Baseline Circulating Blood Cell Counts and Ratios and Changes Therein for Predicting Immune-Related Adverse Events during Immune Checkpoint Inhibitor Therapy: A Multicenter, Prospective, Observational, Pan-Cancer Cohort Study with a Gender Perspective.

Several factors have been associated with the occurrence of immune-related adverse events (irAEs) induced by immune checkpoint inhibitor (ICI) therapy. Despite their availability, the predictive value of circulating blood cell parameters remains underexplored. Our aim was to investigate whether baseline values of and early changes in absolute neutrophil count (ANC), absolute lymphocyte count (ALC), other blood cell counts, and lymphocyte-related ratios can predict irAEs and whether sex may differentially influence this potential predictive ability. Of the 145 patients included, 52 patients (35.8%) experienced at least one irAE, with a 1-year cumulative incidence of 41.6%. Using Fine and Gray competing risk models, we identified female sex (hazard ratio (HR) = 2.17, 95% confidence interval (CI) = 1.20-3.85), high ALC before ICI initiation (HR = 1.63, 95% CI = 1.09-2.45), and low ANC after ICI initiation (HR = 0.81, 95% CI = 0.69-0.96) as predictors of irAEs. However, ALC and ANC may only have an impact on the risk of irAEs in women (stratified for female sex, ALC-related HR = 2.61, 95% CI = 1.40-4.86 and ANC-related HR = 0.57, 95% CI = 0.41-0.81). Priority should be given to developing models to predict ICI-related toxicity and their validation in various settings, and such models should assess the impact of patient sex on the risk of toxicity.

A Novel Prognostic Biomarker Panel for Early-Stage Colon Carcinoma.

Molecular characterization of colorectal cancer has helped us understand better the biology of the disease. However, previous efforts have yet to provide significant clinical value in order to be integrated into clinical practice for patients with early-stage colon cancer (CC). The purpose of this study was to assess PD-L1, GLUT-1, e-cadherin, MUC2, CDX2, and microsatellite instability (dMMR) and to propose a risk-panel with prognostic capabilities. Biomarkers were immunohistochemically assessed through tissue microarrays in a cohort of 144 patients with stage II/III colon cancer. A biomarker panel consisting of PD-L1, GLUT-1, dMMR, and potentially CDX2 was constructed that divided patients into low, medium, and high risk of overall survival or disease-free survival (DFS) in equally sized groups. Compared with low-risk patients, medium-risk patients have almost twice the risk of death (HR = 2.10 (0.99-4.46), p = 0.054), while high-risk patients have almost four times the risk (HR = 3.79 (1.77-8.11), p = 0.001). The multivariate goodness of fit was 0.756 and was correlated with Kaplan-Meier curves (p = 0.002). Consistent results were found for DFS. This study provides a critical basis for the future development of an immunohistochemical assessment capable of discerning early-stage CC patients as a function of their prognosis. This tool may aid with treatment personalization in daily clinical practice and improve survival outcomes.

The Answer to "When to Clip" After Colorectal Endoscopic Mucosal Resection Based on a Cost-Effectiveness Analysis.

INTRODUCTION: Delayed bleeding (DB) is the most common major complication of endoscopic mucosal resection (EMR). Two randomized clinical trials recently demonstrated that clip closure after EMR of large nonpedunculated colorectal polyps (LNPCPs) reduces the risk of DB. We analyzed the cost-effectiveness of this prophylactic measure. METHODS: EMRs of LNCPCPs were consecutively registered in the ongoing prospective multicenter database of the Spanish EMR Group from May 2013 until July 2017. Patients were classified according to the Spanish Endoscopy Society EMR group (GSEED-RE2) DB risk score. Cost-effectiveness analysis was performed for both Spanish and US economic contexts. The average incremental cost-effectiveness ratio (ICER) thresholds were set at 54,000 € or $100,000 per quality-adjusted life year, respectively. RESULTS: We registered 2,263 EMRs in 2,130 patients. Applying their respective DB relative risk reductions after clip closure (51% and 59%), the DB rate decreased from 4.5% to 2.2% in the total cohort and from 13.7% to 5.7% in the high risk of the DB GSEED-RE2 subgroup. The ICERs for the universal clipping strategy in Spain and the United States, 469,706 € and $1,258,641, respectively, were not cost effective. By contrast, selective clipping in the high-risk of DB GSEED-RE2 subgroup was cost saving, with a negative ICER of -2,194 € in the Spanish context and cost effective with an ICER of $87,796 in the United States. DISCUSSION: Clip closure after EMR of large colorectal lesions is cost effective in patients with a high risk of bleeding. The GSEED-RE2 DB risk score may be a useful tool to identify that high-risk population.

Clip Closure After Resection of Large Colorectal Lesions With Substantial Risk of Bleeding.

BACKGROUND & AIMS: It is not clear whether closure of mucosal defects with clips after colonic endoscopic mucosal resection (EMR) prevents delayed bleeding, although it seems to have no protective effects when risk is low. We performed a randomized trial to evaluate the efficacy of complete clip closure of large (≥2 cm) nonpedunculated colorectal lesions after EMR in patients with an estimated average or high risk of delayed bleeding. METHODS: We performed a single-blind trial at 11 hospitals in Spain from May 2016 through June 2018, including 235 consecutive patients who underwent EMR for large nonpedunculated colorectal lesions with an average or high risk of delayed bleeding (based on Spanish Endoscopy Society Endoscopic Resection Group score). Participants were randomly assigned to groups that received closure of the scar with 11-mm through-the-scope clips (treated, n = 119) or no clip (control, n = 116). The primary outcome was proportion of patients in each group with delayed bleeding, defined as evident hematochezia that required medical intervention within 15 days after colonoscopy. RESULTS: In the clip group, complete closure was achieved in 68 (57%) cases, with partial closure in 33 (28%) cases and failure to close in 18 (15%) cases. Delayed bleeding occurred in 14 (12.1%) patients in the control group and in 6 (5%) patients in the clip group (absolute risk difference, reduction of 7% in the clip group; 95% confidence interval, -14.7% to 0.3%). After completion of the clip closure, there was only 1 (1.5%) case of delayed bleeding (absolute risk difference, reduction of 10.6%; 95% confidence interval, -4.3% to 17.9%). CONCLUSIONS: In a randomized trial of patients with large nonpedunculated colorectal lesions undergoing EMR, we found that clip closure of mucosal defects in patients with a risk of bleeding can be a challenge, but also reduces delayed bleeding. Prevention of delayed bleeding required complete clip closure. ClinicalTrials.gov ID: NCT02765022.

Shared component modelling as an alternative to assess geographical variations in medical practice: gender inequalities in hospital admissions for chronic diseases.

BACKGROUND: Small area analysis is the most prevalent methodological approach in the study of unwarranted and systematic variation in medical practice at geographical level. Several of its limitations drive researchers to use disease mapping methods -deemed as a valuable alternative. This work aims at exploring these techniques using - as a case of study- the gender differences in rates of hospitalization in elderly patients with chronic diseases. METHODS: Design and study setting: An empirical study of 538,358 hospitalizations affecting individuals aged over 75, who were admitted due to a chronic condition in 2006, were used to compare Small Area Analysis (SAVA), the Besag-York-Mollie (BYM) modelling and the Shared Component Modelling (SCM). Main endpoint: Gender spatial variation was measured, as follows: SAVA estimated gender-specific utilization ratio; BYM estimated the fraction of variance attributable to spatial correlation in each gender; and, SCM estimated the fraction of variance shared by the two genders, and those specific for each one. RESULTS: Hospitalization rates due to chronic diseases in the elderly were higher in men (median per area 21.4 per 100 inhabitants, interquartile range: 17.6 to 25.0) than in women (median per area 13.7 per 100, interquartile range: 10.8 to 16.6). Whereas Utilization Ratios showed a similar geographical pattern of variation in both genders, BYM found a high fraction of variation attributable to spatial correlation in both men (71%, CI95%: 50 to 94) and women (62%, CI95%: 45 to 77). In turn, SCM showed that the geographical admission pattern was mainly shared, with just 6% (CI95%: 4 to 8) of variation specific to the women component. CONCLUSIONS: Whereas SAVA and BYM focused on the magnitude of variation and on allocating where variability cannot be due to chance, SCM signalled discrepant areas where latent factors would differently affect men and women.