Discordant PD-L1 results between 28-8 and 22C3 assays are associated with outcomes of gastric cancer patients treated with nivolumab plus chemotherapy.

BACKGROUND: We evaluated the concordance/discordance of PD-L1 staining results between the 28-8 and 22C3 assays and its impact on the efficacy outcomes of advanced gastric cancer patients treated with nivolumab plus chemotherapy. METHODS: This retrospective study involved 143 gastric cancer patients treated with first-line nivolumab plus chemotherapy whose PD-L1 results with both 28-8 and 22C3 assays were available. The concordance/discordance between these assays and the inter-observer variability were evaluated for PD-L1 combined positive score (CPS) positivity. Discordant PD-L1 results were analyzed regarding survival outcomes. RESULTS: The agreement rates and Cohen's kappa values between the 28-8 and 22C3 assays were 78.3% and 0.56 (for CPS ≥ 1), 81.8% and 0.60 (for CPS ≥ 5), and 88.8% and 0.66 (for CPS ≥ 10), respectively. Inter-observer variability, as represented by the intra-class correlation coefficient, was 0.89 and 0.88 for the 28-8 and 22C3 assays, respectively. With PD-L1 CPS ≥ 5 defined as positive, 35 (24.5%) and 82 (57.3%) had concordantly positive and negative results, respectively, between the 28-8 and 22C3 assays, whereas 26 (18.2%) had discordant results. Progression-free survival was shorter for those who exhibited negatively concordant PD-L1 results and discordant PD-L1 positivity between the 28-8 and 22C3 assays relative to those with positively concordant PD-L1 results (P = 0.013). CONCLUSION: PD-L1 assays by 28-8 and 22C3 showed suboptimal concordance, while inter-observer variability was not critical in advanced gastric cancer. Discordant PD-L1 results between 28-8 and 22C3 assays may be associated with unfavorable efficacy outcomes in patients treated with nivolumab plus chemotherapy.

Association between HER2 heterogeneity and clinical outcomes of HER2-positive gastric cancer patients treated with trastuzumab.

BACKGROUND: The GASTHER1 study showed that re-evaluation of HER2 status rescued 8% of HER2-positive gastric cancer (GC) patients with initially HER2-negative GC. Since rescued HER2 positivity represents HER2 heterogeneity, we aimed to investigate this in a larger cohort with longer follow-up duration. METHODS: Data of 153 HER2-positive advanced GC patients who received first-line trastuzumab-based chemotherapy were analyzed. Repeat endoscopic biopsy was performed in patients with initially HER2-negative GC. Survival outcomes were analyzed according to the immunohistochemistry (IHC) score (IHC 2+ /in situ hybridization [ISH] + vs IHC 3+), HER2 status (initially vs rescued HER2 positive), and H-score. RESULTS: IHC 2+ /ISH + patients showed worse progression-free survival (PFS) and overall survival (OS) than those with IHC 3+ (p < 0.05). Rescued HER2-positive patients showed worse PFS and OS than initially HER2-positive patients (p < 0.05). Although survival outcomes were comparable according to HER2 status in IHC 2+ /ISH + patients, initially HER2-positive patients showed more favorable PFS and OS than rescued HER2-positive patients (p < 0.05) among those with IHC 3+ . Among the subgroups determined by HER2 status and IHC score, the initially IHC 3+ subgroup had the highest H-score. The low H-score group (H-score ≤ 210) had significantly worse survival outcomes than the high H-score group (H-score > 210) (p < 0.05). An H-score of ≤ 210 was independently associated with shorter OS (HR = 1.54, 95% CI 1.02-2.31, p = 0.04). CONCLUSIONS: Rescued HER2-positive patients showed worse clinical outcomes than initially HER2-positive patients, especially those with IHC 3+ . This finding highlights the impact of HER2 heterogeneity, which can be quantified indirectly as an H-score.

Clinical implications of neutrophil-to-lymphocyte ratio and MDSC kinetics in gastric cancer patients treated with ramucirumab plus paclitaxel.

OBJECTIVE: We aimed to investigate the prognostic value of neutrophil-to-lymphocyte ratio (NLR) and myeloid-derived suppressor cells (MDSCs) in gastric cancer patients treated with second-line ramucirumab plus paclitaxel. METHODS: A total of 116 patients with advanced or metastatic gastric cancer who receive ramucirumab plus paclitaxel were prospectively enrolled. Fresh blood samples were collected before and after treatment, and flow cytometry was performed to assess the proportions of monocytic (mMDSCs) and granulocytic MDSCs (gMDSCs). RESULTS: Median age was 58 years and 71 (61.2%) patients were male. A baseline NLR≥2.94 was associated with significantly poorer progression-free survival (PFS) and overall survival (OS) vs. an NLR<2.94 (P=0.011 and P=0.002, respectively). In multivariate analysis, an NLR≥2.94 was independently associated with poorer PFS [hazard ratio (HR)=1.58; 95% confidence interval (95% CI): 1.01-2.49, P=0.046] and OS (HR=1.77; 95% CI: 1.04-3.04, P=0.036). While mMDSC counts did not significantly change following two cycles of therapy (P=0.530), gMDSC counts decreased significantly after two treatment cycles (P=0.025) but tended to increase in patients with progressive disease after two treatment cycles (P=0.098). A progressive increase in gMDSC counts (≥44%) was associated with a significantly shorter PFS and OSvs. a gMDSC count increase <44% (P=0.001 and P=0.003, respectively). CONCLUSIONS: The baseline NLR may help guide clinical decisions during ramucirumab plus paclitaxel therapy for gastric cancer. Our gMDSC kinetics data warrant further clinical validation and mechanistic investigation.

Increasing the documentation of 48-hour antimicrobial reviews.

Antimicrobial resistance is a growing problem worldwide. Encouraging antimicrobial stewardship can help to reduce the negative consequences of inappropriate antibiotic use. This quality improvement project targets to do this by aiming to improve the proportion of 48-hour antimicrobial reviews completed and documented on two surgical wards at Darent Valley Hospital with a goal of 100% compliance.This project used four PDSA (plan, do, study, act) cycles to achieve our aim: a trust-wide email; education sessions with junior doctors; sticker reminders in patient notes; presenting our study to surgical consultants and displaying posters on the wards.The proportion of antimicrobial reviews completed at 48 hours in the patient notes increased from 18% to 77% over 19 weeks from 10 October 2018 to 20 February 2019. The most successful intervention was providing a presentation for consultants at an audit meeting in conjunction with displaying posters on the wards.The most successful interventions (education sessions with junior doctors and presentation to surgical consultants alongside displaying posters on the wards) were found to be those that required minimal further input after their initial rollout. This project was carried out by medical students and is highly transferrable to other hospitals, and highlighted that a successful quality improvement project can be undertaken by any member of the healthcare team.