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

Introduction: Three doses of SARS-CoV-2 mRNA vaccines have been recommended for cancer patients to reduce the risk of severe disease. Anti-neoplastic treatment, such as chemotherapy, may affect long-term vaccine immunogenicity. Method: Patients with solid or haematological cancer were recruited from 2 hospitals between July 2021 and March 2022. Humoral response was evaluated using GenScript cPASS surrogate virus neutralisation assays. Clinical outcomes were obtained from medical records and national mandatory-reporting databases. Results: A total of 273 patients were recruited, with 40 having haematological malignancies and the rest solid tumours. Among the participants, 204 (74.7%) were receiving active cancer therapy, including 98 (35.9%) undergoing systemic chemotherapy and the rest targeted therapy or immunotherapy. All patients were seronegative at baseline. Seroconversion rates after receiving 1, 2 and 3 doses of SARS-CoV-2 mRNA vaccination were 35.2%, 79.4% and 92.4%, respectively. After 3 doses, patients on active treatment for haematological malignancies had lower antibodies (57.3%±46.2) when compared to patients on immunotherapy (94.1%±9.56, P

Primary Sjögren's syndrome (pSS) is a chronic, systemic autoimmune disease defined as exocrine gland hypofunction resulting in dry eyes and dry mouth. Recent interest in biological therapies for pSS has been garnered, however achieving FDA-approval has been challenging due to the numerous complications in the trials. Current literature lacks insight and a molecular target-based approach to the development of biological therapies. This review focuses on novel research in newly defined drug targets and latest clinical trials for pSS treatment. A literature search was conducted on ClinicalTrials.gov using the search term “Primary Sjögren's syndrome”. Articles published between 2000 and 2021 in English language were included. Our findings revealed the potential targets for pSS treatment in clinical trials and the most recent advances in understand-ing of molecular mechanisms underlying the pathogenesis of pSS. A prominent gap in current trials is overlooking the treatment of extraglandular symptoms such as fatigue, depression and anxiety which pervade most patients with pSS. Based on dryness and these symptom-directed therapies, emerging biological agents targeting inflammatory cytokines, signal pathways and immune reaction have been studied and proved the efficacy and safety. Novel therapies may complement existing non-pharmacological methods of alleviating symptoms of pSS. Better grad-ing systems adding extraglandular symptoms to gauge disease activity and severity should be created. The future of pSS therapies may lie in gene therapy, stem cell and tissue engineering ther-apy.

Background Preoperative hyponatremia is prevalent in patients undergoing surgical procedures, but it is uncertain if hyponatremia will lead to increased risk of surgical mortality and morbidity. Methods A systematic search of Medline (PubMed), Embase, and Cochrane Library from inception through July 2, 2021, was performed. Full-length articles that reported on the association between surgical outcomes among adults aged ≥18 years with documented preoperative hyponatremia were included. Findings We identified 32 observational studies comprising 1 301 346 participants. All studies had low risk of bias. When adjusted for covariates, patients with hyponatremia had significantly higher odds of developing major complications (defined as a composite measure of 9 major complications) compared with patients with normal sodium concentrations (adjusted odds ratio = 1.37; 95% CI, 1.23-1.53; I2 = 78%; N = 10). Additionally, patients with preoperative hyponatremia also significantly higher hazards of early mortality ( Interpretation Our meta-analysis suggests that preoperative hyponatremia is associated with poorer early mortality and major morbidity outcomes in surgical patients. Hyponatremia is also a specific prognosticator for major complications in surgical patients, reiterating its potential use as a clinical indicator of poor outcomes.

Patients with cancer have an increased risk of severe disease and mortality from COVID-19, as the disease and antineoplastic therapy cause reduced vaccine immunogenicity. Booster doses have been proposed to enhance protection, and efficacy data are emerging from several studies.To evaluate the proportion of COVID-19 primary vaccination non-responders with cancer who seroconvert after a booster dose.PubMed, EMBASE, CENTRAL and medRxiv were searched from 1st January 2021 to 10th March 2022. Quality was assessed using the Joanna Briggs Institute Critical Appraisal checklist.After the eligibility assessment, 22 studies were included in this systematic review and 17 for meta-analysis of seroconversion in non-responders, pooling a total of 849 patients with haematological cancer and 82 patients with solid cancer. Haematological cancer non-responders exhibited lower seroconversion at 44% (95% CI 36-53%) than solid cancer at 80% (95% CI 69-87%). Individual patient data meta-analysis found the odds of having a meaningful rise in antibody titres to be significantly associated with increased duration between the second and third dose (OR 1.02, 95% CI 1.00-1.03, P ≤ 0.05), age of patient (OR 0.960, 95% CI 0.934-0.987, P ≤ 0.05) and cancer type. With patients with haematological cancer as a reference, patients with lung cancer had 16.8 times the odds of achieving a meaningful increase in antibody titres (OR 16.8, 95% CI 2.95-318, P ≤ 0.05) and gastrointestinal cancer patients had 25.4 times the odds of achieving a meaningful increase in antibody titres (OR 25.4, 95% CI 5.26-492.21, P ≤ 0.05).administration of a COVID-19 vaccine booster dose is effective in improving seroconversion and antibody levels. Patients with haematological cancer consistently demonstrate poorer response to booster vaccines than patients with solid cancer.

Although low vitamin D levels are associated with statin-associated muscle symptoms (SAMS), it remains unclear if vitamin D supplementation leads to symptom improvement.We performed a systematic review to evaluate the association of vitamin D supplementation with resolution of SAMS.We searched Medline (PubMed), Embase and Cochrane Library till 12 December 2021. Full length articles that reported on the association between vitamin D supplementation in adult patients with SAMS were included.We identified 8 interventional studies comprising 669 participants. Majority of the participants were of Caucasian ethnicity and the mean age of participants ranged from 59.5 to 64.8 years old. The studies recruited patients with initial mean pre-treatment vitamin D levels ranging from 17.8 to 22.0ng/mL. Follow up duration ranged from 2 to 24 months and mean post-treatment vitamin D levels ranged from 34.3 to 56.0ng/mL. We found that vitamin D supplementation was associated with improved statin tolerance in 509 out of 606 (83.9%) patients across the 7 studies which reported patient numbers after supplementation (95% CI = 0.81-0.87, I2 = 72% n = 7). None of the studies were randomized controlled trials (RCTs) and hence placebo effect of vitamin D could not be ruled out. Nocebo effect of statin was also not assessed by any of the studies.Vitamin D supplementation in patients with mild-moderate vitamin D insufficiency was associated with improvement of SAMS. However, quantitative efficacy analysis was not possible and this observed association is likely confounded by nocebo and placebo effects. RCTs are required to conclusively assess the utility of vitamin D supplementation in improving SAMS.