Search

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

4026 Background: Immune checkpoint inhibitors (ICI) are now standard-of-care treatment for patients with metastatic gastric cancer (GC). To guide patient selection for ICI therapy, programmed death ligand-1 (PD-L1) biomarker expression is routinely assessed via immunohistochemistry (IHC). Regulatory approval for ICIs is granted based on PD-L1 expression status, scored using metrics such as the combined positive score (CPS). However, with an increasing number of approved ICIs, each paired with a different PD-L1 antibody IHC assay used in their respective landmark trials, there is an unmet clinical and logistical need for harmonization. We thus investigated the interchangeability between the Dako 22C3, Dako 28-8 and Ventana SP-142 assays in GC PD-L1 IHC. Methods: In this cross-sectional study, samples were obtained via biopsy or resection of gastric cancer at the National University Hospital, Singapore. We scored 362 GC samples for PD-L1 CPS, tumor proportion score (TPS) and immune cells (IC) using a multiplex immunohistochemistry/immunofluorescence technique. 344 samples were developed into a tissue microarray (TMA), while 18 samples were used as whole slides for orthogonal validation. The samples selected for whole slide analysis were obtained from GC patients treated with ICI therapy. Results: The percentage of PD-L1 positive samples at clinically relevant CPS ≥1, ≥5 and ≥10 cut-offs (Table) for the 28-8 assay were approximately two-fold higher than that of the 22C3 (CPS≥1: 70.3% vs 49.4%, p

Glaucoma and chronic kidney disease (CKD) are prevalent and debilitating conditions, with common pathogenic pathways like oxidative stress and fluid dysregulation. We evaluated if there is a bidirectional association between them, as previous studies have yielded conflicting results.In this systematic review and meta-analysis, we searched PubMed, Embase and Cochrane Library from inception until 15 June 2021, including full-length English articles published in peer-reviewed journals reporting on glaucoma and CKD as either exposure or outcome, among participants aged ≥18 years. We pooled overall summary estimates of odds ratios using random-effect meta-analysis and conducted subgroup meta-analyses and univariate meta regression. We assessed risk of bias using the Newcastle-Ottawa Scale (NOS) and quality of evidence using the GRADE framework. Our article is PROSPERO-registered and adherent to both PRISMA and MOOSE guidelines. This review is registered with PROSPERO (CRD42021262846).We identified 14 articles comprising of 3 retrospective cohort studies and 12 cross-sectional studies from 2,428 records, including 1,978,254 participants. Risk of bias was low to moderate. Participants with CKD at baseline had higher pooled odds of glaucoma (odds ratio[OR]=1.18, 95% confidence interval[CI]=1.04-1.33, IOur meta-analysis suggests a bidirectional relationship between glaucoma and CKD, particularly among East Asians. Further studies are required to elucidate underlying mechanisms and account for differential association by ethnicity.Ching-Yu Cheng is supported by Clinician Scientist Award (NMRC/CSA-SI/0012/2017) of the Singapore Ministry of Health's National Medical Research Council.

ObjectiveTo compare the efficacy of covid-19 vaccines between immunocompromised and immunocompetent people.DesignSystematic review and meta-analysis.Data sourcesPubMed, Embase, Central Register of Controlled Trials, COVID-19 Open Research Dataset Challenge (CORD-19), and WHO covid-19 databases for studies published between 1 December 2020 and 5 November 2021. ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform were searched in November 2021 to identify registered but as yet unpublished or ongoing studies.Study selectionProspective observational studies comparing the efficacy of covid-19 vaccination in immunocompromised and immunocompetent participants.MethodsA frequentist random effects meta-analysis was used to separately pool relative and absolute risks of seroconversion after the first and second doses of a covid-19 vaccine. Systematic review without meta-analysis of SARS-CoV-2 antibody titre levels was performed after first, second, and third vaccine doses and the seroconversion rate after a third dose. Risk of bias and certainty of evidence were assessed.Results82 studies were included in the meta-analysis. Of these studies, 77 (94%) used mRNA vaccines, 16 (20%) viral vector vaccines, and 4 (5%) inactivated whole virus vaccines. 63 studies were assessed to be at low risk of bias and 19 at moderate risk of bias. After one vaccine dose, seroconversion was about half as likely in patients with haematological cancers (risk ratio 0.40, 95% confidence interval 0.32 to 0.50, I2=80%; absolute risk 0.29, 95% confidence interval 0.20 to 0.40, I2=89%), immune mediated inflammatory disorders (0.53, 0.39 to 0.71, I2=89%; 0.29, 0.11 to 0.58, I2=97%), and solid cancers (0.55, 0.46 to 0.65, I2=78%; 0.44, 0.36 to 0.53, I2=84%) compared with immunocompetent controls, whereas organ transplant recipients were 16 times less likely to seroconvert (0.06, 0.04 to 0.09, I2=0%; 0.06, 0.04 to 0.08, I2=0%). After a second dose, seroconversion remained least likely in transplant recipients (0.39, 0.32 to 0.46, I2=92%; 0.35, 0.26 to 0.46), with only a third achieving seroconversion. Seroconversion was increasingly likely in patients with haematological cancers (0.63, 0.57 to 0.69, I2=88%; 0.62, 0.54 to 0.70, I2=90%), immune mediated inflammatory disorders (0.75, 0.69 to 0.82, I2=92%; 0.77, 0.66 to 0.85, I2=93%), and solid cancers (0.90, 0.88 to 0.93, I2=51%; 0.89, 0.86 to 0.91, I2=49%). Seroconversion was similar between people with HIV and immunocompetent controls (1.00, 0.98 to 1.01, I2=0%; 0.97, 0.83 to 1.00, I2=89%). Systematic review of 11 studies showed that a third dose of a covid-19 mRNA vaccine was associated with seroconversion among vaccine non-responders with solid cancers, haematological cancers, and immune mediated inflammatory disorders, although response was variable in transplant recipients and inadequately studied in people with HIV and those receiving non-mRNA vaccines.ConclusionSeroconversion rates after covid-19 vaccination were significantly lower in immunocompromised patients, especially organ transplant recipients. A second dose was associated with consistently improved seroconversion across all patient groups, albeit at a lower magnitude for organ transplant recipients. Targeted interventions for immunocompromised patients, including a third (booster) dose, should be performed.Systematic review registrationPROSPERO CRD42021272088.