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Background: Phase 1 oncology trials provide access to new therapies and may improve cancer outcomes. Phase 1 trials conducted in the Asian-Pacific region are increasing at a faster rate than the global trend. This study aimed to describe the changing landscape of phase 1 oncology trials in Australia in the last decade., Methods: This cross-sectional study reviewed phase 1 oncology trials registered on ClinicalTrials.gov conducted in Australia. Phase 1 trials were included for analysis if they enrolled adults with solid organ malignancies, used at least one systemic agent, and were first registered between January 1, 2012, and December 31, 2022. The number of trials, site locations, sponsor type, and drug class were analyzed using descriptive statistics., Results: Over the 10-year period, ClinicalTrials.gov included 493 phase 1 clinical trials across 71 Australian sites. Most sites were in metropolitan locations; in Melbourne, trials were concentrated within selected sites, while in Sydney, trials were spread across a larger number of sites. The number of phase 1 trials per annum increased from 18 in 2012 to 75 in 2022. Since 2020, emerging biopharmaceutical companies have become the predominant sponsor type, a trend that is also seen globally. While most trial sponsors were North American (42%), there was increasing representation from Asian sponsors over the 10-year period (6% in 2012 to 39% in 2022). Immunomodulatory (45%) and targeted approaches (44%) accounted for most drug classes used alone or in combination., Conclusions: There are an increasing number of phase 1 trials conducted within Australia. Sponsors of phase 1 trials are increasingly from Asian countries and are more likely to be emerging biopharmaceutical companies., (© 2024 John Wiley & Sons Australia, Ltd.)

Transparent and precise endpoint definitions are a crucial aspect of clinical trial conduct and reporting, and are used to communicate the benefit of an intervention. Previous studies have identified inconsistencies in endpoint definitions across oncological clinical trials. Here, the Head and Neck Cancer International Group assessed endpoint definitions from phase 3 trials or trials considered practice-changing for patients with recurrent or metastatic mucosal head and neck squamous cell carcinoma, published between 2008 and 2021. We identify considerable and global heterogeneity in endpoint definitions, which undermines the interpretation of results and development of future studies. We show how fundamental components of even incontrovertible endpoints such as overall survival vary widely, highlighting an urgent need for increased rigour in reporting and harmonisation of endpoints., Competing Interests: Declaration of interests AML reports uncompensated consultancy for Eisai; received support from a Peter MacCallum Cancer Centre Discovery Partner Fellowship; and received institutional research funding support from Sanofi Regeneron Pharmaceuticals. CLT has participated in advisory boards for Merck Sharp & Dohme (MSD), Roche, Merck Serono, ALX Oncology, Excientia, Seagen, Kumar Therapeutics, MaxiVax, BMS, PCI Biotech, Nanobiotix, Onxeo, MVX-ONCO, Seattle Genetics, Rakuten, GSK, Celgene, and AstraZeneca. CES has received honoraria for advisory boards for Abbvie, Merck, Bergen Bio, Armo, Mirati, Caris, Sanofi Regeneron, Daiichi, Novocure; and is part of the steering committee for Daiichi. PS has advisory relationships with Merck Serono, Servier, and MSD. JEB has participated in advisory boards for Galera Therapeutics and Castle Biosciences. HM reports grants from the UK National Institute of Health research, Cancer Research UK, the UK Medical Research Council UK, and AstraZeneca; has received advisory board fees from AstraZeneca, MSD, Merck, Nanobiotix, and Seagen; and is Director of Warwickshire Head Neck Clinic and Docspert Health. LM participated in an advisory board for MSD. SSY reports clinical trial research grants from Bristol Myers Squibb, EMD Serono, and Nanobiotix; honoraria for editorial work from Elsevier and ASTRO; and publishing royalties from Sprinter and Up To Date. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Robust time-to-event endpoint definitions are crucial for the assessment of treatment effect and the clinical value of trial interventions. Here, the Head and Neck Cancer International Group investigated endpoint use in phase 3 trials and trials considered potentially practice-changing published between 2008 and 2021 in the curative-intent setting for patients with mucosal head and neck squamous cell carcinoma. Of the 92 trials reviewed, we show that all core components of endpoint reporting were heterogeneous, including definitions of common terms, such as overall survival and progression-free survival. Our report highlights the urgent need for harmonisation of fundamental components of clinical trial endpoints and the engagement of all stakeholders to ensure the transparent reporting of endpoint details., Competing Interests: Declaration of interests AML reports uncompensated consultancy for Eisai; support from a Peter MacCallum Cancer Centre Discovery Partner Fellowship, and institutional research funding support from Sanofi/Regeneron Pharmaceuticals. LM has participated in an advisory board for Merck Sharp & Dohme (MSD). CLT has participated in advisory boards for MSD, Roche, Merck Serono, ALX Oncology, Excientia, Seagen, Kumar Therapeutics, MaxiVax, BMS, PCI Biotech, Nanobiotix, Onxeo, MVX-ONCO, Seattle Genetics, Rakuten, GSK, Celgene, and AstraZeneca. AH has received grants and personal fees from ONO, Taiho, KYORIN, Eisai, and Mitsubishi Tanabe Pharma; grants from Otsuka Pharmaceutical Factory, Iwasakidenshi, and Torii; and personal fees from Bristol Myers Squibb, Bayer Yakuhin, Merck Biopharma, Eli Lilly, Sanofi, Rakuten Medical, Meiji Pharma, Demant, and MSD, outside the submitted work. DJT reports consulting fees from MSD; advisory board participation for Merck Serono; and research grants from Cancer Research UK. AM-P has participated in advisory boards for MSD and Norgine; and has received clinical trial research grants from MSD and Intuitive Surgical, outside the submitted work. CHu has participated in advisory boards for EMD Serono. PS has advisory relationships with Merck Serono, Servier, and MSD. ATD reports grants from the National Health Institute and the Cancer Prevention Institute of Texas. JEB has participated in advisory boards for Galera Therapeutics and Castle Biosciences. AP has participated in advisory boards for MSD, Roche, Merck Serono, BMS, Nanobiotics, GSK, and Seagen; reports honoraria for editorial work from Elsevier; research grants from KURA, BMS, and Ipsen; and received travel grants from Ipsen. HM reports grants from UK National Institute of Health research, Cancer Research UK, the UK Medical Research Council, and AstraZeneca; advisory board fees from AstraZeneca, MSD, Merck, Nanobiotix, and Seagen; and is Director of Warwickshire head and neck clinic and Docspert Health. SSY reports clinical trial research grants from Bristol Myers Squibb, EMD Serono, and Nanobiotix; honoraria for editorial work from Elsevier and ASTRO; and publishing royalties from Springer and Up To Date. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Background: Advancements in medical technologies have led to the development of contact-free methods of haemodynamic monitoring such as remote photoplethysmography (rPPG). rPPG uses video cameras to interpret variations in skin colour related to blood flow, which are analysed to generate vital signs readings. rPPG potentially ameliorates problems like fretfulness and fragile skin contact associated with conventional probes in children. While rPPG has been validated in adults, no prior validation has been performed in children., Methods: A two-phased prospective cross-sectional single-centre study was conducted from January to April 2023 to evaluate the feasibility, acceptability, and accuracy of obtaining heart rate (HR), respiratory rate (RR) and oxygen saturation (SpO 2 ) using rPPG in children, compared to the current standard of care. In Phase 1, we recruited patients ≤16 years from the neonatal and paediatric wards. We excluded preterm neonates with gestational age <35 weeks and newborns <24 hours old. The rPPG webcam was positioned 30 cm from the face. After 1 minute of facial scanning, readings generated were compared with pulse oximetry for HR and SpO 2 , and manual counting for RR. Correlation and Bland-Altman analyses were performed. In Phase 2, we focused on the population in whom there was potential correlation between rPPG and the actual vital signs., Results: Ten neonates and 28 children aged 5 to 16 years were recruited for Phase 1 (765 datapoints). All patients were haemodynamically stable and normothermic. Patients and caregivers showed high acceptability to rPPG. rPPG values were clinically discrepant for children <10 years. For those ≥10 years, moderate correlation was observed for HR, with Spearman's correlation coefficient (Rs) of 0.50 [95% confidence intervals (CI): 0.42, 0.57]. We performed Phase 2 on 23 patients aged 12 to 16 years (559 datapoints). Strong correlation was observed for HR with Rs=0.82 (95% CI: 0.78, 0.85). There was weak correlation for SpO 2 and RR (Rs=-0.25 and -0.02, respectively)., Conclusions: Our study showed that rPPG is acceptable and feasible for neonates and children aged 5 to 16 years, and HR values in older children aged 12 to 16 years correlated well with the current standard. The rPPG algorithms need to be further refined for younger children, and for obtaining RR and SpO 2 in all children. If successful, rPPG will provide a viable contact-free alternative for assessing paediatric vital signs, with potential use in remote monitoring and telemedicine., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://atm.amegroups.com/article/view/10.21037/atm-23-1896/coif). The authors have no conflicts of interest to declare., (2024 Annals of Translational Medicine. All rights reserved.)

Non-melanomatous cutaneous spindle cell neoplasms are a rare group of malignancies that present a diagnostic challenge, and for which there is a lack of consensus on how to best manage patients with advanced disease and only limited reports of immune-checkpoint inhibitor (ICI) responses. In this study, we performed a single-center retrospective review of treatment outcomes for all advanced non-melanomatous cutaneous spindle cell neoplasms treated with ICIs. Blinded histopathology reviews occurred to confirm each diagnosis. Comprehensive tumour profiling included whole exome sequencing for tumour mutational burden (TMB) and ultraviolet(UV) signatures, and immunohistochemistry for immune-cell infiltration (CD4/CD3/CD8/CD103/CD20) and immune-checkpoint expression (PD-L1/LAG3/TIGIT). Seven patients were identified. The objective response rate was 86% (6/7) with five complete responses (CR). Responses were durable with two patients in CR > 30 months after ICI commencement. All patients had high TMB and UV signatures. One patient had PD-L1 100% (combined positive score) with abundant immune-cell infiltration and LAG3 expression. In advanced non-melanomatous cutaneous spindle cell neoplasms, excellent responses to ICIs with durable disease control were observed. ICIs are worthy of further exploration in these patients. UV signatures and high TMB could be used to help select patients for treatment.

Background: Cutaneous squamous cell carcinoma (CSCC) has a propensity for perineural spread (PNS) which is associated with poorer treatment outcomes. Immunotherapy is the new standard of care treatment for advanced CSCC resulting in durable responses. PNS is not captured by traditional response assessment criteria used in clinical trials, e.g. RECIST 1.1, and there is limited literature documenting radiological PNS responses to immunotherapy. In this study we assess PNS responses to immunotherapy using a modified grading system., Methods: This is an Australian single-center retrospective review of patients with advanced CSCC who were treated with immunotherapy between April 2018 and February 2022 who had evidence of PNS on pre-treatment magnetic-resonance imaging (MRI). The primary outcome was blinded overall radiological response in PNS using graded radiological criteria, post-commencement of immunotherapy. Three defined timepoints (< 5 months, 5-10 months, > 10 months) were reviewed. Secondary outcomes included a correlation between RECIST 1.1 and PNS assessments and the assessment of PNS on fluorodeoxyglucose (FDG)-positron emission tomography (PET)/computed tomography (CT)., Results: Twenty CSCC patients treated with immunotherapy were identified. Median age was 75.7 years and 75% (n = 15) were male. All patients had locoregionally advanced disease and no distant metastases. Median follow-up was 18.5 months (range: 2-59). 70% (n = 14) demonstrated a PNS response by 5 months. Three patients experienced pseudoprogression. One patient had PNS progression by the end of study follow up. RECIST 1.1 and PNS responses were largely concordant at > 10 months (Cohen's Kappa 0.62). 5/14 cases had features suspicious for PNS on FDG-PET/CT., Conclusions: PNS response to immunotherapy can be documented on MRI using graded radiological criteria. High response rates were seen in PNS with the use of immunotherapy in this cohort and these responses were largely concordant with RECIST 1.1 assessments. FDG-PET/CT demonstrated limited sensitivity in the detection of PNS., (© 2024. The Author(s).)

Background: Cemiplimab (Libtayo ® ), a human monoclonal immunoglobulin G4 antibody to the programmed cell death-1 receptor, is approved for the treatment of patients with advanced cutaneous squamous cell carcinoma (CSCC), who are not candidates for curative surgery or curative radiation, using an every-3-weeks (Q3W) dosing interval. Pharmacokinetic modeling indicated that C trough of extended intravenous dosing of 600 mg every 4 weeks (Q4W) would be comparable to the approved intravenous dosage of 350 mg Q3W. We examined the efficacy, pharmacokinetics, and safety of cemiplimab dosed Q4W., Methods: In this open-label, phase II trial (ClinicalTrials.gov identifier NCT02760498), the cohort of patients ≥18 years old with advanced CSCC received cemiplimab 600 mg intravenously Q4W for up to 48 weeks. Tumor measurements were recorded every 8 weeks. The primary endpoint was objective response rate by independent central review., Results: Sixty-three patients with advanced CSCC were treated with cemiplimab. The median duration of follow-up was 22.4 months (range: 1.0-39.8). An objective response was observed in 39 patients (62%; 95% CI: 48.8% to 73.9%), with 22% of patients (n = 14) achieving complete response and 40% (n = 25) achieving partial response. The most common treatment-emergent adverse events were diarrhea, pruritus, and fatigue., Conclusions: Extended dosing of cemiplimab 600 mg intravenously Q4W exhibited substantial antitumor activity, rapid and durable responses, and an acceptable safety profile in patients with advanced CSCC. These results confirm that cemiplimab is a highly active therapy for advanced CSCC. Additional data would help ascertain the benefit-risk profile for the 600 mg intravenous dosing regimen compared with the approved regimen., Competing Interests: Competing interests: DR reports institutional research grants and funding from Bristol-Myers Squibb, GlaxoSmithKline, Kura Oncology, Merck Sharp & Dohme, Regeneron Pharmaceuticals, Inc, ALX Oncology, Decibel Therapeutics and Roche; and uncompensated scientific committee and advisory board membership from GlaxoSmithKline, Merck Sharp & Dohme, Regeneron Pharmaceuticals, Inc and Sanofi. BGMH reports consulting or advisory roles at AstraZeneca, Bristol-Myers Squibb, Eisai, Merck Sharp & Dohme, Pfizer and Roche; and institutional research funding from Amgen. NB-S declares no conflict of interest. DS reports institutional patients’ fees from Regeneron Pharmaceuticals, Inc; advisory board, speaker honoraria and patients’ fees from Bristol-Myers Squibb, EMD Serono, Merck Sharp & Dohme, Novarti and Pierre Fabre; steering committee honoraria from 4SC, Bristol-Myers Squibb, InflaRx, Merck Sharp & Dohme, Nektar and Novartis; advisory board fees from Daiichi Sanyo, OncoSec Medical, Pfizer and Replimune; advisory board and patients’ fees from Philogen and Sun Pharma; and research funding to their institution from Amgen, Bristol-Myers Squibb, Merck Sharp & Dohme and Novartis. SB reports an advisory board role or speaker bureau for Sanofi, Ipsen, Lilly, Bristol-Myers Squibb and Merck Sharp & Dohme Australia; and virtual meeting sponsorship from Bristol-Myers Squibb and Merck Sharp & Dohme Australia. ST reports speaker honoraria and advisory board fees from AbbVie, Bristol-Myers Squibb, Novartis, Pierre Fabre and Sun Pharma. FM reports travel support, speaker’s fees or advisor’s honoraria from Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, Roche and Sanofi; and research funding from Novartis and Roche. TE reports consulting or advisory roles at Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Roche and Sanofi Genzyme; speaker’s bureau roles at Merck Sharp & Dohme and Roche; and research funding from Bristol-Myers Squibb and Novartis. VCE reports advisory board honoraria from AstraZeneca, GlaxoSmithKline, Merck Sharp & Dohme and Pharmamar; and speaker honoraria from AstraZeneca and Merck Sharp & Dohme. BS reports advisory board membership for Bristol-Myers Squibb Australia and Merck Sharp & Dohme. MBB reports serving as a speaker without honoraria for Sanofi. SD reports advisory board honoraria and travel expenses from Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, PFO Global and Sun Pharma. BD reports consultancy for Sanofi. MRM reports honoraria and travel expenses from Genentech, Eli Lilly, Novartis, Regeneron Pharmaceuticals, Inc, Sanofi and Sun Pharma; and institutional research funding from Genentech, Eli Lilly, Novartis and Regeneron Pharmaceuticals, Inc. AH reports institutional grants, speaker’s honoraria and consultancy fees from Amgen, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, Provectus and Roche; institutional grants and consultancy fees from EMD Serono, Philogen and Regeneron Pharmaceuticals, Inc; and consultancy fees from OncoSec Medical. CDS reports steering committee membership for Castle Biosciences; steering committee membership and consultancy for Regeneron Pharmaceuticals, Inc; consultancy for Sanofi; research funding from Castle Biosciences, Genentech, Merck, Novartis and Regeneron Pharmaceuticals, Inc; and serving as a chair for the National Comprehensive Cancer Network. AML reports uncompensated advisory board participation from Merck Sharp & Dohme and Bristol-Myers Squibb with travel and accommodation expenses; and uncompensated consultancy for Eisai. S-YY, APaccaly, APapachristos, J-HN, EO, FS, JB and IL are employees of and shareholders in Regeneron Pharmaceuticals, Inc. MGF is an employee of, has patents pending with, and is a shareholder of Regeneron Pharmaceuticals, Inc. AG reports personal fees and nonfinancial support (advisory board and travel support) from Bristol-Myers Squibb and Sun Pharma; personal fees (advisory board) from Eisai, Merck KGaA and Pfizer; non-financial support (travel) from Astellas; and clinical trial unit support from PPD Australia., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: The incidence of human papillomavirus positive oropharyngeal cancer (HPV+OPC) is increasing, and new biomarkers are required to better define prognostic groups and guide treatment. Infiltrating T cells have been well studied in head and neck cancer, however the presence and role of B cells and tertiary lymphoid structures (TLS) in the tumor microenvironment has not, even though the interplay between T and B cells is increasingly being recognised., Materials and Methods: Using CD20 immunohistochemistry (IHC) to identify B cells and TLS in a cohort of 159 HPV + OPC patients, we semi-quantitatively scored abundance and location (intra-tumoral or stromal) and correlated findings with patient survival., Results: 32% (51/157) of patients had high intra-tumoral (IT) abundance of CD20 + B cells (≥5%) and this was prognostic for improved overall survival (OS) with an adjusted hazard ratio (HR) of 0.2 (95 % CI 0.0-0.7, p = 0.014). We validated our results in an independent cohort comprising 171 HPV + OPC where 14% (23/171) were IT CD20 + high, again showing improved survival with an adjusted HR for OS of 0.2 (95 % CI 0.0-1.4, p = 0.003). Neither stromal abundance nor the presence of TLS were prognostic in either cohort. B cells were subtyped by multispectral IHC, identifying CD20 + CD27 + cells, consistent with memory B cells, as the predominant subtype. Combined with validated biomarker CD103, a marker of tissue-resident memory T cells, IT CD20 + B cells abundance was able to prognostically stratify patients further., Conclusions: CD20 + B cell abundance has the potential to be used as a biomarker to identify good and poor prognosis HPV + OPC patients., Competing Interests: Declaration of competing 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., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Older patients are often underrepresented in clinical trials owing to exclusionary comorbidities, which are more common with age. Chemotherapy is poorly tolerated in older comorbid advanced cutaneous squamous cell carcinoma (CSCC) patients; however, little is known on the efficacy and tolerability of immune-checkpoint inhibitors (ICIs) in this population. To our knowledge, this is the largest dedicated report on a cohort of older patients with advanced CSCC treated with immunotherapy to date., Objective: The aim was to report outcomes of ICI use in a real-world older cohort with advanced CSCC., Patients and Methods: A single-centre retrospective audit of all patients treated via an access scheme providing ICIs to patients with advanced CSCC was conducted. Participants were ≥ 70 years of age and had advanced CSCC not amenable to curative surgery or radiotherapy. Best overall response rate (ORR), 12-month overall survival (OS) and progression-free survival (PFS), and toxicity rates were assessed., Results: A total of 53 patients were analysed. The median age was 81.8 years (range 70.1-96.8); 81% were male; 34% were immunocompromised; and 34% had an Eastern Cooperative Oncology Group (ECOG) performance status score of ≥ 2. The ORR was 57%, and 12-month OS and PFS were 63% (95% confidence interval [CI] 44-78) and 41% (95% CI 25-57), respectively. Thirty-two per cent developed an immune-related adverse event (irAE), but only two patients experienced a grade 3 irAE, with no treatment-related deaths. Higher ECOG score was associated with worse OS and PFS. No significant association was identified for increasing age, sex, Charlson Comorbidity Index score, or immunocompromised status., Conclusions: ICIs have demonstrated efficacy and have an acceptable safety profile among older patients with advanced CSCC, with comparable efficacy to what has been demonstrated in current clinical trials., (© 2024. The Author(s).)

Objectives: To review the outcomes of immune checkpoint inhibitor (ICI) treatment of advanced cutaneous squamous cell carcinoma (CSCC) outside clinical trials., Study Design: Retrospective observational study; review of patient records in fifteen Australian institutions., Setting, Participants: All Australian adults with locally advanced or metastatic CSCC not amenable to curative surgery or radiotherapy treated with ICIs, 5 May 2017 - 23 May 2022, through a cemiplimab compassionate access scheme (Therapeutic Goods Administration Special Access Scheme) or who personally covered the cost of pembrolizumab prior to the start of the access scheme., Main Outcome Measures: Best overall response rate (ORR) according to standardised assessment criteria using the hierarchy: Response Evaluation Criteria in Solid Tumors (RECIST 1.1), the modified World Health Organization clinical response criteria, and the Positron Emission Tomography Response Criteria (PERCIST 1.0); overall and progression-free survival., Results: A total of 286 people with advanced CSCC received ICI therapy during May 2017 - May 2022 (cemiplimab, 270; pembrolizumab, 16). Their median age was 75.2 years (range, 39.3-97.5 years) and 232 were men (81%); median follow-up time was 12.2 months (interquartile range, 5.5-20.5 months). Eighty-eight people (31%) were immunocompromised, 27 had autoimmune disease, and 59 of 277 (21%) had ECOG performance scores of 2 or 3. The ORR was 60% (166 of 278 evaluable patients): complete responses were recorded for 74 (27%) and partial responses for 92 patients (33%). Twelve-month overall survival was 78% (95% confidence interval [CI], 72-83%); progression-free survival was 65% (95% CI, 58-70%). Poorer ECOG performance status was associated with poorer overall survival (per unit: adjusted hazard ratio [aHR], 3.0; 95% CI, 2.0-4.3) and progression-free survival (aHR, 2.4; 95% CI, 1.8-3.3), as was being immunocompromised (overall: aHR, 1.8; 95% CI, 1.1-3.0; progression-free: aHR, 1.8; 95% CI, 1.2-2.7). Fifty-five people (19%) reported immune-related adverse events of grade 2 or higher; there were no treatment-related deaths., Conclusion: In our retrospective study, the effectiveness and toxicity of ICI therapy were similar to those determined in clinical trials. Our findings suggest that ICIs could be effective and well tolerated by people with advanced CSCC who are ineligible for clinical trials., (© 2024 The Authors. Medical Journal of Australia published by John Wiley & Sons Australia, Ltd on behalf of AMPCo Pty Ltd.)

Cardiac disease associated with cancer treatment is a common adverse effect that is well-treated with appropriate monitoring. However, some cardiac adverse effects with cancer treatment are not well-understood, in particular rituximab-associated ventricular tachycardia. We present the fourth case of rituximab-associated ventricular tachycardia in a patient who is rituximab-naive and who does not have known cardiac disease history. This patient developed non-sustained polymorphic ventricular tachycardia 14 hours after rituximab was started and 6 hours after it was stopped, and after extensive monitoring including a 30-day event monitor, did not develop further significant runs of ventricular tachycardia., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: We previously reported rates of pathological complete responses (51% [95% CI 39-62] per independent central review, the primary endpoint) and major pathological responses (13% per independent central review, a secondary endpoint) to neoadjuvant cemiplimab (an anti-PD-1 inhibitor) among 79 patients with locoregionally advanced, resectable cutaneous squamous cell carcinoma. Here, we present follow-up data, including event-free, disease-free, and overall survival., Methods: This single-arm, multicentre, phase 2 study included patients aged 18 years or older with resectable stage II-IV (M0) cutaneous squamous cell carcinoma and Eastern Cooperative Oncology Group performance status of 0 or 1. Patients received up to four planned doses of neoadjuvant cemiplimab 350 mg intravenously every 3 weeks followed by curative-intent surgery. After surgery, per investigator discretion, patients received either adjuvant cemiplimab for up to 48 weeks, radiotherapy, or observation alone. Secondary endpoints included in this follow-up analysis are event-free survival, disease-free survival, and overall survival, all summarised using the Kaplan-Meier method. Activity and safety endpoints were analysed for all enrolled patients who received at least one dose of neoadjuvant cemiplimab. In this report, safety data are reported for all patients who received at least one dose of adjuvant cemiplimab. This trial is registered with ClinicalTrials.gov, NCT04154943, has completed enrolment and follow-up is ongoing., Findings: Between March 20, 2020, and July 8, 2021, 79 patients were enrolled. Median age was 73 years (IQR 66-81), 67 (85%) patients were male, 12 (15%) were female, 69 (87%) were White, one was Asian (1%), one was other race (1%), and race was not reported for eight (10%). As of data cutoff (Dec 1, 2022), median follow-up was 18·7 months (IQR 15·6-22·1) for all 79 patients. Among 70 patients who had surgery, 65 (93%) had post-surgical management data: 32 (49%) of 65 were observed postoperatively, 16 (25%) received adjuvant cemiplimab, and 17 (26%) received adjuvant radiotherapy. 11 (14%) of 79 patients had event-free survival events, with an estimated 12-month event-free survival of 89% (95% CI 79-94) for all patients. None of 40 patients who had a pathological complete response and one (10%) of ten patients with major pathological response had recurrence. Six (9%) of 70 patients who completed surgery had a disease-free survival event, with an estimated 12-month disease-free survival of 92% (95% CI 82-97). Nine (11%) of 79 patients died, with an estimated 12-month overall survival for all patients of 92% (95% CI 83-96). Four (25%) of 16 patients who received adjuvant cemiplimab treatment had grade 3 adverse events, including one (6%) who had increased blood potassium, one (6%) who had traumatic limb amputation, and two who had serious adverse events (one [6%] cardiomyopathy and one [6%] hypophysitis). There were no grade 4 adverse events or treatment-related deaths., Interpretation: For patients with resectable stage II-IV cutaneous squamous cell carcinoma, neoadjuvant cemiplimab followed by surgery might be a potential treatment option, addressing a substantial unmet need., Funding: Regeneron Pharmaceuticals and Sanofi., Competing Interests: Declaration of interests NDG reports institutional research funding from Regeneron Pharmaceuticals; speaker honoraria from AiCME; and advisory board and consulting fees from PDS Biotechnology, Replimmune, Regeneron Pharmaceuticals, and Merck. DMM reports honoraria for advisory or consultant roles from Castle Biosciences, EMD Serono, Merck KGaA, Merck Sharpe & Dome, Pfizer, Regeneron Pharmaceuticals, Incyte, Sanofi Genzyme, and Bristol Myers Squibb; equity options from Checkpoint Therapeutics and Avstera Therapeutics Corp; and research funding from Kartos Therapeutics, NeoImmune Tech, and Regeneron Pharmaceuticals. NIK reports grants and advisory board fees from Regeneron Pharmaceuticals, Bristol Myers Squibb, Merck, Replimmune, and Novartis; advisory board fees from Iovance, Instil Bio, Castle Biosciences, Nektar, Incyte (data safety monitoring committee), AstraZeneca (data safety monitoring committee), and Jounce Therapeutics; grants from GlaxoSmithKline, HUYA, and Celgene; honoraria from Genzyme, National Comprehensive Cancer Network (paid by Pfizer), Nektar (study steering committee), Regeneron Pharmaceuticals (study steering committee), Bristol Myers Squibb (study steering committee). and Replimmune (study steering committee); grant from Modulation Therapeutics; travel support from Regeneron Pharmaceuticals; and common stock ownership of Bellicum Pharmaceuticals, Amarin, and Asensus Surgical (formerly Transenetrix). VD reports institutional research funding from Genentech, and advisory board fees from Regeneron Pharmaceuticals. ESR reports advisory board and consulting fees from Genentech, Feldan Therapeutics, Regeneron Pharmaceuticals, and Sanofi, and serves on the board of directors for Checkpoint Therapeutics. EJL reports institutional research funding from Regeneron Pharmaceuticals and Sanofi; institutional grants from Bristol Myers Squibb and Merck; advisory board fees from Bristol Myers Squibb, Eisai, Genentech, Instil Bio, Merck, Natera, Nektar Therapeutics, Odonate Therapeutics, Pfizer, Rain Therapeutics, Regeneron Pharmaceuticals, Replimmune, and Sanofi; payment for speaker's fee from Bristol Myers Squibb; and consulting fees from Bristol Myers Squibb, Macrogenics, OncoSec, Merck, Novartis, CareDX, and Pfizer. FM reports travel support, speaker's fees or advisor's honoraria from Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, Roche, and Sanofi; and research funding from Novartis and Roche. PLS reports institutional research grants from Ascentage Pharma and Pfizer, and advisory board roles for Elevar Therapeutics, Prelude Therapeutics, and Regeneron Pharmaceuticals. JA reports payment or honoraria for speakers bureaus and presentations from Bristol Myers Squibb and Regeneron Pharmaceuticals; advisory board and consulting fees from Bristol Myers Squibb, Castle Biosciences, Pfizer, Regeneron Pharmaceuticals, and Sanofi. JLG reports institutional research funding from Alkermes, EMD Serono, Merck, Regeneron Pharmaceuticals, and Roche/Genentech; and advisory board or consultant fees from Astellas, Exelixis, EMD Serono, Merck, and Regeneron Pharmaceuticals. AH reports grants and personal fees from Amgen, Bristol Myers Squibb, Merck-Pfizer, MSD/Merck, Philogen, Pierre Fabre, Regeneron Pharmaceuticals, Roche, Sanofi-Genzyme, Novartis Pharma, Eisai, Replimmune, NeraCare; consulting fees from Seagen, IO Biotech, Dermagnostix, Incyte, Highlight Therapeutics, and Iovance; speaker's honoraria from Kyowa Kirin; advisory board fees from Immunocore; and institutional grants from Huya Biosciences outside the submitted work. JHC reports consulting or advisory roles for Exelixis, Coherus Biosciences, Merck Sharp & Dohme, Eisai, and Regeneron Pharmaceuticals, and institutional research funding from Arcus Biosciences and Genmab. BGMH reports consulting or advisory roles at AstraZeneca, Bristol Myers Squibb, Eisai, Merck Sharp & Dohme, Pfizer, and Roche, and institutional research funding from Amgen. DS reports honoraria from Roche/Genentech, Novartis, Bristol Myers Squibb, Merck Sharp & Dohme, Immunocore, Merck Serono, Array BioPharma, Pfizer, Pierre Fabre, Philogen, Regeneron Pharmaceuticals, 4SC, Sanofi, Regeneron Pharmaceuticals, NeraCare GmbH, Sun Pharma, InflarxGmbH, Ultimovacs, and Sandoz; consulting fees from Roche/Genentech, Novartis, Bristol Myers Squibb, Merck Sharp & Dohme, Merck Serono, 4SC, Pierre Fabre, Sanofi, Regeneron Pharmaceuticals, and Nektar; speaker fees from Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, Sanofi, Regeneron Pharmaceuticals, and Merck; advisory board fees from AstraZeneca, Daiichi-Sankyo, Roche/Genentech, Novartis, Bristol Myers Squibb, Merck Sharp & Dohme, Merck Serono, 4SC, Pierre Fabre, Sanofi, Regeneron Pharmaceuticals, and Nektar; institutional research funding from Bristol Myers Squibb, Novartis, Roche, MSD Oncology, and Array BioPharma/Pfizer; unpaid leadership or fiduciary roles with Dermatologic Cooperative Oncology Group, European Organisation for Research and Treatment of Cancer-Melanoma Group, Hiege-Stiftung, and Nationale Versorgungskonferenz Hautkrebs; and travel and accommodation expenses from Roche/Genentech, Bristol Myers Squibb, Merck Serono, Novartis, Merck Sharp & Dohme, Pierre Fabre, Sanofi, and Regeneron Pharmaceuticals. VAP reports honoraria for advisory or consulting roles from Sun Pharma, Almirall, Biofrontera, PhD Biosciences, Regeneron Pharmaceuticals, and Sanofi Genzyme; speakers bureau fees from Regeneron Pharmaceuticals, and Sanofi Genzyme, equity in Avstera Therapeutics and Science 37; and research funding from Regeneron Pharmaceuticals. JMT reports honoraria for advisory or consultant roles for Bristol Myers Squibb, Merck & Co, AstraZeneca, Genentech/Roche, Regeneron Pharmaceuticals, Compugen, Lunaphore, and Akoya Biosciences; stock options in Akoya Biosciences; equipment loan and reagent provision from Akoya Biosciences; and research funding from Bristol Myers Squibb and Akoya Biosciences. AML reports uncompensated consultancy for Eisai, research funding support from Sanofi/Regeneron Pharmaceuticals, and support from a Peter MacCallum Cancer Centre Discovery Partner Fellowship. RF reports grants or investigator-initiated trial support from Merck, Pfizer, Gilead, and Ayala; royalties from UpToDate for a chapter on olfactory neuroblastoma; payment for expert testimony from Guidepoint; and advisory board participation with Regeneron Pharmaceuticals, Prelude Therapeutics, Elevar Therapeutics, Eisai, Remix Therapeutics, and Coherus BioSciences. S-YY, HH, FS, and IL are employees and shareholders of Regeneron Pharmaceuticals. MM and MGF report receipt of support for attending meetings or travel, and are also employees, patent holders, and shareholders of Regeneron Pharmaceuticals. DR reports institutional research grant and funding from Regeneron Pharmaceuticals, Genentech, Sanofi, Kura Oncology, Roche, Merck Sharp & Dohme, Decibel Therapeutics, Bristol Myers Squibb, GlaxoSmithKline, and ALX Oncology; and uncompensated scientific committee and advisory board roles for Merck Sharp & Dohme, Regeneron Pharmaceuticals, Sanofi, and Eisai. YBS and JH declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

We describe a case of a premature 24 weeks gestation infant who presented with clinical lability and abdominal distention with initial concerns of necrotising enterocolitis. On further examination, a right inguinal hernia was noted and serial abdominal X-rays showed bowel loop dilatation with intramural air and no perforation. However, the hernia was recurrent and later found to be not reducible. He underwent right groin exploration. Intraoperatively, distal ileal perforation was noted and he was found to have an additional five sites of perforation. He had a stoma sited at the left iliac fossa as well as primary anastomosis at the site of the second to fifth perforations. He had a stormy postoperative period but is currently doing well. Although obstructed hernias are rare in the initial course of an extreme preterm infant, it should not be missed as a cause of intestinal obstruction and early surgical opinion should be sought., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Competing Interests: None

Non-melanoma skin cancers (NMSCs) are the most common form of skin cancer worldwide. The global incidence of cutaneous squamous cell carcinoma (CSCC) is rising, with an estimated 2.4 million cases diagnosed in 2019. Chronic exposure to ultraviolet (UV) radiation is a major risk factor for developing CSCC. Most early-stage CSCCs are treated successfully with surgery or radiotherapy; however, locally advanced or metastatic disease can be associated with significant morbidity or mortality. Recently, the treatment paradigm for advanced CSCC has been revolutionised by the introduction of immunotherapy, which can achieve a response rate of approximately 50% with durable cancer control, and significant improvement in quality of life. With the regulatory approval of programmed death-1 (PD-1)-targeting drugs since 2018, immunotherapy is now recognised as the standard of care for first-line systemic therapy in advanced or metastatic CSCC., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background: In a pilot study involving patients with cutaneous squamous-cell carcinoma, a high percentage of patients had a pathological complete response with the use of two doses of neoadjuvant cemiplimab before surgery. Data from a phase 2 study are needed to confirm these findings., Methods: We conducted a phase 2, confirmatory, multicenter, nonrandomized study to evaluate cemiplimab as neoadjuvant therapy in patients with resectable stage II, III, or IV (M0) cutaneous squamous-cell carcinoma. Patients received cemiplimab, administered at a dose of 350 mg every 3 weeks for up to four doses, before undergoing surgery with curative intent. The primary end point was a pathological complete response (the absence of viable tumor cells in the surgical specimen) on independent review at a central laboratory, with a null hypothesis that a pathological complete response would be observed in 25% of patients. Key secondary end points included a pathological major response (the presence of viable tumor cells that constitute ≤10% of the surgical specimen) on independent review, a pathological complete response and a pathological major response on investigator assessment at a local laboratory, an objective response on imaging, and adverse events., Results: A total of 79 patients were enrolled and received neoadjuvant cemiplimab. On independent review, a pathological complete response was observed in 40 patients (51%; 95% confidence interval [CI], 39 to 62) and a pathological major response in 10 patients (13%; 95% CI, 6 to 22). These results were consistent with the pathological responses determined on investigator assessment. An objective response on imaging was observed in 54 patients (68%; 95% CI, 57 to 78). Adverse events of any grade that occurred during the study period, regardless of whether they were attributed to the study treatment, were observed in 69 patients (87%). Grade 3 or higher adverse events that occurred during the study period were observed in 14 patients (18%)., Conclusions: Neoadjuvant therapy with cemiplimab was associated with a pathological complete response in a high percentage of patients with resectable cutaneous squamous-cell carcinoma. (Funded by Regeneron Pharmaceuticals and Sanofi; ClinicalTrials.gov number, NCT04154943.)., (Copyright © 2022 Massachusetts Medical Society.)

It has recently been found that iridescence, a taxonomically widespread form of animal coloration defined by a change in hue with viewing angle, can act as a highly effective form of camouflage. However, little is known about whether iridescence can confer a survival benefit to prey postdetection and, if so, which optical properties of iridescent prey are important for this putative protective function. Here, we tested the effects of both iridescence and surface gloss (i.e. specular reflection) on the attack behaviour of prey-naïve avian predators. Using real and artificial jewel beetle, Sternocera aequisignata , wing cases, we found that iridescence provides initial protection against avian predation by significantly reducing the willingness to attack. Importantly, we found that the main factor explaining this aversion is iridescence, not multiple colours per se, with surface gloss also having an independent effect. Our results are important because they demonstrate that even when prey are presented up close and against a mismatching background, iridescence may confer a survival benefit by inducing hesitation or even, as sometimes observed, an aversion response in attacking birds. Furthermore, this means that even postdetection, prey do not necessarily need to have secondary defences such as sharp spines or toxins for iridescence to have a protective effect. Taken together, our results suggest that reduced avian predation could facilitate the initial evolution of iridescence in many species of insects and that it is the defining feature of iridescence, its colour changeability, that is important for this effect., Competing Interests: The authors declare no conflict of interest., (© 2022 The Authors.)

Background: There is no registry data on morbidity and mortality of high-risk cutaneous squamous cell carcinoma (cSCC) in Australia., Aim: To examine the clinicopathological features, mortality and morbidity in high-risk cSCC patients in Western Australia (WA)., Methods: A retrospective cohort study was conducted through hospital record review on cSCC patients discussed at multidisciplinary meetings at the two largest WA hospitals between March 2015 and December 2016., Results: Of 141 patients, 129 were evaluable, with median follow up of 43.9 (range 3.0-53.2) months. Patients were predominantly older males (84%) with significant comorbidities (Charlson Comorbidity Index (CCI) ≥5; 76%) and history of previous nonmelanoma skin cancer (57%) with advanced disease (57% stage IV without distant metastasis; American Joint Committee on Cancer, 7th edition). Pathological high-risk features were common including nodal extracapsular extension (47%) and cranial nerve involvement (16%). Clinical morbidity was significant with a median of 2 (range 0-13) excisions and 2 (range 0-21) cSCC-related hospitalisations for any cSCC event following the index case discussion. Recurrences of the primary index lesion occurred in 60% of patients and 20% had ≥2 recurrences. Median overall survival for patients with nonmetastatic disease was 39.8 (range 25.9-53.7) months and 16.1 (range 0.2-32.0) months for metastatic disease. CCI ≥5, advanced nodal stage and ≥2 recurrences were significantly associated with mortality on multivariable analyses (P < 0.05). Nodal extracapsular extension and any recurrences were identified as significant risk factors for disease-specific mortality on multivariable analyses (P < 0.05)., Conclusion: High-risk cSCC patients have significant health needs represented by high-baseline comorbidities, multiplicity of cSCC events and the number of healthcare-associated interventions. There is an unmet need for robust cancer data collection., (© 2021 The Authors. Internal Medicine Journal published by John Wiley & Sons Australia, Ltd on behalf of Royal Australasian College of Physicians.)

Background: Cutaneous squamous cell carcinoma (CSCC) of the head and neck can require complex and disfiguring surgery in order to achieve cure, which can be morbid and negatively impact patient quality of life. The management of advanced CSCC has been revolutionized by immunotherapy with current clinical trials also exploring its role in the neoadjuvant and adjuvant settings. Patients may decline morbid curative surgery, such as orbital exenteration, and the outcomes of immunotherapy use in this unique group of patients require further investigation., Methods: We reviewed the records of 119 patients treated at a major Australian quaternary oncology centre with immunotherapy (either cemiplimab or pembrolizumab) for advanced CSCC., Results: We identified 7 patients recommended curative surgery involving orbital exenteration after multidisciplinary discussion, who declined surgery due to concerns about morbidity and/or disfigurement. All 7 patients demonstrated a response to treatment, and six avoided orbital exenteration. Two patients experienced pseudoprogression., Conclusions: The management of CSCC can be complex and requires the input of a multidisciplinary team. Immunotherapy to avoid or reduce the extent of morbid definitive surgery is an emerging treatment option., Competing Interests: AML uncompensated advisory board from Merck Sharp & Dohme and Bristol-Myers Squibb with travel and accommodation expenses; uncompensated consultancy for Eisai. DR receives institutional research funding from: MSD, GSK, BMS, Roche, Replimune, Kura Oncology, Decibel, Regeneron, Sanofi, Merck KGaA. Trial Steering Committees and/or Advistory Boards (all uncompensated): MSD, GSK, Regeneron, Sanofi. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 McLean, Lim, Webb, Cavanagh, Thai, Magarey, Fox, Kleid and Rischin.)

Cutaneous squamous cell carcinoma (CSCC) is the second most common skin cancer diagnosed worldwide. CSCC is generally localized and managed with local therapies such as excision and/or radiotherapy. For patients with unresectable or metastatic disease, recent improvements in our understanding of the underlying biology have led to significant advancements in treatment approaches-including the use of immune checkpoint inhibition (ICI)-which have resulted in substantial gains in response and survival compared to traditional cytotoxic approaches. However, there is a lack of understanding of the biology underpinning CSCC in immunocompromised patients, in whom the risk of developing CSCC is hundreds of times higher compared to immunocompetent patients. Furthermore, current ICI approaches are associated with significant risk of graft rejection in organ transplant recipients who make up a significant proportion of immunocompromised patients. Ongoing scientific and clinical research efforts are needed in order to maintain momentum to increase our understanding and refine our therapeutic approaches for patients with CSCC.

Background: The role of FDG-PET/CT imaging in assessing response to immunotherapy in advanced cutaneous squamous cell carcinoma (CSCC) is unknown. This study compared complete metabolic response (CMR) rates by FDG-PET and RECIST1.1 via CT or MRI in patients on cemiplimab for > 10 months., Methods: This was a single-centre retrospective study of 15 patients treated with cemiplimab for advanced CSCC who had CT/MRI and FDG-PET/CT at > 10 months to assess metabolic treatment response. The median age was 73 years (range 55-84) and 93% were male. RECIST1.1 and PERCIST1.0 tumor responses were evaluated by blinded readers., Results: Seventy-three percent (11/15) (95%CI 44.9, 92.2%) achieved a CMR on PET. Of these 11, on RECIST1.1 there was one complete response, 9 partial responses and one stable disease., Conclusions: In patients on cemiplimab for > 10 months, there was discordance between CR rates on FDG-PET versus RECIST1.1. FDG-PET/CT may have utility for clarifying depth of response in patients treated with immunotherapy for CSCC., (© 2021. The Author(s).)

Background: To provide pooled longer term data from three groups of a phase 2 study of cemiplimab in patients with advanced cutaneous squamous cell carcinoma (CSCC), and to determine duration of response (DOR) and impact on quality of life (QoL)., Methods: Patients received cemiplimab 3 mg/kg every 2 weeks (group 1, metastatic CSCC [mCSCC], n=59; group 2, locally advanced CSCC, n=78) or cemiplimab 350 mg every 3 weeks (group 3, mCSCC, n=56). Primary endpoint was objective response rate (ORR) per independent central review (ICR). QoL was repeatedly measured at day 1 of each treatment cycle (groups 1 and 2: 8 weeks; group 3: 9 weeks)., Results: Median duration of follow-up was 15.7 months. Overall, ORR per ICR was 46.1% (95% CI: 38.9% to 53.4%). Complete response (CR) rates were 20.3%, 12.8%, and 16.1% for groups 1, 2, and 3, respectively. Median time to CR was 11.2 months. Among patients with partial response or CR, the estimated proportion of patients with ongoing response at 12 months from the first objective response was 87.8% (95% CI: 78.5% to 93.3%), with median DOR not reached. Kaplan-Meier estimated probability of overall survival (OS) was 73.3% (95% CI: 66.1% to 79.2%) at 24 months, with median OS not reached. Global Health Status (GHS)/QoL improvements were observed as early as cycle 2 and were significantly improved and durable until last assessment. Kaplan-Meier estimate of median time to first clinically meaningful improvement for pain was 2.1 (95% CI: 2.0 to 3.7) months and was significantly improved in responders versus non-responders (p<0.0001)., Conclusions: This is the largest (n=193) clinical dataset for a programmed cell death-1 inhibitor against advanced CSCC, confirming the sustained substantial clinical activity of cemiplimab in these patients, including new findings of improved CR rates over time, increasing DOR, and durable pain control and GHS/QoL improvement., Trial Registration Number: ClinicalTrials.gov Registry (NCT02760498), https://clinicaltrialsgov/ct2/show/NCT02760498., Competing Interests: Competing interests: DR—institutional research grant and funding from Regeneron Pharmaceuticals, Roche, Merck Sharp & Dohme, Bristol-Myers Squibb, GlaxoSmithKline, and Sanofi; uncompensated scientific committee and advisory board from Merck Sharp & Dohme, Regeneron Pharmaceuticals, Sanofi, GlaxoSmithKline, and Bristol-Myers Squibb; and travel and accommodation from Merck Sharp & Dohme and GlaxoSmithKline. NIK—grants from Regeneron Pharmaceuticals; grants and advisory board fees from Bristol-Myers Squibb and HUYA Bioscience International; advisory board fees from EMD Serono, Regeneron Pharmaceuticals, Genentech, AstraZeneca (data safety monitoring committee), Incyte (data safety monitoring committee), Iovance, Merck, ARRAY Biopharma, Jounce Therapeutics, and Immunocore; grants from Merck, Novartis, GlaxoSmithKline, Celgene, and Amgen; honorarium from Sanofi; and common stock ownership of Bellicum Pharmaceuticals, Mazor Robotics, Amarin, and Transenetrix. CDS—steering committee member for Castle Biosciences; steering committee member and consultant for Regeneron Pharmaceuticals; consultant for Sanofi; received research funding from Castle Biosciences, Regeneron Pharmaceuticals, Novartis, Genentech, and Merck; and is a chair for the National Comprehensive Cancer Network. AG—personal fees and non-financial support (advisory board and travel support) from Bristol-Myers Squibb and Sun Pharma; personal fees (advisory board) from Merck KGaA, Eisai, and Pfizer; non-financial (travel) support from Astellas; and clinical trial unit support from PPD Australia. ALSC—consulting and advisory roles at Regeneron Pharmaceuticals and Merck; and research funding from Regeneron Pharmaceuticals, Novartis, Galderma, Jounce Therapeutics, and Merck. KDL—grants and personal fees from Regeneron Pharmaceuticals during the conduct of the study. AML—uncompensated advisory board from Merck Sharp & Dohme and Bristol-Myers Squibb with travel and accommodation expenses; and uncompensated consultancy for Eisai. LH-A—performed consulting and advisory roles at Massive Bio; speakers’ bureau roles at Sanofi and Regeneron Pharmaceuticals; received travel, accommodations, and expenses from Regeneron Pharmaceuticals, Sanofi, and Bristol-Myers Squibb; and research funding from Bristol-Myers Squibb, Regeneron Pharmaceuticals, Immunocore, Merck Sharp & Dohme, Polynoma, Corvus Pharmaceuticals, Roche, Merck Serono, Amgen, MedImmune, and Takeda. BGMH—consulting or advisory roles at Merck Sharp & Dohme, Bristol Myers Squibb, AstraZeneca, Pfizer, Roche, Eisai, and Merck; and institutional research funding from Amgen. DS—institutional patients’ fees from Regeneron Pharmaceuticals; advisory board honorarium fees from Amgen and Leo Pharma; speaker fee from Boehringer Ingelheim; advisory board, speaker honorarium, and patients’ fees from Roche, Novartis, Bristol-Myers Squibb, and Merck-EMD; advisory board and speaker honorarium fees from Incyte and Pierre Fabre; advisory board honorarium and patients’ fees from MSD; steering committee honorarium fees from 4SC; advisory board fees from AstraZeneca, Pfizer, and Array; and advisory board and patients’ fees from Philogen. AH—institutional grants, speaker’s honoraria, and consultancy fees from Amgen, Bristol-Myers Squibb, Merck Sharp & Dohme/Merck, Pierre Fabre, Provectus, Roche, and Novartis; institutional grants and consultancy fees from Merck Serono, Philogen, and Regeneron Pharmaceuticals; and consultancy fees from OncoSec. ES, JB, S-YY, SL, ZC, EO, C-IC, VM, IL, MGF—employees of and shareholders in Regeneron Pharmaceuticals. MS—employee and shareholder in Sanofi. MRM—honoraria and travel expenses from Regeneron Pharmaceuticals, Sanofi, Novartis, Genentech, Eli Lilly, and Sun Pharma; and institutional research funding from Regeneron Pharmaceuticals, Novartis, Genentech, and Eli Lilly., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Andrographis paniculata (Burm f.) Nees is a tropical plant native to Southeast Asia that has been used as an effective remedy for a wide variety of illnesses in traditional Chinese and Ayurvedic medicine. The antimicrobial activity of its crude extract had been shown to be due to its quorum quenching activity. The study determined the effect of purified extracted compounds from the leaf of A. paniculata, namely: andrographolide, 14-deoxyandrographolide, 14-deoxy-12-hydroxyandrographolide and neoandrographolide on quorum sensing-mediated virulence mechanisms in clinical isolates of metallo-β-lactamase (MβL)-producing Pseudomonas aeruginosa . Their effect on the expression of the lasR gene, which codes for LasR, a transcription activator protein of the quorum sensing system in P. aeruginosa was also determined using RT-qPCR. All the pure compounds significantly decreased the biofilm formation, protease production and swarming motility of the P. aeruginosa isolates compared to the untreated controls (p < 0.05). Results of the RT-qPCR assay showed that all compounds significantly downregulated the expression of lasR compared to the untreated control (p < 0.05), supporting the position that the lower virulence activities of the treated group were due to quorum quenching activity of the pure compounds. Multiple comparisons using Tukey's HSD analysis revealed that the means of the relative expression of lasR of the isolates treated with the different compounds were not significantly different from each other (p > 0.05), suggesting equal potencies. Results show the potential of the isolated pure compounds from A. paniculata for use as antimicrobial agents as a result of their quorum quenching activities., (© 2021 The Authors.)

Non-melanoma skin cancers are one of the most common cancers diagnosed worldwide, with the highest incidence in Australia and New Zealand. Systemic treatment of locally advanced and metastatic cutaneous squamous cell carcinomas has been revolutionized by immune checkpoint inhibition with PD-1 blockade. We highlight treatment issues distinct to the management of the disease including expansion of the traditional concept of pseudoprogression and describe delayed responses after immune-specific response criteria confirmed progressive disease with and without clinical deterioration. We term this phenomenon "delayed response after confirmed progression (DR)". We also discuss the common development of second primary tumors, heterogeneous disease responses, and expanding clinical boundaries for immunotherapy use., Competing Interests: AL –Uncompensated advisory board7 from Merck Sharp & Dohme and Bristol-Myers Squibb with travel and accommodation expenses; uncompensated consultancy for Eisai. RH - Shareholder in Telix Pharmaceuticals with honoraria and any dividends donated to the Peter MacCallum Cancer Centre. DR - Institutional research grant and trial funding from Regeneron Pharmaceuticals, Inc., Roche, Merck Sharp & Dohme, Bristol-Myers Squibb, and GlaxoSmithKline, Sanofi; uncompensated scientific committee and advisory board from Merck Sharp & Dohme, Regeneron Pharmaceuticals, Inc., Sanofi, GlaxoSmithKline, and Bristol-Myers Squibb, and travel and accommodation from Merck Sharp & Dohme and GlaxoSmithKline. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Lim, Cavanagh, Hicks, McLean, Goh, Webb and Rischin.)

Low-coverage whole-genome sequencing (LC-WGS) can provide insight into oncogenic molecular changes. Serum extracellular vesicles (EV) represent a novel liquid biopsy source of tumoral DNA. This study compared copy number alteration (CNA) profiles generated from LC-WGS of formalin-fixed paraffin-embedded (FFPE) tumoral DNA and EV-DNA obtained from cancer patients. Patients with squamous cell carcinoma of the base of tongue (n = 3) and cutaneous squamous cell carcinoma (n = 2) were included. LC-WGS (0.5-1X coverage) was performed on FFPE-DNA and serum EV-DNA. Similarity between CNA profiles was analysed using QDNAseq. FFPE samples had a mean CNA of 31 (range 17-50) over 1.9 × 10 9 (range 1.0-2.6 × 10 9 ) bp in length, and EV samples had a mean CNA value of 17 (range 7-19) over 7.6 × 10 8 (range 2.9-15 × 10 8 ) bp in length. A mean of 8 (range 0-21) CNA over 5.9 × 10 8 (range 1.6-14 × 10 8 ) bp in length was found to overlap between EV and FFPE-derived samples per patient. Although the mean correlation efficient between samples was r = 0.34 (range - .08 to 0.99), this was not statistically significant (p > 0.05). Regions of highest deletion and duplication in FFPE samples were not well reflected in the EV-DNA. Selected CNA regions in EV-associated DNA were reflective of the primary tumor, however appreciation of global CNA and areas of most significant change was lost. The utility of LC-WGS of EV-derived DNA is likely limited to molecular alterations of known interest.