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Gastroesophageal cancers (GECs) represent a significant clinical challenge. For early resectable GEC, the integration of immune checkpoint inhibitors into the perioperative chemotherapy and chemoradiation treatment paradigms are being explored and showing promising results. Frontline management of metastatic GEC is exploring the role of targeted therapies beyond PD-1 inhibitors, including anti-human epidermal growth factor receptor 2 agents, Claudin 18.2 inhibitors, and FGFR2 inhibitors, which have shown considerable efficacy in recent trials. Looking ahead, ongoing trials and emerging technologies such as bispecific antibodies, antibody-drug conjugates, and adoptive cell therapies like chimeric antigen receptor T cells are expected to define the future of GEC management. These advancements signify a paradigm shift toward personalized and immunotherapy-based approaches, offering the potential for improved outcomes and reduced toxicity for patients with GEC.

Introduction: Single-station N2 (ssN2) versus multi-station N2 has been used as a selection criterion for treatment recommendations between surgical versus non-surgical multimodality treatment in stage III-N2 NSCLC. We hypothesized that clinical staging would be susceptible to upstaging on pathologic staging and, therefore, challenge this practice., Methods: A retrospective study of prospectively collected routine clinical data for patients with stage III-N2 NSCLC that had completed computed tomography (CT), positron emission tomography (PET), and staging endobronchial ultrasound (EBUS) and had been confirmed clinical stage III-ssN2 at multidisciplinary team discussion and went on to complete surgical resection as the first treatment to provide pathologic staging. The study was completed in two cohorts (A) across a single cancer alliance in England (Greater Manchester) January 1, 2015 to December 31, 2018 and (B) across five United Kingdom centers to validate the findings in part A January 1, 2016 to December 31, 2020., Results: A total of 115 patients met the inclusion criteria across cohort A (56 patients) and cohort B (59 patients) across 15 United Kingdom hospitals. The proportion of cases in which clinical stage III-ssN2 was upstaged to pathologic stage III-multi-station N2 was 34% (19 of 56) in cohort A, 32% in cohort B (19 of 59), and 33% across the combined study cohort (38 of 115). Most patients had a single radiologically abnormal lymph node on CT and PET (88%, 105 of 115). In the majority, the reasons for missed N2 disease on staging EBUS were due to inaccessible (stations 5, 6, 8, 9) N2 nodes at EBUS (34%, 13 of 38) and accessible lymph nodes not sampled during staging EBUS as not meeting sampling threshold (40%, 15 of 38) rather than false-negative sampling during EBUS (26%, 10 of 38)., Conclusions: During multidisciplinary team discussions, clinicians must be aware that one-third of patients with stage III-ssN2 on the basis of CT, PET, and staging EBUS do not truly have ssN2 and this questions the use of this criterion to define treatment recommendations., Competing Interests: The authors declare no conflict of interest., (© 2024 The Authors.)

Introduction: Molecular profiling of metastatic breast cancer (MBC) through the widespread use of next-generation sequencing (NGS) has highlighted actionable mutations and driven trials of targeted therapy matched to tumour molecular profiles, with improved outcomes reported using such an approach. Here, we review NGS results and treatment outcomes for a cohort of Asian MBC patients in the phase I unit of a tertiary centre., Methods: Patients with MBC referred to a phase I unit underwent NGS via Ion AmpliSeq Cancer Hotspot v2 (ACH v2, 2014-2017) prior to institutional change to FoundationOne CDx (FM1; 2017-2022). Patients were counselled on findings and enrolled on matched therapeutic trials, where available. Outcomes for all subsequent treatment events were recorded to data cut-off on January 31, 2022., Results: A total of 215 patients were enrolled with successful NGS in 158 patients. The PI3K/AKT/PTEN pathway was the most altered with one or more of the pathway member genes PIK3/AKT/PTEN affected in 62% (98/158) patients and 43% of tumours harbouring a PIK3CA alteration. Tumour mutational burden (TMB) was reported in 96/109 FM1 sequenced patients, with a mean TMB of 5.04 mt/Mb and 13% (12/96) with TMB ≥ 10 mt/Mb. Treatment outcomes were evaluable in 105/158 patients, with a pooled total of 216 treatment events recorded. Matched treatment was administered in 47/216 (22%) events and associated with prolonged median progression-free survival (PFS) of 21.0 weeks [95% confidence interval (CI) 11.7, 26.0 weeks] versus 12.1 weeks (95% CI 10.0, 15.4 weeks) in unmatched, with hazard ratio (HR) for progression or death of 0.63 (95% CI 0.41, 0.97; p = 0.034). In the subgroup of PIK3/AKT/PTEN -altered MBC, the HR for progression or death was 0.57 (95% CI 0.35, 0.92; p = 0.02), favouring matched treatment. Per-patient overall survival (OS) analysis (n = 105) showed improved survival for patients receiving matched treatment versus unmatched, with median OS (mOS) of 30.1 versus 11.8 months, HR = 0.45 (95% CI 0.24, 0.84; p = 0.013). Objective response rate (ORR) in the overall population was similar in matched and unmatched treatment events (23.7% versus 17.2%, odds ratio of response 1.14 95% CI 0.50, 2.62; p = 0.75)., Conclusions: Broad-panel NGS in MBC is feasible, allowing therapeutic matching, which was associated with improvements in PFS and OS., Competing Interests: RW reported serving on the advisory board of Pfizer and Novartis and receiving honoraria from Pfizer, AstraZeneca, Novartis, and Merck MSD and travel funding from Merck MSD outside the submitted work. NN reported honoraria from Merck, MSD, AstraZeneca, and ASGO; research funding from Cyclacel and iOnctura; and travel funding from AstraZeneca and JSGO. SO reported honoraria and consulting with Astra Zeneca, Pfizer, Novartis, Eli Lilly, and Roche. AW reported advisory board membership and/or speaker activity with honoraria with AstraZeneca, Novartis, Eisai, DKSH, Pfizer, and Roache and research funding from Otsuka Pharmaceuticals. VH reported consultancy/advisory activity with DKSH, AstraZeneca, Novartis, MSD, and Pfizer. RS reported serving on the advisory board of Bristol Myers Squibb, Merck, Eisai, Bayer, Taiho, Novartis, MSD, DKSH, and GSK; receiving honoraria from MSD, Eli Lilly, Bristol Myers Squibb, Roche, Taiho, AstraZeneca, Ipsen, and DKSH; and receiving grants from Roche, AstraZeneca, Taiho, Eisai, DKSH, Paxman Coolers, Natera, and MSD outside the submitted work. RAS reported honoraria from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Lilly, Novartis, Pfizer, Roche/Genentech, Takeda, Yuhan, Amgen, Bayer, Merck, Merck Serono, and Puma Biotechnology; consulting or advisory role with AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Novartis, Pfizer, Roche/Genentech, Taiho Pharmaceutical, Yuhan, Takeda, Amgen, Lilly, Merck, Janssen, Puma Biotechnology, Merck Serono, Bayer, and Thermo Fisher Scientific; and research funding from AstraZeneca and Boehringer Ingelheim. WY reported consulting or advisory role with AbbVie/Genentech, Amgen, Bristol Myers Squibb, Ipsen, Novartis, and AstraZeneca; speakers’ bureau with Lilly, Sanofi/Aventis, Taiho Pharmaceutical, Eisai, Bayer, and MSD Oncology; and travel and accommodation expenses from Pfizer. SCL reports honoraria and consulting activity with AstraZeneca, Pfizer, Novartis, Eli Lilly, Roche, ACT Genomics, and Eisai and research funding from Taihi, Eisai, Pfizer, and ACT Genomics. JL reported advisory activity with AstraZeneca, Novartis, Roche, DKSH, Pfizer, and MSD; receiving honoraria from AstraZeneca, Novartis, Roche, DKSH, MSD, Eisai, and Pierre Fabre; receiving research funding from CTI BioPharma, Daiichi Sankyo, and Synthon Pharmaceuticals; and receiving travel grant from AstraZeneca and MSD outside the submitted work. DT is an employee of the National University Health System Singapore and reports personal fees for advisory board membership from AstraZeneca, Bayer, BioNTech Boehringer Ingelheim, Eisai, Genmab, GSK, MSD, PMV Pharma, and Roche; personal fees as an invited speaker from AstraZeneca, Eisai, GSK, Merck Serono, MSD, Roche, and Takeda; ownership of stocks/shares of Asian Microbiome Library AMiLi; institutional research grants from AstraZeneca, Bayer, Karyopharm Therapeutics, and Roche; institutional funding as coordinating PI from AstraZeneca, MSD, Eisai, Roche, and Bergen Bio; institutional funding as local PI from Roche, BioNTech, PMV Pharma, GSK, Sutro Pharma, Bayer, Byondis B.V., and Zeria Pharmaceutical Co., Ltd.; a previous non-renumerated role as Chair of the Asia Pacific Gynecologic Oncology Trials Group APGOT; a previous non-renumerated role as the Society President of the Gynecologic Cancer Group Singapore; non-renumerated membership of the Board of Directors of the GCIG; research funding from the National Medical Research Council NMRC Clinician Scientist Award Senior Investigator Grant CSASI21jun-0003, the Pangestu Family Foundation Gynaecological Cancer Research Fund; and product samples from AstraZeneca, Eisai, and MSD non-financial interest for research trials. 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 © 2024 Walsh, Ong, Cheo, Low, Jayagopal, Lee, Ngoi, Ow, Wong, Lim, Lim, Heong, Sundar, Soo, Chee, Yong, Goh, Lee, Tan and Lim.)

Background and Objectives: Childbirth is mainly thought to be a woman's concern, and mortality can be prevented by making a birth plan constituting birth preparedness and complication readiness with the entire family as one unit. Indian National Plans aim to increase male involvement, but the policies lack directions and monitoring systems; hence, it becomes important to address this issue., Methodology:  A cross-sectional study conducted in a rural hospital and a community-based setup included 350 male participants, consisting of new fathers or expecting fathers, who were interviewed with the help of a questionnaire., Results: Only 28.29% of male participants were well involved in the process of birth preparedness and complication readiness. 83% of the husbands accompanied their respective wives during ANC visits (mean number of visits: 5.76). 33% of males were aware of various danger signs and complications related to pregnancy. The males with better education (p-value < 0.005) and economic status (p-value < 0.0001) had better birth preparedness. Several variables in the study were positively correlated with the amount of money saved.  Interpretation and conclusion: Male involvement during pregnancy significantly impacts maternal and child health outcomes. However, this study highlights a lack of awareness and involvement among males. We strongly recommend enhancing existing maternal and child health (MCH) programs to include components focused on male partner engagement in birth preparedness, complication readiness, and obstetric emergencies., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2024, Arohee et al.)

We performed a systematic literature review to identify and summarize data from studies reporting clinical efficacy and safety outcomes for trifluridine/tipiracil (FTD/TPI) combined with other antineoplastic agents in advanced cancers, including metastatic colorectal cancer (mCRC). We conducted a systematic search on May 29, 2021, for studies reporting one or more efficacy or safety outcome with FTD/TPI-containing combinations. Our search yielded 1378 publications, with 38 records meeting selection criteria: 35 studies of FTD/TPI-containing combinations in mCRC (31 studies second line or later) and 3 studies in other tumor types. FTD/TPI plus bevacizumab was extensively studied, including 19 studies in chemorefractory mCRC. Median overall survival ranged 8.6-14.4 months and median progression-free survival 3.7-6.8 months with FTD/TPI plus bevacizumab in refractory mCRC. Based on one randomized and several retrospective studies, FTD/TPI plus bevacizumab was associated with improved outcomes compared with FTD/TPI monotherapy. FTD/TPI combinations with chemotherapy or other targeted agents were reported in small early-phase studies; preliminary data indicated higher antitumor activity for certain combinations. Overall, no safety concerns existed with FTD/TPI combinations; most common grade ≥ 3 adverse event was neutropenia, ranging 5%-100% across all studies. In studies comparing FTD/TPI combinations with monotherapy, grade ≥ 3 neutropenia appeared more frequently with combinations (29%-67%) vs. monotherapy (5%-41%). Discontinuation rates due to adverse events ranged 0%-11% for FTD/TPI plus bevacizumab and 0%-17% with other combinations. This systematic review supports feasibility and safety of FTD/TPI plus bevacizumab in refractory mCRC. Data on non-bevacizumab FTD/TPI combinations remain preliminary and need further validation., (© The Author(s) 2024. Published by Oxford University Press.)

The 15th annual Frontiers in Cancer Science (FCS) conference gathered scientific experts who shared the latest research converging upon several themes of cancer biology. These themes included the dysregulation of metabolism, cell death, and other signaling processes in cancer cells; using patient "omics" datasets and single-cell and spatial approaches to investigate heterogeneity, understand therapy resistance, and identify targets; innovative strategies for inhibiting tumors, including rational drug combinations and improved drug delivery mechanisms; and advances in models that can facilitate screening for cancer vulnerabilities and drug testing. We hope the insights from this meeting will stimulate further progress in the field., (©2024 American Association for Cancer Research.)

Background: The association between frailty and short-term and long-term outcomes in patients receiving elective surgery for cancer remains unclear, particularly in those admitted to the ICU., Methods: In this multicentre retrospective cohort study, we included adults ≥16 yr old admitted to 158 ICUs in Australia from January 1, 2018 to March 31, 2022 after elective surgery for cancer. We investigated the association between frailty and survival time up to 4 yr (primary outcome), adjusting for a prespecified set of covariates. We analysed how this association changed in specific subgroups (age categories [<65, 65-80, ≥80 yr], and those who survived hospitalisation), and over time by splitting the survival information at monthly intervals., Results: We included 35,848 patients (median follow-up: 18.1 months [inter-quartile range: 8.3-31.1 months], 19,979 [56.1%] male, median age 69.0 yr [inter-quartile range: 58.8-76.0 yr]). Some 3502 (9.8%) patients were frail (defined as clinical frailty scale ≥5). Frailty was associated with lower survival (hazard ratio: 1.72, 95% confidence interval [CI]: 1.59-1.86 compared with clinical frailty scale ≤4); this was concordant across several sensitivity analyses. Frailty was most strongly associated with mortality early on in follow-up, up to 10 months (hazard ratio: 1.39, 95% CI: 1.03-1.86), but this association plateaued, and its predictive capacity subsequently diminished with time up until 4 yr (1.96, 95% CI: 0.73-5.28). Frailty was associated with similar effects when stratified based on age, and in those who survived hospitalisation., Conclusions: Frailty was associated with poorer outcomes after an ICU admission after elective surgery for cancer, particularly in the short term. However, its predictive capacity with time diminished, suggesting a potential need for longitudinal reassessment to ensure appropriate prognostication in this population., (Crown Copyright © 2024. Published by Elsevier Ltd. All rights reserved.)

Electrocardiographic evaluation is performed in rhesus monkeys to establish the cardiovascular safety of candidate molecules before progressing to clinical trials. These animals are usually immobilized chemically by ketamine (KTM) and tiletamine-zolazepam (TZ) to obtain a steady-state heart rate and to ensure adequate human safety. The present study aimed to evaluate the effect of these anesthetic regimens on different electrocardiographic parameters. Statistically significant lower HR and higher P-wave duration, RR, QRS, and QT intervals were observed in the KTM-anesthetized group in comparison to TZ-anesthetized animals. No significant changes were noticed in the PR interval and p-wave amplitude. Sex-based significance amongst these parameters was observed in male and female animals of TZ- and KTM-anesthetized groups. Regression analysis of four QTc formulas in TZ-anesthetized rhesus monkeys revealed that QTcNAK (Nakayama) better corrected the QT interval than QTcHAS (Hassimoto), QTcBZT (Bazett), and QTcFRD (Fridericia) formulas. QTcNAK exhibited the least correlation with the RR interval (slope closest to zero and r = .01) and displayed no statistical significance between male and female animals. These data will prove useful in the selection of anesthetic regimens for chemical restraint of rhesus monkeys in nonclinical safety evaluation studies., 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.

Antimicrobial resistance (AMR) has emerged as one of the most serious worldwide public health issues of the twenty-first century. The expeditious rise of AMR has urged the development of new, natural effective therapeutic strategies against drug-resistant pathogens. Endophytic fungi, which inhabit distinctive environments like endosymbiotic relationships with plants, are gaining interest as alternative reservoirs for novel compounds that exhibit a broad range of chemical diversity and unique modes of action by releasing a variety of secondary metabolites with antimicrobial properties. The objective of the current research was to isolate and identify endophytic fungal species from leaves of Tradescantia pallida and to investigate their antagonistic effects on Multi-Drug-Resistant human pathogens. Endophytic fungus TPL11 and TPL14 showed maximum inhibition in agar plug and agar well diffusion assay. The ethyl acetate crude extract effectively suppressed growth of MRSA (Methicillin-resistant Staphylococcus aureus ) ATCC 43300,700699 strains and VRE (Vancomycin-resistant Enterococcus ) with the Inhibition zone of 22 ± 0.05, 23 ± 0.11 and 24 ± 0.11 mm respectively with minimum inhibitory concentration (MIC) of 3.125 µg/mL. Whereas TPL11 fungus revealed antibiosis of 22 ± 0.05 and 21 ± 0.15 mm against MRSA(ATCC 43300,700699) and 24 ± 0.05 mm for VRE with MIC of 6.25,3.125 and 1.56 μg/mL respectively. The MIC (Minimum inhibitory concentration) index further confirmed that both the extracts were bacteriostatic against MRSA and bactericidal against VRE. The isolates TPL11 and TPL14 were identified as Fusarium oxysporum and Nigrospora sphaerica by 18S rRNA internal transcribed spacer (ITS) sequencing. To our insight, it is the first report to reveal the presence of F.oxysporum and N.sphaerica in T.pallida and their antibacterial activity., Competing Interests: 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., (© 2024 The Author(s).)

This work aims to provide an effective hybrid beam forming method with Dual-Deep-Network to overcome overhead for mm-wave massive MIMO systems. In this paper, a Dual-Deep-Network technique is described for the extraction of statistical structures from a hybrid beam forming model based on mmWave logics, as well as training logic for the network map functions. The proposed approach of DDN is trained with proper data sequences used for communication and the training phase is conducted with the norms of numerous channel variants. With the nature of diverse channel states, a Dual-Deep-Network is required to manipulate the level of presence and abilities even after training as well. The performance level improvements are practically summarized in both the transmission and reception entities with the help of the proposed hybrid network architecture and the associated Dual Deep Network algorithm. Specifically, the BER versus SNR and spectral efficiency versus SNR are evaluated as well as the resulting accuracy levels are cross validated with numerous classical communication techniques. This paper shows the processing difficulties of the proposed approach and typically cross-validates with other beam forming logics. The computational cost and performance estimations are improved, and the metrics are clearly visualized on this paper based on improved beamforming procedures as well as the proposed approach of DDN based Multi-Resolution Code Book performance metrics are estimated clearly with proper mathematical model investigations. With 7Kbits/s/Hz and 1e-1, respectively, the key metrics of spectral efficiency and BER are enhanced., Competing Interests: 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., (© 2024 The Authors.)

Background and objectives Endothelial soluble lectin-type oxidized low-density lipoprotein receptor 1 (sLOX-1) recognizes oxidized low-density lipoprotein (LDL) and triggers downstream signaling leading to atherosclerosis. The objective of this study was to demonstrate the utility of sLOX-1 as a biomarker for detecting acute myocardial infarction (MI) and stable angina (SA) and to develop a diagnostic algorithm for distinguishing coronary vasospasm from coronary plaque rupture. Methods We enrolled 62 patients who underwent diagnostic coronary angiography (CAG) and 30 healthy controls (21 men and nine women) and measured sLOX-1, troponin I, and cardiac myosin-binding protein C (c-MyBPC) using commercial kits. Results Patients with MI exhibited higher sLOX-1 levels (301.55 ± 196.16 pg/ml) than patients with stable angina (220.76 ± 103.65 pg/ml) and healthy controls (121.14 ± 77.10, F: 10.55, p<0.001). Although higher troponin I levels were detected in MI patients (263.00 ± 493.00 vs. 3.19 ± 2.15 ng/ml, p=0.0019), no significant elevation was observed in SA patients (1.91 ± 0.79 ng/ml). Plasma sLOX-1 levels showed a positive association with age (r=0.37, p=0.003), but not with gender (r=0.04, p=0.75). Troponin I showed no association with age (r=0.12, p=0.36) or gender (r=0.06, p=0.62). Receiver operating characteristic (ROC) curves revealed that among the three biomarkers, troponin-I showed a higher area under the curve (AUC) (AUC: 0.941), followed by sLOX-1 (AUC: 0.888), while c-MyBPC showed no clinical utility in the detection of MI (AUC: 0.666). Conclusions A marked elevation of sLOX-1 can detect MI and differentiate the presence or absence of plaque rupture, along with diagnosing stable angina., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Narsini et al.)

Intestinal metaplasia (IM) is a pre-malignant condition of the gastric mucosa associated with increased gastric cancer (GC) risk. Analyzing 1,256 gastric samples (1,152 IMs) across 692 subjects from a prospective 10-year study, we identify 26 IM driver genes in diverse pathways including chromatin regulation (ARID1A) and intestinal homeostasis (SOX9). Single-cell and spatial profiles highlight changes in tissue ecology and IM lineage heterogeneity, including an intestinal stem-cell dominant cellular compartment linked to early malignancy. Expanded transcriptome profiling reveals expression-based molecular subtypes of IM associated with incomplete histology, antral/intestinal cell types, ARID1A mutations, inflammation, and microbial communities normally associated with the healthy oral tract. We demonstrate that combined clinical-genomic models outperform clinical-only models in predicting IMs likely to transform to GC. By highlighting strategies for accurately identifying IM patients at high GC risk and a role for microbial dysbiosis in IM progression, our results raise opportunities for GC precision prevention and interception., Competing Interests: Declaration of interests P.T. has stock in Tempus Healthcare, previous funding from Kyowa Hakko Kirin and Thermo Fisher Scientific, and patents/other intellectual property through the Agency for Science and Technology Research, Singapore (all outside the submitted work). K.G.Y. is a co-inventor on patents “Serum MicroRNA Biomarker for the Diagnosis of Gastric Cancer” and “Methods Related to Real-Time Cancer Diagnostics at Endoscopy Utilizing Fiber-Optic Raman Spectroscopy”; a member of Scientific Advisory Board of MiRXES Pte Ltd. He has no stock or shares in the related companies. He has no conflicts of interest to disclose regarding this submitted work. R.S. has received honoraria from MSD, Eli Lilly, BMS, Roche, Taiho, Astra Zeneca, DKSH, and Ipsen; has advisory activity with Bristol Myers Squibb, Merck, Eisai, Bayer, Taiho, Novartis, MSD, GSK, DKSH, and Astellas; received research funding from Paxman Coolers, MSD, and Natera; and has received travel grants from Roche, Astra Zeneca, Taiho, Eisai, and DKSH., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Competing Interests: The views expressed in this Comment are those of the authors and not necessarily those of the UK National Health Service, the National Institute for Health and Care Research (NIHR), or the UK Department of Health. ECS receives financial support from the NIHR Biomedical Research Centre in Oxford; receives grants and personal fees from Bristol Myers Squibb and AstraZeneca; receives personal fees from Amgen, Daiichi Sankyo, Mirati, Merck, Viracta, Astellas, Novartis, Pfizer, Zymeworks, and Beigene, outside the submitted work; receives non-financial support from Mirati; and is the European Organisation for Research and Treatment of Cancer Gastric Cancer Taskforce Chair and an Ireland Oesophagogastric Cancer Group Trustee. RS is on an advisory board for and receives honoraria for talks from Bristol Myers Squibb; is on an advisory board for and receives fees for travel from Eisai; is on an advisory board for and receives fees for talks and travel from Taiho and DiethelmKellerSiberHegner; is on an advisory board for and receives fees for talks and research funding from Merck Sharp & Dohme; is on an advisory board for Merck, Bayer, Novartis, GlaxoSmithKline, Astellas, Pierre-Fabre, and Tavotek; receives honoraria for talks from Eli Lilly; receives honoraria for talks and travel from Roche, AstraZeneca, and Ipsen; receives research funding and patents from Paxman Coolers; receives research funding from Natera; receives patents from Auristone, outside the submitted work; and has pending patents with Auristone, Paxman.

Background: Recent advances in cancer therapeutics have improved outcomes, resulting in increasing candidacy of patients with metastatic cancer being admitted to intensive care units (ICUs). A large proportion of patients also have frailty, predisposing them to poor outcomes, yet the literature reporting on this is scarce. We aimed to assess the impact of frailty on survival in patients with metastatic cancer admitted to the ICU., Methods: In this retrospective registry-based cohort study, we used data from the Australia and New Zealand Intensive Care Society Adult Patient (age ≥16 years) database to identify patients with advanced (solid and haematological cancer) and a documented Clinical Frailty scale (CFS) admitted to 166 Australian ICUs. Patients without metastatic cancer were excluded. We analysed the effect of frailty (CFS 5-8) on long-term survival, and how this effect changed in specific subgroups (cancer subtypes, age [<65 years or ≥65 years], and those who survived hospitalisation). Because estimates tend to cluster within centres and vary between them, we used Cox proportional hazards regression models with robust sandwich variance estimators to assess the effect of frailty on survival time up to 4 years after ICU admission between groups., Findings: Between Jan 1, 2018, and March 31, 2022, 30 026 patients were eligible, and after exclusions 21 174 patients were included in the analysis; of these, 6806 (32·1%) had frailty, and 11 662 (55·1%) were male, 9489 (44·8%) were female, and 23 (0·1%) were intersex or self-reported indeterminate sex. The overall survival was lower for patients with frailty at 4 years compared with patients without frailty (29·5% vs 10·9%; p<0·0001). Frailty was associated with shorter 4-year survival times (adjusted hazard ratio 1·52 [95% CI 1·43-1·60]), and this effect was seen across all cancer subtypes. Frailty was associated with shorter survival times in patients younger than 65 years (1·66 [1·51-1·83]) and aged 65 years or older (1·40 [1·38-1·56]), but its effects were larger in patients younger than 65 years (p interaction <0·0001). Frailty was also associated with shorter survival times in patients who survived hospitalisation (1·49 [1·40-1·59])., Interpretation: In patients with metastatic cancer admitted to the ICU, frailty was associated with poorer long-term survival. Patients with frailty might benefit from a goal-concordant time-limited trial in the ICU and will need suitable post-intensive care supportive management., Funding: None., Competing Interests: Declaration of interests MA reports travel expenses and advisory board fees from Pfizer and MSD and has been a member of a steering committee for the CP-MGA271 trial (MacroGenics). RRL reports a Dean's Research Development award from National University of Singapore, Singapore. RS reports research grants from Paxman Coolers, MSD, and Natera; consulting fees from Bristol Myers Squibb, Merck, Eisai, Bayer, Taiho, Novartis, GSK, Diethelm Keller Siber Hegner, and Astellas; honoraria from MSD, Eli Lilly, Bristol Myers Squibb, Roche, Taiho, AstraZeneca, Diethelm Keller Siber Hegner, and Ipsen; travel expenses from Roche, AstraZeneca, Taiho, Eisai, and Diethelm Keller Siber Hegner; and patents support from Paxman and Auristone. DP chairs the ANZICS Centre for Outcomes and Resource Evaluation Clinical Quality Registry (the data custodian for the present study); is a Vice-President and Board Member of ANZICS; and has been a clinical lead for Safer Care Victoria Critical Care network. All other authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: Fluoropyrimidines are commonly used in the treatment of metastatic breast cancer (MBC), and trifluridine/tipiracil (FTD/TPI) has shown activity in patients with colorectal and gastric cancers despite prior exposure to fluoropyrimidines. We investigate the role of FTD/TPI in patients with MBC with or without prior fluoropyridines in a single-arm phase II study., Methods: Patients with MBC were enroled first into a run-in dose confirmation phase, followed by two parallel cohorts including patients with (Cohort A) and without (Cohort B) prior exposure to fluoropyrimidines, where they were treated with FTD/TPI. Primary objectives for each cohort included determination of progression-free survival (PFS), and secondary objectives included determination of objective response rates (ORR), safety, and tolerability., Results: Seventy-four patients (42 Cohort A, 32 Cohort B) were enroled, all of whom were evaluable for toxicity and survival, with 72 evaluable for response. Median PFS was 5.7 months (95% confidence interval 3.8-8.3) and 9.4 months (95% CI 5.5-14.0) respectively in Cohorts A and B. Responses were observed regardless of prior exposure to fluoropyrimidines, with ORR of 19.5% (95% CI 8.8-34.9) and 16.1% (95% CI 5.5-33.7) in Cohorts A and B, and 6-month clinical benefit rates of 56.1% (95% CI 39.7-71.5) and 61.3% (95% CI 42.2-78.2) respectively. The safety profile was consistent with known toxicities of FTD/TPI, including neutropenia, fatigue, nausea, and anorexia, mitigated with dose modifications., Conclusion: FTD/TPI showed promising antitumour activity with manageable toxicity and is a clinically valid option in patients with MBC., Competing Interests: Declaration of Competing Interest J SJ Lim: Honoraria and consulting – Astrazeneca, Roche, DKSH, MSD, Eisai, Novartis, Pfizer, Gilead Pharmaceuticals, Research funding – CTI Biopharma, Trael – AZD, Pfizer; A LA Wong: Honoraria and consulting – Astra Zeneca, Pfizer, Norvatis, Eisai, DKSH, Research funding – Otsuka Pharmaceuticals; S GW Ow: Honoraria and consulting – Astra Zeneca, Pfizer, Norvatis, Eli Lilly, Roche; R Sundar: Honoraria and consulting - Bristol-Myers Squibb, Merck, Eisai, Bayer, Taiho, Novartis, MSD, GSK, DKSH, Astellas, Pierre-Fabre, Eili Lilly, BMS, Roche, Astra Zeneca, Ipsen; Research funding – Paxman Coolers, MSD, Natera; Patents – Paxman, Auristone; Travel – Roche, Astra Zeneca, Taiho, Eisai, DKSH. BC Tai: Honoraria and consulting – Boehringer Ingelheim, Royalty – Wiley-Blackwell; SC Lee: Honoraria and consulting – Astra Zeneca, Pfizer, Norvatis, Eli Lilly, Roche, ACT Genomics, Eisai, research funding – Taiho, Eisai, Pfizer, ACT Genomics. G HJ Chan, Y LE Ang, WQ Chong, M Lee, JL Low and J RE Choo, have no competing interests to declare., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Oral SERDs are a novel drug class that have been developed to counteract resistance due to ESR1 mutations. Several SERDs have emerged from phase 2 and 3 trials, with the FDA limiting approval for Elacestrant to patients with ESR1mt tumours despite PFS benefit in the overall population. However, questions remain on whether patients with ESR1wt tumours stand to benefit from oral SERDs., Patients and Methods: Manuscripts and conference presentations of Randomised Controlled Trials were extracted after a systematic search of Embase, PubMed and Cochrane from inception until January 21,2023. RCTs investigating the efficacy of oral SERDs versus endocrine therapy for ER positive, HER2 negative advanced breast cancer, and which reported the Kaplan Meier (KM) curves of PFS in the overall and ESR1 mutant (ESR1mt) population were selected. A graphical reconstructive algorithm was applied to estimate time-to-event outcomes from reported KM curves in all overall and ESR1mt cohorts. A bipartite matching algorithm, KMSubtraction, was used to derive survival data for unreported (ESR1wt) subgroups. An individual patient data (IPD) meta-analysis was then pursued, pooling data by ESR1 mutation status in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and Cochrane Guidelines for IPD., Results: The randomized clinical trials ACELERA, AMEERA-3, EMERALD and SERENA-2 were included, totalling 1290 patients. In the pooled analysis of the overall cohort, PFS benefit was observed with oral SERDs when compared with treatment of physicians choice (TPC) (HR 0.783, 95%CI 0.681-0.900, p<0.001). In the ESR1mt subgroup, oral SERDs demonstrated improved PFS (HR 0.557, 95%CI 0.440-0.705, p<0.001) compared to TPC. In the ESR1wt subgroup, oral SERDs demonstrated no significant PFS benefit (HR 0.944, 95%CI 0.783-1.138, p=0.543) when compared to TPC., Conclusions: The results of this IPD meta-analysis suggests that PFS benefit in the overall population is mainly driven by the ESR1mt subgroup., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: CDK4/6-inhibitors have demonstrated similar efficacy and are considered an effective first-line endocrine treatment of patients with hormone-receptor positive (HR+)/human-epidermal-growth-factor-receptor-2 negative (HER2-) metastatic breast cancer (MBC) in the endpoint of progression-free survival (PFS). Amongst these, palbociclib was first to achieve regulatory approval, followed subsequently by ribociclib and abemaciclib. However, recent updates of overall survival (OS) showed inconsistencies in the OS benefit for palbociclib compared with the other two CDK4/6-inhibitors. With the lack of head-to-head comparison studies, our study sought to compare indirect survival outcomes between CDK4/6-inhibitors in this setting using a novel reconstructive algorithm. Methods: Phase III randomized trials comparing first-line aromatase inhibitor with/without a CDK4/6-inhibitor in post-menopausal patients with HR+/HER2- MBC were identified through systemic review and literature search of online archives of published manuscripts and conference proceedings. A graphical reconstructive algorithm was utilized to retrieve time-to-event data from reported Kaplan-Meier OS and PFS plots to allow for comparison of survival outcomes. Survival analyses were conducted with Cox proportional-hazards model with a shared-frailty term. Results: Three randomized phase III trials-PALOMA-2, MONALEESA-2 and MONARCH-3-comprising 1827 patients were included. Indirect pairwise comparisons of all CDK4/6-inhibitors showed no significant PFS differences (all p > 0.05). Likewise, indirect treatment comparison between ribociclib vs. palbociclib (one-stage: HR = 0.903, 95%-CI: 0.746-1.094, p = 0.297), abemaciclib vs. palbociclib (one-stage: HR = 0.843, 95%-CI: 0.690-1.030, p = 0.094) and abemaciclib vs. ribociclib (one-stage: HR = 0.933, 95%-CI: 0.753-1.157, p = 0.528) failed to demonstrate a significant OS difference. Conclusions: Findings from this indirect treatment comparison suggest no significant PFS or OS differences between CDK4/6-inhibitors in post-menopausal patients with HR+/HER2- MBC.

Alkyl isonitriles, R-NC, have previously been shown to ligate the heme (haem) iron of cytochromes P450 in both accessible oxidation states (ferrous, Fe 2+ , and ferric, Fe 3+ ). Herein, the preparation of four steroid-derived isonitriles and their interactions with several P450s, including the steroidogenic CYP17A1 and CYP106A2, as well as the more promiscuous drug metabolizers CYP3A4 and CYP2D6, is described. It was found that successful ligation of the heme iron by the isonitrile functionality for a given P450 depends on both the position and stereochemistry of the isonitrile on the steroid skeleton. Spectral studies indicate that isonitrile ligation of the ferric heme is stable upon reduction to the ferrous form, with reoxidation resulting in the original complex. A crystallographic structure of CYP17A1 with an isonitrile derived from pregnanalone further confirmed the interaction and identified the absolute stereochemistry of the bound species., (© 2023. Springer Nature Limited.)

Objective: Gastric cancer (GC) is a leading cause of cancer mortality, with ARID1A being the second most frequently mutated driver gene in GC. We sought to decipher ARID1A -specific GC regulatory networks and examine therapeutic vulnerabilities arising from ARID1A loss., Design: Genomic profiling of GC patients including a Singapore cohort (>200 patients) was performed to derive mutational signatures of ARID1A inactivation across molecular subtypes. Single-cell transcriptomic profiles of ARID1A -mutated GCs were analysed to examine tumour microenvironmental changes arising from ARID1A loss. Genome-wide ARID1A binding and chromatin profiles (H3K27ac, H3K4me3, H3K4me1, ATAC-seq) were generated to identify gastric-specific epigenetic landscapes regulated by ARID1A. Distinct cancer hallmarks of ARID1A -mutated GCs were converged at the genomic, single-cell and epigenomic level, and targeted by pharmacological inhibition., Results: We observed prevalent ARID1A inactivation across GC molecular subtypes, with distinct mutational signatures and linked to a NFKB-driven proinflammatory tumour microenvironment. ARID1A -depletion caused loss of H3K27ac activation signals at ARID1A -occupied distal enhancers, but unexpectedly gain of H3K27ac at ARID1A-occupied promoters in genes such as NFKB1 and NFKB2 . Promoter activation in ARID1A -mutated GCs was associated with enhanced gene expression, increased BRD4 binding, and reduced HDAC1 and CTCF occupancy. Combined targeting of promoter activation and tumour inflammation via bromodomain and NFKB inhibitors confirmed therapeutic synergy specific to ARID1A -genomic status., Conclusion: Our results suggest a therapeutic strategy for ARID1A -mutated GCs targeting both tumour-intrinsic (BRD4-assocatiated promoter activation) and extrinsic (NFKB immunomodulation) cancer phenotypes., Competing Interests: Competing interests: PT has stock and other ownership interests in Tempus Healthcare, previous research funding from Kyowa Hakko Kirin and Thermo Fisher Scientific, and patents/other intellectual property through the Agency for Science and Technology Research, Singapore (all outside the submitted work). RS has received honoraria from Bristol-Myers Squibb, Lilly, Roche, Taiho, Astra Zeneca, DKSH and MSD; has advisory activity with Bristol-Myers Squibb, Merck, Eisai, Bayer, Taiho, Novartis, MSD and AstraZeneca; received research funding from MSD and Paxman Coolers; and has received travel grants from AstraZeneca, Eisai, Roche and Taiho Pharmaceutical., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: In the phase III TAGS trial, trifluridine/tipiracil showed survival benefit versus placebo in patients with metastatic gastric/gastroesophageal junction cancer and ≥ 2 prior chemotherapies. This post hoc exploratory analysis assessed the impact of prior therapy type on outcomes., Methods: Based on prior treatment, patients in TAGS (N = 507) were categorized into overlapping subgroups: ramucirumab ± other agents (n = 169), no ramucirumab (n = 338), paclitaxel but no ramucirumab (n = 136), ramucirumab + paclitaxel sequentially or in combination (n = 154), neither paclitaxel nor ramucirumab (n = 202), irinotecan (n = 281), and no irinotecan (n = 226). Overall and progression-free survival, time to Eastern Cooperative Oncology Group performance status (ECOG PS) ≥ 2, and safety were assessed., Results: Baseline characteristics and prior therapy patterns were generally well balanced between trifluridine/tipiracil and placebo arms across subgroups. Trifluridine/tipiracil was associated with survival benefits versus placebo regardless of prior treatment: across subgroups, median overall survival was 4.6-6.1 versus 3.0-3.8 months (hazard ratios, 0.47-0.88), median progression-free survival was 1.9-2.3 versus 1.7-1.8 months (hazard ratios, 0.49-0.67), and median time to ECOG PS ≥ 2 was 4.0-4.7 versus 1.9-2.5 months (hazard ratios, 0.56-0.88). Among trifluridine/tipiracil-randomized patients, median overall and progression-free survival trended longer in those who had not received ramucirumab, paclitaxel and ramucirumab, or irinotecan (6.0-6.1 and 2.1-2.3 months, respectively) than in those who previously received these agents (4.6-5.7 and 1.9 months). The trifluridine/tipiracil safety profile was consistent across subgroups, with similar overall incidences of grade ≥ 3 adverse events. Minor variations in hematologic toxicities were noted., Conclusions: In TAGS, third- or later-line trifluridine/tipiracil treatment demonstrated overall and progression-free survival and functioning benefits versus placebo and a consistent safety profile in patients with metastatic gastric/gastroesophageal junction cancer, regardless of prior treatment type., Clinical Trials Registration: clinicaltrials.gov NCT02500043., (© 2023. The Author(s).)

Importance: Despite patients with cancer being at risk of poor outcomes from COVID-19, there are few published studies for vaccine efficacy in this group, with suboptimal immunogenicity and waning vaccine efficacy described in small studies being a concern., Objective: To assess the incidence rate of severe COVID-19 disease outcomes associated with the number of vaccine doses received and the waning of protection over time., Design, Setting, and Participants: A prospective multicenter observational cohort study was carried out over 2 time periods (September 15, 2021, to December 20, 2021 [delta wave], and January 20, 2022, to November 11, 2022 [omicron wave]) predominated by SARS-CoV-2 delta and omicron variants, respectively. Overall, 73 608 patients with cancer (23 217 active treatment, 50 391 cancer survivors) and 621 475 controls matched by age, sex, race and ethnicity, and socioeconomic status were included., Exposure: Vaccine doses received, from zero to 4 doses, and time elapsed since last vaccine dose., Outcomes: Competing-risk regression analyses were employed to account for competing risks of death in patients with cancer. Main outcomes were incidence rate ratios (IRRs) of COVID-19 infection, hospitalization, and severe disease (defined as requirement for supplemental oxygen, intensive care, or death). The IRRs stratified by time from last vaccine dose served as indicators of waning of vaccine effectiveness over time., Results: The mean (SD) age of actively treated patients with cancer, cancer survivors, and controls were 62.7 (14.7), 62.9 (12.6), and 61.8 (14.7) years, respectively. Of 73 608 patients with cancer, 27 170 (36.9%) were men; 60 100 (81.6%) were Chinese, 7432 (10.1%) Malay, 4597 (6.2%) Indian, and 1479 (2.0%) were of other races and ethnicities. The IRRs for the 3-dose and 4-dose vs the 2-dose group (reference) for COVID-19 hospitalization and severe disease were significantly lower during both the delta and omicron waves in cancer and control populations. The IRRs for severe disease in the 3-dose group for active treatment, cancer survivors, and controls were 0.14, 0.13, and 0.07 during the delta wave and 0.29, 0.19, and 0.21 during omicron wave, respectively. The IRRs for severe disease in the 4-dose group during the omicron wave were even lower at 0.13, 0.10 and 0.10, respectively. No waning of vaccine effectiveness against hospitalization and severe disease was seen beyond 5 months after a third dose, nor up to 5 months (the end of this study's follow-up) after a fourth dose., Conclusion: This cohort study provides evidence of the clinical effectiveness of mRNA-based vaccines against COVID-19 in patients with cancer. Longevity of immunity in preventing severe COVID-19 outcomes in actively treated patients with cancer, cancer survivors, and matched controls was observed at least 5 months after the third or fourth dose.

Background & Aims: Down-staging is commonly used to select patients with hepatocellular carcinoma (HCC) beyond Milan criteria (MC) for liver transplantation (LT), but outcomes are heterogenous. We aimed to estimate pooled down-staging success rates, HCC recurrence, and overall survival (OS), stratified by criteria used for baseline tumor burden., Methods: We searched Pubmed and EMBASE databases from inception until August 2021 for studies reporting down-staging success (reduction of tumor burden to within MC) and outcomes of adult HCC patients. In addition, we performed a pooled analysis using reconstructed individual participant data to obtain robust estimates for OS., Results: We screened 1059 articles and included 25 articles involving 3997 patients. Overall, 55.16% (45.49%-64.46%) underwent successful down-staging, and 31.52% (24.03%-40.11%) received LT (by intention-to-treat analysis [ITT]). Among patients who received LT, 16.01% (11.80%-21.37%) developed HCC recurrence. Comparing studies that used the United Network for Organ Sharing Down-Staging (UNOS-DS) criteria versus studies beyond UNOS-DS or did not specify criteria, down-staging success (by ITT) was 83.21% versus 45.93%, P < .001; the proportion who received LT (by ITT) was 48.61% vs 28.60%, P = .030; and HCC recurrence (among patients who received LT) occurred in 9.06% versus 20.42%, P < .001. Among studies that used UNOS-DS criteria, ITT 1- and 5-year OS from the initiation of down-staging treatment was 86% and 58%, respectively, whereas 1- and 5-year post-LT OS was 94% and 74%, respectively., Conclusions: Among studies that adhered to UNOS-DS criteria, down-staging was successful in four-fifths of patients, >50% received LT, and post-LT outcomes were excellent. These data provide clinical validation for the utilization of UNOS-DS criteria., (Copyright © 2023 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Introduction: By a variety of pathogenic pathways, kidney diseases can have a direct negative impact on the lungs and worsen the prognosis for those with chronic renal disease. Chronic kidney disease (CKD) is a public health concern throughout the world. The relationship between the kidneys and lungs is crucial for maintaining acid-base balance, fluid homeostasis, and blood pressure control. These patients have a higher prevalence of lung dysfunction regardless of the disease's stage, including sleep apnea syndrome, pulmonary hypertension, and chronic obstructive pulmonary disease (COPD). The chance of getting a pulmonary consequence increases with the severity of kidney disease. In individuals with chronic renal disease, this study looked at the prevalence of several respiratory disorders., Materials and Methods: From February 2021 to October 2021, 70 CKD patients who were receiving care at the Saveetha Medical College and Hospital were taken into consideration for the study. Clinical assessment and pertinent tests, such as a pulmonary function test, chest radiography, CT chest, sputum analysis, and pleural fluid analysis were performed. To evaluate left ventricular function, echocardiography was performed. Selected patients underwent polysomnography., Results: The study's population had a mean age of 50 years. There was a 20:50 sex ratio (M:F). Seventy percent of them had respiratory conditions, the most frequent of which was pleural effusion (70%), followed by pulmonary edema (52%). The pleural effusion was primarily transudative and right sided. Both tuberculous pleural effusion and pulmonary tuberculosis were detected in 2% of the population. Seven percent of them developed pneumonia. 10% of patients had thickening of the pleura. Using chest CT and x-ray, 3% of patients had pulmonary calcification visible. In 12 (60%) out of the 20 patients who were studied, sleep apnea was observed. Two patients with tuberculosis and pneumonia lacked the typical signs., Conclusions: In our research study, CKD patients have a much higher preponderance of respiratory illnesses, which has negative effects on patient care., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Parivakkam Mani et al.)

Recently, a wide spectrum of artificial intelligence (AI)-based applications in the broader categories of digital pathology, biomarker development, and treatment have been explored. In the domain of digital pathology, these have included novel analytical strategies for realizing new information derived from standard histology to guide treatment selection and biomarker development to predict treatment selection and response. In therapeutics, these have included AI-driven drug target discovery, drug design and repurposing, combination regimen optimization, modulated dosing, and beyond. Given the continued advances that are emerging, it is important to develop workflows that seamlessly combine the various segments of AI innovation to comprehensively augment the diagnostic and interventional arsenal of the clinical oncology community. To overcome challenges that remain with regard to the ideation, validation, and deployment of AI in clinical oncology, recommendations toward bringing this workflow to fruition are also provided from clinical, engineering, implementation, and health care economics considerations. Ultimately, this work proposes frameworks that can potentially integrate these domains toward the sustainable adoption of practice-changing AI by the clinical oncology community to drive improved patient outcomes.

Background: Phosphatase of regenerating liver-3 (PRL-3) is involved in cellular processes driving metastasis, cell proliferation, invasion, motility and survival. It has been shown to be upregulated and overexpressed in cancer tissue, in contrast to low or no expression in most normal tissue. PRL3-zumab is a first-in-class humanized antibody that specifically binds to PRL-3 oncotarget with high affinity and has been shown to reduce tumor growth and increase survival., Objective: In the study, we aimed to determine the safety and efficacy of PRL3-zumab in patients with advanced solid tumors and hematological malignancies., Methods: We conducted a phase I, first-in-human study in advanced solid tumors and hematological malignancies to investigate the safety, tolerability and efficacy of PRL3-zumab. Response rates were evaluated using the Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1) for solid tumors. For acute myeloid leukemia (AML) patients, bone marrow response criteria based on the European Leukaemia Network (ELN) 2017 guidelines for AML were used. We also explored the pharmacokinetics and pharmacodynamic relationships of PRL3-zumab in patients. This study was registered with ClinicalTrials.gov: NCT03191682., Results: In the dose-escalation cohort, 11 patients with advanced solid tumors were enrolled into the study. An additional 12 patients with solid tumors and four patients with AML were enrolled in the dose-expansion cohort. Maximum tolerability was not achieved in this study, as there were no dose-limiting toxicities. Potential treatment-emergent adverse events were grade 1 increased stoma output and fatigue and grade 2 vomiting. Best response observed was stable disease in three solid-tumor patients (11.1%). The pharmacokinetics of PRL3-zumab were dose proportional, consistent with an IgG type monoclonal antibody., Conclusions: PRL3-zumab, a first-in-class humanized antibody, was safe and tolerable in solid tumors and hematological malignancies., (© 2023. The Author(s).)

Background: We evaluated the relevance of PD-1 + CD8 + T-cells in gastric cancer (GC) including prognostic significance, association with chemotherapy and immunotherapy sensitivity and correlations with the tumor microenvironment (TME)., Methods: Discovery cohort: GC samples were evaluated for AE1/3, CD8, PD-1, Ki-67 and Granzyme-B expression with fluorescence-based multiplex immunohistochemistry (mIHC). Validation cohorts: we analyzed bulk RNAseq GC datasets from TCGA, the "3G" chemotherapy trial and an immunotherapy phase 2 trial. The cox proportional hazards model was used to identify factors that influenced overall survival (OS). To study the TME, we analyzed single-cell RNAseq performed on GCs., Results: In the discovery cohort of 350 GCs, increased PD-1 expression of CD8 T-cells was prognostic for OS (HR 0.822, p = 0.042). PD-1 expression in CD8 T-cells highly correlated with cytolytic [Granzyme-B + ] (r = 0.714, p < 0.001) and proliferative [Ki-67 + ] (r = 0.798, p < 0.001) activity. Analysis of bulk RNAseq datasets showed tumors with high PD-1 and CD8A expression levels had improved OS when treated with immunotherapy (HR 0.117, p = 0.036) and chemotherapy (HR 0.475, p = 0.017). Analysis of an scRNAseq dataset of 152,423 cells from 40 GCs revealed that T-cell and NK-cell proportions were higher (24% vs 18% and 19% vs 15%, p < 0.0001), while macrophage proportions were lower (7% vs 11%, p < 0.0001) in CD8PD-1 high compared to CD8PD-1 low tumors., Conclusion: This is one of the largest GC cohorts of mIHC combined with analysis of multiple datasets providing orthogonal validation of the clinical relevance of PD-1 + CD8 + T-cells being associated with improved OS. CD8PD-1 high tumors have distinct features of an immunologically active, T-cell inflamed TME., (© 2023. The Author(s).)

CYP106A2 (cytochrome P450 meg ) is a bacterial enzyme originally isolated from B. megaterium, and has been shown to hydroxylate a wide variety of substrates, including steroids. The regio- and stereochemistry of CYP106A2 hydroxylation has been shown to be dependent on a variety of factors, and hydroxylation often occurs at more than one site and/or with lack of stereospecificity for some substrates. Comprehensive backbone 15 N, 1 H and 13 C resonance assignments based on multidimensional nuclear magnetic resonance (NMR) experiments performed with uniform and selective isotopically labeled CYP106A2 samples are reported herein, and broadening and splitting of resonances assigned to regions of the enzyme shown to be affected by substrate binding in other P450 enzymes indicate that substrate binding does not reduce structural heterogeneity as has been observed previously in P450 enzymes CYP101A1 and MycG. Paramagnetic relaxation enhancement (PRE) due to proximity between substrate protons and the heme iron were measured for three different substrates, and the relatively uniform nature of the PREs support the proposal that multiple substrate binding modes are occupied at saturating substrate concentrations., 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 © 2023 Elsevier Inc. All rights reserved.)

Introduction: In 2019, the National Institute for Health and Care Excellence (NICE) updated their recommendations with respect to brain imaging in the staging of non-small cell lung cancer (NSCLC) based on an analytic cost-effectiveness model using published data and modelling assumptions from committee experts. In this study, we aimed to re-run this model using real-world multi-centre UK data., Materials and Methods: Retrospective data was collected on consecutive patients with radically treatable clinical stage II and III lung cancer from eleven acute NHS Trusts during the calendar year 01/01/2018 to 31/12/2018. Following a written application to the NICE lung cancer guideline committee, we were granted access to the NG122 brain imaging economic model for the purpose of updating the input parameters in line with the real-world findings from this study., Results: A total of 444 patients had data for analysis. The combined prevalence of occult brain metastases was 6.2% (10/165) in stage II and 6% (17/283) in stage III, compared to 9.5% and 9.3% used in the NICE economic model. 30% of patients with clinical stage III NSCLC and occult BMs on pre-treatment imaging went onto complete the planned curative intent treatment of extracranial disease, 60% completed SRS to the brain and 30% completed WBRT. This compares to 0%, 10% and 0% in the NICE assumptions. The health economic analysis concluded that brain imaging was no longer cost-effective in stage II disease (ICERs £50,023-£115,785) whilst brain imaging remained cost-effective for stage III patients (ICERs 17,000-£22,173), with MRI being the most cost-effective strategy., Conclusion: This re-running of the NICE health economic model with real-world data strongly supports the NICE guideline recommendation for brain imaging prior to curative-intent treatment in stage III lung cancer but questions the cost-effectiveness of CT brain imaging prior to curative-intent treatment in stage II lung cancer., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: RM currently works as Associate Director, Value Access and Devolved Nations, Merck, Sharp and Dohme (UK) Ltd. During the time of this work his role was Technical Adviser, Centre for Guidelines, National Institute for Health and Care Excellence. MSD market treatments for lung cancer but this work was completed entirely while in employment with NICE and there are no obvious COI related to MSD’s activities. The remaining 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 © 2023 Elsevier B.V. All rights reserved.)

Background: Patient selection is key in Phase I studies, and prognosis can be difficult to estimate in heavily pre-treated patients. Previous prognostic models like the Royal Marsden Hospital (RMH) score or using the neutrophil-lymphocyte ratio (NLR) have not been validated in current novel therapies nor in the Asian Phase I population., Methods: We conducted a retrospective review of 414 patients with solid tumours participating in Phase I studies at our centre between October 2013 and December 2020., Results: The RMH model showed poorer prognosis with increasing scores [RMH score 1, HR 1.28 (95% CI: 0.96-1.70); RMH score 2, HR 2.27 (95% CI: 1.62-3.17); RMH score 3, HR 4.14 (95% CI: 2.62-6.53)]. NLR did not improve the AUC of the model. Poorer ECOG status (ECOG 1 vs. 0: HR = 1.59 (95% CI = 1.24-2.04), P < 0.001) and primary tumour site (GI vs. breast cancer: HR = 3.06, 95% CI = 2.16-4.35, P < 0.001) were prognostic., Conclusions: We developed a NCIS prognostic score with excellent prognostic ability for both short-term and longer-term survival (iAUC: 0.71 [95% CI 0.65-0.76]), and validated the RMH model in the largest Asian study to date., (© 2023. The Author(s).)

Background and Objectives: In spite of bone's healing capacity, critical-size bone defect regeneration and peri -implant osseointegration are challenging. Tissue engineering provides better outcomes, but requires expensive adjuncts like stem cells, growth factors and bone morphogenic proteins. Vitamin D (Vit.D) regulates calcium and phosphorus metabolism, and helps maintain bone health. Vit.D supplements in deficient patients, accentuates bone healing and regeneration. Therefore the aim of this systematic review was to evaluate the role of adjunctive Vit.D on bone defect regeneration., Methods: Comprehensive database search of indexed literature, published between January 1990 and June 2022, was carried out. English language articles fulfilling inclusion criteria (clinical/in vivo studies evaluating bone regeneration including osseointegration and in vitro studies assessing osteogenic differentiation, with adjunct Vit.D) were identified and screened., Results: Database search identified 384 titles. After sequential title, abstract and full-text screening, 23 studies (in vitro - 9/in vivo - 14) were selected for review. Vit.D as an adjunct with stem cells and osteoblasts resulted in enhanced osteogenic differentiation and upregulation of genes coding for bone matrix proteins and alkaline phosphatase. When used in vivo, Vit.D resulted in early and increased new bone formation and mineralization within osseous defects, and better bone implant contact and osseointegration, around implants. Adjunct Vit.D in animals with induced systemic illnesses resulted in bone defect regeneration and osseointegration comparable to healthy animals. While systemic and local administration of Vit.D resulted in enhanced bone defect healing, outcomes were superior with systemic route., Conclusions: Based on this review, adjunct Vit.D enhances bone defect regeneration and osseointegration. In vitro application of Vit.D to stem cells and osteoblasts enhances osteogenic differentiation. Vit.D is a potentially non-invasive and inexpensive adjunct for clinical bone regeneration and osseointegration. Long term clinical trials are recommended to establish protocols relating to type, dosage, frequency, duration and route of administration., Competing Interests: 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., (© 2023 The Authors. Production and hosting by Elsevier B.V.)

Objective: Gastric cancer (GC) comprises multiple molecular subtypes. Recent studies have highlighted mesenchymal-subtype GC (Mes-GC) as a clinically aggressive subtype with few treatment options. Combining multiple studies, we derived and applied a consensus Mes-GC classifier to define the Mes-GC enhancer landscape revealing disease vulnerabilities., Design: Transcriptomic profiles of ~1000 primary GCs and cell lines were analysed to derive a consensus Mes-GC classifier. Clinical and genomic associations were performed across >1200 patients with GC. Genome-wide epigenomic profiles (H3K27ac, H3K4me1 and assay for transposase-accessible chromatin with sequencing (ATAC-seq)) of 49 primary GCs and GC cell lines were generated to identify Mes-GC-specific enhancer landscapes. Upstream regulators and downstream targets of Mes-GC enhancers were interrogated using chromatin immunoprecipitation followed by sequencing (ChIP-seq), RNA sequencing, CRISPR/Cas9 editing, functional assays and pharmacological inhibition., Results: We identified and validated a 993-gene cancer-cell intrinsic Mes-GC classifier applicable to retrospective cohorts or prospective single samples. Multicohort analysis of Mes-GCs confirmed associations with poor patient survival, therapy resistance and few targetable genomic alterations. Analysis of enhancer profiles revealed a distinctive Mes-GC epigenomic landscape, with TEAD1 as a master regulator of Mes-GC enhancers and Mes-GCs exhibiting preferential sensitivity to TEAD1 pharmacological inhibition. Analysis of Mes-GC super-enhancers also highlighted NUAK1 kinase as a downstream target, with synergistic effects observed between NUAK1 inhibition and cisplatin treatment., Conclusion: Our results establish a consensus Mes-GC classifier applicable to multiple transcriptomic scenarios. Mes-GCs exhibit a distinct epigenomic landscape, and TEAD1 inhibition and combinatorial NUAK1 inhibition/cisplatin may represent potential targetable options., Competing Interests: Competing interests: PT has stock and other ownership interests in Tempus Healthcare, previous research funding from Kyowa Hakko Kirin and Thermo Fisher Scientific, and patents/other intellectual property through the Agency for Science and Technology Research, Singapore (all outside the submitted work). RS has received honoraria from MSD, Eli Lilly, Bristol Myers Squibb, Roche, Taiho, Astra Zeneca and DKSH; has advisory activity with Bristol Myers Squibb, Merck, Eisai, Bayer, Taiho, Novartis, MSD and GSK; received research funding from MSD and Paxman Coolers; and has received travel grants from Astra Zeneca, Eisai, Roche, Taiho and DKSH. All remaining authors have declared no conflicts of interest., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Importance: Immune checkpoint inhibitors (ICIs) have improved survival outcomes of patients with advanced esophageal squamous cell carcinoma in both first- and second-line settings. However, the benefit of ICIs in patients with low programmed death ligand 1 (PD-L1) expression remains unclear., Objective: To derive survival data for patient subgroups with low PD-L1 expression from clinical trials comparing ICIs with chemotherapy in esophageal squamous cell carcinoma and to perform a pooled analysis., Data Sources: Kaplan-Meier curves from the randomized clinical trials were extracted after a systematic search of Scopus, Embase, PubMed, and Web of Science from inception until October 1, 2021., Study Selection: Randomized clinical trials that investigated the effectiveness of anti-PD-1-based regimens for advanced esophageal squamous cell carcinoma and that reported overall survival (OS), progression-free survival, or duration of response were included in this meta-analysis., Data Extraction and Synthesis: Kaplan-Meier curves of all-comer populations, subgroups with high PD-L1, and those with low PD-L1 (when available) were extracted from published articles. A graphic reconstructive algorithm was used to calculate time-to-event outcomes from these curves. In studies with unreported curves for subgroups with low PD-L1 expression, KMSubtraction was used to impute survival data. KMSubtraction is a workflow to derive unreported subgroup survival data with from subgroups. An individual patient data pooled analysis including previously reported and newly imputed subgroups was conducted for trials with the same treatment line and PD-L1 scoring system. Data analysis was conducted from January 1, 2022, to June 30, 2022., Main Outcomes and Measures: Primary outcomes included Kaplan-Meier curves and hazard ratios (HRs) for OS for subgroups with low PD-L1 expression. Secondary outcomes included progression-free survival and duration of response., Results: The randomized clinical trials CheckMate-648, ESCORT-1st, KEYNOTE-590, ORIENT-15, KEYNOTE-181, ESCORT, RATIONALE-302, ATTRACTION-3, and ORIENT-2 were included, totaling 4752 patients. In the pooled analysis of first-line trials that evaluated a tumor proportion score (CheckMate-648 and ESCORT-1st), no significant benefit in OS was observed with immunochemotherapy compared with chemotherapy in the subgroup of patients who had a tumor proportion score lower than 1% (HR, 0.91; 95% CI, 0.74-1.12; P = .38) compared with chemotherapy. In the pooled analysis of first-line trials that evaluated combined positive score (KEYNOTE-590 and ORIENT-15), there was a significant but modest OS benefit for immunochemotherapy compared with chemotherapy in the subgroup with a combined positive score lower than 10 (HR, 0.77; 95% CI, 0.62-0.94; P = .01)., Conclusions and Relevance: Findings suggest a lack of survival benefit of ICI-based regimens in the first-line setting compared with chemotherapy alone in the subgroup with a tumor proportion score lower than 1%.

Background/aims: Gastric emptying scintigraphy is commonly performed to assess for dysmotility. A standardized meal with associated threshold criteria was established in 2000 to enable robust interpretation. However, no guidance is available to interpret results when patients do not ingest the entire meal. The purpose of this study is to determine the continued appropriateness of the threshold criteria in contemporary clinical practice and its relevance for partially ingested meals., Methods: This retrospective study analyzed patients (n = 1365 total) who underwent solid-phase gastric emptying scintigraphy at an academic medical center. Patients were stratified based on their completion of the standard meal. Patients were further stratified into normal and delayed gastric emptying cohorts based on the current criteria. Percent gastric retention values at 1, 2, 3, and 4 h were compared., Results: Median (95% upper reference) normal gastric retention values for the complete standard meal were 64% (87%) at 1 h, 25% (60%) at 2 h, 13% (54%) at 3 h and 4% (9%) at 4 h. Consumption of at least 50% of the standard meal yielded similar retention; 53% (86%) at 1 h, 19% (58%) at 2 h, 6% (29%) at 3 h and 3% (10%) at 4 h. There was no significant age- or gender-specific differences using the current criteria, and no differences were observed based on diabetic status. Retention values matched well with the current criteria and validated with data-driven clustering., Conclusion: Adult normative standards for gastric emptying scintigraphy are appropriate for differentiating normal and delayed populations and can be applied to partial meals with at least 50% completion., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

To discover the best-in-class Bruton's Tyrosine Kinase (BTK) inhibitors, for th treatment of autoimmune disorders like cancer (B-Cell Lymphoma (BCL)) and rheumatoid arthritis (RA), in the present investigation, novel structural optimizations were carried out. Introduction of novel bicyclic amine linkers and aromatic backbone led to series of compounds 9a-h and 14a-u. Compound 14b was found to be potent, orally bioavailable, selective and irreversible BTK inhibitor. In vitro, 14b showed IC 50 of 1.0 nM and 0.8 nM, in BTK and TMD8 assays, respectively. In vivo,14b displayed robust efficacy in collagen-induced arthritis (CIA) and TMD8 xenograft models, which could be correlated with its improved oral bioavailability. In the repeated dose acute toxicity study, 14b showed no adverse changes, indicating that the BTK inhibitor 14b could be viable therapeutic option for the treatment of autoimmune disorders., 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 © 2022 Elsevier Inc. All rights reserved.)

Introduction: Three doses of SARS-CoV-2 mRNA vaccines have been recommended for cancer patients to reduce the risk of severe disease. Anti-neoplastic treatment, such as chemotherapy, may affect long-term vaccine immunogenicity., Method: Patients with solid or haematological cancer were recruited from 2 hospitals between July 2021 and March 2022. Humoral response was evaluated using GenScript cPASS surrogate virus neutralisation assays. Clinical outcomes were obtained from medical records and national mandatory-reporting databases., Results: A total of 273 patients were recruited, with 40 having haematological malignancies and the rest solid tumours. Among the participants, 204 (74.7%) were receiving active cancer therapy, including 98 (35.9%) undergoing systemic chemotherapy and the rest targeted therapy or immunotherapy. All patients were seronegative at baseline. Seroconversion rates after receiving 1, 2 and 3 doses of SARS-CoV-2 mRNA vaccination were 35.2%, 79.4% and 92.4%, respectively. After 3 doses, patients on active treatment for haematological malignancies had lower antibodies (57.3%±46.2) when compared to patients on immunotherapy (94.1%±9.56, P <0.05) and chemotherapy (92.8%±18.1, P <0.05). SARS-CoV-2 infection was reported in 77 (28.2%) patients, of which 18 were severe. No patient receiving a third dose within 90 days of the second dose experienced severe infection., Conclusion: This study demonstrates the benefit of early administration of the third dose among cancer patients.

Background: Adding intraperitoneal paclitaxel (IP-PTX) to paclitaxel/5-fluoropyrimidine has shown promising results in patients with gastric cancer peritoneal metastases (GCPM) but has not been studied with standard-of-care platinum/fluoropyrimidine combinations. Our goal to was evaluate IP-PTX with capecitabine/oxaliplatin (XELOX) in GCPM., Methods: Forty-four patients with GCPM received IP PTX (40 mg/m 2 , Days 1, 8), oral capecitabine (1000 mg/m 2 twice daily, Days 1-14) and intravenous oxaliplatin (100 mg/m 2 , Day 1) in 21-day cycles. Patients with synchronous GCPM underwent conversion surgery if they had good response after chemotherapy, conversion to negative cytology, no extraperitoneal metastasis, and no peritoneal disease during surgery. The primary endpoint was overall survival and secondary endpoints were progression-free survival and safety. Outcomes from the trial were compared against a matched cohort of 39 GCPM patients who received systemic chemotherapy (SC) comprising platinum/fluoropyrimidine., Results: The median OS for the IP and SC groups was 14.6 and 10.6 months (hazard ratio [HR] 0.44; 95% confidence interval [CI], 0.26-0.74; p = 0.002). The median PFS for the IP and SC group was 9.5 and 4.4 months respectively (HR 0.39; 95% CI 0.25-0.66; p < 0.001). Patients in the SC group were younger (IP vs. SC, 61 vs. 56 years, p = 0.021) and had better performance status (ECOG 0, IP vs. SC, 47.7% vs. 76.9%, p = 0.007) compared with the IP cohort. In IP group, conversion surgery was performed in 36.1% (13/36) of patients, with a median OS of 24.2 (95% CI 13.1-35.3) months and 1-year OS of 84.6%., Conclusions: IP PTX with XELOX is a promising treatment option for GCPM patients. In patients with good response, conversion surgery was feasible with favourable outcomes., (© 2022. Society of Surgical Oncology.)

Parkinson's disease is a nervous system abnormality marked by decreased dopamine levels in the brain. Parkinson's disease inhibits one's ability to move. Speech difficulty, changes in movement and handwriting, and other symptoms are common with Parkinson's disease. A collection of hand drawings is employed to predict Parkinson's disease. There are 102 spiral images in the hand drawing dataset. Due to the minimal size of the dataset, augmentation is utilized to increase it. After that, the augmented images are utilized to train several machine learning and deep learning models, as well as pre-trained networks like RESNET50, VGG16, AlexNet, and VGG19. The performance metrics of hybrid models of deep learning with machine learning and hybrid models of deep learning (for feature extraction) with deep learning (for classification) are then compared. It was observed that the hybrid model of RESNET-50 and SVM performed well with better performance measures compared to other Machine Learning, Deep Learning and Hybrid Models with an accuracy score of 98.45%, sensitivity score of 0.99 and specificity score of 0.98., Competing Interests: Declaration of competing interest The authors have no competing interests to declare that are relevant to the content of this article., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Emerging evidence has shown higher overall cancer incidence in patients with obstructive sleep apnea. Gastrointestinal cancers, including esophageal, stomach, liver, pancreas, and colorectal cancers account for 26% of incident cancers. However, the link between gastrointestinal cancers and obstructive sleep apnea is still unclear. We performed a systematic review and meta-analysis (registered PROSPERO CRD42021220836) to investigate the association between obstructive sleep apnea and incidence of gastrointestinal cancer., Methods: We searched four electronic databases (PubMed, Embase, Cochrane Library, Scopus) and included studies published from inception till 15th November 2020 reporting the association of obstructive sleep apnea with gastrointestinal cancer incidence. Extracted data was meta-analyzed in a random-effects model., Results: A total of seven studies were included, forming a combined cohort of 5,120,837 patients. Studies which adjusted for demographics and comorbidities were included in meta-analysis. Among four studies with 7-11 years of median follow-up, patients with obstructive sleep apnea experienced increased incidence of colorectal cancer (HR 1.70, 95% CI: 1.48-1.96, I 2 =22%). Pancreatic cancer incidence was nominally increased in three studies (HR 1.36, 95% CI: 0.88-2.09, I 2 =96), though this was not statistically significant. There was no association between obstructive sleep apnea and liver cancer incidence among three studies (HR 0.99, 95% CI: 0.81-1.22, I 2 =84). However, the lack of a statistically significant relationship between obstructive sleep apnea and pancreatic cancer in our meta-analysis does not necessarily imply the true absence of an association., Conclusions: An increased risk of colorectal cancer was seen in patients with obstructive sleep apnea among studies with long-term follow-up. Further research is required to explore the utility of incorporating obstructive sleep apnea screening into colorectal cancer screening guidelines to identify high-risk individuals and to confirm a possible association of obstructive sleep apnea with pancreatic cancer., Prospero Registration: CRD42021220836., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-22-153/coif). The authors have no conflicts of interest to declare., (2022 Journal of Gastrointestinal Oncology. All rights reserved.)

Objective: To estimate continuous positive airway pressure (CPAP) length of treatment effect on survival of hospitalised COVID-19 patients in a medium-sized UK Hospital, and how this effect changes according to the patient's comorbidity and COVID-19 route of acquisition (community or nosocomial) during the two waves in 2020., Setting: The acute inpatient unit in Wrightington, Wigan and Leigh Teaching Hospitals National Health Service (NHS) Foundation Trust (WWL), a medium-sized NHS Trust in north-west of England., Design: Retrospective cohort of all confirmed COVID-19 patients admitted in WWL during 2020., Participants: 1830 patients (568 first wave, 1262 s wave) with antigen confirmed COVID-19 disease and severe acute respiratory syndrome admitted between 17 March 2020 (first confirmed COVID-19 case) and 31 December 2020., Outcome Measure: COVID-19 survival rate in all patients and survival rate in potentially hospital-acquired COVID-19 (PHA) patients were modelled using a predictor set which include comorbidities (eg, obesity, diabetes, chronic ischaemic heart disease (IHD), chronic kidney disease (CKD), chronic obstructive pulmonary disease (COPD)), wave, age, sex and care home residency, and interventions (remdesivir, dexamethasone, CPAP, intensive care unit (ICU), intubation). Secondary outcome measure was CPAP length, which was modelled using the same predictors of the survival rate., Results: Mortality rate in the second wave was significantly lower than in the first wave (43.4% vs 28.1%, p<0.001), although for PHA COVID-19 patients mortality did not reduce, remaining at very high levels independently of wave and CPAP length. For all cohort, statistical modelling identified CPAP length (HR 95% CI 0.86 to 0.96) and women (HR 95% CI 0.71 to 0.81) were associated with improved survival, while being older age (HR 95% CI 1.02 to 1.03) admitted from care homes (HR 95% CI 2.22 to 2.39), IHD (HR 95% CI 1.13 to 1.24), CKD (HR 95% CI 1.14 to 1.25), obesity (HR 95% CI 1.18 to 1.28) and COPD-emphysema (HR 95% CI 1.18 to 1.57) were associated with reduced survival. Despite the detrimental effect of comorbidities, patients with CKD (95% CI 16% to 30% improvement in survival), IHD (95% CI 1% to 10% improvement in survival) and asthma (95% CI 8% to 30% improvement in survival) benefitted most from CPAP length, while no significant survival difference was found for obese and patients with diabetes., Conclusions: The experience of an Acute Trust during the COVID-19 outbreak of 2020 is documented and indicates the importance of care home and hospitals in disease acquisition. Death rates fell between the first and second wave only for community-acquired COVID-19 patients. The fall was associated to CPAP length, especially for some comorbidities. While uncovering some risk and protective factors of mortality in COVID-19 studies, the study also unravels how little is known about PHA COVID-19 and the interaction between CPAP and some comorbidities., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

To extract the melanin pigment from marine microbes and their biological potential, the present study was done. Isolation and identification of the melanin-producing Nocardiopsis sp. were obtained from the sediment samples. Zone of inhibition and minimal inhibitory concentration test was performed using melanin. Melanin was extracted from sediment-associated marine Nocardiopsis sp. In the present study, marine actinobacterium was identified by the conventional method, and the isolate was identified as Nocardiopsis sp. Melanin was extracted, and antibacterial activities were performed against different pathogens and the highest zone of inhibition is more in the E. coli while related to another two species. From previous observation done by Fu et al ., they have said that marine actinobacteria have the ability of antimicrobial activity, which is very much helpful in producing the potential antimicrobial drugs this was similar to our study that marine actinobacteria have the capability to produce melanin pigment, and at the same time, it helps as to show the antibacterial activity. We concluded that melanin is produced by the Nocardiopsis sp. We also found that melanin extracted from the Nocardiopsis sp. of marine actinobacterium also has an antibacterial effect., Competing Interests: There are no conflicts of interest., (Copyright: © 2022 Journal of Advanced Pharmaceutical Technology & Research.)

Purpose: Nerve conduction studies (NCS) have been suggested as gold standard for diagnosing and monitoring peripheral neuropathies. However, its value in measuring chemotherapy-induced peripheral neuropathy (CIPN) is not clearly understood. Our study aimed to examine the role and performance of NCS in CIPN assessment through a secondary analysis., Methods: Pooled data pertaining to NCS, clinical examination, symptoms, and quality of life from patients with cancer enrolled in five studies were used. These patients had received taxane- or oxaliplatin-based chemotherapy. The data were grouped in cohorts of before initiation of chemotherapy, during chemotherapy, at the end of chemotherapy, and at recovery stage according to the time points of assessment in the original studies., Results: Data was available from a total of 84 patients (74 females and 10 males) and a total of 160 NCS assessments. NCS results confirmed that damage of sensory nerves is more profound than motor nerves in patients at different stages of neurotoxic chemotherapy. No strong correlation was identified between NCS parameters and clinical examination outcomes as well as patient-reported symptoms and quality of life. NCS did not perform well in discriminating clinically relevant CIPN (area under the curve [AUC] = 0.51-0.77)., Conclusions: Our findings suggest that NCS may have limited value in diagnosing CIPN. Future prospective studies with baseline values are needed to clarify our tentative conclusions., Competing Interests: Declaration of competing interest Dr. Aishwarya Bandla reports paid travel from Paxman Coolers, outside the submitted work; Dr. Raghav Sundar reports being an advisory board member of Bristol Myers Squibb, Merck, Eisai, Bayer, Taiho, Novartis, and MSD, honoraria for talks from MSD, Eli Lilly, BMS, Roche, Taiho, and Astra Zeneca, paid travel from Roche, Astra Zeneca, Taiho, and Eisai, and research grants from Paxman Coolers, MSD, all outside the submitted work; Prof. Alex Molassiotis reports research grants from Helsinn, outside the submitted work; Mr. Mian Wang has no conflicts of interest to disclose., (Copyright © 2022 Elsevier Ltd. All rights reserved.)