Publications by authors named "Larkin J"

996 Publications

5-Year Outcomes with Cobimetinib plus Vemurafenib in Mutation-Positive Advanced Melanoma: Extended Follow-up of the coBRIM Study.

Clin Cancer Res 2021 Jun 22. Epub 2021 Jun 22.

Peter MacCallum Cancer Centre and the University of Melbourne, Melbourne, Victoria, Australia.

Purpose: The randomized phase III coBRIM study (NCT01689519) demonstrated improved progression-free survival (PFS) and overall survival (OS) with addition of cobimetinib to vemurafenib compared with vemurafenib in patients with previously untreated mutation-positive advanced melanoma. We report long-term follow-up of coBRIM, with at least 5 years since the last patient was randomized.

Experimental Design: Eligible patients were randomized 1:1 to receive either oral cobimetinib (60 mg once daily on days 1-21 in each 28-day cycle) or placebo in combination with oral vemurafenib (960 mg twice daily).

Results: 495 patients were randomized to cobimetinib plus vemurafenib ( = 247) or placebo plus vemurafenib ( = 248). Median follow-up was 21.2 months for cobimetinib plus vemurafenib and 16.6 months for placebo plus vemurafenib. Median OS was 22.5 months (95% CI, 20.3-28.8) with cobimetinib plus vemurafenib and 17.4 months (95% CI, 15.0-19.8) with placebo plus vemurafenib; 5-year OS rates were 31% and 26%, respectively. Median PFS was 12.6 months (95% CI, 9.5-14.8) with cobimetinib plus vemurafenib and 7.2 months (95% CI, 5.6-7.5) with placebo plus vemurafenib; 5-year PFS rates were 14% and 10%, respectively. OS and PFS were longest in patients with normal baseline lactate dehydrogenase levels and low tumor burden, and in those achieving complete response. The safety profile remained consistent with previously published reports.

Conclusions: Extended follow-up of coBRIM confirms the long-term clinical benefit and safety profile of cobimetinib plus vemurafenib compared with vemurafenib monotherapy in patients with mutation-positive advanced melanoma.
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http://dx.doi.org/10.1158/1078-0432.CCR-21-0809DOI Listing
June 2021

Radiation Therapy for Brain Metastases: A Systematic Review.

Pract Radiat Oncol 2021 Sep-Oct;11(5):354-365. Epub 2021 Jun 9.

Southern California Evidence-Based Practice Center, RAND Corporation, Santa Monica, California; Southern California Evidence Review Center, Keck School of Medicine, University of Southern California, Los Angeles, California.

Purpose: This evidence report synthesizes the available evidence on radiation therapy for brain metastases.

Methods And Materials: The literature search included PubMed, EMBASE, Web of Science, Scopus, CINAHL, clinicaltrials.gov, and published guidelines in July 2020; independently submitted data, expert consultation, and contacting authors. Included studies were randomized controlled trials (RCTs) and large observational studies (for safety assessments), evaluating whole brain radiation therapy (WBRT) and stereotactic radiosurgery (SRS) alone or in combination, as initial or postoperative treatment, with or without systemic therapy for adults with brain metastases due to lung cancer, breast cancer, or melanoma.

Results: Ninety-seven studies reported in 189 publications were identified, but the number of analyses was limited owing to different intervention and comparator combinations as well as insufficient reporting of outcome data. Risk of bias varied, and 25 trials were terminated early, predominantly owing to poor accrual. The combination of SRS plus WBRT compared with SRS alone or WBRT alone showed no statistically significant difference in overall survival (hazard ratio [HR], 1.09; 95% confidence interval [CI], 0.69%-1.73%; 4 RCTs) or death owing to brain metastases (relative risk [RR], 0.93; 95% CI, 0.48%-1.81%; 3 RCTs). Radiation therapy after surgery did not improve overall survival compared with surgery alone (HR, 0.98; 95% CI, 0.76%-1.26%; 5 RCTs). Data for quality of life, functional status, and cognitive effects were insufficient to determine effects of WBRT, SRS, or postsurgery interventions. We did not find systematic differences across interventions in serious adverse events, number of adverse events, radiation necrosis, fatigue, or seizures. WBRT plus systemic therapy (RR 1.44; 95% CI, 1.03%-2.00%; 14 studies) was associated with increased risks for vomiting compared with WBRT alone.

Conclusions: Despite the substantial research literature on radiation therapy, comparative effectiveness information is limited. There is a need for more data on patient-relevant outcomes such as quality of life, functional status, and cognitive effects.
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http://dx.doi.org/10.1016/j.prro.2021.04.002DOI Listing
September 2021

Exercise Improves Cancer-free Survival and Healthspan in a Model of Radiation-induced Cancer.

Med Sci Sports Exerc 2021 May 28. Epub 2021 May 28.

School of Human Kinetics, Faculty of Health Sciences, University of Ottawa, Ottawa, Canada Department of Pathology and Molecular Medicine, Faculty of Health Sciences, McMaster University, Hamilton, Canada Department of Cellular and Molecular Medicine, Centre on Neuromuscular Disease, and Regenerative Medicine Program, University of Ottawa, Ottawa, Canada.

Introduction: Radiation therapy increases the risk of secondary malignancy and morbidity in cancer survivors. The role of obesity and exercise training in modulating this risk is not well-understood. As such, we used a preclinical model of radiation-induced malignancy to investigate whether diet-induced obesity and/or endurance exercise training altered life-long survival, cancer incidence, and morbidity.

Methods: Male CBA mice were randomly divided into control diet/sedentary group (CTRL/SED), high fat diet (45% fat)/sedentary group (HFD/SED), control diet/exercise group (2-3 days/week; CTRL/EX), or high fat diet/exercise group (HFD/EX) groups, then exposed to whole-body radiation (3 Gy). Endpoint monitoring and pathology determined mortality and cancer incidence, respectively. Healthspan index, a measure of morbidity, was determined by a composite measure of ten anthropometric, metabolic, performance, and behavioral measures.

Results: Overall survival was higher in HFD/SED compared to CTRL/SED (p < 0.05). Risk of cancer-related mortality by 18 months post-radiation was 1.99 and 1.63 in HFD/SED compared to CTRL/EX (RR = 1.99; 95% CI, 1.20-3.31; p = 0.0081) and CTRL/SED (RR = 1.63; 95% CI, 1.06-2.49; p = 0.0250), respectively. The number of mice at endpoint with cancer was higher in HFD/SED compared to CTRL/EX and CTRL/SED (p < 0.05). Healthspan index was highest in CTRL/EX (score = +2.5), followed by HFD/EX (score = +1), and HFD/SED (score = -1) relative to CTRL/SED.

Conclusion: This work provides the basis for future preclinical studies investigating the dose-response relationship between exercise training and late effects of radiation therapy as well as the mechanisms responsible for these effects.
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http://dx.doi.org/10.1249/MSS.0000000000002711DOI Listing
May 2021

Safety of vaccines used for routine immunization in the United States: An updated systematic review and meta-analysis.

Vaccine 2021 06 25;39(28):3696-3716. Epub 2021 May 25.

RAND Corporation, 1776 Main Street, Santa Monica, CA 90401, United States; Southern California Evidence Review Center, University of Southern California, Keck School of Medicine, 2001 N Soto Street, Los Angeles, CA 90033, United States.

Background: Understanding the safety of vaccines is critical to inform decisions about vaccination. Our objective was to conduct a systematic review of the safety of vaccines recommended for children, adults, and pregnant women in the United States.

Methods: We searched the literature in November 2020 to update a 2014 Agency for Healthcare Research and Quality review by integrating newly available data. Studies of vaccines that used a comparator and reported the presence or absence of key adverse events were eligible. Adhering to Evidence-based Practice Center methodology, we assessed the strength of evidence (SoE) for all evidence statements. The systematic review is registered in PROSPERO (CRD42020180089).

Results: Of 56,603 reviewed citations, 338 studies reported in 518 publications met inclusion criteria. For children, SoE was high for no increased risk of autism following measles, mumps, and rubella (MMR) vaccine. SoE was high for increased risk of febrile seizures with MMR. There was no evidence of increased risk of  intussusception with rotavirus vaccine at the latest follow-up (moderate SoE), nor of diabetes (high SoE). There was no evidence of increased risk or insufficient evidence for key adverse events for newer vaccines such as 9-valent human papillomavirus and meningococcal B vaccines. For adults, there was no evidence of increased risk (varied SoE) or insufficient evidence for key adverse events for the new adjuvanted inactivated influenza vaccine and recombinant adjuvanted zoster vaccine. We found no evidence of increased risk (varied SoE) for key adverse events among pregnant women following tetanus, diphtheria, and acellular pertussis vaccine, including stillbirth (moderate SoE).

Conclusions: Across a large body of research we found few associations of vaccines and serious key adverse events; however, rare events are challenging to study. Any adverse events should be weighed against the protective benefits that vaccines provide.
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http://dx.doi.org/10.1016/j.vaccine.2021.03.079DOI Listing
June 2021

Allocation of scarce resources in a pandemic: rapid systematic review update of strategies for policymakers.

J Clin Epidemiol 2021 May 25. Epub 2021 May 25.

RAND Corporation, 1776 Main Street Santa Monica, CA 90401, USA.

Objective: In pandemics like COVID-19, the need for medical resources quickly outpaces available supply. policymakers need strategies to inform decisions about allocating scarce resources.

Study Design And Setting: We updated a systematic review on evidence-based approaches and searched databases through May 2020 for evaluation of strategies for policymakers.

Results: The 201 identified studies evaluated reducing demand for healthcare, optimizing existing resources, augmenting resources, and adopting crisis standards of care. Most research exists to reduce demand (n = 149); 39 higher quality studies reported benefits of contact tracing, school closures, travel restrictions, and mass vaccination. Of 28 strategies to augment resources, 6 higher quality studies reported effectiveness of establishing temporary facilities, use of volunteers, and decision support software. Of 23 strategies to optimize existing resources, 12 higher quality studies reported successful scope of work expansions and building on existing interagency agreements. Of 15 COVID-19 studies, 5 higher quality studies reported on combinations of policies and benefits of community-wide mask policies.

Conclusion: Despite the volume, the evidence base is limited; few strategies were empirically tested in robust study designs. The review provides a comprehensive overview of the effects of strategies to allocate resources and provides critical appraisal to identify the best available evidence.
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http://dx.doi.org/10.1016/j.jclinepi.2021.04.021DOI Listing
May 2021

Cytokine release syndrome in a patient with colorectal cancer after vaccination with BNT162b2.

Nat Med 2021 08 26;27(8):1362-1366. Epub 2021 May 26.

Gastrointestinal and Lymphoma Unit, The Royal Marsden NHS Foundation Trust, Sutton, UK.

Patients with cancer are currently prioritized in coronavirus disease 2019 (COVID-19) vaccination programs globally, which includes administration of mRNA vaccines. Cytokine release syndrome (CRS) has not been reported with mRNA vaccines and is an extremely rare immune-related adverse event of immune checkpoint inhibitors. We present a case of CRS that occurred 5 d after vaccination with BTN162b2 (tozinameran)-the Pfizer-BioNTech mRNA COVID-19 vaccine-in a patient with colorectal cancer on long-standing anti-PD-1 monotherapy. The CRS was evidenced by raised inflammatory markers, thrombocytopenia, elevated cytokine levels (IFN-γ/IL-2R/IL-18/IL-16/IL-10) and steroid responsiveness. The close temporal association of vaccination and diagnosis of CRS in this case suggests that CRS was a vaccine-related adverse event; with anti-PD1 blockade as a potential contributor. Overall, further prospective pharmacovigillence data are needed in patients with cancer, but the benefit-risk profile remains strongly in favor of COVID-19 vaccination in this population.
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http://dx.doi.org/10.1038/s41591-021-01387-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8363501PMC
August 2021

Selection of metastasis competent subclones in the tumour interior.

Nat Ecol Evol 2021 07 17;5(7):1033-1045. Epub 2021 May 17.

Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK.

The genetic evolutionary features of solid tumour growth are becoming increasingly well described, but the spatial and physical nature of subclonal growth remains unclear. Here, we utilize 102 macroscopic whole-tumour images from clear cell renal cell carcinoma patients, with matched genetic and phenotypic data from 756 biopsies. Utilizing a digital image processing pipeline, a renal pathologist marked the boundaries between tumour and normal tissue and extracted positions of boundary line and biopsy regions to X and Y coordinates. We then integrated coordinates with genomic data to map exact spatial subclone locations, revealing how genetically distinct subclones grow and evolve spatially. We observed a phenotype of advanced and more aggressive subclonal growth in the tumour centre, characterized by an elevated burden of somatic copy number alterations and higher necrosis, proliferation rate and Fuhrman grade. Moreover, we found that metastasizing subclones preferentially originate from the tumour centre. Collectively, these observations suggest a model of accelerated evolution in the tumour interior, with harsh hypoxic environmental conditions leading to a greater opportunity for driver somatic copy number alterations to arise and expand due to selective advantage. Tumour subclone growth is predominantly spatially contiguous in nature. We found only two cases of subclone dispersal, one of which was associated with metastasis. The largest subclones spatially were dominated by driver somatic copy number alterations, suggesting that a large selective advantage can be conferred to subclones upon acquisition of these alterations. In conclusion, spatial dynamics is strongly associated with genomic alterations and plays an important role in tumour evolution.
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http://dx.doi.org/10.1038/s41559-021-01456-6DOI Listing
July 2021

Differences in lymphoma patients between chimeric antigen receptor T-cell therapy trials and the general population.

Clin Exp Med 2021 May 17. Epub 2021 May 17.

Southern California Evidence-Based Practice Center, RAND Corporation, 1776 Main St, Santa Monica, CA, 90401-3208, USA.

Chimeric antigen receptor (CAR)-T cell therapies appear to be promising treatments for non-Hodgkin's and B-cell lymphoma. However, several CAR-T therapies approved by the US Food and Drug Administration have only been tested for efficacy in relatively few single-arm clinical trials with small sample sizes. We sought to examine the differences between patients in these trials and the general population of patients with non-Hodgkin's and B-cell lymphoma. Five hundred and twenty-two patients from 15 CAR-T trials found in a systematic review and 417,492 patients from the Surveillance, Epidemiology, and End Results (SEER) Program database were compared. CAR-T study participants appeared to be younger (46.7% under 70 years old vs. 42.2%), more male (68.0% vs. 55.7%), and followed for a shorter period of time compared to patients in the SEER population (mean [M] 45.6 months, 95% confidence interval [CI] 17.7 to 63.3 months follow-up vs. M 57.1 months, 95% CI 57.0 to 57.3 months survival). CAR-T study participants may differ significantly from the general population of patients with non-Hodgkin's and B-cell lymphoma. Effectiveness of CAR-T therapies in the general population of lymphoma patients may differ from effectiveness demonstrated in trials. Newly created CAR-T patient registries are essential to establishing population-level effectiveness of the therapies.
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http://dx.doi.org/10.1007/s10238-021-00724-wDOI Listing
May 2021

Lifileucel, a Tumor-Infiltrating Lymphocyte Therapy, in Metastatic Melanoma.

J Clin Oncol 2021 Aug 12;39(24):2656-2666. Epub 2021 May 12.

James Graham Brown Cancer Center, University of Louisville, Louisville, KY.

Purpose: Effective treatment options are limited for patients with advanced (metastatic or unresectable) melanoma who progress after immune checkpoint inhibitors and targeted therapies. Adoptive cell therapy using tumor-infiltrating lymphocytes has demonstrated efficacy in advanced melanoma. Lifileucel is an autologous, centrally manufactured tumor-infiltrating lymphocyte product.

Methods: We conducted a phase II open-label, single-arm, multicenter study in patients with advanced melanoma who had been previously treated with checkpoint inhibitor(s) and BRAF ± MEK targeted agents. Lifileucel was produced from harvested tumor specimens in central Good Manufacturing Practice facilities using a streamlined 22-day process. Patients received a nonmyeloablative lymphodepletion regimen, a single infusion of lifileucel, and up to six doses of high-dose interleukin-2. The primary end point was investigator-assessed objective response rate (ORR) per RECIST, version 1.1.

Results: Sixty-six patients received a mean of 3.3 prior therapies (anti-programmed death 1 [PD-1] or programmed death ligand 1 [PD-L1]: 100%; anticytotoxic T-lymphocyte-associated protein-4: 80%; BRAF ± MEK inhibitor: 23%). The ORR was 36% (95% CI, 25 to 49), with two complete responses and 22 partial responses. Disease control rate was 80% (95% CI, 69 to 89). Median duration of response was not reached after 18.7-month median study follow-up (range, 0.2-34.1 months). In the primary refractory to anti-PD-1 or PD-L1 therapy subset, the ORR and disease control rate were 41% (95% CI, 26 to 57) and 81% (95% CI, 66 to 91), respectively. Safety profile was consistent with known adverse events associated with nonmyeloablative lymphodepletion and interleukin-2.

Conclusion: Lifileucel demonstrated durable responses and addresses a major unmet need in patients with metastatic melanoma with limited treatment options after approved therapy, including the primary refractory to anti-PD-1 or PD-L1 therapy subset.
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http://dx.doi.org/10.1200/JCO.21.00612DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8376325PMC
August 2021

Making the patient voice heard in a research consortium: experiences from an EU project (IMI-APPROACH).

Res Involv Engagem 2021 May 10;7(1):24. Epub 2021 May 10.

Lygature, Jaarbeursplein 6, Utrecht, 3521 AL, The Netherlands.

APPROACH is an EU-wide research consortium with the goal to identify different subgroups of knee osteoarthritis to enable future differential diagnosis and treatment. During a 2-year clinical study images, biomarkers and clinical data are collected from people living with knee osteoarthritis and data are analyzed to confirm patterns that can indicate such different subgroups. A Patient Council (PC) has been set up at project initiation and consists of five people from Norway, The Netherlands and UK. Initially, this group of individuals had to learn how to effectively work with each other and with the researchers. Today, the PC is a strong team that is fully integrated in the consortium and acknowledged by researchers as an important sounding board. The article describes this journey looking at formal processes of involvement - organizational structure, budget, meetings - and more informal processes such as building relationships and changing researcher perceptions. It describes how the PC helped improve the experience and engagement of study participants by providing input to the clinical protocol and ensuring effective communication (e.g. through direct interactions with participants and newsletters). Furthermore, the PC is helping with dissemination of results and project advocacy, and overall provides the patient perspective to researchers. Additionally, the authors experienced and describe the intangible benefits such as a shift in researcher attitudes and a sense of community and purpose for PC members. Importantly, learnings reported in this article also include the challenges, such as effective integration of the PC with researchers' work in the early phase of the project. TRIAL REGISTRATION: US National Library of Medicine, NCT03883568 , retrospectively registered 21 March 2019.
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http://dx.doi.org/10.1186/s40900-021-00267-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8107424PMC
May 2021

'This is not part of my life plan': A qualitative study on the psychosocial experiences and practical challenges in young adults with cancer age 25 to 39 years at diagnosis.

Eur J Cancer Care (Engl) 2021 Sep 3;30(5):e13458. Epub 2021 May 3.

Institute of Cancer Research, London, UK.

Objective: Adolescents and young adults with cancer face unique psychosocial and practical issues. However, patients across this group encounter different life experiences, cancer diagnoses and treatment settings given the tailored services for patients ages 15 to 24. Here, we qualitatively explore the psychosocial experiences and practical challenges of young adults (YAs) with cancer diagnosed between ages 25 and 39 in the United Kingdom.

Methods: We invited YAs diagnosed with cancer in the 5 years prior to enrolment at participating sites to take part in semi-structured interviews or focus groups. Transcripts were analysed using inductive thematic analysis. Two YA patients reviewed the results to ensure robustness.

Results: Sixty-five YAs with varied diagnoses participated. Participants struggled to balance work, childcare and financial solvency with treatment. The halt in family and work life as well as changes in image and ability threatened participants' identity and perceived 'normality' as a YA, however, these also stimulated positive changes. YAs experienced social isolation from friends and family, including children. Many struggled to cope with uncertainty around treatment outcomes and disease recurrence.

Conclusion: The disruption of family and work life can lead to age-specific issues in YAs diagnosed with cancer. Age-tailored psychological and practical services must be considered.
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http://dx.doi.org/10.1111/ecc.13458DOI Listing
September 2021

Efficacy and correlative analyses of avelumab plus axitinib versus sunitinib in sarcomatoid renal cell carcinoma: post hoc analysis of a randomized clinical trial.

ESMO Open 2021 Jun 23;6(3):100101. Epub 2021 Apr 23.

Department of Medical Oncology, Institut Gustave Roussy, Villejuif, France.

Background: Among patients with advanced renal cell carcinoma (RCC), those with sarcomatoid histology (sRCC) have the poorest prognosis. This analysis assessed the efficacy of avelumab plus axitinib versus sunitinib in patients with treatment-naive advanced sRCC.

Methods: The randomized, open-label, multicenter, phase III JAVELIN Renal 101 trial (NCT02684006) enrolled patients with treatment-naive advanced RCC. Patients were randomized 1 : 1 to receive either avelumab plus axitinib or sunitinib following standard doses and schedules. Assessments in this post hoc analysis of patients with sRCC included efficacy (including progression-free survival) and biomarker analyses.

Results: A total of 108 patients had sarcomatoid histology and were included in this post hoc analysis; 47 patients in the avelumab plus axitinib arm and 61 in the sunitinib arm. Patients in the avelumab plus axitinib arm had improved progression-free survival [stratified hazard ratio, 0.57 (95% confidence interval, 0.325-1.003)] and a higher objective response rate (46.8% versus 21.3%; complete response in 4.3% versus 0%) versus those in the sunitinib arm. Correlative gene expression analyses of patients with sRCC showed enrichment of gene pathway scores for cancer-associated fibroblasts and regulatory T cells, CD274 and CD8A expression, and tumors with The Cancer Genome Atlas m3 classification.

Conclusions: In this subgroup analysis of JAVELIN Renal 101, patients with sRCC in the avelumab plus axitinib arm had improved efficacy outcomes versus those in the sunitinib arm. Correlative analyses provide insight into this subtype of RCC and suggest that avelumab plus axitinib may increase the chance of overcoming the aggressive features of sRCC.
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http://dx.doi.org/10.1016/j.esmoop.2021.100101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8099757PMC
June 2021

Promoting physical health among people with enduring mental illness: a qualitative study of healthcare providers' perspectives.

BMJ Open 2021 04 21;11(4):e044855. Epub 2021 Apr 21.

Research Centre, Irish College of General Practitioners, Dublin, Ireland.

Background: People with enduring mental illness (EMI) have higher morbidity and mortality from chronic diseases than the general population, and this results in a significantly reduced relative life expectancy-accounted for primarily by physical illness. This gap may be partly influenced by the reduced likelihood of access to and uptake of regular physical health screening.

Aim: To establish Irish service providers' perspectives regarding the care of the physical health of people with EMI in an effort to inform future service developments aimed at improving the physical health of people with EMI.

Design And Setting: Qualitative study of healthcare providers-general practitioners (GPs) and members of the community mental health teams-in Ireland.

Participants: GPs and mental health service providers.

Methods: Qualitative semi-structured interviews were conducted with 34 service providers. Thematic analysis was undertaken.

Results: Participants considered that the physical health of people with EMI is not currently regularly addressed by the patient's GP or the mental health team. Factors associated with this include patient compliance with attendance, time constraints in consultations to adequately support patient self-management, communication difficulties with the patient and between primary and secondary care, and lack of clarity as to whose responsibility it is to ensure physical health is monitored. In participants' view, a barrier to improvement is the present funding approach.

Conclusion: The evidence from this study has the potential to form the basis for innovation and change in service delivery for people with an EMI in Ireland and internationally, specifically in countries where it is not clear who has the overall responsibility to monitor the physical health of patients with EMI. This role requires time and regular contact, and both the organisation and the funding of the health system need to support it.
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http://dx.doi.org/10.1136/bmjopen-2020-044855DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8061849PMC
April 2021

Adjuvant pembrolizumab versus placebo in resected stage III melanoma (EORTC 1325-MG/KEYNOTE-054): health-related quality-of-life results from a double-blind, randomised, controlled, phase 3 trial.

Lancet Oncol 2021 05 12;22(5):655-664. Epub 2021 Apr 12.

EORTC Headquarters, Brussels, Belgium.

Background: The European Organisation for Research and Treatment of Cancer (EORTC) 1325-MG/KEYNOTE-054 trial in patients with resected, high-risk stage III melanoma demonstrated improved recurrence-free survival with adjuvant pembrolizumab compared with placebo (hazard ratio 0·57 [98·4% CI 0·43-0·74]; p<0·0001). This study reports the results from the health-related quality-of-life (HRQOL) exploratory endpoint.

Methods: This double-blind, randomised, controlled, phase 3 trial was done at 123 academic centres and community hospitals across 23 countries. Patients aged 18 years or older with previously untreated histologically confirmed stage IIIA, IIIB, or IIIC resected cutaneous melanoma, and an Eastern Cooperative Oncology Group performance status score of 1 or 0 were eligible. Patients were randomly assigned (1:1) using a central interactive voice-response system on the basis of a minimisation technique stratified for stage and geographic region to receive intravenously 200 mg pembrolizumab or placebo. Treatment was administered every 3 weeks for 1 year, or until disease recurrence, unacceptable toxicity, or death. The primary endpoint of the trial was recurrence-free survival (reported elsewhere). HRQOL was a prespecified exploratory endpoint, with global health/quality of life (GHQ) over 2 years measured by the EORTC QLQ-C30 as the primary analysis. Analyses were done in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT02362594, and EudraCT, 2014-004944-37, and long-term follow-up is ongoing.

Findings: Between Aug 26, 2015, and Nov 14, 2016, 1019 patients were assigned to pembrolizumab (n=514) or placebo (n=505). Median follow-up was 15·1 months (IQR 12·8-16·9) at the time of this analysis. HRQOL compliance was greater than 90% at baseline, greater than 70% during the first year, and greater than 60% thereafter for both groups. Because of low absolute compliance numbers at later follow-up, the analysis was truncated to week 84. Baseline GHQ scores were similar between groups (77·55 [SD 18·20] in the pembrolizumab group and 76·54 [17·81] in the placebo group) and remained stable over time. The difference in average GHQ score between the two groups over the 2 years was -2·2 points (95% CI -4·3 to -0·2). The difference in average score during treatment was -1·1 points (95% CI -3·2 to 0·9) and the difference in average score after treatment was -2·2 points (-4·8 to 0·4). These differences are within the 5-point clinical relevance threshold for the QLQ-C30 and are therefore clinically non-significant.

Interpretation: Pembrolizumab does not result in a clinically significant decrease in HRQOL compared with placebo when given as adjuvant therapy for patients with resected, high-risk stage III melanoma. These results support the use of adjuvant pembrolizumab in this setting.

Funding: Merck Sharp & Dohme.
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http://dx.doi.org/10.1016/S1470-2045(21)00081-4DOI Listing
May 2021

Adjuvant pembrolizumab versus placebo in resected stage III melanoma (EORTC 1325-MG/KEYNOTE-054): distant metastasis-free survival results from a double-blind, randomised, controlled, phase 3 trial.

Lancet Oncol 2021 05 12;22(5):643-654. Epub 2021 Apr 12.

EORTC Headquarters, Brussels, Belgium.

Background: The European Organisation for Research and Treatment of Cancer (EORTC) 1325/KEYNOTE-054 trial assessed pembrolizumab versus placebo in patients with resected high-risk stage III melanoma. At 15-month median follow-up, pembrolizumab improved recurrence-free survival (hazard ratio [HR] 0·57 [98·4% CI 0·43-0·74], p<0·0001) compared with placebo, leading to its approval in the USA and Europe. This report provides the final results for the secondary efficacy endpoint, distant metastasis-free survival and an update of the recurrence-free survival results.

Methods: This double-blind, randomised, controlled, phase 3 trial was done at 123 academic centres and community hospitals across 23 countries. Patients aged 18 years or older with complete resection of cutaneous melanoma metastatic to lymph node, classified as American Joint Committee on Cancer staging system, seventh edition (AJCC-7) stage IIIA (at least one lymph node metastasis >1 mm), IIIB, or IIIC (without in-transit metastasis), and with an Eastern Cooperative Oncology Group performance status of 0 or 1 were eligible. Patients were randomly assigned (1:1) via a central interactive voice response system to receive intravenous pembrolizumab 200 mg or placebo every 3 weeks for up to 18 doses or until disease recurrence or unacceptable toxicity. Randomisation was stratified according to disease stage and region, using a minimisation technique, and clinical investigators, patients, and those collecting or analysing the data were masked to treatment assignment. The two coprimary endpoints were recurrence-free survival in the intention-to-treat (ITT) population and in patients with PD-L1-positive tumours. The secondary endpoint reported here was distant metastasis-free survival in the ITT and PD-L1-positive populations. This study is registered with ClinicalTrials.gov, NCT02362594, and EudraCT, 2014-004944-37.

Findings: Between Aug 26, 2015, and Nov 14, 2016, 1019 patients were assigned to receive either pembrolizumab (n=514) or placebo (n=505). At an overall median follow-up of 42·3 months (IQR 40·5-45·9), 3·5-year distant metastasis-free survival was higher in the pembrolizumab group than in the placebo group in the ITT population (65·3% [95% CI 60·9-69·5] in the pembrolizumab group vs 49·4% [44·8-53·8] in the placebo group; HR 0·60 [95% CI 0·49-0·73]; p<0·0001). In the 853 patients with PD-L1-positive tumours, 3·5-year distant metastasis-free survival was 66·7% (95% CI 61·8-71·2) in the pembrolizumab group and 51·6% (46·6-56·4) in the placebo group (HR 0·61 [95% CI 0·49-0·76]; p<0·0001). Recurrence-free survival remained longer in the pembrolizumab group 59·8% (95% CI 55·3-64·1) than the placebo group 41·4% (37·0-45·8) at this 3·5-year follow-up in the ITT population (HR 0·59 [95% CI 0·49-0·70]) and in those with PD-L1-positive tumours 61·4% (56·3-66·1) in the pembrolizumab group and 44·1% (39·2-48·8) in the placebo group (HR 0·59 [95% CI 0·49-0·73]).

Interpretation: Pembrolizumab adjuvant therapy provided a significant and clinically meaningful improvement in distant metastasis-free survival at a 3·5-year median follow-up, which was consistent with the improvement in recurrence-free survival. Therefore, the results of this trial support the indication to use adjuvant pembrolizumab therapy in patients with resected high risk stage III cutaneous melanoma.

Funding: Merck Sharp & Dohme.
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http://dx.doi.org/10.1016/S1470-2045(21)00065-6DOI Listing
May 2021

Predictive biomarkers for response to immune checkpoint inhibition.

Semin Cancer Biol 2021 Apr 2. Epub 2021 Apr 2.

Renal and Skin Units, The Royal Marsden Hospital, London SW3 6JJ, UK; Cancer Dynamics Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK. Electronic address:

Immune checkpoint inhibitors have transformed the prognosis and treatment paradigm of many cancer types, through the potential for durable responses. However, the majority of patients still do not benefit. Response to checkpoint inhibition is determined by dynamic host, tumour and tumour microenvironment factors that display spatial and temporal variability, but our understanding of these interactions is incomplete. Through investigating biomarkers of resistance and response, opportunities arise to discover new therapeutic targets and shape personalised treatment strategies. Here we review approved and emerging biomarkers of response to immune checkpoint inhibitors, in particular the recent rapid progress in host and tumour genomics. It is unlikely that a single biomarker will precisely predict response, but multivariate multiomic markers may provide a balanced assessment of these factors and more accurately identify patients who will benefit. Further efforts are required to translate these groundbreaking discoveries into novel therapeutics and biomarker driven clinical trials, to provide durable treatment response to a greater population of patients.
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http://dx.doi.org/10.1016/j.semcancer.2021.03.036DOI Listing
April 2021

Obesity and anastomotic leak rates in colorectal cancer: a meta-analysis.

Int J Colorectal Dis 2021 Sep 1;36(9):1819-1829. Epub 2021 Apr 1.

Department of Colorectal Surgery, St James's Hospital, Dublin, Ireland.

Purpose: Anastomotic leak (AL) following colorectal cancer resection is associated with considerable morbidity and mortality with an impact on recurrence rates and survival. The impact of obesity on AL rates is debated. This meta-analysis aims to investigate the relationship between obesity and AL.

Methods: A search was conducted of the PubMed/MEDLINE, and Web of Science databases and included studies were split into Western and Asian groups based on population-specific body mass index (BMI) ranges for obesity. A meta-analysis was performed to assess the impact of obesity on AL rate following colorectal cancer resection.

Results: Two thousand three hundred and four articles were initially screened. Thirty-one studies totaling 32,953 patients were included. Patients with obesity had a statistically significant increase in AL rate in all Western and Asian study groups. However, this increase was only clinically significant in the rectal anastomotic subgroups-Western: 10.8% vs 8.4%, OR 1.57 (1.01-2.44) and Asian: 9.4% vs 7.4%, OR 1.58 (1.07-2.32).

Conclusions: The findings of this analysis confirm that obesity is a significant risk factor for anastomotic leak, particularly in rectal anastomoses. This effect is thought to be primarily mediated via technical difficulties of surgery although metabolic and immunological factors may also play a role. Obesity in patients undergoing restorative CRC resection should be discussed and considered as part of the pre-operative counselling.
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http://dx.doi.org/10.1007/s00384-021-03909-7DOI Listing
September 2021

Systematic literature review for the association of biomarkers with efficacy of anti-PD-1 inhibitors in advanced melanoma.

Future Oncol 2021 Jul 30;17(20):2683-2692. Epub 2021 Mar 30.

The Royal Marsden NHS Foundation Trust, London, SW3 6JJ, UK.

Summarize the literature assessing biomarkers in predicting efficacy of anti-PD-1 therapy for patients with high-risk unresectable or metastatic melanoma. Relevant studies were identified via a systematic literature review. About 334 unique biomarkers or biomarker combinations were identified from 121 citations. Neutrophil-to-lymphocyte ratio was the most frequently studied biomarker, followed by C-reactive protein. Fifty-nine biomarkers were significantly associated with overall survival (OS), 51 with progression-free survival (PFS) and 44 with response. Twenty biomarkers were associated with both OS and PFS; two were associated with OS, PFS and response (MHC-II and tumor mutational burden). Numerous biomarkers could potentially predict the efficacy of anti-PD-1-based therapy for melanoma patients. However, confirmatory studies are needed as well as determination of implications for clinical decision-making.
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http://dx.doi.org/10.2217/fon-2021-0154DOI Listing
July 2021

Prevalence and predictors of medication non-adherence among patients with multimorbidity: A systematic review protocol.

HRB Open Res 2019 17;2:29. Epub 2021 Mar 17.

School of Psychology, National University of Ireland, Galway, Galway, Ireland.

Patients with multimorbidity are expected to adhere to complex medication regimens in order to manage their multiple chronic conditions. It has been reported the likelihood of adherence decreases as patients are prescribed more medications. Much medication adherence research to date is dominated by a single-disease focus, which is at odds with the rising prevalence of multimorbidity and may artificially underestimate the complexity of managing chronic illness. This review aims to describe the prevalence of medication non-adherence among patients with multimorbidity, and to identify potential predictors of non-adherence in this population. A systematic review will be conducted and reported according to PRISMA guidelines. PubMed, EMBASE, CINAHL and PsycINFO will be searched using a predefined search strategy from 2009-2019. Quantitative studies will be considered eligible for review if prevalence of medication non-adherence among adults with two or more chronic conditions is reported. Studies will be included in the review if available in English full text. Titles and abstracts will be screened by single review, with 20% of screening cross-checked by a second reviewer. Full-text articles will be screened by two independent reviewers, noting reasons for exclusions. Data extraction will be performed using a predefined extraction form. Quality and risk of bias assessment will be conducted using criteria for observational studies outlined by Sanderson et al. (2007). A narrative synthesis and, if feasible, meta-analysis will be conducted. By exploring medication non-adherence from a multimorbidity perspective, the review aims to inform an evidence base for intervention development which accounts for the rising prevalence of patients with multiple chronic conditions.  The systematic review is prospectively registered in PROSPERO ( CRD42019133849); registered on 12 June 2019.
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http://dx.doi.org/10.12688/hrbopenres.12961.2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7140769.2PMC
March 2021

Immunotherapy use outside clinical trial populations: never say never?

Ann Oncol 2021 07 24;32(7):866-880. Epub 2021 Mar 24.

Cancer Dynamics Laboratory, The Francis Crick Institute, London, UK; Renal and Skin Units, The Royal Marsden NHS Foundation Trust, London, UK. Electronic address:

Background: Based on favourable outcomes in clinical trials, immune checkpoint inhibitors (ICIs), most notably programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte antigen-4 (CTLA-4) inhibitors, are now widely used across multiple cancer types. However, due to their strict inclusion and exclusion criteria, clinical studies often do not address challenges presented by non-trial populations.

Design: This review summarises available data on the efficacy and safety of ICIs in trial-ineligible patients, including those with autoimmune disease, chronic viral infections, organ transplants, organ dysfunction, poor performance status, and brain metastases, as well as the elderly, children, and those who are pregnant. In addition, we review data concerning other real-world challenges with ICIs, including timing of therapy switch, relationships to radiotherapy or surgery, re-treatment after an immune-related toxicity, vaccinations in patients on ICIs, and current experience around ICI and coronavirus disease-19. Where possible, we provide recommendations to aid the often-difficult decision-making process in those settings.

Conclusions: Data suggest that ICIs are often active and have an acceptable safety profile in the populations described above, with the exception of PD-1 inhibitors in solid organ transplant recipients. Decisions about whether to treat with ICIs should be personalised and require multidisciplinary input and careful counselling of patients with respect to potential risks and benefits. Clinical judgements need to be carefully weighed, considering factors such as underlying cancer type, feasibility of alternative treatment options, or activity in trial-eligible patients.
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http://dx.doi.org/10.1016/j.annonc.2021.03.199DOI Listing
July 2021

Objectively assessed sleep-disordered breathing during pregnancy and infant birthweight.

Sleep Med 2021 05 27;81:312-318. Epub 2021 Feb 27.

Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.

Background: Sleep-disordered breathing (SDB) in pregnancy is associated with adverse maternal outcomes. The relationship between SDB and infant birthweight is unclear. This study's primary aim is to determine if objectively measured SDB in pregnancy is associated with infant birthweight.

Methods: We measured SDB objectively in early (6-15 weeks' gestation) and mid (22-31 weeks' gestation) pregnancy in a large cohort of nulliparous women. SDB was defined as an Apnea-Hypopnea Index ≥5 and in secondary analyses we also examined measures of nocturnal hypoxemia. We used a modified Poisson regression approach to estimate relative risks (RR) of large-for-gestational-age (LGA: >90th percentile for gestational age) and small-for-gestational-age (SGA: <10th percentile for gestational age) birthweights.

Results: The prevalence of early-pregnancy SDB was nearly 4%. The incidence of mid-pregnancy SDB was nearly 6.0%. The prevalence of LGA and SGA was 7.4% and 11.9%, respectively. Early-pregnancy SDB was associated with a higher risk of LGA in unadjusted models (RR 2.2, 95% CI 1.3-3.5) but not BMI-adjusted models (aRR 1.0, 95% CI 0.6-1.8). Mid-pregnancy SDB was not associated with SGA or LGA. Mid-pregnancy nocturnal hypoxemia (% of sleep time <90% oxygen saturation) and increasing nocturnal hypoxemia from early to mid-pregnancy were associated with a higher risk of LGA in BMI-adjusted models. SDB and nocturnal hypoxemia were not associated with SGA.

Conclusions: SDB in pregnancy was not associated with an increased risk of LGA or SGA birthweight, independent of BMI. Some measures nocturnal hypoxemia were associated with an increase in LGA risk, independent of BMI. ClinicalTrials.gov Registration number NCT02231398.
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http://dx.doi.org/10.1016/j.sleep.2021.02.043DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8341176PMC
May 2021

Suppressor of cytokine signaling-1 mimetic peptides attenuate lymphocyte activation in the MRL/lpr mouse autoimmune model.

Sci Rep 2021 03 18;11(1):6354. Epub 2021 Mar 18.

Department of Microbiology & Cell Science, University of Florida, Museum Road Building 981, PO Box 110700, Gainesville, FL, 32611, USA.

Autoimmune diseases are driven largely by a pathogenic cytokine milieu produced by aberrantly activated lymphocytes. Many cytokines, including interferon gamma (IFN-γ), utilize the JAK/STAT pathway for signal propagation. Suppressor of Cytokine Signaling-1 (SOCS1) is an inducible, intracellular protein that regulates IFN-γ signaling by dampening JAK/STAT signaling. Using Fas deficient, MRL/MpJ-Fas/J (MRL/lpr) mice, which develop lupus-like disease spontaneously, we tested the hypothesis that a peptide mimic of the SOCS1 kinase inhibitory region (SOCS1-KIR) would inhibit lymphocyte activation and modulate lupus-associated pathologies. Consistent with in vitro studies, SOCS1-KIR intraperitoneal administration reduced the frequency, activation, and cytokine production of memory CD8 and CD4 T lymphocytes within the peripheral blood, spleen, and lymph nodes. In addition, SOCS1-KIR administration reduced lymphadenopathy, severity of skin lesions, autoantibody production, and modestly reduced kidney pathology. On a cellular level, peritoneal SOCS1-KIR administration enhanced Foxp3 expression in total splenic and follicular regulatory T cells, reduced the effector memory/naïve T lymphocyte ratio for both CD4 and CD8 cells, and reduced the frequency of GL7 germinal center enriched B cells. Together, these data show that SOCS1-KIR treatment reduced auto-reactive lymphocyte effector functions and suggest that therapeutic targeting of the SOCS1 pathway through peptide administration may have efficacy in mitigating autoimmune pathologies.
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http://dx.doi.org/10.1038/s41598-021-86017-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7973732PMC
March 2021

Beyond Teenage and Young Adult Cancer Care: Care Experiences of Patients Aged 25-39 Years Old in the UK National Health Service.

Clin Oncol (R Coll Radiol) 2021 Aug 12;33(8):494-506. Epub 2021 Mar 12.

Royal Marsden NHS Foundation Trust, London, UK; Institute of Cancer Research, London, UK; Netherlands Cancer Institute - Antoni van Leeuwenhoek, Amsterdam, the Netherlands.

Aims: Adolescents and young adults aged 15-39 years with cancer face unique medical, practical and psychosocial issues. In the UK, principal treatment centres and programmes have been designed to care for teenage and young adult patients aged 13-24 years in an age-appropriate manner. However, for young adults (YAs) aged 25-39 years with cancer, little access to age-specific support is available. The aim of this study was to examine this possible gap by qualitatively exploring YA care experiences, involving patients as research partners in the analysis to ensure robust results.

Materials And Methods: We conducted a phenomenological qualitative study with YAs diagnosed with any cancer type between ages 25 and 39 years old in the last 5 years. Participants took part in interviews or focus groups and data were analysed using inductive thematic analysis. Results were shaped in an iterative process with the initial coders and four YA patients who did not participate in the study to improve the rigor of the results.

Results: Sixty-five YAs with a range of tumour types participated. We identified seven themes and 13 subthemes. YAs found navigating the healthcare system difficult and commonly experienced prolonged diagnostic pathways. Participants felt under-informed about clinical details and the long-term implications of side-effects on daily life. YAs found online resources overwhelming but also a source of information and treatment support. Some patients regretted not discussing fertility before cancer treatment or felt uninformed or rushed when making fertility preservation decisions. A lack of age-tailored content or age-specific groups deterred YAs from accessing psychological support and rehabilitation services.

Conclusions: YAs with cancer may miss some benefits provided to teenagers and young adults in age-tailored cancer services. Improving services for YAs in adult settings should focus on provision of age-specific information and access to existing relevant support.
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http://dx.doi.org/10.1016/j.clon.2021.02.010DOI Listing
August 2021

Evaluation of a Novel Ostomy Barrier Ring with Assisted Flow for Individuals with an Ileostomy.

Adv Skin Wound Care 2021 Jun;34(6):1-5

Mary Quigley, CNS, is Stoma Nurse, Stoma Department, University Hospital, Galway, Ireland. Ailish Hannigan, PhD, BSc, is Professor of Biomedical Statistics, Graduate Entry Medical School, University of Limerick. At St James Hospital, Dublin, Catherine Dowling, CNS; AnneMarie Stuart, CNS; and Siobhan McGovern, CNS, are Stoma Nurses. Larry Untoy, CNS, is Stoma Nurse, Stoma Department, Tallaght University Hospital, Dublin. Myles Joyce, MD, MMedSci, FRCS (Gen), is Colorectal Surgeon, Department of Colorectal Surgery, University Hospital, Galway. John Larkin, PhD, FRCSI, is Colorectal Surgeon, Department of Surgery, St James Hospital. Dara Kavanagh, MCh, FRCSI, is Colorectal Surgeon, Department of Surgery, Tallaght University Hospital. The authors have disclosed no financial relationships related to this article. Submitted February 22, 2020; accepted in revised form April 7, 2020.

Objective: To determine the performance and user experience of a novel ostomy barrier ring over a 4-week period.

Methods: This single-arm investigation conducted across three clinical sites included 25 adult participants with an ileostomy for 3 months or longer. The participants used their standard ostomy pouching appliance along with a novel barrier ring for a period of 4 weeks. Skin condition was assessed using the Ostomy Skin Tool. Change in skin condition over the study period was recorded for each participant. The participants' experience in using the novel barrier ring was measured using a five-point Likert-type scale.

Results: Twenty of the 25 participants (80%) completed the trial. Of those participants, the median Ostomy Skin Tool score at both the beginning (range, 0-8) and end was 0 (range, 0-6). In terms of skin condition, 7 participants experienced an improvement in skin condition, 11 experienced no change, and 2 got worse. A median score of 5 out of 5 was recorded for all questions relating to user experience.

Conclusions: Although not statistically significant, there was a clear trend toward improvements in peristomal skin condition using the novel barrier ring, even for participants who were already using a barrier ring. User feedback was positive with respect to comfort, device handling, and the perception of the device's ability to protect the skin. Further, most participants who already used a barrier ring indicated that the novel barrier ring would result in a longer wear time.
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http://dx.doi.org/10.1097/01.ASW.0000734368.48756.20DOI Listing
June 2021

Phototactic T-maze Behavioral Assay for Comparing the Functionality of Color-sensitive Photoreceptor Subtypes in the Visual System.

Bio Protoc 2020 Mar 20;10(6):e3558. Epub 2020 Mar 20.

Department of Biology, McGill University, 1205 Dr Penfield Avenue, Montreal, Quebec H3A 1B1, Canada.

The retina contains light-sensitive photoreceptors (R cells) with distinct spectral sensitivities that allow them to distinguish light by its spectral composition. R7 and R8 photoreceptors are important for color vision, and can be further classified into pale (p) or yellow (y) subtypes depending on the rhodopsin expressed. While both R7y and R7p are sensitive to UV light, R8y and R8p detect light in the green and blue spectrum, respectively. The ability of R7 and R8 photoreceptors to distinguish different spectral sensitivities and the natural preference for towards light sources (phototaxis), allow for the development of a phototactic T-maze assay that compares the functionality of different R7 and R8 subtypes. A "UV vs. blue" choice can compare the functionalities of R7p and R8p photoreceptors, while a "UV vs. green" choice can compare the functionalities of R7y and R8y photoreceptors. Additionally, a "blue vs. green" choice could be used to compare R8p and R8y photoreceptors, while a "dark vs. light" choice could be used to determine overall vision functionality. Although electrophysiological recordings and calcium imaging have been used to examine functionality of R7 and R8 photoreceptors, these approaches require expensive equipment and are technically challenging. The phototactic T-maze assay we present here is a robust, straight-forward and an inexpensive method to study genetic and developmental factors that contribute to the individual functionality of R7 and R8 photoreceptors, and is especially useful when performing large-scale genetic screens.
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http://dx.doi.org/10.21769/BioProtoc.3558DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7842357PMC
March 2020

Transmission of SARS-CoV-2 Considering Shared Chairs in Outpatient Dialysis: A Real-World Case-Control Study.

medRxiv 2021 Feb 23. Epub 2021 Feb 23.

Background: SARS-CoV-2 is primarily transmitted through aerosolized droplets; however, the virus can remain transiently viable on surfaces.

Objective: We examined transmission within hemodialysis facilities, with a specific focus on the possibility of indirect patient-to-patient transmission through shared dialysis chairs.

Design: We used real-world data from hemodialysis patients treated between February 1 and June 8 , 2020 to perform a case-control study matching each SARS-CoV-2 positive patient (case) to a non-SARS-CoV-2 patient (control) in the same dialysis shift and traced back 14 days to capture possible exposure from chairs sat in by SARS-CoV-2 patients. Cases and controls were matched on age, sex, race, facility, shift date, and treatment count.

Setting: 2,600 hemodialysis facilities in the United States.

Patients: Adult (age ≥18 years) hemodialysis patients.

Measurements: Conditional logistic regression models tested whether chair exposure after a positive patient conferred a higher risk of SARS-CoV-2 infection to the immediate subsequent patient.

Results: Among 170,234 hemodialysis patients, 4,782 (2.8%) tested positive for SARS-CoV-2 (mean age 64 years, 44% female). Most facilities (68.5%) had 0 to 1 positive SARS-CoV-2 patient. We matched 2,379 SARS-CoV-2 positive cases to 2,379 non-SARS-CoV-2 controls; 1.30% (95%CI 0.90%, 1.87%) of cases and 1.39% (95%CI 0.97%, 1.97%) of controls were exposed to a chair previously sat in by a shedding SARS-CoV-2 patient. Transmission risk among cases was not significantly different from controls (OR=0.94; 95%CI 0.57 to 1.54; p=0.80). Results remained consistent in adjusted and sensitivity analyses.

Limitation: Analysis used real-world data that could contain errors and only considered vertical transmission associated with shared use of dialysis chairs by symptomatic patients.

Conclusions: The risk of indirect patient-to-patient transmission of SARS-CoV-2 infection from dialysis chairs appears to be low.

Primary Funding Source: Fresenius Medical Care North America; National Institute of Diabetes and Digestive and Kidney Diseases (R01DK130067).
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http://dx.doi.org/10.1101/2021.02.20.21251855DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7924295PMC
February 2021

Activation and transcriptional profile of monocytes and CD8 T cells are altered in checkpoint inhibitor-related hepatitis.

J Hepatol 2021 Jul 22;75(1):177-189. Epub 2021 Feb 22.

Department of Metabolism, Digestion & Reproduction, Imperial College London, London, UK. Electronic address:

Background & Aims: Checkpoint inhibitor-related hepatitis (CPI-Hep) is an emerging clinical challenge. We aimed to gain insights into the immunopathology of CPI-Hep by comprehensively characterising myeloid and lymphoid subsets.

Methods: CPI-treated patients with or without related hepatitis (CPI-Hep; n = 22 and CPI-noHep; n = 7) were recruited. Phenotypic and transcriptional profiling of peripheral immune subsets was performed and compared with 19 healthy controls (HCs). In vitro monocyte-derived macrophages (MoMFs) were assessed for activation and cytokine production. CD163, CCR2, CD68, CD3, CD8 and granzyme B expression was assessed using immunohistochemistry/immunofluorescence (n = 4).

Results: A significant total monocyte depletion was observed in CPI-Hep compared with HCs (p = 0.04), along with a proportionate increase in the classical monocyte population (p = 0.0002) and significant upregulation of CCR2, CD163 and downregulation of CCR7. Soluble CD163 levels were significantly elevated in CPI-Hep compared with HCs (p <0.0001). In vitro MoMFs from CPI-Hep showed enhanced production of pro-inflammatory cytokines. CD8 T cells demonstrated increased perforin, granzyme B, ICOS and HLA-DR expression in CPI-Hep. Transcriptional profiling indicated the presence of activated monocyte and enhanced effector CD8 T cell populations in CPI-Hep. Immunohistochemistry demonstrated co-localisation of CD8/granzyme B T cells with CD68CCR2/CD68CD163 macrophages in CPI-Hep liver tissue.

Conclusions: CPI-Hep is associated with activation of peripheral monocytes and an enhanced cytotoxic, effector CD8 T cell phenotype. These changes were reflected by liver inflammation composed of CD163/CCR2 macrophages and CD8 T cells.

Lay Summary: Some patients who receive immunotherapy for cancer develop liver inflammation, which requires cessation of cancer treatment. Herein, we describe ways in which the white blood cells of patients who develop liver inflammation differ from those of patients who receive the same immunotherapy but do not experience liver-related side effects. Targeting some of the pathways we identify may help to prevent or manage this side effect and facilitate cancer treatment.
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http://dx.doi.org/10.1016/j.jhep.2021.02.008DOI Listing
July 2021

The efficacy of immunotherapy for in-transit metastases of melanoma: an analysis of randomized controlled trials.

Melanoma Res 2021 04;31(2):181-185

Department of Surgical Oncology, Netherlands Cancer Institute - Antoni van Leeuwenhoek, Amsterdam, The Netherlands.

Nearly 10% of patients with high-risk early-stage melanoma will develop satellite or in-transit metastases (ITM), classified as stage III disease similar to lymph node metastases. The pivotal registration trials of the CTLA-4 antibody ipilimumab, and the PD-1 antibodies nivolumab and pembrolizumab, also included patients with unresectable stage III disease. However, there has been no analysis of patients with ITM, and anecdotal retrospective small series have indicated a potential lesser effect. This study aimed to identify patients with unresectable ITM within the randomized trials, and to determine response, progression-free survival and overall survival. The pivotal phase III randomized intervention trials that included melanoma patients with ITM, with or without nodal metastasis, and were treated with ipilimumab, nivolumab or pembrolizumab was identified. The datasets from each trial were then searched to identify the specific details of the investigated patient population for a pooled analysis. The primary endpoint was complete response rate. Seven trials that included stage III patients, and with accessible datasets, were identified. There was a total of 4711 patients, however, no patients with ITM could be identified, as this data was not captured by the case report forms. Evidence from prospective clinical trials on the use of immunotherapy in patients with ITM is lacking. We recommend pooling data from multiple institutions to examine efficacy of available drug therapies in this patient population, but more importantly, prospective clinical trials of locoregional treatments with or without systemic drug therapies are required.
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http://dx.doi.org/10.1097/CMR.0000000000000719DOI Listing
April 2021

Pituitary enlargement following ipilimumab without long term endocrine dysfunction.

Curr Probl Cancer 2021 Feb 10:100710. Epub 2021 Feb 10.

Department of Endocrinology, Chelsea and Westminster NHS Foundation Trust, London, UK; Skin Unit, Royal Marsden NHS Foundation Trust, London, UK; Correspondence to: DL Morganstein, Department of Endocrinology, Chelsea and Westminster NHS Foundation Trust, 369 Fulham Road, London, SW10 9NH, UK. Electronic address:

Ipilimumab, a monoclonal antibody against CTLA-4, is used in the treatment of melanoma and renal cell cancer. Hypophysitis is one of the more common adverse events, usually presenting with headache, pituitary enlargement and hypopituitarism, mostly ACTH deficiency, which is usually permanent. We describe a series of 3 cases developing pituitary enlargement in keeping with hypophysitis after ipilimumab without any long-term pituitary hormone deficiencies. This illustrates that a comprehensive endocrine assessment is required even when pituitary enlargement is present.
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http://dx.doi.org/10.1016/j.currproblcancer.2021.100710DOI Listing
February 2021
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