Comparison of atezolizumab,durvalumab, pembrolizumab,and nivolumab as first-line treatment in patients with extensive-stage small cell lung cancer: A systematic review and network meta-analysis

Background:In recent years, immune checkpoint inhibitors (ICIs) including atezolizumab, durvalumab, pembrolizumab, and nivolumab have reported their efficacy and safety profile in patients with extensive-stage small cell lung cancer (ES-SCLC). However, given the diverse efficacy and inconsistent safety among the ICIs, with the absence of head-to-head researches designed to evaluate the efficacy among them, it might bring with confusion on selection in clinical practice.Objectives:The present systematic review and network meta-analysis was performed to conduct indirect comparisons on efficacy and safety profile among ICIs, including atezolizumab, durvalumab, pembrolizumab, and nivolumab as first-line treatment in patients with ES-SCLC.Design:Several databases were retrieved with established criteria until June 20, 2020, with the main MeSH Terms and their similarities. Hazard ratios of overall survival (OS) and progression-free survival (PFS), odds ratios (ORs) of disease control rate (DCR), objective response rate (ORR), and adverse events (AEs) were compared indirectly with network meta-analysis.Data sources:Medline, Cochrane library, and Embase.Eligibility criteria:Prospective, randomized, controlled clinical studies, which reported PFS, OS, and AEs.Data extraction and synthesis:Clinical characteristics were extracted by the 2 authors independently. Comparisons of HRs were calculated for PFS and OS by random effect model. ORR, DCR, and AEs were presented with ORs. Based on surface under the cumulative ranking curve, and forest plots, efficacy and safety of the treatments were ranked, with predicted histogram described.Results:In total, there were 4 studies including 1547 patients who met the eligibility criteria and enrolled. For indirect comparisons, no significant difference on PFS was observed between atezolizumab and durvalumab (HR 0.96, 95% CI, 0.72–1.29), or between atezolizumab and pembrolizumab (HR 1.05, 95% CI, 0.78–1.43), or between atezolizumab and nivolumab (HR 1.18, 95% CI, 0.79–1.79), or between durvalumab and pembrolizumab (HR 1.10, 95% CI, 0.84–1.43). or between durvalumab and nivolumab (HR 1.23, 95% CI, 0.83–1.82), or between pembrolizumab and nivolumab (HR 1.12, 95% CI, 0.76–1.66), nor significant difference on OS observed between atezolizumab and durvalumab (HR 0.93, 95% CI, 0.67–1.30), or between atezolizumab and pembrolizumab (HR 0.88, 95% CI, 0.62–1.24), or between atezolizumab and nivolumab (HR 1.04, 95% CI, 0.66–1.66), or between durvalumab and pembrolizumab (HR 0.94, 95% CI, 0.70–1.25), or between durvalumab and nivolumab (HR 1.12, 95% CI, 0.73–1.71), or between pembrolizumab and nivolumab (HR 1.19, 95% CI, 0.77–1.84). However, durvalumab was shown statistical superiority on ORR when compared with atezolizumab (HR 0.79, 95% CI, 0.64–0.98), also with significantly higher risk on immune-related AEs when compared with atezolizumab (OR 0.22, 95% CI, 0.10–0.50), and pembrolizumab (OR 3.12, 95% CI, 1.27–7.64).Conclusions:Results of the study revealed that there was no statistical difference on PFS or OS among agents of atezolizumab, durvalumab, pembrolizumab, and nivolumab as first-line treatment in patients with ES-SCLC. However, durvalumab was shown superiority on ORR when compared with atezolizumab, also with significantly higher risk on immune-related AEs.     

Validation of a model to predict all-cause in-hospital mortality in vascular surgical patients

Objective

To develop and validate a pre- and postoperative model of all-cause in-hospital mortality in South African vascular surgical patients.

Methods

We carried out a retrospective cohort study. A multivariate analysis using binary logistic regression was conducted on a derivation cohort using clinical, physiological and surgical data. Interaction and colinearity between covariates were investigated. The models were validated using the Homer-Lemeshow goodness-of-fit test.

Results

Independent predictors of in-hospital mortality in the pre-operative model were: (1) age (per one-year increase) [odds ratio (OR) 1.03, 95% confidence interval (CI) 1.0–1.06), (2) creatinine > 180 μmol.l^-1 (OR 6.43, 95% CI: 3.482–11.86), (3) chronic beta-blocker therapy (OR 2.48, 95% CI: 1.38–4.48), and (4) absence of chronic statin therapy (OR 2.81, 95% CI: 1.15–6.83). Independent predictors of mortality in the postoperative model were: (1) age (per oneyear increase) (OR 1.05, 95% CI: 1.02–1.09), (2) creatinine > 180 μmol.l^-1 (OR 5.08, 95% CI: 2.50–10.31), (3) surgery out of hours without statin therapy (OR 8.27, 95% CI: 3.36–20.38), (4) mean daily postoperative heart rate (HR) (OR 1.02, 95% CI: 1.0–1.04), (5) mean daily postoperative HR in the presence of a mean daily systolic blood pressure of less than 100 beats per minute or above 179 mmHg (OR 1.02, 95% CI: 1.01–1.03) and (6) mean daily postoperative HR associated with withdrawal of chronic beta-blockade (OR 1.02, 95% CI: 1.01–1.03). Both models were validated.

Conclusion

The pre-operative model may predict the risk of in-hospital mortality associated with vascular surgery. The postoperative model may identify patients whose risk increases as a result of surgical or physiological factors.     

Safety Profile of Thiopurines in Crohn Disease: Analysis of 893 Patient-Years Follow-Up in a Southern China Cohort

Thiopurines have been associated with both clinical improvement and mucosal healing in treating Crohn disease (CD). Unfortunately, the high rate of adverse events (AEs) leading to drug withdrawal represents a major limitation in the use of these drugs.To evaluate the safety of thiopurines in patients with CD. To identify predictive factors associated with the development of thiopurine-induced AEs and withdrawal.This longitudinal cohort study examined patients from a university-based IBD referral center. Time-to-event analysis was performed with the Kaplan–Meier curve. Cox regression analysis was performed to identify potential predictive factors of AEs.Two hundred sixty-seven CD patients on thiopurines were included. A total of 143 AEs occurred at a median of 7.4 months (interquartile range, 3.7–15.3 months) after starting treatment. The cumulative incidence of AEs was 26%, with an annual risk of 4.3% per patient-year of treatment. The most frequent was leucopenia (41/267, 15.36%), followed by infections (29/267, 10.86%). Independent factors predictive of leucopenia were lower baseline hemoglobin (hazard ratio (HR), 0.34; 95% confidence interval (CI) 0.18–0.67) and the concomitant use of 5-aminosalicylic acid (HR, 3.05; 95% CI 1.44–8.76). Of the 28.44% (76/267) CD patients discontinued therapy, 14.61% due to AEs. A lower body mass index, the presence of extraintestinal manifestation, and the incidence of leucopenia independently predicted thiopurine withdrawal. In total, 37.5% of these patients restarted thiopurines and 52.3% of them had AEs again.About a quarter of patients on thiopurine therapy had AEs during follow-up and 1 of 7 patients had to discontinue thiopurines due to AEs.     

Prevalence and Risk Factors of Acute Lower Gastrointestinal Bleeding in Crohn Disease

Acute lower gastrointestinal bleeding (ALGIB) is a rare but potentially life-threatening complication of Crohn disease (CD). Thus far, few studies of ALGIB in the context of CD have been published, most of which were case reports with limited value. We aimed to explore the prevalence of ALGIB in CD patients, evaluate risk factors for hemorrhagic CD and its recurrence, and analyze clinical data of the death cases.A total of 1374 CD patients registered from January 2007 to June 2013 were examined. Medical records of 73 patients with ALGIB and 146 matched as controls were reviewed and analyzed retrospectively. Logistic regression and Cox proportional hazards analyses were performed to identify risk factors for ALGIB and the cumulative probability of rebleeding. Kaplan–Meier curves with log-rank tests were used to demonstrate the cumulative survival rates of rebleeding.The prevalence of ALGIB was 5.31% (73/1374) in this study. In the univariate analysis, possible risk factors for ALGIB were duration of CD (odds ratio [OR] 0.60, 95% confidence interval [CI] 0.33–1.09, P = 0.095), perianal disease (OR 1.96, 95% CI 0.92–4.20, P = 0.082), left colon involvement (OR 2.16, 95% CI 1.10–4.24, P = 0.025), azathioprine use ≥1 year (OR 0.46, 95% CI 0.23–0.90, P = 0.023), and previous hemorrhage history (OR 11.86, 95% CI 5.38–26.12, P < 0.0001). In the multivariate analysis, left colon involvement (OR 2.26, 95% CI 1.04–4.91, P = 0.039), azathioprine use ≥1 year (OR 0.44, 95% CI 0.20–0.99, P = 0.044), and previous hemorrhage history (OR 13.04, 95% CI 5.66–30.04, P < 0.0001) remained independent influencing factors. Older age (HR 0.23, 95% CI 0.07–0.77, P = 0.018), surgical treatment (HR 0.17, 95% CI 0.06–0.50, P < 0.001), and having bleeding episodes >3 months ago (HR 0.24, 95% CI 0.07–0.82, P = 0.022) resulted to be predictors associated with rebleeding after discharge. Patients who died often suffered severe concomitant diseases, and the overall mortality rate was 8.22% (6/73).We speculated that a special hemorrhagic phenotype of CD that was predisposed to rebleeding may exist. Further studies are warranted to investigate the pathogenesis and discover the optimum treatments of choice.     

A Meta-analysis Reveals S-1-based Chemotherapy Improves the Survival of Patients With Advanced Gastric Cancer

The aim of this study was to compare the efficacy and safety of S-1-based therapy versus non-S-1-based therapy in advanced gastric cancer (AGC) patients.Eligible studies stratifying objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and adverse events (AEs) in AGC patients were identified from Embase, Pubmed, Cochrane Library, and China National Knowledge Infrastructure databases. The STATA package (version 11.0) was used to pool the data from the eligible studies.Fifteen studies with 2973 AGC cases, of which 1497 (50.4%) received S-1-based therapy and 1476 (49.6%) received non-S-1-based therapy, were identified in the meta-analysis. AGC patients who had received S-1-based therapy had a higher median OS, median PFS, and ORR than those who had received 5-fluorouracil (FU)-based therapy (OS: hazard ratio [HR] 0.89, 95% confidence interval [CI] 0.80–0.98, P = 0.015; PFS: HR 0.88, 95% CI 0.80–0.98, P = 0.016; ORR: OR 1.25, 95% CI 1.08–1.45, P = 0.003, respectively). S-1-based therapy had similar efficacy to capecitabine-based therapy in terms of median OS (HR 1.14, 95% CI 0.91–1.41, P = 0.253), median PFS (HR 1.01, 95% CI 0.82–1.25, P = 0.927), and ORR (OR 0.84, 95% CI 0.63–1.12, P = 0.226). Subgroup analysis for grade 3 to 4 toxicity showed higher incidence of neutropenia (relative risk [RR] = 0.827, P = 0.006), nausea (RR = 0.808, P = 0.040), and lower diarrhea (RR = 1.716, P = 0.012) in 5-FU-based arm, and higher diarrhea (RR = 0.386, P = 0.007) in capecitabine-based arm.S-1-based chemotherapy is favorable to AGC patients with better clinical benefit than 5-FU-based chemotherapy and with equivalent antitumor compare with capecitabine-based therapy.     

Prognostic and Clinicopathological Value of Survivin in Diffuse Large B-cell Lymphoma: A Meta-Analysis

Up to date, survivin, a well-known inhibitor of apoptosis, has attracted considerable attention as a potential biomarker and therapeutic target in diffuse large B-cell lymphoma (DLBCL). Nevertheless, there still remains no consensus on heterogeneous results. Herein, a meta-analysis was performed to clarify a convincing significance of survivin status on prognosis and clinicopathology of DLBCL patients.Eligible studies were identified by searching Medline, Embase, Scopus, CNKI, and Wanfang databases (last updated on November 30, 2014). Pooled hazard ratios (HRs) and odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. Heterogeneity and sensitivity were also analyzed. Moreover, Begg, Egger test, and funnel plots were applied to evaluate the publication bias.We finally included 17 eligible studies with the total number of 1352 patients in the meta-analysis. The pooled results showed that positive survivin expression in DLBCL was associated with inferior overall survival (OS) (HR: 1.880, 95% CI: 1.550–2.270) in patients. Moreover, a significant association was revealed between survivin expression and advanced clinical stage (III + IV) (OR: 0.611, 95% CI: 0.452–0.827), higher International Prognosis Index (IPI) score (Score 3–5) (OR: 0.559; 95% CI: 0.410–0.761), elevated serum lactic dehydrogenase (LDH) (OR: 0.607, 95% CI: 0.444–0.831), presence of bone marrow involvement (OR: 2.127, 95% CI: 1.154–3.921) together with reduced complete remission (CR) rate (OR: 0.478, 95% CI: 0.345–0.662).The results suggest that survivin could be a useful prognostic biomarker, and a promising target for DLBCL therapeutic intervention. Considering limited HR data adjusted for standard prognostic variables could be retrieved, future high-quality studies will be needed in evaluating the independent prognostic value of survivin expression in DLBCL.     

Risk factors for recurrent primary biliary cirrhosis after liver transplantation: A systematic review and meta-analysis

BackgroundRecurrent primary biliary cirrhosis (PBC) is frequently observed in patients with PBC after liver transplantation (LT). We performed a meta-analysis to evaluate the risk factors for PBC recurrence.MethodsWe searched the EMBASE, PubMed and the Cochrane Library databases for studies published before August 2020. Studies that identified the risk factors of PBC recurrence were eligible for inclusion. We extracted the hazard ratio (HR) data with 95% confidence intervals (CI) for the risk factors.ResultsOur meta-analysis included 6 studies, which comprised 3184 patients (88.5% females) who underwent liver transplantation from 1982 to 2017, and of these patients, 935 (29.4%) developed PBC recurrence. The use of tacrolimus (HR = 2.62, 95% CI = 1.35, 5.09) and preventive ursodeoxycholic acid (UDCA) (HR = 0.40, 95% CI = 0.28, 0.57) were significantly associated with the risk of PBC recurrence based on the pooled analysis of the results obtained from the multivariate analysis.ConclusionsThe use of tacrolimus is associated with an increased risk of PBC recurrence. Preventive UDCA after LT for PBC can help to prevent disease recurrence.     

Adjuvant ovarian suppression for premenopausal hormone receptor-positive breast cancer: A network meta-analysis

Background:Ovarian function suppressor (OFS) plus either tamoxifen (TAM) or aromatase inhibitor (AI) could improve the survival outcome for premenopausal hormone receptor-positive (HR+) breast cancer. However, the optimal OFS-based regimen and medication duration remain uncertain. This article aims to systematically evaluate the OFS-based adjuvant endocrine therapy for premenopausal breast cancer.Methods:We searched several public databases from January 1980 to November 2020. A random model was adopted in this meta-analysis. We used the hazard ratio (HR) with a 95% confidence interval (CI) for the statistical analysis of efficacy. The primary outcome measures included overall survival and disease-free survival.Results:A total of 32 articles with 37,224 cases were included in this network meta-analysis. OFS+TAM improved 5-year disease-free survival (HR –0.09, 95% CI –0.16 to –0.01) and 5-year overall survival (HR –0.18, 95% CI –0.33 to –0.03) compared with TAM monotherapy. For OFS+AI, although the 5-year disease-free survival was improved (HR –0.18, 95% CI –0.29 to –0.08), the 5-year overall survival was not improved (HR –0.13, 95% CI –0.43 to 0.18). In subgroup analysis, both OFS+AI and OFS+TAM showed a protective effect in stage I–III patients compared with stage I–II patients. For the course of therapy, OFS+TAM for 2-years could achieve clinical benefit and the best course of therapy of OFS+AI still waits for further study.Conclusions:OFS+TAM might be a better option than OFS+AI for premenopausal intensive adjuvant endocrine therapy. Stage III patients are more suitable for the OFS-based therapy. For the medication duration, the 2-years course of OFS+TAM could be effective. This analysis provides helpful information for selecting therapeutic regimen in intensive adjuvant endocrine therapy and identifying the target population.     

Determinants of Mortality from Severe Dengue in Brazil: A Population-Based Case-Control Study

Although increases in severity of mortality from dengue infection have been observed in Brazil, their determinants are not fully known. A case–control study was conducted by using the National Notifiable Diseases Surveillance System, including patients with severe dengue during 2000–2005. Cases were defined as patients that died and controls were those who survived. Hierarchical multivariate logistic regression was performed. During the study period, there were 12,321 severe cases of dengue and 1,062 deaths. Factors independently associated with death included age ≥ 50 years (odds ratio [OR] = 2.29, 95% confidence interval [CI] = 1.59–3.29), < 4 years of schooling (OR = 1.83, 95% CI = 1.47–2.28), a rural area (OR =2.84, 95% CI = 2.19–3.69), hospitalization (OR = 1.42, 95% CI = 1.17–1.73), and a high hematocrit (OR = 2.46, 95% CI = 1.85–3.28). Factors associated with a lower chance of dying were female sex (OR = 0.76, 95% CI = 0.67–0.87), history of previous dengue (OR = 0.78, 95% CI = 0.62–0.99), positive tourniquet test result (OR = 0.47, 95% CI = 0.33–0.66), laboratory diagnosis of dengue (OR = 0.75, 95% CI = 0.61–0.92), and a platelet count of 50,000–100,000 cells/mm³ (OR = 0.56, 95% CI = 0.36–0.87). The risk profile identified in this study should serve to direct public health interventions to minimize deaths.     

Braun Enteroenterostomy Following Pancreaticoduodenectomy: A Systematic Review and Meta-Analysis

Pancreaticoduodenectomy (PD) holds high postoperative morbidity. How to resolve this issue is challenged. An additional anastomosis (Braun enteroenterostomy) following PD may decrease the postoperative morbidity, but holds conflicting results. The objective of this study is to investigate the advantages and disadvantages of Braun enteroenterostomy in PD.Clinical studies compared perioperative outcomes between the Braun group and the non-Braun group following PD before December 21, 2014 were retrieved and filtered from PubMed, EMBASE, Web of Science, the Cochrane Library, and Chinese electronic databases (VIP database, WanFang database, and CNKI database). Relevant data were extracted according to predesigned sheets. Blood loss, operating time, and postoperative mortality and morbidity were evaluated using odds ratio (OR), weighted mean difference, or standard mean difference (SMD).Ten studies concerning 1614 patients were included. No significant differences between the Braun and the non-Braun group were identified in mortality (OR: 0.65, 95% confidence interval [CI]: 0.26–1.60), intraoperative blood loss (SMD: −0.035, 95% CI: −0.253 to 0.183), postoperative pancreatic fistula (POPF) (OR: 0.67, 95% CI: 0.35–1.67), bile leakage (OR: 0.537, 95% CI: 0.287–1.004), postoperative gastrointestinal hemorrhage (OR: 1.17, 95% CI: 0.578–2.385), intraabdominal abscesses (OR: 0.793, 95% CI: 0.444–1.419), wound complications (OR: 0.806, 95% CI: 0.490–1.325), and hospital stay (SMD: −0.098, 95% CI: −0.23 to 0.033). Braun enteroenterostomy extended operating time (SMD: 0.39, 95% CI: 0.02–0.78), but it was associated with lower reoperation rate (OR: 0.380, 95% CI: 0.149–0.968), lower morbidity rate (OR: 0.66, 95% CI: 0.49–0.91), lower clinically relevant delayed gastric emptying (Grades B and C) (OR: 0.375, 95% CI: 0.164–0.858), lower nasogastric tube reinsertion (OR: 0.436, 95% CI: 0.232–0.818), and less postoperative vomiting (OR: 0.444, 95% CI: 0.262–0.755).Braun enteroenterostomy can be safely performed during PD. It is beneficial for patients and could be recommended in PD from the current published data.PROSPERO registration number: CRD42015016198.     

Systematic Review With Network Meta-Analysis: Adjuvant Chemotherapy for Resected Colorectal Liver Metastases

There are 5 major adjuvant chemotherapies (ACTs) for hepatic metastases for colorectal cancer; however, the optimal treatment regimen remains inconclusive. Here, we aim to compare these therapies in terms of patient survival rate, intrahepatic recurrence rate, and adverse events.Different databases were searched for controlled trials up to June 30, 2014. The pooled hazards ratios for death and odds ratios (ORs) for intrahepatic recurrence and adverse events were estimated. A mean ranking and the probability of optimal therapeutic regime was obtained for each treatment analyzed in the network meta-analysis.Eleven eligible articles were included. Systemic chemotherapy (SCT) was ranked the most efficacious intervention among ACTs in both 1-year and 5-year survival; however, no statistical difference could be determined. Combination of bevacizumab (BEV) and hepatic arterial infusion (HAI) plus SCT was the most effective in preventing intrahepatic recurrence when compared with HAI alone (OR 1.21, 95% confidence interval [CI] 0.01–131.12), SCT (OR 2.37, 95% CI 0.03–234.16), HAI plus SCT (OR 0.97, 95% CI 0.03–35.30), SCT plus irinotecan (OR 1.01, 95% CI 0.00–278.14) and observation alone (OR 0.83, 95% CI 0.01–59.53). BEV and HAI plus SCT provided the least survival benefit after both 1 and 5 years compared with remaining therapies, and also was ranked the regiment with the least favorable adverse event profile among ACTs.SCT may be the most efficacious intervention, however, the potential benefit should be carefully considered with the regime''s associated toxicities. Combination of BEV and HAI plus SCT was effective in preventing intrahepatic relapse but was associated with the highest risk for adverse events in patients with resected hepatic metastases for colorectal cancer.     

Psychosocial risk factors associated with esophageal cancer in Chinese cohort: A systematic review and meta-analysis

Previous studies were controversial about the role of psychosocial factors in the pathogenesis of esophageal cancer (EC). This study aimed to systematically evaluate the effect size of psychosocial risk factors for EC in Chinese cohort.A literature search was conducted in both English and Chinese databases, and odds ratios (OR) with the corresponding 95% confidence intervals (CI) were pooled using a random-effects model.28 studies were identified with a total of 6951 EC cases and 7469 controls. The meta-analysis indicated a higher risk of EC among the individuals with psychological trauma (OR: 2.36, 95% CI: 1.71–3.26), Type A behavior (OR: 1.40, 95% CI: 1.17–1.67), depression (OR: 4.00, 95% CI: 2.44–6.55), melancholy (OR: 2.06, 95% CI: 1.32–3.20), always in sulks (OR: 2.49, 95% CI: 1.21–5.12), and irritable personality (OR: 2.13, 95% CI: 1.58–2.89). A lower EC risk was found in the individuals with good interpersonal relationship (OR: 0.35, 95% CI: 0.17–0.70) and outgoing personality (OR: 0.39, 95% CI: 0.19–0.78).This meta-analysis suggested a potential association between psychosocial factors and EC risk. For the individuals with psychosocial risk factors, physicians should pay more attention to EC screening.     

Meta-analysis of patent foramen ovale closure versus medical therapy for prevention of recurrent ischemic neurological events: Impact of medication type

BackgroundThe optimal treatment strategy for patent foramen ovale (PFO) patients with cryptic stroke remains controversial. We performed this meta-analysis to evaluate the effect of PFO closure versus different types of medical therapy.MethodsWe searched PubMed, Embase, and Cochrane databases. The primary efficacy endpoints were the composite outcome of recurrent stroke and/or transient ischemic attack (TIA). Secondary efficacy endpoints included separate stroke and TIA. Safety endpoints included new-onset atrial fibrillation (AF)/atrial flutter and bleeding.ResultsCompared with antiplatelet therapy, PFO closure significantly reduced the risk of composite outcome (odds ratio [OR] 0.37, 95% confidence interval [CI] 0.27–0.51), stroke (OR 0.22, 95% CI 0.13–0.36], and TIA (OR 0.57, 95% CI 0.34–0.98); Compared with the mixed medical therapy group (consist of antiplatelet therapy, anticoagulant therapy, or both), PFO closure still showed some benefits, but the effect was not as significant as that of antiplatelet therapy (composite outcome: OR 0.53, 95% CI 0.41–0.69; stroke: OR 0.48, 95% CI 0.34–0.68; TIA: OR 0.69, 95% CI 0.50–0.96); Compared with anticoagulant therapy, PFO closure showed no benefit (composite outcome: OR 0.77, 95% CI 0.46–1.28; stroke: OR 0.59, 95% CI 0.28–1.25; TIA: OR 1.01, 95% CI 0.50–2.04). In terms of safe endpoints, compared with antiplatelet therapy and anticoagulant therapy, PFO closure increased the risk of AF/atrial flutter (OR 9.56, 95% CI 2.85–32.06; OR 18.96, 95% CI 1.11–323.8, respectively) and reduced the risk of bleeding (OR 0.50, 95% CI 0.24–1.05; OR 0.13, 95% CI 0.04–0.46, respectively); compared with mixed medical therapy, PFO closure increased the risk of AF/atrial flutter (OR 4.40,95% CI 2.24–8.67), but there was no difference in bleeding (OR 0.97, 95% CI 0.56–1.68).ConclusionsWith the addition of anticoagulants, the benefit of PFO closure decreased gradually. Patient groups that adopt individualized medical therapy strategies may benefit more.     

Loss of BAP1 Expression Occurs Frequently in Intrahepatic Cholangiocarcinoma

BRCA1-associated protein 1 (BAP1) is a deubiquitinating enzyme that functions as a tumor suppressor gene. Double hit BAP1 inactivation has been reported in a range of tumor types, including intrahepatic cholangiocarcinoma (ICC), sometimes in association with germline mutation.We performed immunohistochemistry for BAP1 on a well-characterized cohort of 211 ICC patients undergoing surgical resection with curative intent at 3 institutions based in 3 different countries. The median age at diagnosis was 65 years (range, 36.5–86) and 108 (51%) were men. Negative staining for BAP1 (defined as completely absent nuclear staining in the presence of positive internal controls in nonneoplastic cells) occurred in 55 ICCs (26%). BAP1 loss predicted a strong trend toward improved median survival of 40.80 months (95% CI, 28.14–53.46) versus 24.87 months (95% CI, 18.73–31.01), P = 0.059). In a multivariate model including age, sex, BAP1 status, tumor stage, tumor grade, lymphovascular invasion, and tumor size, female sex was associated with improved survival (hazard ratio [HR] 0.54; 95% CI, 0.34–0.85), while advanced tumor stage and lymphovascular invasion (HR 1.89; 95% CI, 1.09–3.28) correlated with decreased survival. In a multivariate analysis, high grade tumors were associated with BAP1 loss (odds ratio [OR] 3.32; 95% CI, 1.29–8.55), while lymphatic invasion was inversely associated with BAP1 loss (OR 0.36; 95% CI, 0.13–0.99).In conclusion, we observed a trend toward improved prognosis in ICC associated with absent expression of BAP1 and an association of BAP1 loss with higher histological grade and absent lymphatic invasion. Female sex was associated with improved survival while advanced tumor stage and lymphatic invasion were associated with decreased survival.     

Risk factors for postoperative pneumonia and prognosis in lung cancer patients after surgery: A retrospective study

Postoperative pneumonia (POP) is one of the most frequent complications following lung surgery. The aim of this study was to identify the risk factors for developing POP and the prognostic factors in lung cancer patients after lung resection.We performed a retrospective review of 726 patients who underwent surgery for stages I–III lung cancer at a single institution between August 2017 and July 2018 by conducting logistic regression analysis of the risk factors for POP. The Cox risk model was used to analyze the factors influencing the survival of patients with lung cancer.We identified 112 patients with POP. Important risk factors for POP included smoking (odds ratio [OR], 2.672; 95% confidence interval [CI], 1.586–4.503; P < .001), diffusing capacity for carbon monoxide (DLCO) (40–59 vs ≥80%, 4.328; 95% CI, 1.976–9.481; P < .001, <40 vs ≥80%, 4.725; 95% CI, 1.352–16.514; P = .015), and the acute physiology and chronic health evaluation (APACHE) II score (OR, 2.304; 95% CI, 1.382–3.842; P = .001). In the Cox risk model, we observed that age (hazard ratios (HR), 1.633; 95% CI, 1.062–2.513; P = .026), smoking (HR, 1.670; 95% CI, 1.027–2.716; P = .039), POP (HR, 1.637; 95% CI, 1.030–2.600; P = .037), etc were predictor variables for patient survival among the factors examined in this study.The risk factors for POP and the predictive factors affecting overall survival (OS) should be taken into account for effective management of patients with lung cancer undergoing surgery.     

Effects of preoperative radiotherapy on survival of patients with stage II and III esophageal squamous cell carcinoma: A population-based study

The impact of preoperative radiotherapy (PRT) on survival in patients with stage II and III esophageal squamous cell carcinoma (ESCC) remains controversial. The aim of this study was to explore the effect of PRT on survival of these patients.Patients with stage II and III ESCC who underwent chemotherapy ± PRT were identified and retrieved from the SEER database from 2010 to 2015. Cox regression analysis was used to identify independent prognostic factors in patients. Subgroup analysis stratified by T stage and N stage was performed. Kaplan–Meier survival analysis was performed to assess disease specific survival (DSS).A total of 1160 patients were retrieved, of whom 289 (24.9%) underwent PRT plus chemotherapy, and 871 (75.1%) did not receive PRT. In multivariate analysis, PRT plus chemotherapy was a favorable prognostic factor for patients with stage T2 (hazard ratio [HR], 0.364, 95% CI, 0.202–0.658; P < .001), T3 (HR, 0.536, 95% CI, 0.413–0.695; P < .001) and T4 (HR, 0.318, 95% CI, 0.125–0.805; P = .016), but PRT plus chemotherapy was not statistically significant on DSS in patients with T1 disease (HR, 0.556, 95% CI, 0.262–1.179; P = .126). All 3 different N stages (N0, N1, and N2 + N3) were statistically significant (P < .05) in chemotherapy with or without PRT.In conclusion, patients with stage II and III ESCC at the T2-T4 stage gained significant survival benefit from PRT plus chemotherapy.     

Clinical Outcomes of Revascularization Strategies for Patients With MVD/LMCA Disease: A Systematic Review and Network Meta-Analysis

Hybrid coronary revascularization (HCR), a new minimally invasive procedure for patients requiring revascularization for multivessel coronary lesions, combines coronary artery bypass grafting (CABG) for left anterior descending (LAD) lesions and percutaneous coronary intervention (PCI) for non-LAD coronary lesions. However, available data related to outcomes comparing the 3 revascularization therapies is limited to small studies.We conducted a search in MEDLINE, EMBASE, and the Cochrane Library of Controlled Trials up to December 31, 2014, without language restriction. A total of 16 randomized trials (n=4858 patients) comparing HCR versus PCI or off-pump CABG (OPCAB) were included in this meta-analysis. The primary outcomes were major adverse cardiac and cerebrovascular events (MACCE), all-cause death, myocardial infarction (MI), cerebrovascular events (CVE), and target vessel revascularization (TVR). Odds ratios (OR) and 95% confidence intervals (CI) were calculated using random-effect and fixed-effect models. Ranking probabilities were used to calculate a summary numerical value: the surface under the cumulative ranking (SUCRA) curve.No significant differences were seen between the HCR and PCI in short term (in hospital and 30 days) with regard to MACCE (odds ratio [OR] = 0.51, 95% confidence interval [CI] 0.00–2.35), all-cause death (OR = 2.09, 95% CI 0.34–7.66), MI (OR = 1.02, 95% CI 0.19–2.95), CVE (OR = 4.45, 95% CI 0.39–19.16), and TVR (OR = 6.99, 95% CI 0.17–39.39). However, OPCAB had lower MACCE than HCR (OR = 0.19, 95% CI 0.00–0.95). In midterm (1 year and 3 year), in comparison with HCR, PCI had higher all-cause death (OR = 5.66, 95% CI 0.00–13.88) and CVE (OR = 4.40, 95% CI 0.01–5.68), and lower MI (OR = 0.51, 95% CI 0.00–2.86), TVR (OR = 0.53, 95% CI 0.05–2.26), and thus the MACCE (OR = 0.51, 95% CI 0.00–2.35). Off-pump CABG presented a better outcome than HCR with significant lower MACCE (OR = 0.17, 95% CI 0.01–0.68). Surface under the cumulative ranking probabilities showed that HCR may be the superior strategy for MVD and LMCA disease when regarded to MACCE (SUCRA = 0.84), MI (SUCRA = 0.76) in short term, and regarded to MACCE (SUCRA = 0.99), MI (SUCRA = 0.94), and CVE (SUCRA = 0.92) in midterm.Hybrid coronary revascularization seemed to be a feasible and acceptable option for treatment of LMCA disease and MVD. More powerful evidences are required to precisely evaluate risks and benefits of the 3 therapies for patients who have different clinical characteristics.     

Granulomatosis With Polyangiitis (Wegener’s): Impact of Maintenance Therapy Duration

To determine outcomes in relation to duration of maintenance therapy in patients with granulomatosis with polyangiitis (Wegener’s) (GPA), we conducted a retrospective chart review of patients with GPA seen at a single vasculitis center from 1992 to 2010. All patients achieved remission defined by a Birmingham Vasculitis Activity Score for Wegener Granulomatosis (BVAS/WG) of 0 with either cyclophosphamide or methotrexate. After achieving remission all patients were started on maintenance therapy with either methotrexate or azathioprine.The study comprised 157 patients with a median follow-up of 3.1 years. Using a univariate model, the continuation of maintenance medications for >18 months showed a 29% reduction in hazard ratio (HR) for relapse (HR, 0.71; 95% confidence interval [CI], 0.42–1.19; p = 0.19). Treatment for >36 months showed a 66% reduction in hazard ratio for relapse (HR, 0.34; 95% CI, 0.15–0.76; p = 0.008). When length of treatment was considered as a continuous factor, longer courses had an inverse relationship with the risk of relapse (HR, 0.70; 95% CI, 0.58–0.84; p < 0.001), which remained significant after adjusting for prednisone dose (HR, 0.59; 95% CI, 0.42–0.83; p = 0.003). Fifty-two percent of relapses occurred while the patients were off maintenance therapy. Among all patients who relapsed on therapy, 52% of those receiving methotrexate were on <15 mg/week, and 67% of those receiving azathioprine were on ≤50 mg/d. There were no differences between the short- and long-term maintenance therapy groups in overall adverse events or GPA-related morbidity.Discontinuation or use of low doses of maintenance therapy is associated with a higher relapse rate.Abbreviations: ANCA = antineutrophil cytoplasmic antibody, AZA = azathioprine, BVAS/WG = Birmingham Vasculitis Activity Score for Wegener Granulomatosis, CI = confidence interval, CYC = cyclophosphamide, GPA = granulomatosis with polyangiitis, HR = hazard ratio, IV = intravenous, MMF = mycophenolate mofetil, MPA = microscopic polyangiitis, MPO = myeloperoxidase, MTX = methotrexate, PR3 = proteinase 3, RTX = rituximab     

Initial Metastatic Site as a Prognostic Factor in Patients With Stage IV Pancreatic Ductal Adenocarcinoma

Few studies have evaluated the presence of hepatic or peritoneal metastasis as a prognostic factor in patients with metastatic pancreatic ductal adenocarcinoma (PDAC). This study aimed to elucidate the prognostic value of the initial metastatic, extrahepatic, or hepatic site in patients with metastatic PDAC.Between January 2007 and December 2013, the medical records of 343 patients with metastatic PDAC treated at Seoul National University Bundang Hospital were retrospectively reviewed. Patients were classified as having extrahepatic metastasis alone (EH), hepatic metastasis alone (LV), and both hepatic and extrahepatic metastasis (BOTH).The median age was 67 years; 207 patients were men. Patients were classified as having EH (111 patients), LV (106), and BOTH (126). Totally, 212 patients underwent chemotherapy with a FOLFIRINOX (23 patients) or gemcitabine-based regimen (189). On multivariate analysis, an ECOG score ≥2 (hazard ratio [HR]: 3.2, 95% confidence interval [CI]: 2.2–4.5), albumin < 35 g/L (HR: 1.6, 95% CI: 1.1–2.3), C-reactive protein > 10 mg/L (HR: 2.3, 95% CI: 1.6–3.2), neutrophil-lymphocyte ratio > 5 (HR: 1.4, 95% CI: 1.0–2.0), no chemotherapy (HR: 2.0, 95% CI: 1.0–4.1), and metastatic site (LV, HR: 2.1, 95% CI: 1.4–3.1; BOTH, HR: 2.2, 95% CI: 1.6–3.2) were significantly associated with shorter overall survival (OS). Considering the initial metastatic site, the median OS of patients with EH, LV, and BOTH were 7.5 (95% CI: 6.3–8.8), 4.8 (95% CI: 4.1–5.5), and 2.4 (95% CI: 1.9–2.9) months, respectively.The initial metastatic site is significantly and independently associated with OS in patients with metastatic PDAC, serving as an effective prognostic factor.     

Adjuvant Chemotherapy for the Completely Resected Stage IB Nonsmall Cell Lung Cancer: A Systematic Review and Meta-Analysis

Adjuvant chemotherapy is recommended for postoperative stage II-IIIB nonsmall cell lung cancer patients. However, its effect remains controversial in stage IB patients. We, therefore, performed a meta-analysis to compare the efficacy of adjuvant chemotherapy versus surgery alone in stage IB patients.Six electronic databases were searched for relevant articles. The primary and secondary outcomes were overall survival (OS) and disease-free survival (DFS). The time-to-event outcomes were compared by hazard ratio using log-rank test.Sixteen eligible trials were identified. A total of 4656 patients were included and divided into 2 groups: 2338 in the chemotherapy group and 2318 in the control group (surgery only). Patients received platinum-based therapy, uracil-tegafur, or a combination of them. Our results demonstrated that patients can benefit from the adjuvant chemotherapy in terms of OS (HR 0.74 95% CI 0.63–0.88) and DFS (HR 0.64 95% CI 0.46–0.89). Patients who received 6-cycle platinum-based therapy (HR 0.45 95% CI 0.29–0.69), uracil-tegafur (HR 0.71 95% CI 0.56–0.90), or a combination of them (HR 0.51 95% CI 0.36–0.74) had better OS, but patients who received 4 or fewer cycles platinum-based therapy (HR 0.97 95% CI 0.85–1.11) did not. Moreover, 6-cycle platinum-based therapy (HR 0.29 95% CI 0.13–0.63) alone or in combination with uracil-tegafur (HR 0.44 95% CI 0.30–0.66) had advantages in DFS. However, 4 or fewer cycles of platinum-based therapy (HR 0.89 95% CI 0.76–1.04) or uracil-tegafur alone (HR 1.19 95% CI 0.79–1.80) were not beneficial.Six-cycle platinum-based chemotherapy can improve OS and DFS in stage IB NSCLC patients. Uracil-tegafur alone or in combination with platinum-based therapy is beneficial to the patients in terms of OS, but uracil-tegafur seems to have no advantage in prolonging DFS, unless it is administered with platinum-based therapy.