Efficacy and safety of first-line PD-L1/PD-1 inhibitors in limited-stage small cell lung cancer: a multicenter propensity score matched retrospective study.

Background: The prognosis of small cell lung cancer (SCLC) patients is poor, and the standard first-line treatment for limited-stage small cell lung cancer (LS-SCLC) is still chemotherapy and thoracic radiotherapy. The primary objectives of our study were to confirm the superior efficacy of first-line immune checkpoint inhibitors (ICIs) plus etoposide and platinum (EP) for LS-SCLC and find crucial biomarkers. Methods: We analyzed LS-SCLC patients from three medical centers, employing propensity score matching for group comparability. Survival outcomes were estimated by Kaplan-Meier and Cox regression analyses. Additionally, we conducted univariate and multivariate analyses to investigate potential predictive factors. Results: Among 150 patients in our study, we successfully matched 41 pairs. The median overall survival (OS) was 29.5 months in the EP + ICIs group and 20.0 months in the EP group {hazard ratio (HR) =0.64 [95% confidence interval (CI): 0.41-1.02], P=0.059}. The median progression-free survival (PFS) was significantly extended in the EP + ICIs group (14.6 months), compared to the EP group (8.6 months) [HR =0.42 (95% CI: 0.28-0.63), P<0.001]. After matching, patients receiving chemo-immunotherapy had a median OS of 36.1 months, significantly surpassing those receiving chemotherapy alone (19.0 months) [HR =0.51 (95% CI: 0.28-0.93), P=0.02]. And the patients in the EP + ICIs group also had longer PFS after matching [HR =0.42 (95% CI: 0.25-0.71), P=0.001]. No significant difference in the objective response rate (ORR) and treatment-related adverse events (trAEs) between the two groups was found (ORR: EP: 81.0%, EP + ICIs: 90.0%, P=0.14; trAEs: EP: grade 1-2, 49.3%; grade 3-4, 42.5%; EP + ICIs: grade 1-2, 40.0%; grade 3-4, 49.1%, P=0.62). The multivariate analysis presented that the history of immunotherapy [EP + PD-1 inhibitors: HR =0.33 (95% CI: 0.17-0.62), P=0.001; EP + PD-L1 inhibitors: HR =0.18 (95% CI: 0.06-0.60), P=0.005] and baseline lung immune prognostic index (LIPI) [intermediate: HR =2.22 (95% CI: 1.20-4.13), P=0.01; poor: HR =2.03 (95% CI: 0.71-5.77), P=0.18] were independent prognostic factors for PFS among all LS-SCLC cases. However, no independent prognostic factor was identified for OS. Conclusions: Our real-world data showed promising clinical efficacy and tolerable safety of first-line programmed cell death protein 1 (PD-1) inhibitors or programmed cell death ligand 1 (PD-L1) inhibitors in cases with LS-SCLC. Additionally, LIPI may serve as a valuable prognostic factor.

Globotriaosylsphingosine improves risk stratification of kidney progression in Fabry disease patients.

BACKGROUND: Kidney damage is common in patients with Fabry disease (FD), but more accurate information about the risk of progression to kidney failure is needed for clinical decision-making. In particular, FD patients with mild renal involvement often lack timely intervention and treatment. We aimed to utilize a model to predict the risk of renal progression in FD patients. METHODS: Between November 2011 and November 2019, ERT-naive patients with FD were recruited from three medical centers in China. To assess the risk of a 50% decline in the estimated glomerular filtration rate (eGFR) or end-stage kidney disease (ESKD), Cox proportional hazards models were utilized. The performance of these models was assessed using discrimination, calibration, and reclassification. RESULTS: A total of 117 individuals were enrolled. The mean follow-up time was 4.8 years, during which 35 patients (29.9 %) progressed to the composite renal outcomes. Male sex, baseline proteinuria, eGFR and globotriaosylsphingosine (Lyso-Gb3) were found to be independent risk factors for kidney progression by the Cox model, based on which a combined model containing those clinical variables and Lyso-Gb3 and clinical models including only clinical indicators were constructed. The two prediction models had relatively good performance, with similar model fit measured by R2 (59.8 % vs. 61.1 %) and AIC (51.54 vs. 50.08) and a slight increase in the C statistic (0.949 vs. 0.951). Calibration curves indicated closer alignment between predicted and actual renal outcomes in the combined model. Furthermore, subgroup analysis revealed that Lyso-Gb3 significantly improved the predictive performance of the combined model for kidney prognosis in low-risk patients with a baseline eGFR over 60 ml/min/1.73 m2 or proteinuria levels less than 1 g/d when compared to the clinical model. CONCLUSIONS: Lyso-Gb3 improves the prediction of kidney outcomes in FD patients with a low risk of progression, suggesting that these patients may benefit from early intervention to assist in clinical management. These findings need to be externally validated.

Psychological profile of Chinese peritoneal dialysis patients during the Omicron pandemic in 2022.

OBJECTIVE: The aim of this study was to determine the psychological status of peritoneal dialysis (PD) patients who were blocked during the 2022 Omic Pandemic in Shanghai. METHODS: This was an observational and cross-sectional study. We selected 172 PD patients from the peritoneal dialysis center of Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, during the quarantine of the Omicron pandemic in Shanghai from April to May 2022. General data and biochemical indices were collected. The Kidney Disease Quality of Life (SF-36) questionnaire was used to evaluate the psychological state of the patients during the quarantine. RESULTS: According to the assessment of the SF-36 scale, the physiological and psychological health status of PD patients was better than that before quarantine (P < 0.05). According to the comparison of biochemical indices, the high-density lipoprotein, total cholesterol and body mass index (BMI) levels were lower in patients after quarantine than before quarantine, while the blood phosphorus, blood calcium and haemoglobin levels were greater after quarantine (P < 0.05). Logistic regression analysis revealed that health changes were positively correlated with age of penetration (years) (OR = 1.031, 95% CI = 1.005-1.058); however, physiological function was negatively correlated with sex (OR = 0.198, 95% CI = 0.044-0.899). Energy was significantly positively correlated with closed-loop time (OR = 1.063, 95% CI = 1.001-1.128) (P < 0.05). There were no significant differences in biochemical indices or quality of life between APD patients and non-APD patients (P > 0.05). According to the results of the abstract independent sample T test, when comparing the various dimensions of the SF-36 scale, for the dimensions of physiological function, pain and energy, the PD patients were better than the HD patients were (P < 0.05). Similarly, for the dimension of physiological function, the HD patients were better than the PD patients were (P < 0.05). During the quarantine period from April to May in Shanghai, the infection rate of PD patients was lower than usual (P < 0.05). CONCLUSIONS: During the Omicron pandemic in Shanghai in 2022, PD patients exhibited relatively stable psychological and physiological states and a low infection rate. Compared with HD patients, PD patients had better adaptability. Especially in the context of the COVID-19 pandemic, peritoneal dialysis has more advantages.

The safety and efficacy of anti-PD-1 inhibitor-based combinational therapy in non-small cell lung cancer patients with oncogenic alterations.

Background: The anti-programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) immunotherapy has been extensively used in patients with non-small cell lung cancer (NSCLC) in which the tumors are negative for oncogenic alterations. However, whether PD-1/PD-L1 blockade therapy could be applicable in patients harboring oncogenic mutations is largely unknown. Methods: In this retrospective study, we analyzed the safety and efficacy of anti-PD-1 inhibitor-based combinational therapy in a NSCLC cohort of 84 patients who harbored oncogenic alterations in epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), k-Ras, RET, HER2 and BRAF. The patients were followed up till disease progression or death. The adverse effects associated with the treatment were carefully evaluated and timely interrupted. Results: There were 50 patients harboring EGFR mutations, 17 patients with k-Ras mutation, 2 patients with ALK rearrangement, 6 patients with RET rearrangement, 6 patients with HER2 exon20 insertion and 3 patients with BRAF V600E mutation. About 58.8% of the k-Ras mutant patients responded to the combinational treatment. The median progression-free survival (mPFS) of the k-Ras cohort was 14 months, with the 12-month median overall survival (mOS) ratio and the 24-month OS ratio of 86.7% and 75.8%, respectively. Patients with EGFR exon21 L858R mutation or RET rearrangement tended to have a more favorable response, while patients harboring ALK rearrangement, HER2 exon20 insertion and BRAF V600E mutation did not respond well to anti-PD-1 inhibitor-based combinational therapy. The incidence of treatment-related toxicity was 52.3% and the most common immune-related adverse events (irAEs) were PD-1 inhibitors-related hypothyroidism and pneumonitis. The PD-L1 status and lung immune prognostic index (LIPI) could be used as biomarkers dictating therapeutic outcomes of the combinational therapy. Conclusions: The anti-PD-1 inhibitor-based combinational therapy elicited exciting anti-tumor efficacy and prolonged patient survival with manageable adverse effects in NSCLC patients harboring oncogenic alterations. The PD-L1 status and LIPI could be used as a biomarker predicting response to anti-PD-1 inhibitor-based combinational treatment in these patients.

Combined Serologic and Genetic Risk Score and Prognostication of Phospholipase A2 receptor-Associated Membranous Nephropathy.

INTRODUCTION: The aim of this study was to test whether a combined risk score on the basis of genetic risk and serology can improve the prediction of kidney failure in phospholipase A2 receptor (PLA2R)-associated primary membranous nephropathy. METHODS: We performed a retrospective analysis of 519 biopsy-proven PLA2R-associated primary membranous nephropathy patients with baseline eGFR ≥25 ml/min per 1.73 m 2 . The combined risk score was calculated by combining the genetic risk score with PLA2R ELISA antibody titers. The primary end point was kidney disease progression defined as a 50% reduction in eGFR or kidney failure. Cox proportional hazard regression analysis and C-statistics were applied to compare the performance of PLA2R antibody, genetic risk score, and combined risk score, as compared with clinical factors alone, in predicting primary outcomes. RESULTS: The median age was 56 years (range, 15-82 years); the male-to-female ratio was 1:0.6, the median eGFR at biopsy was 99 ml/min per 1.73 m 2 (range: 26-167 ml/min per 1.73 m 2 ), and the median proteinuria was 5.3 g/24 hours (range: 1.5-25.8 g/24 hours). During a median follow-up of 67 (5-200) months, 66 (13%) had kidney disease progression. In Cox proportional hazard regression models, PLA2R antibody titers, genetic risk score, and combined risk score were all individually associated with kidney disease progression with and without adjustments for age, sex, proteinuria, eGFR, and tubulointerstitial lesions. The best-performing clinical model to predict kidney disease progression included age, eGFR, proteinuria, serum albumin, diabetes, and tubulointerstitial lesions (C-statistic 0.76 [0.69-0.82], adjusted R 2 0.51). Although the addition of PLA2R antibody titer improved the performance of this model (C-statistic: 0.78 [0.72-0.84], adjusted R 2 0.61), replacing PLA2R antibody with the combined risk score improved the model further (C-statistic: 0.82 [0.77-0.87], adjusted R 2 0.69, difference of C-statistics with clinical model=0.06 [0.03-0.10], P < 0.001; difference of C-statistics with clinical-serologic model=0.04 [0.01-0.06], P < 0.001). CONCLUSIONS: In patients with PLA2R-associated membranous nephropathy, the combined risk score incorporating inherited risk alleles and PLA2R antibody enhanced the prediction of kidney disease progression compared with PLA2R serology and clinical factors alone.

Racial and ethnic differences in COVID-19 vaccine readiness among adults in the United States, January 2021-April 2023.

Racial and ethnic minority groups have been disproportionately affected by COVID-19 and have experienced systemic, attitudinal, and access-related barriers to COVID-19 vaccination. We examined differences in COVID-19 vaccine readiness-a composite measure of vaccination intention and behavior-between non-Hispanic White, non-Hispanic Black, Hispanic, non-Hispanic Asian American/Pacific Islander, and American Indian/Alaska Native U.S. adults. Using data from a cross-sectional survey administered to nationally representative samples of âˆ¼ 5,000 U.S. adults each month from January 2021 to April 2023 (n = 135,989), we conducted weighted ttests comparing the monthly percentage of participants from racial/ethnic groups who were "Vaccine Ready." Initial racial/ethnic disparities in vaccine readiness were attenuated within a 7-month period, after which adults from most minority racial/ethnic groups became equally or more vaccine ready compared to non-Hispanic White adults (p < 0.05). Findings suggest that barriers to vaccine readiness that were more prevalent in non-White racial/ethnic groups may have largely been addressed.

Management of nocturnal hypertension: An expert consensus document from Chinese Hypertension League.

Nocturnal hypertension is highly prevalent among Chinese and Asian populations, which is mainly attributed to high salt intake and high salt sensitivity. Nocturnal hypertension increases the risk of cardiovascular and all-cause mortality, independent of daytime blood pressure (BP). However, it can usually be detected by 24-h ambulatory BP monitoring, rather than routine office or home BP measurement, thus is often underdiagnosed in clinical practice. Currently, no specific guidance is available for the management of nocturnal hypertension in China or worldwide. Experts from the Chinese Hypertension League summarized the epidemiologic and pathophysiologic characteristics and clinical phenotype of nocturnal hypertension and provided consensus recommendations on optimal management of nocturnal hypertension, with the goal of maximally reducing the cardiovascular disease risks. In this consensus document, 24-h ABPM is recommended for screening and diagnosis of nocturnal hypertension, especially in the elderly, patients with diabetes, chronic kidney diseases, obstructive sleep apnea and other conditions prone to high nocturnal BP. Lifestyle modifications including salt intake restriction, exercise, weight loss, sleep improvement, and mental stress relief are recommended. Long-acting antihypertensive medications are preferred for nocturnal and 24-h BP control. Some newly developed agents, renal denervation, and other device-based therapy on nocturnal BP reduction are evaluated.

Oral glucocorticoids with intravenous cyclophosphamide or oral glucocorticoids alone in the treatment of IgA nephropathy present with nephrotic syndrome and mesangioproliferative glomerulonephritis.

Background: Few studies have evaluated the treatment of immunoglobulin A nephropathy (IgAN) patients with nephrotic syndrome (NS) and mesangioproliferative glomerulonephritis (MPGN). The aim of this study was to compare the therapeutic effects of oral glucocorticoids (GCS) combined with intravenous cyclophosphamide (CTX) and oral GCS alone in the treatment of the MPGN-IgAN patients with NS. Methods: Biopsy-proven primary IgAN patients who were aged ≥14 years at diagnosis, had coexistent NS and MPGN and estimated glomerular filtration rate (eGFR) ≥15 mL/min/1.73 m2, and were treated by oral GCS combined with intravenous CTX or oral GCS alone for 6-12 months were retrospectively included. The patients in the GCS + CTX (prednisone 0.6-0.8 mg/kg/day and intravenous CTX 0.6-1.0 g monthly) or GCS (prednisone 0.8-1 mg/kg/day) group were rather matched at a 1:1 ratio on key characteristics by propensity score matching. The primary outcome was defined as either complete remission or partial remission at Month 24. The secondary outcome was a composite renal endpoint defined as a 50% decline in eGFR, doubling of serum creatinine or progression to end-stage kidney disease. Results: Among the 146 IgAN patients who met the inclusion criteria, 42 patients were enrolled in the GCS + CTX group, and 42 patients were enrolled in the GCS group after propensity score matching. The clinical and histological parameters were similar between the two groups. Remission occurred more frequently in the GCS + CTX group at Month 6 (88.1% vs 52.4%, P < 0.001), Month 12 (88.1% vs 56.1%, P = 0.001) and Month 24 (85.0% vs 47.5%, P < 0.001) than in the GCS group. Moreover, subgroup analysis revealed that the higher response rate at Month 24 in the GCS + CTX group than in the GCS group was also present in different subgroups defined by sex, age, eGFR or Oxford MEST-C. Notably, we found that eGFR decreased at a lower rate in patients from the GCS + CTX group than in patients from the GCS group [eGFR slope: 0.05(-3.09, 3.67) vs -2.56 (-11.30, 0.86) mL/min/1.73 m2/year, P = 0.03]. Based on multivariate Cox regression analysis, GCS + CTX treatment was found to be independently associated with a decrease in risk for the composite endpoint after adjusted by the International Risk Prediction Score with race (hazard ratio = 0.17, 95% confidence interval 0.04-0.83, P = .03). There was no significant difference in adverse events (50.0% vs 42.9%, P = 0.51) or serious adverse events (7.1% vs 11.9%, P = .71) between the two groups. Conclusions: Oral GCS combined with intravenous CTX is superior to GCS alone in treating MPGN-IgAN patients combined with NS. As the retrospective design and small sample size, our findings need to be validated by a prospective study.

Finerenone in Patients with Chronic Kidney Disease and Type 2 Diabetes: The FIDELIO-DKD Subgroup from China.

Background: This prespecified subgroup analysis of the FIDELIO-DKD trial aimed to evaluate the efficacy and safety of finerenone in patients with chronic kidney disease (CKD) and type 2 diabetes mellitus (T2DM) in China. Methods: 372 participants were recruited from 67 centers in China and randomized 1:1 to oral finerenone or placebo with standard therapy for T2DM. The primary composite outcome included kidney failure, sustained decrease of estimated glomerular filtration rate ≥40% from baseline over at least 4 weeks, or renal death. The key secondary composite outcome included death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. Results: After a median follow-up of 30 months, the finerenone group showed a relative risk reduction (RRR) of 41% (hazard ratio [HR] = 0.59, 95% confidence interval [CI], 0.39-0.88; p = 0.009) for the primary composite outcome compared with placebo, consistent across its components with treatment benefits with finerenone. Based on an absolute between-group difference of 12.2% after 30 months, the number of patients who needed to be treated with finerenone to prevent one primary outcome event was eight (95% CI: 4-84). For the key secondary composite outcome, the finerenone group showed a RRR of 25% (HR = 0.75, 95% CI, 0.38-1.48; p = 0.408). Adverse events were similar between the two groups. The effects of finerenone on blood pressure were modest. No gynecomastia events were reported in the study. Hyperkalemia leading to discontinuation occurred in eight (4.3%) and two (1.1%) participants in the finerenone and control groups, respectively. The incidence of acute kidney injury was comparable between the two groups (1.6% vs. 1.6%). Conclusions: Finerenone resulted in lower risks of CKD progression than placebo and a balanced safety profile in Chinese patients with CKD and T2DM.

Rapid Initiation of Peritoneal Dialysis by Automated Peritoneal Dialysis or Hemodialysis: A Randomized Clinical Trial.

Introduction: It is still controversial whether automated peritoneal dialysis (APD) or hemodialysis (HD) is a more favorable choice for the rapid initiation of peritoneal dialysis (PD). Methods: A pilot randomized prospective controlled trial was carried out in Shanghai Ruijin Hospital. Sixty-seven patients who chose long-term PD treatment and needed unplanned dialysis were enrolled and randomized into HD-CAPD group (33 cases) or APD-CAPD group (34 cases) based on the dialysis modality during the transition period (within 14 days from the day PD catheter was implanted). Continuous ambulatory PD started after the transition period. The primary outcome was the decline rates of residual glomerular filtration rate (GFR). Secondary outcomes included the rates of mechanical complications, the rates of infectious complications, and complications of end-stage renal disease. Results: We found residual GFR decline was faster in HD-CAPD group than in APD-CAPD group (0.06 mL/min/w vs. 0.03 mL/min/w, p < 0.01). The incidences of mechanical complications were similar in APD-CAPD group comparing with HD-CAPD group, including hernia (2.9% vs. 3.0%, p = 1.00), catheter malposition (0.02 episodes/patient-months vs. 0.02 episodes/patient-months, p = 0.70), leakage (5.9% vs. 6.1%, p = 1.00), and omental wrap (0 episode vs. 3 episodes, p = 0.368). Though the 1-year overall infection rates were similar (0.03 episodes/patient-months vs. 0.05 episodes/patient-months, p = 0.10), APD-CAPD group had lower rate of bacteremia compared to HD-CAPD group (0 episodes/patient-months vs. 0.02 episodes/patient-months, p < 0.01). Conclusions: Both APD and HD could be used for patients who need to start dialysis in an unplanned manner. APD may have the advantage in protecting residual renal functions among these patients.

Safety and efficacy of thoracic radiotherapy combined with chemo-immunotherapy in patients with extensive-stage small cell lung cancer: a multicenter retrospective analysis.

Background: Immunotherapy has greatly increased the survival time of patients with extensive-stage small cell lung cancer (ES-SCLC), and is now a standard first-line treatment for these patients. Increasing evidence suggests a possible synergistic effect between immunotherapy and radiotherapy, yet there is a paucity of evidence regarding the efficacy and safety of thoracic radiotherapy (TRT) combined with chemo-immunotherapy for ES-SCLC. Methods: The medical records of 78 consecutive patients with ES-SCLC who received TRT in combination with chemo-immunotherapy at Jinling Hospital and Jiangsu Cancer Hospital from January 2019 to January 2023 were retrospectively reviewed. The median overall survival (mOS) time and median progression-free survival (mPFS) time were used to evaluate efficacy, and the incidence of adverse events (AEs) was used to evaluate safety. Results: The median follow-up time was 31.9 months, the objective response rate (ORR) was 59%, and the disease control rate (DCR) was 89.8%. The mOS time was 20.0 months, and the 6-month OS rate was 95%. The mPFS time was 9.2 months, and the 6-month PFS rate was 78%. There were no treatment-related deaths. The incidence of pneumonitis was 23.1%, the incidence of radiation esophagitis was 5.1%, and 2 patients experienced high-grade pneumonitis. Primary liver metastasis was a predictor of poor OS and PFS. Patients who received consolidative TRT after chemo-immunotherapy experienced more benefit than those who received TRT as palliative or salvage treatment for superior vena cava syndrome or disease progression. Conclusions: TRT is a feasible treatment for patients who receive chemo-immunotherapy for the management of ES-SCLC in consideration of its considerable efficacy and tolerable safety risk. This treatment is especially useful for patients without primary liver metastasis and who receive consolidative TRT after chemo-immunotherapy. Large-scale prospective studies are needed to confirm the efficacy and safety of this treatment modality.

Develop and Validate a Risk Score in Predicting Renal Failure in Focal Segmental Glomerulosclerosis.

Introduction: The aim of this study was to develop and validate a risk score (RS) for end-stage kidney disease (ESKD) in patients with focal segmental glomerulosclerosis (FSGS). Methods: Patient with biopsy-proven FSGS was enrolled. All the patients were allocated 1:1 to the two groups according to their baseline gender, age, and baseline creatinine level by using a stratified randomization method. ESKD was the primary endpoint. Results: We recruited 359 FSGS patients, and 177 subjects were assigned to group 1 and 182 to group 2. The clinicopathological variables were similar between two groups. There were 23 (13%) subjects reached to ESKD in group 1 and 22 (12.1%) in group 2. By multivariate Cox regression analyses, we established RS 1 and RS 2 in groups 1 and 2, respectively. RS 1 consists of five parameters including lower eGFR, higher urine protein, MAP, IgG level, and tubulointerstitial lesion (TIL) score; RS 2 also consists of five predictors including lower C3, higher MAP, IgG level, hemoglobin, and TIL score. RS 1 and RS 2 were cross-validated between these two groups, showing RS 1 had better performance in predicting 5-year ESKD in group 1 (c statics, 0.86 [0.74-0.98] vs. 0.82 [0.69-0.95]) and group 2 (c statics, 0.91 [0.83-0.99] vs. 0.89 [0.79-0.99]) compared to RS 2. We then stratified the risk factors into four groups, and Kaplan-Meier survival curve revealed that patients progressed to ESKD increased as risk levels increased. Conclusions: A predictive model incorporated clinicopathological feature was developed and validated for the prediction of ESKD in FSGS patients.

Risk factors for symptomatic malignant pleural effusion recurrence in patients with actionable mutations in advanced lung adenocarcinoma.

Background: Malignant pleural effusion (MPE) comes generally with high mortality and poor prognosis. Recurrence of symptomatic MPE is always accompanied by poor survival quality. In lung adenocarcinoma, researchers speculate whether patients with actionable mutation or without are applicable to different management models for MPE. Under the background of the high mutation probability and the encouraging therapeutic response in Asians, researches on the risk factors of MPE are in need. Methods: This retrospective review included 343 metastatic lung adenocarcinoma patients with MPE. Recurrence was defined as recurrent symptomatic MPE requiring the second thoracentesis to relieve symptoms within 300 days after the first thoracentesis. Univariable and multivariable Cox regression analysis were utilized to investigate independent risk factors for MPE recurrence. Results: Of the 343 patients involved, 139 experienced MPE recurrence within 300 days; 34.3% in 201 patients with actionable mutations and 51.2% in 129 patients without actionable mutations are in the recurrence. The median recurrence-free survival (RFS) of the group without mutations was 161 days. The median RFS of the other group with mutations was 300 days. Patients with actionable mutations showed a significantly lower hazard of MPE recurrence on univariate analysis. The multivariate analysis indicated that receiving targeted therapy after the first thoracentesis within 30 days, lower neutrophil-to-lymphocyte ratio (NLR) level, lower serum lactate dehydrogenase (s-LDH) level, and lower serum carcinoembryonic antigen (s-CEA) level were independent protective factors. In subgroup analysis, risk factors differed. Receiving targeted therapy after the first thoracentesis within 30 days remained an independent factor in the mutated patients. Conclusions: The findings herein indicated the characteristics of specific patients at high risk for MPE recurrence in lung adenocarcinoma. Patients with actionable mutations benefit more in MPE recurrence and could benefit from targeted therapy and active intrapleural management.

COL4A3 Mutation Induced Podocyte Apoptosis by Dysregulation of NADPH Oxidase 4 and MMP-2.

Introduction: Podocyte apoptosis is a common mechanism driving progression in Alport syndrome (AS). This study aimed to investigate the mechanism of podocyte apoptosis caused by COL4A3 mutations. Methods: We recruited patients with autosomal dominant AS (ADAS). Patients with minimal change disease (MCD) were recruited as controls. Microarray analysis was carried out on isolated glomeruli from the patients and validated. Then, corresponding mutant human podocytes (p.C1616Y) and 129 mice (p.C1615Y, the murine homolog to the human p.C1616Y) were constructed. The highest differentially expressed genes (DEGs) from microarray analysis were validated in transgenic mice and podocytes before and after administration of MMP-2 inhibitor (SB-3CT) and NOX4 inhibitor (GKT137831). We further validated NOX4/MMP-2/apoptosis pathway by real-time polymerase chain reaction (PCR), immunohistochemistry, and western blot in renal tissues from the ADAS patients. Results: Using microarray analysis, we observed that DEGs, including NOX4/H2O2, MMP-2, and podocyte apoptosis-related genes were significantly upregulated. These genes were validated by real-time PCR, histologic analysis, and western blot in corresponding mutant human podocyte (p.C1616Y) and/or mice models (p.C1615Y). Moreover, we found podocyte apoptosis was abrogated and MMP-2 expression was down-regulated both in vivo and in vitro by NOX4 inhibition, urinary albumin-to-creatinine ratio, 24-hour proteinuria; and renal pathologic lesion was attenuated by NOX4 inhibition in vivo. Furthermore, podocyte apoptosis was attenuated whereas NOX4 expression remained the same by inhibition of MMP-2 both in vivo and in vitro. Conclusion: These results indicated that NOX4 might induce podocyte apoptosis through the regulation of MMP-2 in patients with COL4A3 mutations. Our findings provided new insights into the mechanism of ADAS.

Validity of the SARC-F questionnaire in assessing sarcopenia in patients with chronic kidney disease: a cross-sectional study.

Objective: To examine the validity of the 5-component SARC-F questionnaire for screening sarcopenia among patients with chronic kidney disease (CKD). Methods: Eligible participants were enrolled from the Department of Nephrology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine from March 2019 to November 2019. Evaluations were performed using the self-administered SARC-F questionnaire. Sarcopenia was diagnosed by grip strength, the chair stand test and appendicular skeletal muscle mass. The severity of sarcopenia was evaluated by gait speed. We calculated the sensitivity and specificity of the SARC-F to evaluate construct validity. Moreover, receiver operating characteristic (ROC) curve analysis was performed to identify the cutoff value for nondialysis-dependent (NDD) CKD patients' and maintenance hemodialysis (MHD) patients' scores. Results: A total of 105 NDD-CKD patients and 125 MHD patients were included, and the prevalence of sarcopenia was 5.7 and 31.2%, respectively. Among them, there were 21 (16.8%) MHD patients with severe sarcopenia but no NDD-CKD patients with severe sarcopenia. The sensitivity and specificity of the SARC-F were 16.7 and 98.0% for NDD-CKD patients, and 48.7 and 89.5% for MHD patients, respectively. For NDD-CKD patients, the area under the receiver operating characteristic curve (AUROC) of the total SARC-F score was 0.978 (95% confidence interval (CI): 0.929-0.997, p < 0.001), and the cutoff value of 1 reached the highest Youden index of 0.950 and max ROC curve area of 0.974. For MHD patients, the AUROC of the total SARC-F score was 0.730 (95% CI: 0.644-0.806, p < 0.001), and the cutoff value of 4 reached the highest Youden index of 0.383 and max ROC curve area of 0.691. Conclusion: CKD patients, especially MHD patients, were at high risk of suffering sarcopenia. The SARC-F had low-to-moderate sensitivity but high specificity for screening sarcopenia among patients with CKD. The best cutoff values of the SARC-F score were different for screening sarcopenia among NDD-CKD and MHD patients.

Efficacy of different therapies for brain metastases of non-small cell lung cancer: a systematic review and meta-analysis.

Background: As one of the most common causes of death in advanced non-small cell lung cancer (NSCLC), brain metastases (BM) have attracted attention and debate about treatment options, especially for patients with negative driver genes or resistance to targeted agents. Therefore, we conducted a meta-analysis to investigate the potential benefit of different therapeutic regimens for intracranial lesions in non-targeted therapy NSCLC patients. Methods: A comprehensive search was conducted in databases including PubMed, Embase, and the Cochrane Library. The primary endpoints included the intracerebral objective response rate (icORR) and intracerebral progression-free survival (iPFS) in patients with BM. Results: Thirty-six studies involving 1,774 NSCLC patients with baseline BM were included in this meta-analysis. Antitumor agents plus radiotherapy (RT) showed the most significant synergistic effects; the highest pooled icORR that appeared in the combination of immune checkpoint inhibitor (ICI) and RT was 81% [95% confidence interval (CI): 16-100%], and the median iPFS was 7.04 months (95% CI: 2.54-11.55 months). The pooled icORR and median iPFS of RT plus chemotherapy were 46% (95% CI: 34-57%) and 5.7 months (95% CI: 3.90-7.50 months), respectively. The highest median iPFS in nivolumab plus ipilimumab plus chemotherapy was 13.5 months (95% CI: 8.35-18.65 months). ICI plus chemotherapy also showed potent antitumor activity in BM, with a pooled icORR of 56% (95% CI: 29-82%) and a median iPFS of 6.9 months (95% CI: 3.20-10.60 months). Notably, the subgroup analysis indicated that the pooled icORR of patients in programmed cell death-ligand 1 (PD-L1) (≥50%) who received ICI was 54% (95% CI: 30-77%), and that of patients who received first-line ICI was 69.0% (95% CI: 51-85%). Conclusions: ICI-based combination treatment provides a long-term survival benefit for non-targeted therapy patients, with the most significant benefits observed in improving icORR and prolonging overall survival (OS) and iPFS. In particular, patients who received first-line treatment or who were PD-L1-positive had a more significant survival benefit from aggressive ICI-based therapies. For patients with a PD-L1-negative status, chemotherapy plus RT led to better clinical outcomes than other treatment regimens. These innovative findings could help clinicians to better select therapeutic strategies for NSCLC patients with BM.

Clinical impact of first-line PD-1 or PD-L1 inhibitors combined with chemotherapy in extensive-stage small cell lung cancer patients: A real-world multicenter propensity score-matched study.

OBJECTIVES: Our research aimed to evaluate the effectiveness of first-line immune checkpoint inhibitors (ICIs) with etoposide and platinum (EP) for extensive-stage small cell lung cancer (ES-SCLC) and identify prognostic factors, as real-world outcomes and the inconsistency of PD-1 and PD-L1 inhibitors are uncertain. METHODS: We selected ES-SCLC patients in three centers and conducted a propensity score-matched analysis. The Kaplan-Meier method and Cox proportional hazards regression were conducted to compare the survival outcomes. We also performed univariate and multivariate Cox regression analyses to investigate predictors. RESULTS: Among 236 patients included, 83 pairs of cases were matched. The EP plus ICIs cohort had a longer median overall survival (OS) (17.3 months) than the EP cohort (13.4 months) (hazard ratio [HR], 0.61 [0.45, 0.83]; p = 0.001). The median progression-free survival (PFS) was also longer in the EP plus ICIs cohort (8.3 months) than in the EP cohort (5.9 months) (HR, 0.44 [0.32, 0.60]; p < 0.001). The EP plus ICIs group had a higher objective response rate (ORR) (EP: 62.3%, EP + ICIs: 84.3%, p < 0.001). Multivariate analysis presented that liver metastases (HR, 2.08; p = 0.018) and lymphocyte-monocyte ratio (LMR) (HR, 0.54; p = 0.049) were independent prognostic factors for OS, and performance status (PS) (HR, 2.11; p = 0.015), liver metastases (HR, 2.64; p = 0.002), and neutrophil-lymphocyte ratio (NLR) (HR, 0.45; p = 0.028) were for PFS in patients with chemo-immunotherapy. CONCLUSION: Our real-world data demonstrated that ICIs with chemotherapy as the first-line setting for ES-SCLC are effective and safe. PS, liver metastases, and inflammatory markers could serve as valuable risk factors.

Genome-Wide Association Study in Acute Tubulointerstitial Nephritis.

SIGNIFICANCE STATEMENT: Polymorphisms of HLA genes may confer susceptibility to acute tubulointerstitial nephritis (ATIN), but small sample sizes and candidate gene design have hindered their investigation. The first genome-wide association study of ATIN identified two significant loci, risk haplotype DRB1*14-DQA1*0101-DQB1*0503 (DR14 serotype) and protective haplotype DRB1*1501-DQA1*0102-DQB1*0602 (DR15 serotype), with amino acid position 60 in the peptide-binding groove P10 of HLA-DR ß 1 key. Risk alleles were shared among different causes of ATIN and HLA genotypes associated with kidney injury and immune therapy response. HLA alleles showed the strongest association. The findings suggest that a genetically conferred risk of immune dysregulation is part of the pathogenesis of ATIN. BACKGROUND: Acute tubulointerstitial nephritis (ATIN) is a rare immune-related disease, accounting for approximately 10% of patients with unexplained AKI. Previous elucidation of the relationship between genetic factors that contribute to its pathogenesis was hampered because of small sample sizes and candidate gene design. METHODS: We undertook the first two-stage genome-wide association study and meta-analysis involving 544 kidney biopsy-defined patients with ATIN and 2346 controls of Chinese ancestry. We conducted statistical fine-mapping analysis, provided functional annotations of significant variants, estimated single nucleotide polymorphism (SNP)-based heritability, and checked genotype and subphenotype correlations. RESULTS: Two genome-wide significant loci, rs35087390 of HLA-DQA1 ( P =3.01×10 -39 ) on 6p21.32 and rs2417771 of PLEKHA5 on 12p12.3 ( P =2.14×10 -8 ), emerged from the analysis. HLA imputation using two reference panels suggested that HLA-DRB1*14 mainly drives the HLA risk association . HLA-DRB1 residue 60 belonging to pocket P10 was the key amino acid position. The SNP-based heritability estimates with and without the HLA locus were 20.43% and 10.35%, respectively. Different clinical subphenotypes (drug-related or tubulointerstitial nephritis and uveitis syndrome) seemed to share the same risk alleles. However, the HLA risk genotype was associated with disease severity and response rate to immunosuppressive therapy. CONCLUSIONS: We identified two candidate genome regions associated with susceptibility to ATIN. The findings suggest that a genetically conferred risk of immune dysregulation is involved in the pathogenesis of ATIN.