Trends in weight gain recorded in English primary care before and during the Coronavirus-19 pandemic: An observational cohort study using the OpenSAFELY platform.

BACKGROUND: Obesity and rapid weight gain are established risk factors for noncommunicable diseases and have emerged as independent risk factors for severe disease following Coronavirus Disease 2019 (COVID-19) infection. Restrictions imposed to reduce COVID-19 transmission resulted in profound societal changes that impacted many health behaviours, including physical activity and nutrition, associated with rate of weight gain. We investigated which clinical and sociodemographic characteristics were associated with rapid weight gain and the greatest acceleration in rate of weight gain during the pandemic among adults registered with an English National Health Service (NHS) general practitioner (GP) during the COVID-19 pandemic. METHODS AND FINDINGS: With the approval of NHS England, we used the OpenSAFELY platform inside TPP to conduct an observational cohort study of routinely collected electronic healthcare records. We investigated changes in body mass index (BMI) values recorded in English primary care between March 2015 and March 2022. We extracted data on 17,742,365 adults aged 18 to 90 years old (50.1% female, 76.1% white British) registered with an English primary care practice. We estimated individual rates of weight gain before (δ-prepandemic) and during (δ-pandemic) the pandemic and identified individuals with rapid weight gain (>0.5 kg/m2/year) in each period. We also estimated the change in rate of weight gain between the prepandemic and pandemic period (δ-change = δ-pandemic-δ-prepandemic) and defined extreme accelerators as the 10% of individuals with the greatest increase in their rate of weight gain (δ-change ≥1.84 kg/m2/year) between these periods. We estimated associations with these outcomes using multivariable logistic regression adjusted for age, sex, index of multiple deprivation (IMD), and ethnicity. P-values were generated in regression models. The median BMI of our study population was 27.8 kg/m2, interquartile range (IQR) [24.3, 32.1] in 2019 (March 2019 to February 2020) and 28.0 kg/m2, IQR [24.4, 32.6] in 2021. Rapid pandemic weight gain was associated with sex, age, and IMD. Male sex (male versus female: adjusted odds ratio (aOR) 0.76, 95% confidence interval (95% CI) [0.76, 0.76], p < 0.001), older age (e.g., 50 to 59 years versus 18 to 29 years: aOR 0.60, 95% CI [0.60, 0.61], p < 0.001]); and living in less deprived areas (least-deprived-IMD-quintile versus most-deprived: aOR 0.77, 95% CI [0.77, 0.78] p < 0.001) reduced the odds of rapid weight gain. Compared to white British individuals, all other ethnicities had lower odds of rapid pandemic weight gain (e.g., Indian versus white British: aOR 0.69, 95% CI [0.68, 0.70], p < 0.001). Long-term conditions (LTCs) increased the odds, with mental health conditions having the greatest effect (e.g., depression (aOR 1.18, 95% CI [1.17, 1.18], p < 0.001)). Similar characteristics increased odds of extreme acceleration in the rate of weight gain between the prepandemic and pandemic periods. However, changes in healthcare activity during the pandemic may have introduced new bias to the data. CONCLUSIONS: We found female sex, younger age, deprivation, white British ethnicity, and mental health conditions were associated with rapid pandemic weight gain and extreme acceleration in rate of weight gain between the prepandemic and pandemic periods. Our findings highlight the need to incorporate sociodemographic, physical, and mental health characteristics when formulating research, policies, and interventions targeting BMI in the period of post pandemic service restoration and in future pandemic planning.

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.

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.

Association of active oncologic treatment and risk of death in cancer patients with COVID-19: a systematic review and meta-analysis of patient data.

BACKGROUND: Cancer patients suffer from worse coronavirus disease-2019 (COVID-19) outcomes. Whether active oncologic treatment is an additional risk factor in this population remains unclear. Therefore, here we have conducted a systematic review and meta-analysis to summarize the existing evidence for the effect of active oncologic treatment on COVID-19 outcomes. METHODS: Systematic search of databases (PubMed, Embase) was conducted for studies published from inception to July 1, 2020, with a subsequent search update conducted on 10 October 2020. In addition, abstracts and presentations from major conference proceedings (ASCO, ESMO, AACR) as well as pre-print databases (medxriv, bioxriv) were searched. Retrospective and prospective studies reporting clinical outcomes in cancer patients with laboratory confirmation or clinical diagnosis of COVID-19 and details of active or recent oncologic treatment were selected. Random-effects model was applied throughout meta-analyses. Summary outcome measure was the pooled odds ratio (OR) of death for active cancer therapy versus no active cancer therapy for each of the following modalities: recent surgery, chemotherapy, targeted therapy, immunotherapy, or chemoimmunotherapy. RESULTS: Sixteen retrospective and prospective studies (3558 patients) were included in the meta-analysis. Active chemotherapy was associated with higher risk of death compared to no active chemotherapy (OR, 1.60, 95% CI, 1.14-2.23). No significant association with risk of death was identified for active targeted therapy, immunotherapy, chemoimmunotherapy, or recent surgery. Meta-analysis of multivariate adjusted OR of death for active chemotherapy was consistently associated with higher risk of death compared to no active chemotherapy (OR, 1.42, 95% CI, 1.01-2.01). CONCLUSIONS: Active chemotherapy appears to be associated with higher risk of death in cancer patients with COVID-19. Further research is necessary to characterize the complex interactions between active cancer treatment and COVID-19.

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.

Proteomic analysis reveals a role for Bcl2-associated athanogene 3 and major vault protein in resistance to apoptosis in senescent cells by regulating ERK1/2 activation.

Senescence is a prominent solid tumor response to therapy in which cells avoid apoptosis and instead enter into prolonged cell cycle arrest. We applied a quantitative proteomics screen to identify signals that lead to therapy-induced senescence and discovered that Bcl2-associated athanogene 3 (Bag3) is up-regulated after adriamycin treatment in MCF7 cells. Bag3 is a member of the BAG family of co-chaperones that interacts with Hsp70. Bag3 also regulates major cell-signaling pathways. Mass spectrometry analysis of the Bag3 Complex revealed a novel interaction between Bag3 and Major Vault Protein (MVP). Silencing of Bag3 or MVP shifts the cellular response to adriamycin to favor apoptosis. We demonstrate that Bag3 and MVP contribute to apoptosis resistance in therapy-induced senescence by increasing the level of activation of extracellular signal-regulated kinase1/2 (ERK1/2). Silencing of either Bag3 or MVP decreased ERK1/2 activation and promoted apoptosis in adriamycin-treated cells. An increase in nuclear accumulation of MVP is observed during therapy-induced senescence and the shift in MVP subcellular localization is Bag3-dependent. We propose a model in which Bag3 binds to MVP and facilitates MVP accumulation in the nucleus, which sustains ERK1/2 activation. We confirmed that silencing of Bag3 or MVP shifts the response toward apoptosis and regulates ERK1/2 activation in a panel of diverse breast cancer cell lines. This study highlights Bag3-MVP as an important complex that regulates a potent prosurvival signaling pathway and contributes to chemotherapy resistance in breast cancer.

Calcium channels: the potential therapeutic targets for inflammatory bone destruction of rheumatoid arthritis.

INTRODUCTION: Inflammatory bone resorption causes progressive joint destruction which ultimately leads to functional disability in rheumatoid arthritis (RA). The primary cell responsible for bone resorption is the osteoclast, which means it is a potential therapeutic target against bone destruction. In fact, experimental and clinical findings suggest that blockade of osteoclast differentiation and function is highly effective in inhibiting bone destruction in RA. DISCUSSION AND CONCLUSION: In this report, we show several lines of experimental evidence which suggest that a variety of Ca(2+) channels are essential in osteoclast differentiation and function, and present a hypothesis that modulation of Ca(2+) channels is a highly effective therapeutic strategy in preventing osteoclast-induced structural damage in RA.

Unique gene expression profile in osteoarthritis synovium compared with cartilage: analysis of publicly accessible microarray datasets.

The purpose of this study was to identify a gene expression signature in osteoarthritis (OA) synovium and genomic pathways likely to be involved in the pathogenesis of OA. Four publicly accessible microarray studies from synovium of OA patients were integrated, and a transcriptomic and network-based meta-analysis was performed. Based on pathways according to the Kyoto Encyclopedia of Genes and Genomes, functional enrichment analysis was performed. Meta-analysis results of OA synovium were compared to two previously published studies of OA cartilage to determine the relative number of common and specific DEGs of the cartilage and synovium. According to our meta-analysis, a total of 1350 genes were found to be differentially expressed in the synovium of OA patients as compared to that of healthy controls. Pathway analysis found 41 significant pathways in the total DEGs, and 22 and 16 pathways in the upregulated and downregulated DEGs, respectively. Cell adhesion molecules and cytokine-cytokine receptor interaction were the most significant pathway in the upregulated and downregulated DEGs, respectively. Comparison of meta-analysis results of OA synovium with results of two previous studies of OA cartilage identified 85 common genes and 1632 cartilage-specific DEGs and 1265 synovium-specific DEGs in the first study; and 142 common genes, and 856 cartilage-specific DEGs and 1208 synovium-specific DEGs in the second study. Our results show a small overlap between the DEGs of the synovium compared to DEGs of the cartilage, suggesting different pathogenic mechanisms that are specific to the synovium.

Immunotherapy in Colorectal Cancer - Finding the Achilles' Heel.

AbstractColorectal cancer treatment has evolved considerably in the last decade with the development of immunotherapies. Immune checkpoint inhibitor therapies have brisk and durable responses in patients with advanced microsatellite instability-high colorectal cancer, both surgically resectable and unresectable; however, patients with microsatellite stable colorectal cancer in general do not respond to the same therapy. Emerging evidence shows that immune checkpoint inhibitors may elicit responses in subsets of patients with microsatellite stable colorectal cancer, especially when combined with other anticancer agents that can modulate the tumor microenvironment. Therefore, rationally designed therapeutic combinations involving immune checkpoint inhibitors, as well as the development of predictive biomarkers for optimal patient selection, have emerged as two key areas of active research. In addition, other immunotherapeutic agents such as cell-based therapies and bispecific T-cell engagers are beginning to be studied in preclinical and early-phase settings. Although by no means a universal treatment strategy, immunotherapy can elicit responses in microsatellite stable colorectal cancer and further research is needed to extend their benefit to patients with microsatellite stable colorectal cancer. Here, we review the current state of immunotherapeutic regimens for microsatellite stable colorectal cancer.

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.

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.

Changes in sick notes associated with COVID-19 from 2020 to 2022: a cohort study in 24 million primary care patients in OpenSAFELY-TPP.

OBJECTIVES: Long-term sickness absence from employment has negative consequences for the economy and can lead to widened health inequalities. Sick notes (also called 'fit notes') are issued by general practitioners when a person cannot work for health reasons for more than 7 days. We quantified the sick note rate in people with evidence of COVID-19 in 2020, 2021 and 2022, as an indication of the burden for people recovering from COVID-19. DESIGN: Cohort study. SETTING: With National Health Service (NHS) England approval, we used routine clinical data (primary care, hospital and COVID-19 testing records) within the OpenSAFELY-TPP database. PARTICIPANTS: People 18-64 years with a recorded positive test or diagnosis of COVID-19 in 2020 (n=365 421), 2021 (n=1 206 555) or 2022 (n=1 321 313); general population matched in age, sex and region in 2019 (n=3 140 326), 2020 (n=3 439 534), 2021 (n=4 571 469) and 2022 (n=4 818 870); people hospitalised with pneumonia in 2019 (n=29 673). PRIMARY OUTCOME MEASURE: Receipt of a sick note in primary care. RESULTS: Among people with a positive SARS-CoV-2 test or COVID-19 diagnosis, the sick note rate was 4.88 per 100 person-months (95% CI 4.83 to 4.93) in 2020, 2.66 (95% CI 2.64 to 2.67) in 2021 and 1.73 (95% CI 1.72 to 1.73) in 2022. Compared with the age, sex and region-matched general population, the adjusted HR for receipt of a sick note over the entire follow-up period (up to 10 months) was 4.07 (95% CI 4.02 to 4.12) in 2020 decreasing to 1.57 (95% CI 1.56 to 1.58) in 2022. The HR was highest in the first 30 days postdiagnosis in all years. Among people hospitalised with COVID-19, after adjustment, the sick note rate was lower than in people hospitalised with pneumonia. CONCLUSIONS: Given the under-recording of postacute COVID-19-related symptoms, these findings contribute a valuable perspective on the long-term effects of COVID-19. Despite likely underestimation of the sick note rate, sick notes were issued more frequently to people with COVID-19 compared with those without, even in an era when most people are vaccinated. Most sick notes occurred in the first 30 days postdiagnosis, but the increased risk several months postdiagnosis may provide further evidence of the long-term impact.

Phase Ib trial of IRX-2 plus durvalumab in patients with recurrent and/or metastatic head and neck squamous cell carcinoma.

OBJECTIVES: IRX-2 is a multi-cytokine immune-activating agent with anti-tumor activity in non-metastatic head and neck squamous cell carcinoma (HNSCC). Here, we evaluated combined IRX-2 and durvalumab in patients with recurrent and/or metastatic HNSCC. MATERIALS AND METHODS: This was a phase Ib trial consisting of dose escalation and expansion. Primary endpoints were safety and biomarkers to assess the immune response in the tumor microenvironment including significant increases in PD-L1 expression and CD8 + tumor infiltrating lymphocytes (TIL) comparing pre- and on-treatment tumor biopsies. Secondary endpoints were objective response rates (ORR) and survival outcomes. RESULTS: Sixteen patients were evaluable for response, and nine patients were evaluable for biomarkers. Thirteen patients (68 %) had exposure to prior anti-PD-1 therapy. No dose-limiting or grade ≥ 3 treatment-related adverse events were observed. On-treatment biopsies showed significantly increased PD-L1 (p = 0.005), CD3+ (p = 0.020), CD4+ (p = 0.022), and CD8 + T cells (p = 0.017) compared to pre-treatment. Median overall survival and progression-free survival (PFS) were 6.18 months (95 % CI, 2.66-8.61) and 2.53 months (95 % CI, 1.81-4.04), respectively. One patient had an objective response (ORR, 5.3 %) with an ongoing PFS of > 25 months. Disease control rate was 42 %. The responder harbored an ARID1A variant of unknown significance (VUS) that was predicted to bind her HLA-I alleles with a higher affinity than the reference peptide. CONCLUSIONS: IRX-2 and durvalumab were safe and elicited the evidence of immune activation in the tumor microenvironment determined by increased PD-L1 expression and CD8+ TILs. CLINICAL TRIAL REGISTRATION NUMBER: NCT03381183.

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.

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.

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.

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.

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.

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.