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Abstract Background Cardiovascular risk factors (CVRF) were collected as part of a randomised controlled trial of a multi-component intervention to reduce smoking among male prisoners. Cross-sectional baseline data on CVRF were compared among smoking male prisoners and males of similar age in the general population. Methods 425 smoking prisoners were recruited (n = 407 in New South Wales; 18 in Queensland), including 15% of Aboriginal descent (mean age 33 years; median sentence length 3.6 years). We measured CVRF such as smoking, physical activity, blood pressure, risky alcohol use, symptoms of depression, and low socioeconomic status. Results We found that 39% of prisoners had 3+ CVRF, compared to 10% in a general community sample of most disadvantaged men of a similar age. Significantly more Aboriginal prisoners had 3+ CVRF than non-Aboriginal prisoners (55% vs 36%, p < 0.01) and were twice as likely to have 4+ CVRF (27% vs 12%). In addition to all prisoners in this study being a current smoker (with 70% smoking 20+ cigarettes per day), the prevalence of other CVRF was very high: insufficient physical activity (23%); hypertension (4%), risky drinking (52%), symptoms of depression (14%) and low socioeconomic status (SES) (44%). Aboriginal prisoners had higher levels of risky alcohol use, symptoms of depression, and were more likely to be of low SES. Conclusion Prisoners are at high risk for developing cardiovascular disease compared to even the most disadvantaged in their community and should be the focus of specific public health interventions. Trial Registration This trial is registered with the Australian New Zealand Clinical Trials Registry ACTRN#12606000229572.

The LMO2 gene associated with T cell acute leukaemia has been used as an example of a gene activated by association with the T cell receptor genes after chromosomal translocations. The gene is shown to encode a LIM protein which is involved in protein interactions and during normal haematopoiesis is necessary for erythroid development. LMO2 has been shown to cause tumours when aberrantly expressed and to be able to heterodimerise with TAL1 to facilitate tumour development. [ABSTRACT FROM AUTHOR]

Background: This placebo-controlled phase III study investigated the effect on survival of gefitinib as second-line or third-line treatment for patients with locally advanced or metastatic non-small-cell lung cancer.Methods: 1692 patients who were refractory to or intolerant of their latest chemotherapy regimen were randomly assigned in a ratio of two to one either gefitinib (250 mg/day) or placebo, plus best supportive care. The primary endpoint was survival in the overall population of patients and those with adenocarcinoma. The primary analysis of the population for survival was by intention to treat. This study has been submitted for registration with ClinicalTrials.gov, number 1839IL/709.Findings: 1129 patients were assigned gefitinib and 563 placebo. At median follow-up of 7.2 months, median survival did not differ significantly between the groups in the overall population (5.6 months for gefitinib and 5.1 months for placebo; hazard ratio 0.89 [95% CI 0.77-1.02], p=0.087) or among the 812 patients with adenocarcinoma (6.3 months vs 5.4 months; 0.84 [0.68-1.03], p=0.089). Preplanned subgroup analyses showed significantly longer survival in the gefitinib group than the placebo group for never-smokers (n=375; 0.67 [0.49-0.92], p=0.012; median survival 8.9 vs 6.1 months) and patients of Asian origin (n=342; 0.66 [0.48-0.91], p=0.01; median survival 9.5 vs 5.5 months). Gefitinib was well tolerated, as in previous studies.Interpretation: Treatment with gefitinib was not associated with significant improvement in survival in either coprimary population. There was pronounced heterogeneity in survival outcomes between groups of patients, with some evidence of benefit among never-smokers and patients of Asian origin. [ABSTRACT FROM AUTHOR]

Although comprehensive biomarker testing is recommended for all patients with advanced/metastatic non-small cell lung cancer (NSCLC) before initiation of first-line treatment, tissue availability can limit testing. Genomic testing in liquid biopsies can be utilized to overcome the inherent limitations of tissue sampling and identify the most appropriate biomarker-informed treatment option for patients. The Blood First Assay Screening Trial is a global, open-label, multicohort trial that evaluates the efficacy and safety of multiple therapies in patients with advanced/metastatic NSCLC and targetable alterations identified by liquid biopsy. We present data from Cohort D (ROS1-positive). Patients ≥18 years of age with stage IIIB/IV, ROS1-positive NSCLC detected by liquid biopsies received entrectinib 600 mg daily. At data cutoff (November 2021), 55 patients were enrolled and 54 had measurable disease. Cohort D met its primary endpoint: the confirmed objective response rate (ORR) by investigator was 81.5%, which was consistent with the ORR from the integrated analysis of entrectinib (investigator-assessed ORR, 73.4%; data cutoff May 2019, ≥12 months of follow-up). The safety profile of entrectinib was consistent with previous reports. These results demonstrate consistency with those from the integrated analysis of entrectinib in patients with ROS1-positive NSCLC identified by tissue-based testing, and support the clinical value of liquid biopsies to inform clinical decision-making. The integration of liquid biopsies into clinical practice provides patients with a less invasive diagnostic method than tissue-based testing and has faster turnaround times that may expedite the reaching of clinical decisions in the advanced/metastatic NSCLC setting. ClinicalTrials.gov registration: NCT03178552 ., (© 2024. The Author(s).)

Introduction: Previous results from the phase 3 ALESIA study (NCT02838420) revealed that alectinib (a central nervous system [CNS]-active, ALK inhibitor) had clinical benefits in treatment-naïve Asian patients with advanced ALK -positive NSCLC, consistent with the global ALEX study. We present updated data after more than or equal to 5 years of follow-up from the "last patient in" date., Methods: Adult patients with treatment-naïve, advanced ALK -positive NSCLC from mainland China, South Korea, and Thailand were randomized 2:1 to receive twice-daily 600 mg alectinib (n = 125) or 250 mg crizotinib (n = 62). The primary endpoint was investigator-assessed progression-free survival. Secondary or exploratory endpoints included overall survival, objective response rate, time to CNS progression, and safety., Results: At the data cutoff (May 16, 2022), the median survival follow-up was 61 and 51 months in the alectinib and crizotinib arms, respectively. Median progression-free survival was 41.6 months with alectinib versus 11.1 months with crizotinib (stratified hazard ratio = 0.33, 95% confidence interval: 0.23-0.49). Overall survival data remain immature; 5-year overall survival rates were 66.4% (alectinib arm) versus 56.1% (crizotinib arm). Objective response rate was 91.2% versus 77.4% with alectinib and crizotinib, respectively. CNS progression was delayed with alectinib versus crizotinib (cause-specific hazard ratio = 0.16, 95% confidence interval: 0.08-0.32). Median treatment duration was longer with alectinib versus crizotinib (42.3 versus 12.6 mo). No new safety signals were observed., Conclusions: With four additional years of follow-up, these updated results confirm the clinical benefit and manageable safety of alectinib in Asian patients with advanced ALK -positive NSCLC, and confirm alectinib as a standard-of-care treatment for patients with advanced ALK -positive NSCLC., Competing Interests: Prof. Caicun Zhou reports receiving consulting fees from Innovent Biologics, Jiangsu Hengrui Pharmaceuticals, Qilu Pharmaceutical, and TopAlliance Biosciences; and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Alice Pharma, AnHeart Therapeutics, Amoy Diagnostics, Boehringer Ingelheim, CStone Pharmaceuticals, Eli Lilly, F. Hoffmann-La Roche Ltd., Innovent Biologics, Jiangsu Hengrui Pharmaceuticals, Luye Pharma Group, Merck Sharp & Dohme, Qilu Pharmaceutical, Sanofi, and TopAlliance Biosciences. Prof. You Lu reports invited speaker roles for BeiGene, Roche/Genentech, AstraZeneca, Pfizer; advisory roles for Roche/Genentech, AstraZeneca, Pfizer, Bristol-Myers Squibb, Merck Sharp & Dohme, and BeiGene; and leadership roles for Roche/Genentech, AstraZeneca, and BeiGene. Dr. Sang-We Kim reports invited speaker roles for Amgen, Boehringer Ingelheim, Janssen, Novartis, and Takeda; receiving research funding from 10.13039/100019265Yuhan; and advisory roles from Amgen, AstraZeneca, Boehringer Ingelheim, Janssen, Novartis, Takeda, and Yuhan. Dr. Thanyanan Reungwetwattana reports advisory board roles from Amgen, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, F. Hoffmann-La Roche Ltd., Johnson & Johnson, Merck Sharp & Dohme, Novartis, and Yuhan; participation in clinical research for AstraZeneca, Boehringer Ingelheim, F. Hoffmann-La Roche Ltd., Merck Sharp & Dohme, Novartis, and Yuhan; and speaker roles for Amgen, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, F. Hoffmann-La Roche Ltd., Merck Sharp & Dohme, Novartis, Yuhan, and Zuellig Pharma. Prof. Jianying Zhou, Prof. Yiping Zhang, Prof. Jianxing He, Prof. Jin-Ji.Yang and Prof. Ying Cheng report no conflicts of interest. Prof. Se-Hoon Le reports receiving research funding (institution) from 10.13039/100004325AstraZeneca, 10.13039/100019703Lunit, and 10.13039/100004334Merck; and consulting/advisory roles from AstraZeneca, Bristol-Myers Squibb/Ono Pharmaceuticals, F. Hoffmann-La Roche Ltd., IMBdx, Janssen, Eli Lilly, Merck, Novartis, Pfizer, and Takeda. Prof. Jianhua Chang, Dr. Jian Fang and Prof. Zhe Liu report no conflicts of interest. Ms. Lilian Bu, Dr. Li Qian and Dr. Tingting Xu report employment with F. Hoffmann-La Roche Ltd. Dr. Venice Archer and Ms. Magalie Hilton report employment and stocks/shares with F. Hoffmann-La Roche Ltd. Dr. Mingzhu Zhou reports employment with F. Hoffmann-La Roche Ltd. Prof. Li Zhang reports consulting/advisory roles for AstraZeneca and Innovent Biologics; and receiving research funding (institution) from Akeso Biopharma, AstraZeneca, Bristol-Myers Squibb, Chia Tai Tianqing Pharmaceutical Group, Junshi Biosciences, and Qilu Pharmaceutical., (© 2024 The Authors.)

Purpose: The aim of this systematic review and meta-analysis was to evaluate whether Enhanced Recovery After Surgery (ERAS) protocols for patients undergoing emergency intra-abdominal surgery improve postoperative outcomes as compared to conventional care., Methods: MEDLINE, EMBASE, WoS, CENTRAL, and Pubmed were searched from inception to December 2022. Articles were eligible if they were randomized controlled trials (RCT) or non-randomized studies comparing ERAS protocols to conventional care for patients undergoing emergency intra-abdominal surgery. The outcomes included postoperative length of stay (LOS), postoperative morbidity, prolonged postoperative ileus (PPOI), and readmission. An inverse variance random effects meta-analysis was performed. A risk of bias was assessed with Cochrane tools. Certainty of evidence was assessed with GRADE., Results: After screening 1018 citations, 20 studies with 1615 patients in ERAS programs and 1933 patients receiving conventional care were included. There was a reduction in postoperative LOS in the ERAS group for patients undergoing upper gastrointestinal (GI) surgery (MD3.35, 95% CI 2.52-4.17, p < 0.00001) and lower GI surgery (MD2.80, 95% CI 2.62-2.99, p < 0.00001). There was a reduction in postoperative morbidity in the ERAS group for patients undergoing upper GI surgery (RR0.56, 95% CI 0.30-1.02, p = 0.06) and lower GI surgery (RR 0.66, 95%CI 0.52-0.85, p = 0.001). In the upper and lower GI subgroup, there were nonsignificant reductions in PPOI in the ERAS groups (RR0.59, 95% CI 0.30-1.17, p = 0.13; RR0.49, 95% CI 0.21-1.14, p = 0.10). There was a nonsignificant increased risk of readmission in the ERAS group (RR1.60, 95% CI 0.57-4.50, p = 0.50)., Conclusion: There is low-to-very-low certainty evidence supporting the use ERAS protocols for patients undergoing emergency intra-abdominal surgery. The currently available data are limited by imprecision., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Aim: While postoperative C-reactive protein (CRP) is used routinely as an early indicator of anastomotic leak (AL), preoperative CRP remains to be established as a potential predictor of AL for elective colorectal surgery. The aim of this systematic review and meta-analysis is to examine the association between preoperative CRP and postoperative complications including AL., Method: MEDLINE, EMBASE, Web of Science, PubMed, Cochrane Library and CINAHL databases were searched. Studies with reported preoperative CRP values and short-term surgical outcomes after elective colorectal surgery were included. An inverse variance random effects meta-analysis was performed for all meta-analysed outcomes to determine if patients with or without complications and AL differed in their preoperative CRP levels. Risk of bias was assessed with MINORS and certainty of evidence with GRADE., Results: From 1945 citations, 23 studies evaluating 7147 patients were included. Patients experiencing postoperative infective complications had significantly greater preoperative CRP values [eight studies, n = 2421 patients, mean difference (MD) 8.0, 95% CI 3.77-12.23, p < 0.01]. A significant interaction was observed with subgroup analysis based on whether patients were undergoing surgery for inflammatory bowel disease (X 2  = 8.99, p < 0.01). Preoperative CRP values were not significantly different between patients experiencing and not experiencing AL (seven studies, n = 3317, MD 2.15, 95% CI -2.35 to 6.66, p = 0.35), nor were they different between patients experiencing and not experiencing overall postoperative morbidity (nine studies, n = 2958, MD 4.54, 95% CI -2.55 to 11.62, p = 0.31) after elective colorectal surgery., Conclusion: Higher preoperative CRP levels are associated with increased rates of overall infective complications, but not with AL alone or with overall morbidity in patients undergoing elective colorectal surgery., (© 2024 The Authors. Colorectal Disease published by John Wiley & Sons Ltd on behalf of Association of Coloproctology of Great Britain and Ireland.)

The Ataxia telangiectasia and Rad3-related (ATR) inhibitor ceralasertib in combination with the PD-L1 antibody durvalumab demonstrated encouraging clinical benefit in melanoma and lung cancer patients who progressed on immunotherapy. Here we show that modelling of intermittent ceralasertib treatment in mouse tumor models reveals CD8 + T-cell dependent antitumor activity, which is separate from the effects on tumor cells. Ceralasertib suppresses proliferating CD8 + T-cells on treatment which is rapidly reversed off-treatment. Ceralasertib causes up-regulation of type I interferon (IFNI) pathway in cancer patients and in tumor-bearing mice. IFNI is experimentally found to be a major mediator of antitumor activity of ceralasertib in combination with PD-L1 antibody. Improvement of T-cell function after ceralasertib treatment is linked to changes in myeloid cells in the tumor microenvironment. IFNI also promotes anti-proliferative effects of ceralasertib on tumor cells. Here, we report that broad immunomodulatory changes following intermittent ATR inhibition underpins the clinical therapeutic benefit and indicates its wider impact on antitumor immunity., (© 2024. The Author(s).)

Objectives: The main objective of this study was to assess the level of knowledge and information received by patients regarding their implants and to discuss the role of community pharmacists., Methods: A prospective survey was conducted in 3 pharmacies among patients presenting for various reasons. Firstly, on the same day, all patients visiting the pharmacy were asked if they had an implant. Secondly, patients with implants were offered a short survey consisting of 16 questions concerning the implant and the information received., Results and Discussion: The survey was conducted with 178 patients, among whom 11.4% had implants. The majority of them reported having osteoarticular, dental, or ophthalmic implants. Women were 67.1% of the cohort. None of the 178 patients with implants in the survey had complete information about their implant and its follow-up, which would enable optimal care and effective reporting in case of potential complications., Conclusion: The majority of patients visiting the pharmacy had received limited or inadequate information about their implants. Community pharmacists, as local healthcare providers, in collaboration with hospitals, could play a crucial role in patient education. During the initial dispensing of postoperative treatments, pharmacists could inform and advise patients to enhance their patient journey., (Copyright © 2023 Académie Nationale de Pharmacie. Published by Elsevier Masson SAS. All rights reserved.)

Introduction: Enhanced Rehabilitation After Surgery (ERAS) pathways significantly improve the care of patients in orthopedic surgery. However, patient knowledge and memorization of the information provided are currently poorly documented., Hypothesis: The information provided by a postoperative pharmacist could have a positive impact on patient care, in particular by improving knowledge about their prosthesis., Material and Method: This prospective feasibility study included a cohort of 80 patients operated on for a hip or knee prosthesis and who received postoperative pharmacist interviews (POPI). These POPIs informed the patient about the prosthesis, the complications, positions to avoid, as well as the postoperative follow-up. The objective was to measure the patient's knowledge before and after the POPI. Qualitative and quantitative analyses, by indication and patient pathway, were performed., Results: The patient's knowledge before POPI was 70% correct. After POPI this rate rose to 91%., Discussion: Patients' knowledge was weak and heterogeneous, especially regarding the implanted prosthesis. The POPI led to significant improvement and standardization of knowledge which should contribute to the prevention of iatrogenic harm (positions to avoid, infection prevention, compliance with analgesics and anticoagulants)., Conclusion: A POPI with a pharmacist improves overall patient management during hip or knee arthroplasty., Level of Evidence: III; non-randomized prospective feasibility study., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

The NLRP3 inflammasome is a multiprotein complex that plays a critical role in activating the immune system in response to danger signals. Small molecule agonists of NLRP3 may offer clinical benefits in cancer immunology either as a monotherapy or in combination with checkpoint blockade, where it is hypothesised that their application can help to initiate an antitumor immune response. In this study, we report the discovery of quinazolines and 8-azaquinazolines as NLRP3 agonists and their chemical optimization to afford compounds with oral bioavailability in mice. We confirm that these compounds engage the NLRP3 inflammasome by verifying their dependence upon lipopolysaccharide (LPS) priming for cytokine release and the activation of Caspase-1. We further demonstrate pathway engagement through loss of activity in an NLRP3-knockout THP1 cell line. Based on their pharmacokinetic profile and biological activity, these compounds represent valuable tools to evaluate the therapeutic potential of NLRP3 activation in a pre-clinical setting., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: All authors are past or present employees and/or shareholders of AstraZeneca PLC., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Health literacy is an important factor for enabling people to manage their health and live long fulfilling lives. People in prison are frequently from marginalised communities, often out of reach of conventional community based health organisations, and have poorer health outcomes. It is essential to understanding the health literacy profiles of people in prison, and its contribution to the well-established health inequities and outcomes of this population. This study aimed to use a multi-dimensional health literacy measurement tool to describe the strengths and challenges of adults incarcerated in NSW prisons., Methods: A cross-sectional survey was conducted for people in prison across 14 publicly operated metropolitan prisons. Data were collected from 471 participants using the Health Literacy Questionnaire (HLQ). Participant characteristics and health conditions were also collected. Data were analysed using descriptive statistics. Effect sizes (ES) for standardised differences in means were used to describe the magnitude of difference between participant characteristic groups., Results: Participants' median age was 38.0 (range 19 - 91) years. Males comprised 81% of the sample, 21% identified as Aboriginal and/or Torres Strait Islander, and 53% reported a health problem. People in prison had lower scores for all nine HLQ scales when compared to the general Australian population. Small to medium ES were seen for mean differences between most demographic groups. Compared to males, females had lower scores for several of the HLQ scales including 'having sufficient information to manage health' (ES 0.30 [95% Confidence Interval (CI) 0.07, 0.53]), 'ability to actively engage with health care professionals' (ES 0.30 [95% CI 0.06, 0.53]), 'navigating the healthcare system' (ES 0.30 [95% CI 0.06, 0.53]), and, 'ability to find good health information' (ES 0.33 [95% CI 0.10, 0.57]). Differing health literacy scale scores with small to medium ES were found when comparing participants by legal status. Mainly small ES were seen when comparing other participant characteristic groups., Conclusions: This study provides insights into the health literacy strengths and challenges for people in NSW prisons. These findings highlight the important role health literacy could have in addressing health disparities in this vulnerable population and can inform prison health services., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Single-cell technologies have elucidated mechanisms responsible for immune checkpoint inhibitor (ICI) response, but are not amenable to a clinical diagnostic setting. In contrast, bulk RNA sequencing (RNA-seq) is now routine for research and clinical applications. Our workflow uses transcription factor (TF)-directed coexpression networks (regulons) inferred from single-cell RNA-seq data to deconvolute immune functional states from bulk RNA-seq data. Regulons preserve the phenotypic variation in CD45+ immune cells from metastatic melanoma samples (n = 19, discovery dataset) treated with ICIs, despite reducing dimensionality by >100-fold. Four cell states, termed exhausted T cells, monocyte lineage cells, memory T cells, and B cells were associated with therapy response, and were characterized by differentially active and cell state-specific regulons. Clustering of bulk RNA-seq melanoma samples from four independent studies (n = 209, validation dataset) according to regulon-inferred scores identified four groups with significantly different response outcomes (P < 0.001). An intercellular link was established between exhausted T cells and monocyte lineage cells, whereby their cell numbers were correlated, and exhausted T cells predicted prognosis as a function of monocyte lineage cell number. The ligand-receptor expression analysis suggested that monocyte lineage cells drive exhausted T cells into terminal exhaustion through programs that regulate antigen presentation, chronic inflammation, and negative costimulation. Together, our results demonstrate how regulon-based characterization of cell states provide robust and functionally informative markers that can deconvolve bulk RNA-seq data to identify ICI responders., (©2023 The Authors; Published by the American Association for Cancer Research.)

Background: Several management options exist for colonic decompression in the setting of malignant large bowel obstruction, including oncologic resection, surgical diversion, and SEMS as a bridge-to-surgery. Consensus has yet to be reached on optimal treatment pathways. The aim of the present study was to perform a network meta-analysis comparing short-term postoperative morbidity and long-term oncologic outcomes between oncologic resection, surgical diversion, and self-expanding metal stents (SEMS) in left-sided malignant colorectal obstruction with curative intent., Methods: Medline, Embase, and CENTRAL were systematically searched. Articles were included if they compared two or more of the following in patients presenting with curative left-sided malignant colorectal obstruction: (1) emergent oncologic resection; (2) surgical diversion; and/or (3) SEMS. The primary outcome was overall 90-day postoperative morbidity. Pairwise meta-analyses were performed with inverse variance random effects. Random-effect Bayesian network meta-analysis was performed., Results: From 1277 citations, 53 studies with 9493 patients undergoing urgent oncologic resection, 1273 patients undergoing surgical diversion, and 2548 patients undergoing SEMS were included. Network meta-analysis demonstrated a significant improvement in 90-day postoperative morbidity in patients undergoing SEMS compared to urgent oncologic resection (OR0.34, 95%CrI0.01-0.98). Insufficient RCT data pertaining to overall survival (OS) precluded network meta-analysis. Pairwise meta-analysis demonstrated decreased five-year OS for patients undergoing urgent oncologic resection compared to surgical diversion (OR0.44, 95%CI0.28-0.71, p < 0.01)., Conclusions: Bridge-to-surgery interventions may offer short- and long-term benefits compared to urgent oncologic resection for malignant colorectal obstruction and should be increasingly considered in this patient population. Further prospective study comparing surgical diversion and SEMS is needed., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: Alectinib was found to have superior efficacy to crizotinib in the phase 3 ALEX study and is a preferred initial treatment for patients with advanced ALK -positive NSCLC. To understand the efficacy of alectinib in U.S. clinical practice, we conducted a retrospective real-world comparative effectiveness analysis of first-line alectinib versus crizotinib., Methods: Adults with advanced ALK -positive NSCLC who received first-line alectinib (from December 11, 2015) or crizotinib (from January 1, 2014) were included from a real-world database. Propensity scores were applied to balance baseline characteristics. Real-world data (RWD), including real-world progression-free survival (rwPFS), real-world overall survival, real-world time to new central nervous system (CNS) metastases, and outcomes in patients with or without baseline CNS metastases were analyzed. The ALEX-like RWD cohort (filtered by ALEX laboratory eligibility criteria) was used to compare real-world comparative effectiveness with ALEX., Results: The RWD cohort comprised 364 patients (141 alectinib; 223 crizotinib); rwPFS (weighted hazard ratio [wHR] = 0.46, 95% confidence interval [CI]: 0.33-0.65) and real-world overall survival (wHR = 0.46, 95% CI: 0.31-0.69) were significantly improved with alectinib versus crizotinib. In patients with baseline brain scans, a substantial rwPFS benefit was found regardless of baseline CNS metastases. Real-world time to new CNS metastases was delayed with alectinib versus crizotinib in patients with (wHR = 0.28, 95% CI: 0.16-0.52) and without (wHR = 0.42, 95% CI: 0.24-0.76) baseline CNS metastases. The ALEX-like RWD cohort comprised 325 patients (120 alectinib; 205 crizotinib); alectinib was found to have similar rwPFS benefits with ALEX., Conclusions: Outcomes were significantly improved with first-line alectinib versus crizotinib in patients with advanced ALK -positive NSCLC in the U.S. real-world setting., (© 2023 The Authors.)

Myofibroblastic cancer-associated fibroblast (myoCAF)-rich tumors generally contain few T cells and respond poorly to immune-checkpoint blockade. Although myoCAFs are associated with poor outcome in most solid tumors, the molecular mechanisms regulating myoCAF accumulation remain unclear, limiting the potential for therapeutic intervention. Here, we identify ataxia-telangiectasia mutated (ATM) as a central regulator of the myoCAF phenotype. Differentiating myofibroblasts in vitro and myoCAFs cultured ex vivo display activated ATM signaling, and targeting ATM genetically or pharmacologically could suppress and reverse differentiation. ATM activation was regulated by the reactive oxygen species-producing enzyme NOX4, both through DNA damage and increased oxidative stress. Targeting fibroblast ATM in vivo suppressed myoCAF-rich tumor growth, promoted intratumoral CD8 T-cell infiltration, and potentiated the response to anti-PD-1 blockade and antitumor vaccination. This work identifies a novel pathway regulating myoCAF differentiation and provides a rationale for using ATM inhibitors to overcome CAF-mediated immunotherapy resistance., Significance: ATM signaling supports the differentiation of myoCAFs to suppress T-cell infiltration and antitumor immunity, supporting the potential clinical use of ATM inhibitors in combination with checkpoint inhibition in myoCAF-rich, immune-cold tumors., (©2022 The Authors; Published by the American Association for Cancer Research.)

Pediatric opioid exposure increases short- and long-term adverse events (AE). The addition of intravenous acetaminophen (IVA) to pediatric pain regimes to may reduce opioids but is not well studied postoperatively. Our objective was to quantify the impact of IVA on postoperative pain, opioid use, and AEs in pediatric patients after major abdominal and thoracic surgery. Medline, Embase, CINAHL, Web of Science, and Cochrane Library were searched systematically for randomized controlled trials (RCTs) comparing IVA to other modalities. Five RCTs enrolling 443 patients with an average age of 2.12 years (± 2.81) were included. Trials comparing IVA with opioids to opioids alone were meta-analyzed. Low to very low-quality evidence demonstrated equivalent pain scores between the groups (-0.23, 95% CI -0.88 to 0.40, p 0.47) and a reduction in opioid consumption (-1.95 morphine equivalents/kg/48 h, 95% CI -3.95 to 0.05, p 0.06) and minor AEs (relative risk 0.39, 95% CI 0.11 to 1.43, p 0.15). We conclude that the addition of IVA to opioid-based regimes in pediatric patients may reduce opioid use and minor AEs without increasing postoperative pain. Given the certainty of evidence, further research featuring patient-important outcomes and prolonged follow-up is necessary to confirm these findings., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: Short-stay admissions, with lengths of stay less than 24 h, are used for various surgeries without increasing adverse events. However, it is unclear if short-stay admissions would be safe for loop ileostomy reversals. This review aimed to compare outcomes between short (≤24 hours) and long (>24 hours) admissions for adults undergoing loop ileostomy reversals., Methods: Medline, Embase, CINAHL, Web of Science, and the Cochrane Library were systematically searched for studies comparing short- to long-stay admissions in adults undergoing loop ileostomy reversals. Meta-analyses were conducted for mortality, reoperation, readmission, and non-reoperative complications. Quality of evidence was assessed with grading of recommendations, assessment, development, and evaluations (GRADE) guidelines., Results: Four observational studies enrolling 24,628 patients were included. Moderate certainty evidence suggests there is no difference in readmissions between short- and long-stay admissions (relative risk (RR) 0.98, 95% CI 0.75 to 1.28, p 0.86). Low certainty evidence demonstrates that short stays may reduce non-reoperative complications (RR 0.44, 95% CI 0.31 to 0.62, p < 0.01). Very low certainty evidence demonstrates that there is no difference in reoperations between short and long stays (RR 1.14, 95% CI 0.26 to 5.04, p 0.87)., Conclusions: Moderate certainty evidence demonstrates that there is no difference in readmission rates between short- and long-stay admissions for loop ileostomy reversals. Less robust evidence suggests equivalence in reoperations and a decrease in non-reoperative complications. Future prospective trials are required to evaluate the feasibility and efficacy of short-stay admissions., Trial Registration: https://www.crd.york.ac.uk/prospero/display&#95;record.php?RecordID=307381 Prospero (CRD42022307381), January 30, 2022., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The concept of exploiting tumor intrinsic deficiencies in DNA damage repair mechanisms by inhibiting compensatory DNA repair pathways is well established. For example, ATM-deficient cells show increased sensitivity to the ATR inhibitor ceralasertib. DNA damage response (DDR)-deficient cells are also more sensitive to DNA damaging agents like the DNA crosslinker pyrrolobenzodiazepine (PBD) SG-3199. However, additional antitumor benefits from targeting the DDR pathways, which could operate through the activation of the innate immune system are less well studied. DNA accumulation in the cytosol acts as an immunogenic danger signal, inducing the expression of type-I interferon (IFN) stimulated genes (ISGs) by the activation of the cGAS-STING pathway. Here, we demonstrate that ATM -/- FaDu tumor cells have higher basal expression of ISGs when compared to WT cells and respond to ceralasertib and PBD SG-3199 by inducing higher levels of ISGs in a cGAS-STING-dependent manner. We show that sensitive tumor cells treated with ceralasertib and PBD SG-3199 activate dendritic cells (DCs) via a type-I IFN-dependent mechanism. However, STING deficiency in tumor cells does not prevent DC activation, suggesting that transactivation of the STING pathway occurs within DCs. Furthermore, depletion of the cytosolic DNA exonuclease TREX1 in tumor cells increases DC activation in response to PBD SG-3199-treated tumor cells, indicating that an increase in tumor-derived cytosolic DNA may further enhance DC activation. In summary, in this study, we show that ceralasertib and PBD SG-3199 treatment not only intrinsically target tumor cells but also extrinsically increase tumor cell immunogenicity by inducing DC activation, which is enhanced in ATM-deficient cells., Competing Interests: All authors were employees at and stock holders of AstraZeneca at the time of the study., (© 2022 The Author(s). Published with license by Taylor & Francis Group, LLC.)

PARP inhibitors are synthetically lethal with BRCA1/2 mutations, and in this setting, accumulation of DNA damage leads to cell death. Because increased DNA damage and subsequent immune activation can prime an anti-tumor immune response, we studied the impact of olaparib ± immune checkpoint blockade (ICB) on anti-tumor activity and the immune microenvironment. Concurrent combination of olaparib, at clinically relevant exposures, with ICB gave durable and deeper anti-tumor activity in the Brca1m BR5 model vs. monotherapies. Olaparib and combination treatment modulated the immune microenvironment, including increases in CD8+ T cells and NK cells, and upregulation of immune pathways, including type I IFN and STING signaling. Olaparib also induced a dose-dependent upregulation of immune pathways, including JAK/STAT, STING and type I IFN, in the tumor cell compartment of a BRCA1m (HBCx-10) but not a BRCA WT (HBCx-9) breast PDX model. In vitro , olaparib induced BRCAm tumor cell-specific dendritic cell transactivation. Relevance to human disease was assessed using patient samples from the MEDIOLA (NCT02734004) trial, which showed increased type I IFN, STING, and JAK/STAT pathway expression following olaparib treatment, in line with preclinical findings. These data together provide evidence for a mechanism and schedule underpinning potential benefit of ICB combination with olaparib., Competing Interests: All the authors were employees and shareholders of AstraZeneca at the time of this research., (© 2022 AstraZeneca. Published with license by Taylor & Francis Group, LLC.)

Background: Despite elevated risk of cardiometabolic disease among those with serious mental illness, and widespread recognition that physical activity interventions are required, there are multiple barriers to implementing typically recommended physical activity programmes in secure inpatient settings. Due to low mood, negative symptoms and poor socio-occupational functioning, psychiatric inpatients often lack motivation to engage in physical activity programmes. Moreover, regular access to outdoor spaces and exercise equipment is limited. As such, there is a need for novel physical activity interventions that are suitable for secure settings. This study aims to investigate the feasibility, acceptability and potential effectiveness of an intervention (exergaming) to promote physical activity among patients in a secure mental health setting., Methods: This non-randomised, two-arm pilot study will employ a pre-test/post-test parallel group design, comparing the exergaming intervention with a "routine treatment" control. Two high-secure, sub-acute wards in the Long Bay Hospital Mental Health Unit will be non-randomly allocated to either the exergaming intervention or the "routine treatment" control group. The intervention group will receive a 12-week programme comprising three 30-min exergaming sessions per week using various Xbox Kinect TM activity-based games designed to simulate moderate intensity exercise. The "routine treatment" group will continue to receive the standard model of care delivered by the Justice Health and Forensic Mental Health Network. Accelerometers will be distributed to all participants to collect daily energy expenditure, number of steps taken, intensity of physical activity and heart rate data throughout the study. The primary outcomes are (1) intervention feasibility and acceptability, and (2) baseline to post-intervention changes in physical health outcomes (levels of physical activity; cardiovascular fitness; clinical measures of cardiometabolic risk). Secondary outcomes are baseline to post-intervention changes in mental health outcomes (depression, anxiety, stress, positive psychiatric symptoms). Outcomes will be assessed at baseline, mid-intervention, and post-intervention., Discussion: This research will contribute to evidence-based practice in the care of patients with serious mental illness: a vulnerable population with complex physical and mental health needs and a markedly elevated risk of cardiovascular disease. The findings will inform cardiovascular health promotion strategies and the implementation of physical activity interventions in secure inpatient settings., Trial Registration: ANZCTR, ACTRN12619000202167. Registered on 12 February 2019, https://www.anzctr.org.au . ANZCTR mandatory data items comply with the minimum dataset requirements of the World Health Organisation (WHO). The ANZCTR contributes trial registration data to the WHO International Clinical Trials Registry Platform (WHO ICTRP)., (© 2022. The Author(s).)

Introduction: The Blood First Assay Screening Trial revealed the clinical applicability of blood-based next-generation sequencing to identify patients with ALK -positive NSCLC for alectinib treatment. To understand the relationship between tissue-based versus blood-based testing, we retrospectively investigated concordance between VENTANA ALK (D5F3) CDx immunohistochemistry and the FoundationACT (FACT; Foundation Medicine, Inc.) plasma assay, and compared clinical efficacy between phase 3 ALEX study subpopulations., Methods: Patients with advanced ALK -positive (by immunohistochemistry) NSCLC were randomized 1:1 to alectinib 600 mg or crizotinib 250 mg, twice daily. Assessable baseline plasma samples were analyzed for ALK positivity by FACT; positive percent agreement with immunohistochemistry was evaluated. Progression-free survival (PFS), duration of response, and objective response rate were compared between intention-to-treat (ITT) and biomarker-evaluable populations, and plasma ALK- positive and plasma ALK -negative subpopulations., Results: In the ITT population (303 patients; alectinib, 152; crizotinib, 151), all patients had ALK -positive tumors by immunohistochemistry. In the biomarker-evaluable population (149 patients; alectinib, 76; crizotinib, 73), 105 had plasma ALK -positive and 44 had plasma ALK -negative tumors. Positive percent agreement between immunohistochemistry and FACT was 70.5% (105 of 149; 95% confidence interval: 62.5-77.7). Baseline characteristics were generally balanced, with some exceptions, notably tumor burden. Median PFS in plasma ALK -positive and ALK -negative patients was 22.4 months and not estimable with alectinib and 7.3 months and 12.9 months with crizotinib, respectively; median duration of response was 25.9 months and not estimable with alectinib and 5.6 months and 11.5 months with crizotinib, respectively., Conclusions: Reasonable concordance between FACT and immunohistochemistry was observed; both methods are valuable in identifying ALK -positive patients, separately or concurrently. Alectinib was found to have superior PFS in the plasma ALK -positive population, as in the ITT population., (© 2022 The Authors.)

Purpose: Combining radiotherapy (RT) with DNA damage response inhibitors may lead to increased tumor cell death through radiosensitization. DNA-dependent protein kinase (DNA-PK) plays an important role in DNA double-strand break repair via the nonhomologous end joining (NHEJ) pathway. We hypothesized that in addition to a radiosensitizing effect from the combination of RT with AZD7648, a potent and specific inhibitor of DNA-PK, combination therapy may also lead to modulation of an anticancer immune response., Experimental Design: AZD7648 and RT efficacy, as monotherapy and in combination, was investigated in fully immunocompetent mice in MC38, CT26, and B16-F10 models. Immunologic consequences were analyzed by gene expression and flow-cytometric analysis., Results: AZD7648, when delivered in combination with RT, induced complete tumor regressions in a significant proportion of mice. The antitumor efficacy was dependent on the presence of CD8 + T cells but independent of NK cells. Analysis of the tumor microenvironment revealed a reduction in T-cell PD-1 expression, increased NK-cell granzyme B expression, and elevated type I IFN signaling in mice treated with the combination when compared with RT treatment alone. Blocking of the type I IFN receptor in vivo also demonstrated a critical role for type I IFN in tumor growth control following combined therapy. Finally, this combination was able to generate tumor antigen-specific immunologic memory capable of suppressing tumor growth following rechallenge., Conclusions: Blocking the NHEJ DNA repair pathway with AZD7648 in combination with RT leads to durable immune-mediated tumor control., (©2021 The Authors; Published by the American Association for Cancer Research.)

Natural killer (NK) cells are innate lymphocytes that play a pivotal role in the immune surveillance and elimination of transformed or virally infected cells. Using a chemo-genetic approach, we identify BET bromodomain containing proteins BRD2 and BRD4 as central regulators of NK cell functions, including direct cytokine secretion, NK cell contact-dependent inflammatory cytokine secretion from monocytes as well as NK cell cytolytic functions. We show that both BRD2 and BRD4 control inflammatory cytokine production in NK cells isolated from healthy volunteers and from rheumatoid arthritis patients. In contrast, knockdown of BRD4 but not of BRD2 impairs NK cell cytolytic responses, suggesting BRD4 as critical regulator of NK cell mediated tumor cell elimination. This is supported by pharmacological targeting where the first-generation pan-BET bromodomain inhibitor JQ1(+) displays anti-inflammatory effects and inhibit tumor cell eradication, while the novel bivalent BET bromodomain inhibitor AZD5153, which shows differential activity towards BET family members, does not. Given the important role of both cytokine-mediated inflammatory microenvironment and cytolytic NK cell activities in immune-oncology therapies, our findings present a compelling argument for further clinical investigation., Competing Interests: VV-A was employed by AstraZeneca. HO was employed by Roche Innovation Center Copenhagen A/S. 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.​ The authors declare that this study received funding from AstraZeneca. The funder was involved in the interpretation of the data and reviewed the article before the decision to submit it for publication., (Copyright © 2021 Cribbs, Filippakopoulos, Philpott, Wells, Penn, Oerum, Valge-Archer, Feldmann and Oppermann.)

We report the first disclosure of IRAK3 degraders in the scientific literature. Taking advantage of an opportune byproduct obtained during our efforts to identify IRAK4 inhibitors, we identified ready-to-use, selective IRAK3 ligands in our compound collection with the required properties for conversion into proteolysis-targeting chimera (PROTAC) degraders. This work culminated with the discovery of PROTAC 23 , which we demonstrated to be a potent and selective degrader of IRAK3 after 16 h in THP1 cells. 23 induced proteasome-dependent degradation of IRAK3 and required both CRBN and IRAK3 binding for activity. We conclude that PROTAC 23 constitutes an excellent in vitro tool with which to interrogate the biology of IRAK3.

Purpose: Surgery for pectus excavatum is associated with significant postoperative pain. The aim of this study was to summarize the current literature regarding postoperative pain control for pediatric patients undergoing minimally invasive repair of pectus excavatum (MIRPE)., Methods: A systematic search of Medline, Embase, PubMed, CINAHL, Web of Science, and the Cochrane Library for randomized controlled trials (RCT) comparing methods of pain control in pediatric patients undergoing MIRPE was conducted. Studies were restricted to the English language., Results: After screening 1304 references, 9 randomized control trials (RCTs) enrolling 485 patients were included. The average age was 11.9 years (±3.1). Pain scores were decreased with ropivacaine compared to bupivacaine-based epidurals. In studies comparing ketamine to opioid based patient-controlled anesthesia (PCA) pumps, the results were variable. Intercostal and paravertebral nerve blocks had decreased pain scores in 75% of the studies compared to opioid-based PCA. Opioid consumption was decreased in 50% of the trials assessing ketamine-based infusions and 75% of the studies comparing intercostal and paravertebral nerve blocks. Nausea was decreased in several of the ketamine-based infusion and intercostal and paravertebral nerve block studies., Conclusion: Ketamine-including infusions or paravertebral and intercostal nerve blocks may represent superior methods of postoperative pain control for MIRPE. Further work is needed to confirm results., Level of Evidence: 2A [1]., (Copyright © 2020. Published by Elsevier Inc.)

Background and Objectives: There is a limited appreciation of the epidemiology of dialysis-receiving AKI in children. The primary objective of the study was to evaluate changes in the incidence of dialysis-receiving AKI among children over a period of 20 years in Ontario, Canada. The secondary objectives were to assess temporal trends in the utilization of various dialysis modalities and 30-day mortality among children with dialysis-receiving AKI., Design, Setting, Participants, & Measurements: All children (29 days to 18 years) who received their first dialysis for AKI between 1996 and 2015 were identified from healthcare administrative databases. Those who received dialysis for ESKD, inborn errors of metabolism, and poisonings were excluded. The incidence rates of dialysis-receiving AKI were reported annually. The Cochran-Armitage test was used to assess trends in the incidence and short-term mortality after dialysis-receiving AKI., Results: We identified 1394 children treated with dialysis for AKI during a hospital stay. There was a significant increase in the incidence of dialysis-receiving AKI among hospitalized children from 1996 (0.58 per 1000 person-years) to 2015 (0.65 per 1000 person-years) ( P =0.01). The use of continuous kidney replacement therapy and intermittent hemodialysis increased whereas the relative use of peritoneal dialysis declined over time. Thirty-day mortality rates after dialysis-receiving AKI increased from 14% to 25% between 1996 and 2009 and reduced to 19% in the more recent years ( P =0.03)., Conclusions: In Ontario, the incidence of dialysis-receiving AKI among children has increased between 1996 and 2015. The use of peritoneal dialysis for AKI has declined and the short-term mortality after dialysis-receiving AKI has increased., (Copyright © 2019 by the American Society of Nephrology.)

Background: Atezolizumab (a monoclonal antibody against PD-L1), which restores anticancer immunity, improved overall survival in patients with previously treated non-small-cell lung cancer and also showed clinical benefit when combined with chemotherapy as first-line treatment of non-small-cell lung cancer. IMpower130 aimed to assess the efficacy and safety of atezolizumab plus chemotherapy versus chemotherapy alone as first-line therapy for non-squamous non-small-cell lung cancer., Methods: IMpower130 was a multicentre, randomised, open-label, phase 3 study done in 131 centres across eight countries (the USA, Canada, Belgium, France, Germany, Italy, Spain, and Israel). Eligible patients were aged 18 years or older, and had histologically or cytologically confirmed stage IV non-squamous non-small-cell lung cancer, an Eastern Cooperative Oncology Group performance status of 0 or 1, and received no previous chemotherapy for stage IV disease. Patients were randomly assigned (2:1; permuted block [block size of six] with an interactive voice or web response system) to receive atezolizumab (1200 mg intravenously every 3 weeks) plus chemotherapy (carboplatin [area under the curve 6 mg/mL per min every 3 weeks] plus nab-paclitaxel [100 mg/m 2 intravenously every week]) or chemotherapy alone for four or six 21-day cycles followed by maintenance therapy. Stratification factors were sex, baseline liver metastases, and PD-L1 tumour expression. Co-primary endpoints were investigator-assessed progression-free survival and overall survival in the intention-to-treat wild-type (ie, EGFR wt and ALK wt ) population. The safety population included patients who received at least one dose of the study drug. This study is registered with ClinicalTrials.gov, number NCT02367781., Findings: Between April 16, 2015, and Feb 13, 2017, 724 patients were randomly assigned and 723 were included in the intention-to-treat population (one patient died before randomisation, but was assigned to a treatment group; this patient was excluded from the intention-to-treat population) of the atezolizumab plus chemotherapy group (483 patients in the intention-to-treat population and 451 patients in the intention-to-treat wild-type population) or the chemotherapy group (240 patients in the intention-to-treat population and 228 patients in the intention-to-treat wild-type population). Median follow-up in the intention-to-treat wild-type population was similar between groups (18·5 months [IQR 15·2-23·6] in the atezolizumab plus chemotherapy group and 19·2 months [15·4-23·0] in the chemotherapy group). In the intention-to-treat wild-type population, there were significant improvements in median overall survival (18·6 months [95% CI 16·0-21·2] in the atezolizumab plus chemotherapy group and 13·9 months [12·0-18·7] in the chemotherapy group; stratified hazard ratio [HR] 0·79 [95% CI 0·64-0·98]; p=0·033) and median progression-free survival (7·0 months [95% CI 6·2-7·3] in the atezolizumab plus chemotherapy group and 5·5 months [4·4-5·9] in the chemotherapy group; stratified HR 0·64 [95% CI 0·54-0·77]; p<0·0001]). The most common grade 3 or worse treatment-related adverse events were neutropenia (152 [32%] of 473 in the atezolizumab plus chemotherapy group vs 65 [28%] of 232 in the chemotherapy group), anaemia (138 [29%] vs 47 [20%]), and decreased neutrophil count (57 [12%] vs 19 [8%]). Treatment-related serious adverse events were reported in 112 (24%) of 473 patients in the atezolizumab plus chemotherapy group and 30 (13%) of 232 patients in the chemotherapy group. Treatment-related (any treatment) deaths occurred in eight (2%) of 473 patients in the atezolizumab plus chemotherapy group and one (<1%) of 232 patients in the chemotherapy group., Interpretation: IMpower130 showed a significant and clinically meaningful improvement in overall survival and a significant improvement in progression-free survival with atezolizumab plus chemotherapy versus chemotherapy as first-line treatment of patients with stage IV non-squamous non-small-cell lung cancer and no ALK or EGFR mutations. No new safety signals were identified. This study supports the benefit of atezolizumab, in combination with platinum-based chemotherapy, as first-line treatment of metastatic non-small-cell lung cancer., Funding: F. Hoffmann-La Roche., (Copyright © 2019 Elsevier Ltd. All rights reserved.)