Identifying potential drug targets for idiopathic pulmonary fibrosis: a mendelian randomization study based on the druggable genes.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic fibrotic interstitial lung disease characterized by progressive dyspnea and decreased lung function, yet its exact etiology remains unclear. It is of great significance to discover new drug targets for IPF. METHODS: We obtained the cis-expression quantitative trait locus (cis-eQTL) of druggable genes from eQTLGen Consortium as exposure and the genome wide association study (GWAS) of IPF from the International IPF Genetics Consortium as outcomes to simulate the effects of drugs on IPF by employing mendelian randomization analysis. Then colocalization analysis was performed to calculate the probability of both cis-eQTL of druggable genes and IPF sharing a causal variant. For further validation, we conducted protein quantitative trait locus (pQTL) analysis to reaffirm our findings. RESULTS: The expression of 45 druggable genes was significantly associated with IPF susceptibility at FDR < 0.05. The expression of 23 and 15 druggable genes was significantly associated with decreased forced vital capacity (FVC) and diffusing capacity of the lungs for carbon monoxide (DLco) in IPF patients, respectively. IPF susceptibility and two significant genes (IL-7 and ABCB2) were likely to share a causal variant. The results of the pQTL analysis demonstrated that high levels of IL-7 in plasma are associated with a reduced risk of IPF (OR = 0.67, 95%CI: 0.47-0.97). CONCLUSION: IL-7 stands out as the most promising potential drug target to mitigate the risk of IPF. Our study not only sheds light on potential drug targets but also provides a direction for future drug development in IPF.

Predictive value of pretreatment PD-L1 expression in EGFR-mutant non-small cell lung cancer: a meta-analysis.

OBJECTIVE: To investigate the predictive value of programmed death-ligand 1 (PD-L1) expression in non-small cell lung cancer (NSCLC) patients treated with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). METHODS: We conducted a systemic search of PubMed, EMBASE, and the Cochrane Library from 1 January 2000 to 30 August 2020, to identify related studies. We combined the hazard ratio (HR) and 95% confidence interval (CI) to assess the correlation of PD-L1 expression with progression-free survival (PFS) and overall survival (OS). We assessed the quality of the included studies by the Newcastle-Ottawa Scale (NOS). We performed subgroup analyses based on immunohistochemistry (IHC) scoring system, IHC antibodies, sample size, countries, and survival analysis mode. Sensitivity analysis and evaluation of publication bias were also performed. RESULTS: Twelve studies including 991 patients met the criteria. The mean NOS score was 7.42 ± 1.19. Patients with high PD-L1 expression was associated with poorer PFS (HR = 1.90; 95% CI = 1.16-3.10; P = 0.011), while there was no association between PD-L1 expression and OS (HR = 1.19; 95% CI = 0.99-1.43; P = 0.070). Subgroup analysis prompted IHC scoring systems, IHC antibodies, and sample size have important effects on heterogeneity. The pooled results were robust according to the sensitivity analysis. CONCLUSIONS: The result of this meta-analysis suggested that PD-L1 expression might be a predictive biomarker for EGFR-mutant non-small cell lung cancer treated with EGFR-TKIs.

Differential efficacy of segmentectomy and wedge resection in sublobar resection compared to lobectomy for solid-dominant stage IA lung cancer: a systematic review and meta-analysis.

BACKGROUND: Currently, the impact of sublobar resection versus lobectomy on the prognosis of solid-dominant stage IA lung cancer is contradictory in different studies, which requires further exploration. METHODS: The authors analyzed 26 studies, including one randomized controlled trial and retrospective cohort studies. Pooled hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using fixed-effects or random-effects models based on heterogeneity levels. RESULTS: The analysis included 12 667 patients, with 3488 undergoing sublobar resections and 9179 receiving lobectomies. The overall analysis revealed no statistically significant difference in overall survival (OS) (HR=1.28, 95% CI: 0.98-1.69) between sublobar resection and lobectomy, but lobectomy was associated with better recurrence-free survival (RFS) (HR=1.39, 95% CI: 1.10-1.75). Subgroup analyses revealed that, for tumors with a diameter ≤2 cm, sublobar resection versus lobectomy showed no significant difference in OS but sublobar resection had lower RFS. For 2-3 cm tumors, both OS and RFS were significantly lower in the sublobar resection group. When consolidation-to-tumor ratio (CTR) ranged from 0.5 to <1, OS did not differ significantly, but RFS was significantly lower in sublobar resection. Lung cancers with CTR=1 showed significantly lower OS and RFS in the sublobar resection group. Segmentectomy provided similar OS and RFS compared to lobectomy, while wedge resection had a detrimental effect on patient prognosis. However, wedge resection may have provided comparable outcomes for patients aged 75 years or older. CONCLUSION: Our findings suggest that segmentectomy and lobectomy yield similar oncological outcomes. However, compared to lobectomy, wedge resection is associated with a poorer prognosis. Nevertheless, for elderly patients, wedge resection is also a reasonable surgical option.

Exploring the causal relationships between cholelithiasis, cholecystitis, cholecystectomy, and gastroesophageal reflux disease: A bidirectional two-sample mendelian randomization study.

BACKGROUND: Biliary disorders and gastroesophageal reflux disease (GERD) frequently coexist. However, precise linkages between these conditions remain to be clarified. METHODS: Univariable Mendelian randomization (MR), Bayesian weighted MR (BWMR) along with multivariable MR approaches were conducted using genetic instruments to evaluate the causality involving biliary disorders and GERD. Furthermore, an investigation was conducted on the potential mediating roles of biliary disorders (or GERD), on the linkage involving body mass index (BMI) and GERD (or biliary disorders). RESULTS: Univariable MR analyses revealed significant causal effects of genetically predicted cholelithiasis (odds ratio (OR)=1.04, P=0.0001), cholecystitis (OR=1.06, P=0.0004), and cholecystectomy (OR=2.56, P=1.05×10-6) on GERD. These findings were replicated in the FinnGen cohort and were also confirmed by BWMR and multivariable MR analyses. Additionally, mediation analyses demonstrated that cholelithiasis and cholecystitis acted as partial mediators, linking BMI causally to GERD. Conversely, GERD exhibited causal effect on cholelithiasis (OR=1.52, P=9.17×10-30) and cholecystitis (OR=1.90, P=3.32×10-28), which remained significant after BWMR and multivariable MR analyses. Mediation analyses further revealed significant mediating effect of GERD on how BMI influenced cholelithiasis/cholecystitis. CONCLUSION: Our study elucidates the bidirectional causal linkages involving cholelithiasis, cholecystitis, cholecystectomy, and GERD. These results highlight the significance of GERD risk assessment in individuals suffering from biliary diseases and vice versa.

Video-assisted thoracic surgery drainage is feasible and safe for acute necrotizing mediastinitis: a retrospective cohort study.

Background: Acute necrotizing mediastinitis (ANM) is a severe infection of the mediastinal loose connective tissue. Traditionally, it has been treated with thoracotomy, but video-assisted thoracic surgery (VATS) is been increasingly used in patients with this condition. This study aimed to compare the outcomes of VATS and open thoracotomy in treating ANM. Methods: The medical records of patients with ANM who underwent surgery between March 2012 and April 2021 were retrieved. A retrospective screening was conducted based on clinical characteristics, bacterial pathogens, surgical approach, and outcomes. The patients were divided into a VATS group and an open thoracotomy (Open) group. The patient characteristics and surgical outcomes of the two groups were summarized and compared. Results: A total of 64 cases were enrolled in this study, including 48 in the VATS group (75%) and 16 in the Open group (25%). The most common site of infection was the neck (n=26, 40.6%). Streptococcus constellatus and Acinetobacter baumannii (A. baumannii) were the most frequently found pathogens in secretion culture. In sputum culture, the most common pathogens were Klebsiella pneumonia and A. baumannii. Postoperative outcomes, including blood transfusion (33.3% vs. 43.8%; P=0.45), duration of postoperative drainage {14 [1-47] vs. 17 [4-54] days; P=0.15}, length of antibiotic medication {14.5 [1-54] vs. 18 [4-54] days; P=0.29}, admission to intensive care unit (ICU) (87.5% vs. 75.0%; P=0.43), length of ICU stay {5 [1-58] vs. 8.5 [1-37] days; P=0.20}, postoperative hospital stay {17 [2-61] vs. 21 [5-56] days; P=0.22}, reoperation rate (12.5% vs. 6.25%; P=0.82), and mortality rate (14.6% vs. 12.5%; P>0.99) were comparable between the two groups. Conclusions: ANM treated by both the VATS and open approach had comparable outcomes. Therefore, VATS is a viable option for patients with ANM.

Adjuvant chemotherapy may improve long-term outcomes in stage IB non-small cell lung cancer patients with previous malignancies: A propensity score-matched analysis.

Background: Routine administration of adjuvant chemotherapy for stage IB non-small cell lung cancer (NSCLC) remains controversial. To our knowledge, no available studies have assessed the outcomes of chemotherapy in patients with stage IB NSCLC who had prior malignancies. Methods: Patients with pathological stage IB NSCLC with previous malignancies who underwent surgery between 2004 and 2015 were identified from the Surveillance, Epidemiology, and End Results (SEER) database. The patients were categorized into chemotherapy and observation group based on whether they received adjuvant chemotherapy. Propensity score matching was performed to reduce confounding bias, and Kaplan-Meier curves and log-rank tests were used to compare overall survival (OS) and cancer-specific survival (CSS) between the two groups. Subgroup analyses of the matched cohorts were then conducted to evaluate the relationship between clinical features and chemotherapy. Results: A total of 894 eligible patients were identified; 90 (10.1%) patients received postoperative chemotherapy. Patients who received adjuvant chemotherapy obtained obvious OS benefits compared with those who received observation alone (HR = 0.68, 95% CI: 0.48-0.97, P = 0.031). In addition, the 5-year OS rate and median OS time in the chemotherapy group were higher and longer, respectively. Although chemotherapy offered no obvious benefits for CSS (HR = 0.80, 95% CI: 0.57-1.14, P = 0.35), patients who received chemotherapy showed a better 5-year CSS rate. On subgroup analyses, a chemotherapy advantage was observed in advanced age (≥65 years, HR = 0.62, 95% CI: 0.38-0.99, P = 0.045). The same chemotherapy advantages were observed in patients diagnosed with higher histological grades (poorly differentiated to undifferentiated) (HR = 0.56, 95% CI: 0.33-0.96, P = 0.033) and tumor sizes >3.1-4 cm (HR = 0.57, 95% CI: 0.37-0.87, P = 0.010). Interestingly, NSCLC patients with previous malignancies originating from the kidney and bladder (HR = 0.34, 95% CI: 0.12-0.99, P = 0.049) showed a chemotherapy advantage. The same chemotherapy advantages were observed in patients diagnosed with NSCLC within 3 to 5 years after prior cancers (HR = 0.39, 95% CI: 0.16-0.98, P = 0.044) and with localized SEER stage of prior cancers (HR = 0.49, 95% CI: 0.29-0.86, P = 0.012). Conclusion: These findings indicate that adjuvant chemotherapy may improve long-term outcomes for stage IB NSCLC patients with previous malignancies. It is recommended that physicians consider the clinical features of previous cancers when making adjuvant chemotherapy decisions for these patients.

Surgery and chemotherapy cannot improve the survival of patients with early-stage mucosa-associated lymphoid tissue derived primary pulmonary lymphoma.

Background: To date, there is no treatment consensus on mucosa-associated lymphoid tissue (MALT) derived primary pulmonary lymphoma (PPL). Methods: We identified patients with early-stage MALT-type PPL from the National Cancer Institute's Surveillance, Epidemiology, and End Results program database. The patients were divided into four groups according to treatment modalities: None of surgery or chemotherapy (None) group, Surgery alone group, Chemotherapy alone (Chemo alone) group, and Surgery plus chemotherapy (Surgery + chemo) group. Overall survival (OS) and cancer-specific survival (CSS) were study endpoints. We performed Cox regression analyses, propensity score-matched analyses (PSM) and Kaplan-Meier (KM) survival curves to compare the survival among different groups. Results: A total of 953 patients were included in our analysis with 302, 403, 175, and 73 cases in the None, Surgery alone, Chemo alone, and Surgery + chemo groups, respectively. In this cohort, the estimated 3-year, 5-year and 10-year OS rates were 86.95%, 78.91%, and 55.89%, respectively. Meanwhile, the estimated 3-year, 5-year and 10-year CSS rates were 96.71%, 93.73%, and 86.84%, respectively. Multivariate Cox regression analyses demonstrated that increasing age, tumors located in the lower lobe, and stage II were significant predictors of poorer OS while increasing age and tumors located in the bilateral lungs were associated with lower CSS. After PSM analyses, the KM survival curves showed no significant differences in OS or CSS among the four groups. Conclusion: Early-stage MALT-type PPL is indolent in nature. Neither surgery, chemotherapy nor a combination of surgery and chemotherapy can improve OS and CSS, suggesting that "watch and wait" may be a reasonable alternative.

Prognostic role of the platelet to lymphocyte ratio (PLR) in the clinical outcomes of patients with advanced lung cancer receiving immunotherapy: A systematic review and meta-analysis.

Background: It remains controversial whether the platelet to lymphocyte ratio (PLR) serves as a potential indicator for the efficacy of immunotherapy in advanced lung cancer. This meta-analysis aimed to address this concern. Methods: Up to March 2022, we searched PubMed, Embase, Web of Science and the Cochrane Library to retrieve potentially eligible articles. Combined hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated to assess the relationship between PLR and progression-free survival (PFS) as well as overall survival (OS), while the combined odds ratios (ORs) and 95% CIs were estimated to evaluate the relationship between PLR and the objective response rate (ORR) as well as the disease control rate (DCR). Subgroup analyses were further performed to detect the source of heterogeneity and potential predictive value of PLR in different groups in terms of OS and PFS. Results: A total of 21 included studies involving 2312 patients with advanced lung cancer receiving immunotherapy were included. The combined results suggested that elevated PLR was associated with poorer OS (HR=2.24; 95% CI: 1.87-2.68; I² =44%; P=0.01) and PFS (HR=1.66; 95% CI: 1.36-2.04; I² =64%; P<0.01). Furthermore, elevated PLR showed a lower ORR (OR= 0.61; 95% CI: 0.43-0.87, I²=20%; P=0.29) and DCR (OR= 0.44; 95% CI: 0.27-0.72, I²=61%; P=0.02). In subgroup analyses, pretreatment PLR was significantly associated with adverse OS and PFS. The same results were observed in different PLRs in terms of cutoff value (>200 vs. ≤200). Furthermore, high PLR was significantly associated with poor OS and PFS in advanced non-small cell lung cancer (NSCLC); however, PLR was not associated with OS and PFS in advanced small cell lung cancer (SCLC). In addition, PLR predicted poor OS irrespective of regions and types of immune checkpoint inhibitors (ICIs). Conclusion: On the whole, patients with low PLR had better OS and PFS, as well as higher ORR and DCR when receiving immunotherapy in advanced lung cancer especially for advanced NSCLC. And further investigations are warranted to confirm the prognostic value of PLR in advanced SCLC. Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42022315976.