnofsky performance status <70%/Eastern Cooperative Oncology Group performance status >1 (40%, 158 of 395), brain metastases (32%, 126 of 395), haemoglobin < 9 g/dL (16%, 63 of 395) and estimated glomerular filtration rate <40 mL/min (15%, 61 of 395). Between the ineligible vs. eligible groups, the median OS, ORR, median TD and median TTNT were 10.2 vs. 39.7 months (p < 0.01), 36% vs. 47% (p < 0.01), 2.7 vs. 6.9 months (p < 0.01) and 6.0 vs. 16.8 months (p < 0.01), respectively. Subgroup analyses showed statistically significant inferior OS, TD and TTNT for trial-ineligible vs. -eligible patients across all tumour types. Adjusted hazard ratios for death in RCC, NSCLC and melanoma were 1.84 (95% confidence interval [CI] 1.22-2.77), 2.21 (95% CI 1.58-3.11) and 1.82 (95% CI 1.21-2.74), respectively.., Conclusions: Thirty-two percent of real-world patients treated with contemporary 1L IO-based therapies were ineligible for clinical trials. Although one-third of the trial-ineligible patients responded to treatment, the overall trial-ineligible population had inferior outcomes than trial-eligible patients. These data may guide patient counselling and temper expectations of benefit., Competing Interests: Conflict of interest statement The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: C.L.G., I.S., D.E.M., Sh.D., H.A.I.G., Sa.D., B.W.E., S.G., M.S, A.P., D.M., L.A.W. and T.C. have no conflicts of interest to report. J.C.W. reports travel and accommodation expenses from Pfizer. J.M. is a member in the advisory board of Amgen, BMS, Merck, Novartis and Sanofi and reports research funding from Merck. N.S.B. reports honoraria and is a member in the advisory board of BMS, Merck, Pfizer, EMD Serono, Roche, Eisai, Ipsen and AstraZeneca. S.K.P. has a consulting or advisory role in Pfizer, Novartis, Aveo, Myriad Pharmaceuticals, Genentech, Exelixis, Bristol Myers Squibb, Astellas Pharma, Ipsen and Eisai and reports honoraria from Novartis, Medivation and Astellas Pharma and research funding from Medivation. E.D. reports research funding from Pfizer and Ipsen. T.K.C. has a consulting or advisory role in Pfizer, Bayer, Novartis, GlaxoSmithKline, Merck, Bristol Myers Squibb, Roche/Genentech, Eisai, Foundation Medicine, Cerulean Pharma, AstraZeneca, Prometheus Laboratories, Alligent, Ipsen, Corvus Pharmaceuticals, Lpath, Alexion Pharmaceuticals, Sanofi/Aventis, Peloton Therapeutics, UpToDate, NCCN, Michael J. Hennessy Associates, Analysis Group, Kidney cancer Association, Clinical Care options, PlatformQ Health, Navinata Health, Harborside Press, ASCO, The New England Journal of Medicine, Lancet Oncology, EMD Serono, HERON, Lilly and ESMO; acts as a leader in Dana-Farber Cancer Institute, NCCN, Kidney cancer Association, KidneyCAN and ASCO; has stock and other ownership interests in Pionyr and Tempest Therapeutics; reports honoraria from NCCN, UpToDate, Michael J. Hennessy Associates, ASCO, Harborside Press, Analysis Group, AstraZeneca, Alexion Pharmaceuticals, Sanofi/Aventis, Bayer, Bristol Myers Squibb, Genentech/Roche, GlaxoSmithKline, Merck, Novartis, Peloton Therapeutics, Pfizer, Corvus Pharmaceuticals, Ipsen, Foundation Medicine, Eisai, PlatformQ Health, Clinical Care options, Navinata Health, Kidney cancer association, Exelixis, Prometheus, Lpath, The New England Journal of Medicine, Lancet Oncology, Cerulean Pharma, Alligent, EMD Serono, Heron and Lilly and reports research funding from Pfizer, Novartis, Merck, Exelixis, Tracon Pharma, GlaxoSmithKline, Bristol Myers Squibb, AstraZeneca, Peloton Therapeutics, Roche/Genentech, Celldex, Agensys, Eisai, Takeda, Prometheus, Ipsen, Corvus Pharmaceuticals, Cerulean Pharma, Seattle Genetics/Astellas, Bayer, Foundation Medicine, Roche, Calithera Biosciences, Analysis Group, NCI, CDMRP/DOD and Gateway for Cancer Research. Medical writing and editorial assistance support may have been funded by communications companies funded by pharmaceutical companies such as ClinicalThinking, Health Interactions, Envision Pharma Group, Fishawack Group of Companies and Parexel. D.Y.C.H. has a consulting or advisory role in Pfizer, Novartis, Bristol Myers Squibb, Janssen, Astellas Pharma, Ipsen, Eisai and Merck and reports research funding from Pfizer, Novartis, Exelixis, Bristol Myers Squibb and Ipsen., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objectives: The aim of this study was to [1] characterize distribution of Erdheim-Chester Disease (ECD) by 18 F-FDG PET/CT and [2] determine the utility of metabolic ( 18 F-FDG PET/CT) imaging versus anatomic imaging (CT or MRI) in evaluating ECD patients for clinical trial eligibility., Methods: 18 F-FDG PET/CT and corresponding CT or MRI studies for ECD patients enrolled in a prospective registry study were reviewed. Sites of disease were classified as [1] detectable by 18 F-FDG PET only, CT/MRI only, or both and as [2] measurable by modified PERCIST (mPERCIST) only, RECIST only, or both. Descriptive analysis was performed and paired t test for between-group comparisons., Results: Fifty patients were included (mean age 51.5 years; range 18-70 years). Three hundred thirty-three disease sites were detected among all imaging modalities, 188 (56%) by both 18 F-FDG PET and CT/MRI, 67 (20%) by 18 F-FDG PET only, 75 (23%) by MRI brain only, and 3 (1%) by CT only. Of 178 disease sites measurable by mPERCIST or RECIST, 40 (22%) were measurable by both criteria, 136 (76%) by mPERCIST only, and 2 (1%) by RECIST only. On the patient level, 17 (34%) had mPERCIST and RECIST measurable disease, 30 (60%) had mPERCIST measurable disease only, and 0 had RECIST measurable disease only (p < 0.0001)., Conclusion: Compared with anatomic imaging, 18 F-FDG PET/CT augments evaluation of disease extent in ECD and increases identification of disease sites measurable by formal response criteria and therefore eligibility for clinical trials. Complementary organ-specific anatomic imaging offers the capacity to characterize sites of disease in greater anatomic detail., Trial Registration: ClinicalTrials.gov Identifier: NCT03329274.

Background: A history of prior cancer commonly results in exclusion from cancer clinical trials. However, whether a prior cancer history has an adversely impact on clinical outcomes for patients with advanced prostate cancer (APC) remains largely unknown. We therefore aimed to investigate the impact of prior cancer history on these patients., Methods: We identified patients with advanced prostate cancer diagnosed from 2004 to 2010 in the Surveillance, Epidemiology, and End Results (SEER) database. Propensity score matching (PSM) was used to balance baseline characteristics. Kaplan-Meier method and the Cox proportional hazard model were utilized for survival analysis., Results: A total of 19,772 eligible APC patients were included, of whom 887 (4.5 %) had a history of prior cancer. Urinary bladder (19 %), colon and cecum (16 %), melanoma of the skin (9 %) malignancies, and non-hodgkin lymphoma (9 %) were the most common types of prior cancer. Patients with a history of prior cancer had slightly inferior overall survival (OS) (AHR = 1.13; 95 % CI [1.02-1.26]; P = 0.017) as compared with that of patients without a prior cancer diagnosis. Subgroup analysis further indicated that a history of prior cancer didn't adversely impact patients' clinical outcomes, except in patients with a prior cancer diagnosed within 2 years, at advanced stage, or originating from specific sites, including bladder, colon and cecum, or lung and bronchus, or prior chronic lymphocytic leukemia., Conclusions: A large proportion of APC patients with a prior cancer history had non-inferior survival to that of patients without a prior cancer diagnosis. These patients may be candidates for relevant cancer trials.

Background: Patients with a prior history of cancer are commonly excluded from clinical trial. Increasing number of studies implied that a prior cancer did not adversely affect the clinical outcome among various types of cancer patients. However, the impact of prior cancer on survival of larynx cancer patients remains largely unknown. The aim of this study was to evaluate the prevalence of prior cancer and assess its impact on survival of patients diagnosed with larynx cancer., Methods: Patients with larynx cancer as the first or second primary malignancy diagnosed from 2004 to 2015 were extracted from the Surveillance, Epidemiology, and End Results (SEER) database. Propensity score matching (PSM) was conducted to balance baseline characteristics. Kaplan-Meier method, multivariate Cox proportional hazard model, and multivariate competing risk model were performed for survival analysis., Results: A total of 24,812 eligible patients with larynx cancer were included in the study, wherein a total of 2436 patients (9.8%) had a prior history of cancer. Prostate (36%), lung and bronchus (10%), urinary bladder (7%), and breast (6%) were the most common types of prior cancer. A prior cancer history served as a risk factor for overall survival (AHR =1.30; 95% CI [1.21-1.41]; P < 0.001) but a protective factor for cancer-specific mortality (AHR = 0.83; 95% CI [0.72-0.94]; P = 0.004) in comparison with those without prior cancer. The subgroup analysis showed that a prior history of cancer adversely affected overall survival of patients with larynx cancer in most subgroups stratified by timing and types of prior cancer, as well as by different clinicopathologic features., Conclusion: Our study indicated an adverse survival impact of a prior history of cancer on patients with larynx cancer. Except for a few particular prior cancer, clinical trials should be considered prudently for laryngeal cancer patients with prior cancers.

With heighted interest in causal inference based on real-world evidence, this empirical study sought to understand differences between the results of observational analyses and long-term randomized clinical trials. We hypothesized that patients deemed "eligible" for clinical trials would follow a different survival trajectory from those deemed "ineligible" and that this factor could partially explain results. In a large observational registry dataset, we estimated separate survival trajectories for hypothetically trial-eligible vs ineligible patients under both coronary artery bypass surgery (CABG) and percutaneous coronary intervention (PCI). We also explored whether results would depend on the causal inference method (inverse probability of treatment weighting vs optimal full propensity matching) or the approach to combine propensity scores from multiple imputations (the "across" vs "within" approaches). We found that, in this registry population of PCI/CABG multivessel patients, 32.5% would have been eligible for contemporaneous RCTs, suggesting that RCTs enroll selected populations. Additionally, we found treatment selection bias with different distributions of propensity scores between PCI and CABG patients. The different methodological approaches did not result in different conclusions. Overall, trial-eligible patients appeared to demonstrate at least marginally better survival than ineligible patients. Treatment comparisons by eligibility depended on disease severity. Among trial-eligible three-vessel diseased and trial-ineligible two-vessel diseased patients, CABG appeared to have at least a slight advantage with no treatment difference otherwise. In conclusion, our analyses suggest that RCTs enroll highly selected populations, and our findings are generally consistent with RCTs but less pronounced than major registry findings., (© 2020 John Wiley & Sons, Ltd.)

Background: The CELESTIAL, RESORCE, and REACH-2 trials showed survival benefit of cabozantinib, regorafenib, and ramucirumab, respectively, in hepatocellular carcinoma (HCC) patients treated with sorafenib who had good performance status (ECOG 0-1) and liver function (Child-Pugh-A). This study characterizes subsequent treatments received by HCC patients after sorafenib, and determines the proportion of patients eligible for novel therapies if strict eligibility criteria (SEC) were utilized compared to more liberal modified eligibility criteria (MEC, including ECOG 2, Child-Pugh-B7)., Methods: HCC patients who received sorafenib between 2008 and 2017 were included from the Canadian HCC CHORD Database. Patients were classified as eligible or ineligible based on available CELESTIAL, RESORCE, and REACH-2 trial SEC or MEC. Median overall survival (mOS) was assessed using the Kaplan-Meier method., Results: A total of 730 patients were identified; and 172 (23.6%) received subsequent treatment. Patients who received subsequent treatment had longer mOS than those who did not (12.1 vs 3.3 months; P < .001). Using SEC, only 13.1% of patients would be eligible for cabozantinib, regorafenib, or ramucirumab. Expanding eligibility to include patients who meet MEC increased the proportion of eligible patients to 31.7%. Higher ineligibility for regorafenib and ramucirumab was driven by trial-specific criteria, including sorafenib intolerance (28%) for RESORCE and AFP <400 (58.9%) for REACH-2., Conclusions: A small proportion of real-world HCC patients would be eligible for cabozantinib, regorafenib, or ramucirumab if SEC in clinical trials were followed, while more than double would be eligible if MEC were applied. Patients who received subsequent treatment had improved mOS, regardless of whether they met SEC or MEC., (© 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Purpose: Metformin has plausible direct and indirect anti-cancer properties against pancreatic adenocarcinoma cells. However, metformin may only be efficacious in patients with inoperable pancreatic ductal adenocarcinoma (PDAC) without liver metastases. Absorption may be decreased by gastrointestinal symptoms and proton pump inhibitors (PPIs). We aimed to justify and inform a future phase III trial of metformin versus placebo on survival in inoperable PDAC by documenting prevalence of patients meeting eligibility criteria, gastrointestinal symptoms and PPI use., Methods: Patient notes with PDAC were reviewed at a large teaching hospital over 2 years. Study variables were obtained from multiple sources of information., Results: 141 participants were identified (51.8% female), of which 37.6% were not prescribed metformin at diagnosis and had no radiological hepatic metastases. Characteristics were similar between non-metformin and metformin users. In eligible patients, 65.2% reported nausea and vomiting and 46.2% were prescribed PPIs., Conclusion: Approximately, a third of all patients with inoperable PDAC are eligible for a future trial of metformin, allowing an estimate of the number of hospitals required for recruitment. Nausea and vomiting are common and should be managed effectively to prevent trial dropouts. PPI use is frequent and their influence on metformin's pharmacodynamic actions needs to be clarified.

Background: Cabazitaxel has been shown to improve overall survival (OS) in metastatic castration-resistant prostate cancer (mCRPC) patients after docetaxel in the TROPIC trial. However, trial populations may not reflect the real-world population. We compared patient characteristics and outcomes of cabazitaxel within and outside trials (standard of care, SOC)., Patients and Methods: mCRPC patients treated with cabazitaxel directly after docetaxel therapy before 2017 were retrospectively identified and followed to 2018. Patients were grouped on the basis of treatment within a trial or SOC. Outcomes included OS and prostate-specific antigen (PSA) response., Results: From 3616 patients in the CAPRI registry, we identified 356 patients treated with cabazitaxel, with 173 patients treated in the second line. Trial patients had favorable prognostic factors: fewer symptoms, less visceral disease, lower lactate dehydrogenase, higher hemoglobin, more docetaxel cycles, and longer treatment-free interval since docetaxel therapy. PSA response (≥ 50% decline) was 28 versus 12%, respectively (P = .209). Median OS was 13.6 versus 9.6 months for trial and SOC subgroups, respectively (hazard ratio = 0.73, P = .067). After correction for prognostic factors, there was no difference in survival (hazard ratio = 1.00, P = .999). Longer duration of androgen deprivation therapy treatment, lower lactate dehydrogenase, and lower PSA were associated with longer OS; visceral disease had a trend for shorter OS., Conclusion: Patients treated with cabazitaxel in trials were fitter and showed outcomes comparable to registration trials. Conversely, those treated in daily practice showed features of more aggressive disease and worse outcome. This underlines the importance of adequate estimation of trial eligibility and health status of mCRPC patients in daily practice to ensure optimal outcomes., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objective: In cancer trials, prior cancer is a common exclusion criterion. We evaluated the characteristics of prior cancer exclusion criteria in nasopharyngeal carcinoma (NPC) trials and determined its prognostic effect on patients with NPC., Methods: We reviewed NPC trials for prior cancer exclusion criteria. Then we estimated the effect of prior cancer among NPC patients using the Surveillance, Epidemiology, and End Results database.Propensity score-matching was used to compensate for differences in baseline characteristics between patients with and without prior cancer., Results: There were 109 clinical trials involving 10,437 patients; 49 trials (45%) excluded patients with prior cancer. Prior cancer exclusion was more common in recent or phase III trials. We identified 10,195 NPC patients; 6.2% had prior cancer. More than 70% of these cancers were in situ/localized/regional and diagnosed relatively close to the NPC diagnosis (median 3.3 years). Patients with certain prior cancer type (prostate, breast, gynecological, hematological), time of diagnosis (>5 years ago), or stage (in situ/localized) did not have inferior survival compared with patients with no prior cancer. We tested one form of prior cancer exclusion criteria in an NPC cohort resembling a modern trial population: it did not adversely affect overall and NPC-specific survival., Conclusions: Many NPC trials excluded patients with prior cancer, whichimpacts trialaccrual and generalizability. Our findings suggest that broader inclusion in trials of patients with NPC with prior cancer might not affect trial outcomes. More research is needed to understand the appropriateness of this exclusion policy across cancer types and trials., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Objective: To investigate the depression severity and quality of life of qualified and unqualified patients with a mood disorder for a research study based on anhedonia severity., Methods: Diagnosis of major depressive disorder (MDD) or bipolar disorder (BPD) was ascertained with the MINI International Neuropsychiatric Interview. The severity of depression was measured with the 16-item Quick Inventory of Depressive Symptomatology-Self-Report (QIDS-16-SR), and Item 5, "feeling sad (sadness)," QIDS-16-SR Item 13, "change in general interest," was used to measure the severity of anhedonia. The quality of life was measured with the Quality of Life, Enjoyment and Satisfaction Questionnaire (Q-LES-Q)., Results: Of 96 patients with MDD and 147 with bipolar I or II disorder, the severity rating on sadness and anhedonia was similar. The severities of anhedonia and sadness were highly correlated with R 2 of ≥0.91. Without considering depressive severity, 55% of patients would be eligible for a study if≥mild anhedonia was used as a severity criterion, but only 26% of patients eligible for a study if≥moderate anhedonia was used without considering substance use and medical comorbidities. If patients with ≥ moderate overall depressive symptoms were considered, 88.1% of patients would be eligible if≥mild anhedonia was required for a study, and 45.2% of patients would be eligible for a study if≥moderate anhedonia was required. For those who were unqualified for the study based on≥moderate anhedonia, about 1/3 had≥moderate overall depressive symptoms and less than 40% of maximum possible scores of Q-LES-Q. If only patients in remission based on overall depressive symptom severity were considered for a study of anhedonia, no patient would be eligible for the study., Conclusion: Depressive mood and anhedonia are highly correlated. Screening patients with a mood disorder and an overall moderate depressive severity is a cost-effective approach for a study targeting anhedonia, especially for a study requiring≥moderate severity of anhedonia. However, 1/3 of the unqualified patients will have≥moderate overall depressive symptoms and poor quality of life., (Copyright © 2017 Elsevier B.V. All rights reserved.)