Association Between Obesity and Chronic Kidney Disease: Multivariable Mendelian Randomization Analysis and Observational Data From a Bariatric Surgery Cohort.

Obesity is postulated to independently increase chronic kidney disease (CKD), even after adjusting for type 2 diabetes (T2D) and hypertension. Dysglycemia below T2D thresholds, frequently seen with obesity, also increases CKD risk. Whether obesity increases CKD independent of dysglycemia and hypertension is unknown and likely influences the optimal weight loss (WL) needed to reduce CKD. T2D remission rates plateau with 20-25% WL after bariatric surgery (BS), but further WL increases normoglycemia and normotension. We undertook bidirectional inverse variance weighted Mendelian randomization (IVWMR) to investigate potential independent causal associations between increased BMI and estimated glomerular filtration rate (eGFR) in CKD (CKDeGFR) (<60 mL/min/1.73 m2) and microalbuminuria (MA). In 5,337 BS patients, we assessed whether WL influences >50% decline in eGFR (primary outcome) or CKD hospitalization (secondary outcome), using <20% WL as a comparator. IVWMR results suggest that increased BMI increases CKDeGFR (b = 0.13, P = 1.64 × 10-4; odds ratio [OR] 1.14 [95% CI 1.07, 1.23]) and MA (b = 0.25; P = 2.14 × 10-4; OR 1.29 [1.13, 1.48]). After adjusting for hypertension and fasting glucose, increased BMI did not significantly increase CKDeGFR (b = -0.02; P = 0.72; OR 0.98 [0.87, 1.1]) or MA (b = 0.19; P = 0.08; OR 1.21 [0.98, 1.51]). Post-BS WL significantly reduced the primary outcome with 30 to <40% WL (hazard ratio [HR] 0.53 [95% CI 0.32, 0.87]) but not 20 to <30% WL (HR 0.72 [0.44, 1.2]) and ≥40% WL (HR 0.73 [0.41, 1.30]). For CKD hospitalization, progressive reduction was seen with increased WL, which was significant for 30 to <40% WL (HR 0.37 [0.17, 0.82]) and ≥40% WL (HR 0.24 [0.07, 0.89]) but not 20 to <30% WL (HR 0.60 [0.29, 1.23]). The data suggest that obesity is likely not an independent cause of CKD. WL thresholds previously associated with normotension and normoglycemia, likely causal mediators, may reduce CKD after BS.

Associations of Clinical and Molecular Characteristics with the Response to Immune Checkpoint Blockade in Advanced Gastric Cancers.

Purpose: Immunotherapy provides a new treatment option for advanced gastric cancer (AGC). This study aims to explore the response markers of immunotherapy in AGCs. Methods: Next-generation sequencing was performed on 44 AGC patients who received immune checkpoint inhibitors and the associations between their outcomes after combination immunotherapy, and the clinicopathological/molecular characteristics were analyzed. Results: The current study cohort had a median progression-free survival (PFS) of 5.9 months, an overall survival (OS) of 12.1 months, and an objective response rate (ORR) of 36.4%. Through multivariable analysis of the clinical characteristics, primary tumor resection (HR = 2.66, 95% CI: 1.06-6.70, p=0.037) and increased proportion of lymphocytes after combination immunotherapy (HR = 0.40, 95% CI: 0.16-0.99, p=0.048) were revealed as independent predictors for patient outcomes. All the 18 patients who underwent genetic profiling were microsatellite-stable with a median TMB of four mutations per Mb. ATM alterations, PI3K pathway mutations, increased TMB, and positive PD-L1 expression were associated with the increased trend of PFS and ORR. According to the combination of baseline lymphocyte count, ATM mutation, TMB status, and PD-L1 expression, patients were stratified into higher- and lower-risk groups, with the lower-risk group showing improved PFS (HR = 4.7e-10, 95% CI: 0-inf, p=0.02) and ORR (75% vs. 0%, p=0.007). Conclusion: Several highly relevant potential biomarkers predictive of immunotherapy response in AGC patients have been identified in this research.

Clinicopathological Characteristics and Prognosis of Signet Ring Gastric Cancer: A Population-Based Study.

BACKGROUND: To better define the clinicopathologic characteristics of signet ring cell (SRC) gastric cancer and build a prognostic model for it. METHODS: SRC patient information from 2010 to 2015 were identified using Surveillance, Epidemiology, and End Results (SEER) database. Kaplan-Meier method and log-rank test were used to estimate Overall survival (OS) and to determine associations with histologic subtypes. In COX proportional hazards regression model-based univariate and multivariate analyses, significant variables for construction of a nomogram were screened out. The nomogram was validated by means of the concordance index (CI), calibration plots, and receiver operating characteristics (ROCs) curves. RESULTS: A total of 11,363 gastric cancer patients were enrolled. On dividing the patients into SRC, well-to-moderately differentiated (WMD) adenocarcinoma, and poorly differentiated (PD) adenocarcinoma, differences among these subgroups emerged. SRC patients were more likely to occur in female and young patients than other histologic subtypes. Larger tumors, stage T4, and node stage N3 were more likely to be found in the SRC group. The survival for SRC patients was better than non-SRC patients in stage I. Univariate and multivariate analyses identified age, tumor site, larger tumor size, advanced T classification, advanced N classification, advanced TNM stage, and surgery of primary site as independent prognostic indicators. Then an OS nomogram was formulated. CONCLUSIONS: SRC had distinct clinicopathological characteristics. The nomogram provided an accurate tool to evaluate the prognosis of SRC.