Clinical and biomarker results from a phase II trial of combined cabozantinib and durvalumab in patients with chemotherapy-refractory colorectal cancer (CRC): CAMILLA CRC cohort.

CAMILLA is a basket trial (NCT03539822) evaluating cabozantinib plus the ICI durvalumab in chemorefractory gastrointestinal cancer. Herein, are the phase II colorectal cohort results. 29 patients were evaluable. 100% had confirmed pMMR/MSS tumors. Primary endpoint was met with ORR of 27.6% (95% CI 12.7-47.2%). Secondary endpoints of 4-month PFS rate was 44.83% (95% CI 26.5-64.3%); and median OS was 9.1 months (95% CI 5.8-20.2). Grade≥3 TRAE occurred in 39%. In post-hoc analysis of patients with RAS wild type tumors, ORR was 50% and median PFS and OS were 6.3 and 21.5 months respectively. Exploratory spatial transcriptomic profiling of pretreatment tumors showed upregulation of VEGF and MET signaling, increased extracellular matrix activity and preexisting anti-tumor immune responses coexisting with immune suppressive features like T cell migration barriers in responders versus non-responders. Cabozantinib plus durvalumab demonstrated anti-tumor activity, manageable toxicity, and have led to the activation of the phase III STELLAR-303 trial.

Geographic and Racial Disparities in Chimeric Antigen Receptor-T Cells and Bispecific Antibodies Trials Access for Diffuse Large B-Cell Lymphoma.

BACKGROUND: We investigate the geographical and racial disparities in accessing CAR-T and bispecific antibodies trials for DLBCL. MATERIALS AND METHODS: ClinicalTrials.gov was searched, and 75 trials with at least 1 open site in the US were included. 2020 US Census Bureau data was used to obtain data on race and ethnicity. SPSS version 26 was used for analysis. RESULTS: There were 62 CAR-T and 13 bispecific antibodies trials with 6221 enrolled or expected to enroll patients. Eighty-five percent of the clinical trials were only open in the US, and the majority 64% were pharmaceutical-funded. There were 126 unique study sites distributed over 31 states with 11 (0-51) mean number of trials per state and 4.5 (1-26) and 4.4 (1-24) mean number of CAR-T and bispecific antibodies trials per site, respectively. Southern states had the most number of trials 31%, followed by Midwestern 25%, Northeastern 24%, and Western 20%. The highest number of study locations were in California 13, New York 9, and Pennsylvania 9, while the highest number of open studies were in California 51, Texas 32, and New York 23. Twenty states had no open CAR-T or bispecific antibodies trials. Only 33% of African Americans (AA) lived in a county with a trial, and 7 out of 10 states with the highest proportion of AA residents (18.6%-41.4%) have no or less than 4 trial sites. Of the 62 counties analyzed, 92% were White predominant, while only 8% were AA predominant (P = .009). CONCLUSIONS: Strategies should be framed to address the observed disparities and to improve access.

Targeting Angiogenesis Alone and in Combination with Immune Checkpoint Inhibitors in Advanced Gastroesophageal Malignancies.

PURPOSE OF REVIEW: This review critically examines the latest approaches in treating advanced gastroesophageal malignancies. It emphasizes the significance of angiogenesis as a therapeutic target and discusses the potential synergy of combining angiogenesis inhibitors with immune checkpoint inhibitors (ICIs) to enhance treatment efficacy. RECENT FINDINGS: Emerging evidence from clinical trials, such as the INTEGRATE IIa trial with regorafenib and studies involving apatinib and sunitinib, underscores the efficacy of targeting the VEGFR pathway. These studies indicate substantial benefits in progression-free survival (PFS) and overall survival (OS) in patients with advanced stages of the disease who have limited treatment options. Additionally, the recent introduction of combination therapies involving ICIs has shown an increased response rate, suggesting a promising direction for future treatment protocols. The landscape of treatment for gastroesophageal malignancies is rapidly evolving. Research is now pivoting from conventional chemotherapy to a more nuanced approach that includes targeted therapy and immunotherapy.

Weight trends amongst adults with diabetes or hypertension during the COVID-19 pandemic: an observational study using OpenSAFELY.

BACKGROUND: COVID-19 pandemic restrictions may have influenced behaviours related to weight. AIMS: To describe patterns of weight change amongst adults living in England with Type 2 Diabetes (T2D) and/or hypertension during the COVID-19 pandemic. Design and Setting With the approval of NHS England, we conducted an observational cohort study using the routinely collected health data of approximately 40% of adults living in England, accessed through the OpenSAFELY service inside TPP. METHOD: We investigated clinical and sociodemographic characteristics associated with rapid weight gain (>0·5kg/m2/year) using multivariable logistic regression. RESULTS: We extracted data on adults with T2D (n=1,231,455, 44% female, 76% white British) or hypertension (n=3,558,405, 50% female, 84% white British). Adults with T2D lost weight overall (median δ = -0.1kg/m2/year [IQR: -0.7, 0.4]), however, rapid weight gain was common (20.7%) and associated with sex (male vs female: aOR 0.78[95%CI 0.77, 0.79]); age, older age reduced odds (e.g. 60-69-year-olds vs 18-29-year-olds: aOR 0.66[0.61, 0.71]); deprivation, (least-deprived-IMD vs most-deprived-IMD: aOR 0.87[0.85, 0.89]); white ethnicity (Black vs White: aOR 0.95[0.92, 0.98]); mental health conditions (e.g. depression: aOR 1.13 [1.12, 1.15]); and diabetes treatment (non-insulin treatment vs no pharmacological treatment: aOR 0.68[0.67, 0.69]). Adults with hypertension maintained stable weight overall (median δ = 0.0kg/m2/year [ -0.6, 0.5]), however, rapid weight gain was common (24.7%) and associated with similar characteristics as in T2D. CONCLUSION: Amongst adults living in England with T2D and/or hypertension, rapid pandemic weight gain was more common amongst females, younger adults, those living in more deprived areas, and those with mental health condition.

The immune regulatory function of B7-H3 in malignancy: spotlight on the IFN-STAT1 axis and regulation of tumor-associated macrophages.

B7-H3 is a member of the B7 superfamily and a putative inhibitory immune checkpoint molecule. Several early-phase clinical trials have reported promising anti-tumor activity and safety of anti-cancer drugs targeting B7-H3, suggesting that it may be a promising target for a potential next-generation immune checkpoint inhibitor. Despite ongoing clinical studies, most B7-H3-targeted drugs being currently investigated rely on direct cytotoxicity as their mechanisms of action rather than modulating its function as an immune checkpoint, at least in part due to its incompletely understood immune regulatory function. Recent studies have begun to elucidate the role of B7-H3 in regulating the tumor microenvironment (TME). Emerging evidence suggests that B7-H3 may regulate the interferon-STAT1 axis in the TME and promote immune suppression. Similarly, increasing evidence shows B7-H3 may be implicated in promoting M1 to M2 polarization of tumor-associated macrophages (TAMs). There is also accumulating evidence suggesting that B7-H3 may play a role in the heterotypic fusion of cancer stem cells and macrophages, thereby promoting tumor invasion and metastasis. Here, we review the recent advances in the understanding of B7-H3 cancer immunobiology with a focus on highlighting its potential role in the interferon priming of TAMs and the heterotypic fusion of TAMs with cancer stem cells and suggest future direction in elucidating its immune checkpoint function.

Analysis of the Tropism of SARS-CoV-2 Based on the Host Interactome of the Spike Protein.

The ß-coronavirus SARS-CoV-2 causes severe acute respiratory syndrome (COVID-19) in humans. It enters and infects epithelial airway cells upon binding of the receptor binding domain (RBD) of the virus entry protein spike to the host receptor protein Angiotensin Converting Enzyme 2 (ACE2). Here, we used coimmunoprecipitation coupled with bottom-up mass spectrometry to identify host proteins that engaged with the spike protein in human bronchial epithelial cells (16HBEo-). We found that the spike protein bound to extracellular laminin and thrombospondin and endoplasmatic reticulum (ER)-resident DJB11 and FBX2 proteins. The ER-resident proteins UGGT1, CALX, HSP7A, and GRP78/BiP bound preferentially to the original Wuhan D614 over the mutated G614 spike protein in the more rapidly spreading Alpha SARS-CoV-2 strain. The increase in protein binding to the D614 spike might be explained by higher accessibility of cryptic sites in "RDB open" and "S2 only" D614 spike protein conformations and may enable SARS-CoV-2 to infect additional, ACE2-negative cell types. Moreover, a novel proteome-based cell type set enrichment analysis (pCtSEA) found that host factors like laminin might render additional cell types such as macrophages and epithelial cells in the nephron permissive to SARS-CoV-2 infection.

Promising Novel Biomarkers for Hepatocellular Carcinoma: Diagnostic and Prognostic Insights.

The systemic therapy landscape for hepatocellular carcinoma is rapidly evolving, as the recent approvals of checkpoint inhibitor-based regimens such as atezolizumab-bevacizumab and durvalumab-tremelimumab in advanced disease have led to an expanding therapeutic armamentarium. The development of biomarkers, however, has not kept up with the approvals of new agents. Nevertheless, biomarker research for hepatocellular carcinoma has recently been growing at a rapid pace. The most active areas of research are biomarkers for early detection and screening, accurate prognostication, and detection of minimal residual disease following curative intent therapies, and, perhaps most importantly, predictive markers to guide selection and sequencing of the individual agents, including tyrosine kinase inhibitors and immunotherapy. In this review, we briefly summarize the recent developments in systemic therapeutics for hepatocellular carcinoma, introduce the key completed and ongoing prospective and retrospective studies evaluating diagnostic, prognostic, and predictive biomarkers with high clinical relevance, highlight several potentially important areas of future research, and share our insights for each biomarker.

Trends, variation, and clinical characteristics of recipients of antiviral drugs and neutralising monoclonal antibodies for covid-19 in community settings: retrospective, descriptive cohort study of 23.4 million people in OpenSAFELY.

Objective: To ascertain patient eligibility status and describe coverage of antiviral drugs and neutralising monoclonal antibodies (nMAB) as treatment for covid-19 in community settings in England. Design: Retrospective, descriptive cohort study, approved by NHS England. Setting: Routine clinical data from 23.4 million people linked to data on covid-19 infection and treatment, within the OpenSAFELY-TPP database. Participants: Outpatients with covid-19 at high risk of severe outcomes. Interventions: Nirmatrelvir/ritonavir (paxlovid), sotrovimab, molnupiravir, casirivimab/imdevimab, or remdesivir, used in the community by covid-19 medicine delivery units. Results: 93 870 outpatients with covid-19 were identified between 11 December 2021 and 28 April 2022 to be at high risk of severe outcomes and therefore potentially eligible for antiviral or nMAB treatment (or both). Of these patients, 19 040 (20%) received treatment (sotrovimab, 9660 (51%); molnupiravir, 4620 (24%); paxlovid, 4680 (25%); casirivimab/imdevimab, 50 (<1%); and remdesivir, 30 (<1%)). The proportion of patients treated increased from 9% (190/2220) in the first week of treatment availability to 29% (460/1600) in the latest week. The proportion treated varied by high risk group, being lowest in those with liver disease (16%; 95% confidence interval 15% to 17%); by treatment type, with sotrovimab favoured over molnupiravir and paxlovid in all but three high risk groups (Down's syndrome (35%; 30% to 39%), rare neurological conditions (45%; 43% to 47%), and immune deficiencies (48%; 47% to 50%)); by age, ranging from ≥80 years (13%; 12% to 14%) to 50-59 years (23%; 22% to 23%); by ethnic group, ranging from black (11%; 10% to 12%) to white (21%; 21% to 21%); by NHS region, ranging from 13% (12% to 14%) in Yorkshire and the Humber to 25% (24% to 25%) in the East of England); and by deprivation level, ranging from 15% (14% to 15%) in the most deprived areas to 23% (23% to 24%) in the least deprived areas. Groups that also had lower coverage included unvaccinated patients (7%; 6% to 9%), those with dementia (6%; 5% to 7%), and care home residents (6%; 6% to 7%). Conclusions: Using the OpenSAFELY platform, we were able to identify patients with covid-19 at high risk of severe outcomes who were potentially eligible to receive treatment and assess the coverage of these new treatments among these patients. In the context of a rapid deployment of a new service, the NHS analytical code used to determine eligibility could have been over-inclusive and some of the eligibility criteria not fully captured in healthcare data. However targeted activity might be needed to resolve apparent lower treatment coverage observed among certain groups, in particular (at present): different NHS regions, ethnic groups, people aged ≥80 years, those living in socioeconomically deprived areas, and care home residents.

Cabozantinib plus durvalumab in advanced gastroesophageal cancer and other gastrointestinal malignancies: Phase Ib CAMILLA trial results.

This is the phase Ib part of the phase I/II CAMILLA trial evaluating cabozantinib plus durvalumab in advanced chemo-refractory proficient mismatch repair or microsatellite stable (pMMR/MSS) gastrointestinal malignancies including gastric/gastroesophageal junction/esophageal (G/GEJ/E) adenocarcinoma, colorectal cancer (CRC), and hepatocellular carcinoma (HCC). Thirty-five patients are enrolled. There are no observed dose-limiting toxicities during dose escalation. The overall grade 3/4 treatment-related adverse event rate is 34%. Among evaluable patients (n = 30), the objective response rate (ORR) is 30%, disease control rate (DCR) 83.3%, 6-month progression-free survival (PFS) 36.7%, median PFS 4.5 months, and median overall survival (OS) 8.7 months. Responses are seen in 4 of 17, 3 of 10, and 2 of 3 patients with CRC, G/GEJ/E adenocarcinoma, and HCC, respectively. Participants with a PD-L1 combined positive score (CPS) ≥5 have numerically higher ORR, PFS, and OS. Cabozantinib plus durvalumab demonstrates a tolerable safety profile and potential efficacy in previously treated advanced pMMR/MSS gastrointestinal malignancies.

Temozolomide duration and secondary hematological neoplasms: A literature review and implications for patients with neuroendocrine neoplasms.

Evidence-based recommendations for the optimal duration and sequencing of temozolomide-based treatments in advanced neuroendocrine neoplasms are lacking. Here, we conducted a systematic review of the literature for a descriptive analysis of temozolomide-associated myelodysplasias and leukemias to guide treatment planning. A database search of PubMed and Embase was conducted to identify case reports and/or case series reporting secondary myelodysplasias or leukemias in the setting of temozolomide therapy. Key data items extracted from the studies were the temozolomide dose and duration, latency to hematological disorder, type of secondary malignancy and cytogenetics. Reported cases were summarized graphically. A total of 16 studies with 27 patient cases of therapy-related hematologic neoplasms were identified, all of which were case reports or case series. The median treatment duration and cumulative dose were 19 months and 18,000 mg/m2 , respectively. Most patients (21/27) were diagnosed on, or after, 12 months, while only one patient was diagnosed before 6 months of treatment. Most of the patients were diagnosed, while still on treatment with temozolomide. Graphically, cases clustered around a cumulative dose of 10,000 to 30,000 mg/m2 and a latency period of 10 to 40 months which translates to an approximate treatment duration of 12.5 to 37.5 months. Taken together, most reported treatment-related hematological neoplasms appear to develop on or beyond the 12-month mark, while patients are still on treatment with temozolomide. For patients with neuroendocrine neoplasms, where sequencing of multiple therapies is important, we suggest an approach to optimizing treatment duration by establishing disease response at 6 months before continuing further treatment and restricting treatment to or establishing closer vigilance beyond 12 months.

Waning effectiveness of BNT162b2 and ChAdOx1 covid-19 vaccines over six months since second dose: OpenSAFELY cohort study using linked electronic health records.

OBJECTIVE: To estimate waning of covid-19 vaccine effectiveness over six months after second dose. DESIGN: Cohort study, approved by NHS England. SETTING: Linked primary care, hospital, and covid-19 records within the OpenSAFELY-TPP database. PARTICIPANTS: Adults without previous SARS-CoV-2 infection were eligible, excluding care home residents and healthcare professionals. EXPOSURES: People who had received two doses of BNT162b2 or ChAdOx1 (administered during the national vaccine rollout) were compared with unvaccinated people during six consecutive comparison periods, each of four weeks. MAIN OUTCOME MEASURES: Adjusted hazard ratios for covid-19 related hospital admission, covid-19 related death, positive SARS-CoV-2 test, and non-covid-19 related death comparing vaccinated with unvaccinated people. Waning vaccine effectiveness was quantified as ratios of adjusted hazard ratios per four week period, separately for subgroups aged ≥65 years, 18-64 years and clinically vulnerable, 40-64 years, and 18-39 years. RESULTS: 1 951 866 and 3 219 349 eligible adults received two doses of BNT162b2 and ChAdOx1, respectively, and 2 422 980 remained unvaccinated. Waning of vaccine effectiveness was estimated to be similar across outcomes and vaccine brands. In the ≥65 years subgroup, ratios of adjusted hazard ratios for covid-19 related hospital admission, covid-19 related death, and positive SARS-CoV-2 test ranged from 1.19 (95% confidence interval 1.14 to 1.24)to 1.34 (1.09 to 1.64) per four weeks. Despite waning vaccine effectiveness, rates of covid-19 related hospital admission and death were substantially lower among vaccinated than unvaccinated adults up to 26 weeks after the second dose, with estimated vaccine effectiveness ≥80% for BNT162b2, and ≥75% for ChAdOx1. By weeks 23-26, rates of positive SARS-CoV-2 test in vaccinated people were similar to or higher than in unvaccinated people (adjusted hazard ratios up to 1.72 (1.11 to 2.68) for BNT162b2 and 1.86 (1.79 to 1.93) for ChAdOx1). CONCLUSIONS: The rate at which estimated vaccine effectiveness waned was consistent for covid-19 related hospital admission, covid-19 related death, and positive SARS-CoV-2 test and was similar across subgroups defined by age and clinical vulnerability. If sustained to outcomes of infection with the omicron variant and to booster vaccination, these findings will facilitate scheduling of booster vaccination.

Evaluating Internal Medicine Residents' Awareness on Cancer Survivorship Care Plan: A Pilot Survey.

Introduction: Survivorship care plan (SCP) is a tool to improve communication between oncologists and primary care physicians. Internal medicine residency curricula are lacking training for cancer survivorship and SCPs. Here, we aimed to assess the awareness and utilization of SCPs in medicine trainees. Methods: A pilot survey investigating awareness and experience with SCPs was distributed among internal medicine trainees in an outpatient setting. Participants were stratified by program type (transitional and categorical) and year of training. Differences in proportions were tested with parametric and non-parametric tests. Results: All thirty-seven participants who were administered a survey responded; 32.4% and 67.6% were transitional and categorical trainees, respectively; 54% were PGY-1, 21.6% PGY-2, and 24.3% PGY-3. None of the trainees reported following a SCP for cancer-free patients nor plans to use SCP as a source to obtain information. Up to 78.3% and 92.6% of participants reported that they were not taught about SCPs during their residency or medical school, respectively. The most frequent barriers to discuss cancer history and SCP with their patients were: insufficient or lack of information about SCPs (83.8%), patients' information as a source deemed "unreliable" (81.1%), and uncertainty if the patient has SCP (81.1%). Conclusions: Awareness and use of cancer SCPs among internal medicine trainees is limited, furthermore, a sizeable proportion reported not having accessed or received any training for SCPs. Efforts intended to facilitate SCP use and educate trainees about cancer survivorship may prove to be an effective strategy to increase the quality of care to cancer survivors.

Pre-operative Carboplatin/Paclitaxel Versus 5-Fluorouracil (5-FU)-based Chemoradiotherapy for Older Adults With Esophageal Cancer.

BACKGROUND/AIM: This study aimed to compare the efficacy and tolerability of pre-operative platinum/5-fluorouracil (P5F) and carboplatin/paclitaxel (CP), in combination with radiation therapy in older adults with locally advanced, stage I-III esophageal cancer. PATIENTS AND METHODS: We retrospectively reviewed 51 patients aged ≥70 years who underwent chemoradiotherapy followed by esophagectomy for stage I-III esophageal cancer between 2008 and 2018. Pathological complete response (pCR) and survival rates were compared across the two chemotherapy regimen arms. RESULTS: Treatment completion (p=0.28), pCR (p=0.89), and partial response rates were similar across both chemotherapy groups. Overall survival (OS) and disease-free survival (DFS) were similar across both groups with HR=0.80 (p=0.62) and HR=0.72 (p=0.72) respectively. CONCLUSION: The lesser toxic CP regimen may be used in older patients with locally advanced esophageal cancer, with tumor response and survival rates similar to P5F chemotherapy.

B7-H3 regulates osteoclast differentiation via type I interferon-dependent IDO induction.

While their function, as immune checkpoint molecules, is well known, B7-family proteins also function as regulatory molecules in bone remodeling. B7-H3 is a receptor ligand of the B7 family that functions primarily as a negative immune checkpoint. While the regulatory function of B7-H3 in osteoblast differentiation has been established, its role in osteoclast differentiation remains unclear. Here we show that B7-H3 is highly expressed in mature osteoclasts and that B7-H3 deficiency leads to the inhibition of osteoclastogenesis in human osteoclast precursors (OCPs). High-throughput transcriptomic analyses reveal that B7-H3 inhibition upregulates IFN signaling as well as IFN-inducible genes, including IDO. Pharmacological inhibition of type-I IFN and IDO knockdown leads to reversal of B7-H3-deficiency-mediated osteoclastogenesis suppression. Although synovial-fluid macrophages from rheumatoid-arthritis patients express B7-H3, inhibition of B7-H3 does not affect their osteoclastogenesis. Thus, our findings highlight B7-H3 as a physiologic positive regulator of osteoclast differentiation and implicate type-I IFN-IDO signaling as its downstream mechanism.

GSK-3ß in Pancreatic Cancer: Spotlight on 9-ING-41, Its Therapeutic Potential and Immune Modulatory Properties.

Glycogen synthase kinase-3 beta is a ubiquitously and constitutively expressed molecule with pleiotropic function. It acts as a protooncogene in the development of several solid tumors including pancreatic cancer through its involvement in various cellular processes including cell proliferation, survival, invasion and metastasis, as well as autophagy. Furthermore, the level of aberrant glycogen synthase kinase-3 beta expression in the nucleus is inversely correlated with tumor differentiation and survival in both in vitro and in vivo models of pancreatic cancer. Small molecule inhibitors of glycogen synthase kinase-3 beta have demonstrated therapeutic potential in pre-clinical models and are currently being evaluated in early phase clinical trials involving pancreatic cancer patients with interim results showing favorable results. Moreover, recent studies support a rationale for the combination of glycogen synthase kinase-3 beta inhibitors with chemotherapy and immunotherapy, warranting the evaluation of novel combination regimens in the future.

Advances in immune therapies for the treatment of microsatellite instability­high/deficient mismatch repair metastatic colorectal cancer (Review).

Microsatellite instability­high/deficient mismatch repair colorectal cancer (MSI­H/dMMR CRC) is a molecular subtype characterized by high­frequency mutations within DNA mismatch repair genes. Defects in the DNA mismatch repair machinery lead to subsequent frame­shift mutations, resulting in the generation of frame­shift peptides that serve as neoantigens. This has translated into exquisite sensitivity to immune checkpoint inhibitors (ICIs) and a significant clinical benefit from immune therapies in this patient population. The present article provides a comprehensive review of the advances in the field of immune therapies for MSI­H/dMMR metastatic CRC, with a focus on the major randomized clinical trials that led to Food and Drug Administration approval of specific ICIs for this population, a detailed review of the molecular background responsible for tumor response, as well as the mechanisms of resistance to ICI therapy. Finally, ongoing investigations of other immunotherapeutic strategies to address and overcome the challenges that currently limit response and long­term response to ICIs were presented.

The prognostic and predictive impact of BRAF mutations in deficient mismatch repair/microsatellite instability-high colorectal cancer: systematic review/meta-analysis.

Aims: The authors present a systematic review/meta-analysis of the impact of BRAF mutations on prognosis and immune checkpoint inhibitor (ICI) response in deficient mismatch repair/microsatellite instability-high colorectal cancer. Methods: Hazard ratios for overall survival and odds ratios for objective response rate to ICIs were calculated in BRAF-mutated versus BRAF wild-type patients. Results: After screening, nine and three studies, respectively, were included for analysis of prognosis (analysis A) and ICI response (analysis B). Analysis A showed worse overall survival in BRAF-mutated compared with BRAF wild-type stage I-IV patients (hazard ratio: 1.57; 95% CI: 1.23-1.99), and analysis B showed no difference in objective response rate (odds ratio: 1.04; 95% CI: 0.48-2.25). Conclusion: BRAF mutations are associated with worse overall survival but not differential response to ICIs in deficient mismatch repair/microsatellite instability-high colorectal cancer.

Lay abstract Patients with colorectal cancer who have mutations in the BRAF gene fare worse compared with those without the mutation, whereas those who have a feature called microsatellite instability-high tend to live longer compared with those who do not have this feature. However, it is unclear whether the presence of BRAF gene mutation changes the course of the disease or response to novel immunotherapy treatment in patients with microsatellite instability-high colorectal cancer. The authors found that patients without the BRAF mutation live longer than their counterparts with the mutation. The two groups did not respond differently to immunotherapy. Therefore, BRAF mutations are important in dictating the disease course in patients with microsatellite instability-high colorectal cancer.

Increased risk of acute kidney injury in coronavirus disease patients with renin-angiotensin-aldosterone-system blockade use: a systematic review and meta-analysis.

Acute kidney injury (AKI) is a severe complication of coronavirus disease (COVID-19) that negatively affects its outcome. Concern had been raised about the potential effect of renin-angiotensin-aldosterone system (RAAS) blockades on renal outcomes in COVID-19 patients. However, the association between RAAS blockade use and incident AKI in COVID-19 patients has not been fully understood. We investigated the association between RAAS blockade exposure and COVID-19-related AKI in hospitalized patients through meta-analysis. Electronic databases were searched up to 24th December 2020. Summary estimates of pooled odds ratio (OR) of COVID-19-related AKI depending on RAAS blockade exposure were obtained through random-effects model. The random-effect meta-analysis on fourteen studies (17,876 patients) showed that RAAS blockade use was significantly associated with increased risk of incident AKI in hospitalized COVID-19 patients (OR 1.68; 95% confidence interval 1.19-2.36). Additional analysis showed that the association of RAAS blockade use on COVID-19-related AKI remains significant even after stratification by drug class and AKI severity. RAAS blockade use is significantly associated with the incident AKI in hospitalized COVID-19 patients. Therefore, careful monitoring of renal complications is recommended for COVID-19 patients with recent RAAS blockade use due to the potential risk of AKI.