Germline Mutations of Holliday Junction Resolvase Genes in Multiple Primary Malignancies Involving Lung Cancer Lead to PARP Inhibitor Sensitization.

PURPOSE: The incidence of multiple primary malignancies (MPM) involving lung cancer has increased in recent decades. There is an urgent need to clarify the genetic profile of such patients and explore more efficacious therapy for them. EXPERIMENTAL DESIGN: Peripheral blood samples from MPM involving patients with lung cancer were assessed by whole-exome sequencing (WES), and the identified variants were referenced for pathogenicity using the public available database. Pathway enrichment analysis of mutated genes was performed to identify the most relevant pathway. Next, the effects of mutations in relevant pathway on function and response to targeted drugs were verified by in vitro and in vivo experiments. RESULTS: Germline exomes of 71 patients diagnosed with MPM involving lung cancer were sequenced. Pathway enrichment analysis shows that the homologous recombination repair (HRR) pathway has the strongest correlation. Moreover, HRR genes, especially key Holliday junction resolvases (HJR) genes (GEN1, BLM, SXL4, and RMI1), were most frequently mutated, unlike the status in the samples from patients with lung cancer only. Next, we identified a total of seven mutations in HJR genes led to homologous recombination DNA repair deficiency and rendered lung cancer cells sensitive to PARP inhibitor treatment, both in vitro and in vivo. CONCLUSIONS: This is the first study to map the profile of germline mutations in patients with MPM involving lung cancer. This study may shed light on early prevention and novel targeted therapies for MPM involving patients with lung cancer with HJR mutations.

Exploring the chemical composition, medicinal benefits, and antioxidant activity of Plumula nelumbinis essential oil from different habitats in China.

Plumula nelumbinis, a widely used traditional Chinese medicine known for its calming and nerve-soothing properties, contains essential oil as a primary component. However, research on P. nelumbinis essential oil (PNEO) is limited. This study aimed to investigate PNEO components, network target analysis, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses, and antioxidant activity of P. nelumbinis from ten different habitats. GC-MS analysis identified 14 compounds in the essential oil, with CP12 (ß-Sitosterol) having the highest concentration. Five compounds were identified for the first time in P. nelumbinis, with three of them reported for the first time in the Nelumbo. Network target analysis revealed 185 potential targets for 11 compounds and GO and KEGG enrichment analyses showed that PNEO was mainly located in the plasma membrane and could regulate a variety of molecular functions. KEGG pathway enrichment analysis revealed that the essential oil was primarily enriched in pathways related to cancer and the nervous system. PNEO demonstrated strong antioxidant activity, with N8 (Fujiannanping) showing the highest ABTS scavenging capacity and N7 (Hunanxiangtan) showing the highest DPPH radical scavenging capacity. Cell experiments showed that CP4, CP5 and CP10 had protective effects against H2O2-induced oxidative damage. The study suggests that P. nelumbinis from different regions may have slightly different pharmacological effects due to the presence of unique compounds, and further research is necessary to explore the potential therapeutic benefits of PNEO.

Association between duration of smoking abstinence before non-small-cell lung cancer diagnosis and survival: a retrospective, pooled analysis of cohort studies.

BACKGROUND: The association between duration of smoking abstinence before non-small-cell lung cancer (NSCLC) diagnosis and subsequent survival can influence public health messaging delivered in lung-cancer screening. We aimed to assess whether the duration of smoking abstinence before diagnosis of NSCLC is associated with improved survival. METHODS: In this retrospective, pooled analysis of cohort studies, we used 26 cohorts participating in Clinical Outcomes Studies of the International Lung Cancer Consortium (COS-ILCCO) at 23 hospitals. 16 (62%) were from North America, six (23%) were from Europe, three (12%) were from Asia, and one (4%) was from South America. Patients enrolled were diagnosed between June 1, 1983, and Dec 31, 2019. Eligible patients had smoking data before NSCLC diagnosis, epidemiological data at diagnosis (obtained largely from patient questionnaires), and clinical information (retrieved from medical records). Kaplan-Meier curves and multivariable Cox models (ie, adjusted hazard ratios [aHRs]) were generated with individual, harmonised patient data from the consortium database. We estimated overall survival for all causes, measured in years from diagnosis date until the date of the last follow-up or death due to any cause and NSCLC-specific survival. FINDINGS: Of 42 087 patients with NSCLC in the COS-ILCCO database, 21 893 (52·0%) of whom were male and 20 194 (48·0%) of whom were female, we excluded 4474 (10·6%) with missing data. Compared with current smokers (15 036 [40·0%] of 37 613), patients with 1-3 years of smoking abstinence before NSCLC diagnosis (2890 [7·7%]) had an overall survival aHR of 0·92 (95% CI 0·87-0·97), patients with 3-5 years of smoking abstinence (1114 [3·0%]) had an overall survival aHR of 0·90 (0·83-0·97), and patients with more than 5 years of smoking abstinence (10 841 [28·8%]) had an overall survival aHR of 0·90 (0·87-0·93). Improved NSCLC-specific survival was observed in 4301 (44%) of 9727 patients who had quit cigarette smoking and was significant at abstinence durations of more than 5 years (aHR 0·87, 95% CI 0·81-0·93). Results were consistent across age, sex, histology, and disease-stage distributions. INTERPRETATION: In this large, pooled analysis of cohort studies across Asia, Europe, North America, and South America, overall survival was improved in patients with NSCLC whose duration of smoking abstinence before diagnosis was as short as 1 year. These findings suggest that quitting smoking can improve overall survival, even if NSCLC is diagnosed at a later lung-cancer screening visit. These findings also support the implementation of public health smoking cessation strategies at any time. FUNDING: The Alan B Brown Chair, The Posluns Family Fund, The Lusi Wong Fund, and the Princess Margaret Cancer Foundation.

Impact of Repeated Infantile Exposure to Surgery and Anesthesia on Gut Microbiota and Anxiety Behaviors at Age 6-9.

(1) Background: Preclinical as well as population studies have connected general anesthesia and surgery with a higher risk of abnormal cognitive development, including emotional development. Gut microbiota dysbiosis in neonatal rodents during the perioperative period has been reported, however, the relevance of this to human children who undergo multiple anesthesia for surgeries is unknown. Given the emerging role of altered gut microbes in propagating anxiety and depression, we sought to study whether repeated infantile exposures to surgery and anesthesia affect gut microbiota and anxiety behaviors later in life. (2) Methods: This is a retrospectively matched cohort study comparing 22 pediatric patients of less than 3 years of age with multiple exposures (≥3) to anesthesia for surgeries and 22 healthy controls with no history of exposure to anesthesia. The parent report version of the Spence Children's Anxiety Scale (SCAS-P) was applied to evaluate anxiety in children aged between 6 and 9 years old. Additionally, the gut microbiota profiles of the two groups were compared using 16S rRNA gene sequencing. (3) Results: In behavioral tests, the p-SCAS score of obsessive compulsive disorder and social phobia were significantly higher in children with repeated anesthesia exposure relative to the controls. There were no significant differences between the two groups with respect to panic attacks and agoraphobia, separation anxiety disorder, physical injury fears, generalized anxiety disorder, and the total SCAS-P scores. In the control group, 3 children out of 22 were found to have moderately elevated scores, but none of them had abnormally elevated scores. In the multiple-exposure group, 5 children out of 22 obtained moderately elevated scores, while 2 scored as abnormally elevated. However, no statistically significant differences were detected in the number of children with elevated and abnormally elevated scores. The data show that repeated anesthesia and surgical exposures in children led to long-lasting severe gut microbiota dysbiosis. (4) Conclusions: In this preliminary study, our findings demonstrated that early repeated exposures to anesthesia and surgical predisposes children to anxiety as well as long-term gut microbiota dysbiosis. We should confirm these findings in a larger data population size and with detailed analysis. However, the authors cannot confirm an association between the dysbiosis and anxiety.

Association between length of stay and postoperative survival in patients with lung cancer: a propensity score matching analysis based on National Cancer Database.

Background: Postoperative complications tend to result in prolonged hospitalization. The aim of this study was to investigate whether prolonged postoperative length of stay (LOS) can predict patient survival, particularly long-term survival. Methods: All patients undergoing lung cancer surgery between 2004 and 2015 were identified in the National Cancer Database (NCDB). The highest quintile of LOS (more than 8 days) was defined as prolonged length of stay (PLOS). We performed 1:1 propensity score matching (PSM) between the groups with and without PLOS (Non-PLOS). Excluding confounding factors, postoperative LOS was used as a surrogate for postoperative complications. Kaplan-Meier and Cox proportional hazards survival analyses were performed to analyze survival. Results: A total of 88,007 patients were identified. After matching, 18,585 patients were enrolled in the PLOS and Non-PLOS groups, respectively. Before and after matching, 30-day rehospitalization rate and 90-day mortality in the PLOS group were significantly higher than they were in the Non-PLOS group (P<0.001), indicating a potential worse short-term postoperative survival. After matching, the median survival of the PLOS group was significantly lower than that of the Non-PLOS group (53.2 vs. 63.5 months, P<0.0001). Multivariable analysis revealed that PLOS is independent negative predictor of overall survival [OS; hazard ratio (HR) =1.263, 95% confidence interval (CI): 1.227 to 1.301, P<0.001]. In addition, age (<70 or ≥70), gender, race, income, year of diagnosis, surgery type, pathological stage, and neoadjuvant therapy also were independent prognostic factors of postoperative survival for patients with lung cancer (all P<0.001). Conclusions: Postoperative LOS could be taken as the quantitative indicator of postoperative complications of lung cancer in NCDB. In this study, PLOS predicted worse short-term and long-term survival independent of other factors. Avoiding PLOS could be considered to benefit patient survival after lung cancer surgery.

Corrigendum: Pre-existing proton pump inhibitor treatment and short-term prognosis of acute myocardial infarction patients.

[This corrects the article DOI: 10.3389/fcvm.2022.919716.].

Abnormal blood 25-hydroxyvitamin D in critically ill patients: prevalence, predictors, and its association with in-hospital mortality.

BACKGROUND: Abnormal vitamin D is prevalent in critical care settings, but its association with prognosis remains unclear. The study aimed to investigate the prevalence and predictors of abnormal blood 25-hydroxyvitamin D (25(OH)D), as well as its association with prognosis in critically ill patients. METHODS: Patients aged ≥ 18 years who were once admitted to the intensive care units (ICUs) of the Beth Israel Deaconess Medical Center between 2008 and 2019 with at least one measurement record of blood 25(OH)D were included as study population. Baseline characteristics associated with deficient or elevated blood 25(OH)D were investigated by univariable logistic regression analysis. The association between abnormal blood 25(OH)D and hospital mortality was examined by multivariable logistic regression analysis. RESULTS: A total of 1091 patients were included. Deficient 25(OH)D (< 30 ng/mL) was found in 790 (72.41%) patients and 17 (1.56%) were with an elevated level (> 60 ng/mL). A younger age, male, comorbid liver disease, and dialysis were risk factors of deficient blood 25(OH)D, while comorbid myocardial infarction, dementia, and rheumatic disease were protective factors evaluated by univariable logistic regression. Being admitted to cardiac vascular ICU or coronary care unit were associated with increased risk of elevated blood 25(OH)D. Patients with elevated blood 25(OH)D showed non-significantly higher hospital mortality compared to those with normal or deficient blood 25(OH)D (35.29% versus 14.44% and 14.56%, P = 0.058). After adjusted for potential confounding factors, elevated blood 25(OH)D was associated with increased risk of hospital mortality [odds ratio (OR) 3.80, 95% confidence interval (CI) 1.22-11.82, P = 0.021] when compared to those with normal blood 25(OH)D, but there was no significant association between deficient blood 25(OH)D and hospital mortality (OR 1.12, 95% CI 0.74-1.72, P = 0.589). CONCLUSIONS: These findings suggest deficient blood 25(OH)D was rather common in critically ill patients, but was not an independent risk factor of hospital mortality, while elevated blood 25(OH)D was associated with worse prognosis.

Pre-existing Proton Pump Inhibitor Treatment and Short-Term Prognosis of Acute Myocardial Infarction Patients.

Introduction: Evidence suspects proton pump inhibitor (PPI) use is a risk factor of poor prognosis of acute myocardial infarction (AMI). We aimed to investigate the association between pre-existing PPI use before emergency department (ED) visit and short-term prognosis of AMI patients. Materials and Methods: AMI patients admitted to ED were included and categorized as cohorts with or without pre-existing PPI use. Hospital mortality, length of hospital stay, being admitted to intensive care unit (ICU), and length of (total) ICU stay were studied as prognostic outcomes. Multivariable logistic regression or linear regression were used to estimate the associations between pre-existing PPI use and the outcomes after adjusting for potential confounders. Results: A total of 2001 AMI patients were included. No significant difference was found in hospital mortality and length of ICU stay between cohorts; patients with pre-existing PPI use showed a significantly longer length of hospital stay (median 3.81 vs. 3.20 days, P = 0.002) but lower proportion of being admitted to ICU (25.59% vs. 40.83%, P < 0.001) compared to those without pre-existing PPI use. Pre-existing PPI use was not associated with hospital mortality [odds ratio (OR) 1.08, 95% confidence interval (CI) 0.58-1.99], length of hospital stay (ß = 0.23, 95% CI -0.35 to 0.82), and length of ICU stay (ß = -0.18, 95% CI -1.06 to 0.69), but was statistically significantly associated with lower risk of being admitted to ICU (OR 0.69, 95% CI 0.52-0.92). Conclusion: The current study does not support newly diagnosed AMI patients with pre-existing PPI use before ED visit would experience worse short-term prognosis than those without.

Percutaneous ultrasound-guided cholecystocholangiography with microbubbles combined with liver biopsy for the assessment of suspected biliary atresia.

BACKGROUND: Percutaneous ultrasound (US)-guided cholecystocholangiography is effective in diagnosing biliary atresia for infants with a gallbladder >1.5 cm in length on US. However, whether it is still effective for other types of gallbladders needs further clarification. OBJECTIVE: To evaluate the diagnostic performance and safety of percutaneous US-guided cholecystocholangiography combined with liver biopsy in children with suspected biliary atresia and with different types of gallbladders on US. MATERIALS AND METHODS: Sixty-five infants were referred for percutaneous US-guided cholecystocholangiography with microbubbles and liver biopsy after an equivocal (n=39) or highly suspected (n=26) US diagnosis of biliary atresia. Two radiologists evaluated US and percutaneous US-guided cholecystocholangiography images in consensus. One pathologist independently evaluated liver specimens. We used the unpaired t-test, Mann-Whitney U test and chi-square test to analyze the data. RESULTS: Of the 65 infants, 59 (90.8%) underwent a successful percutaneous US-guided cholecystocholangiography, with both sensitivity and specificity of 100%. All six infants for whom puncture failed had contracted gallbladders. The sensitivity and specificity of liver biopsy in the diagnosis of biliary atresia were 89.7% (26/29) and 83.3% (30/36), respectively. When percutaneous US-guided cholecystocholangiography and liver biopsy were combined, all infants gained correct diagnosis, and in 35 infants (97.2%, 35/36) biliary atresia could be excluded without intraoperative cholangiography. Twenty-two of 65 infants (33.8%) had fluid collections around the liver related to puncture. None of these complications needed treatment. CONCLUSION: Percutaneous US-guided cholecystocholangiography combined with liver biopsy appears safe and effective for excluding or confirming biliary atresia in cholestatic infants with a dilated gallbladder on US.

Accounting for EGFR Mutations in Epidemiologic Analyses of Non-Small Cell Lung Cancers: Examples Based on the International Lung Cancer Consortium Data.

BACKGROUND: Somatic EGFR mutations define a subset of non-small cell lung cancers (NSCLC) that have clinical impact on NSCLC risk and outcome. However, EGFR-mutation-status is often missing in epidemiologic datasets. We developed and tested pragmatic approaches to account for EGFR-mutation-status based on variables commonly included in epidemiologic datasets and evaluated the clinical utility of these approaches. METHODS: Through analysis of the International Lung Cancer Consortium (ILCCO) epidemiologic datasets, we developed a regression model for EGFR-status; we then applied a clinical-restriction approach using the optimal cut-point, and a second epidemiologic, multiple imputation approach to ILCCO survival analyses that did and did not account for EGFR-status. RESULTS: Of 35,356 ILCCO patients with NSCLC, EGFR-mutation-status was available in 4,231 patients. A model regressing known EGFR-mutation-status on clinical and demographic variables achieved a concordance index of 0.75 (95% CI, 0.74-0.77) in the training and 0.77 (95% CI, 0.74-0.79) in the testing dataset. At an optimal cut-point of probability-score = 0.335, sensitivity = 69% and specificity = 72.5% for determining EGFR-wildtype status. In both restriction-based and imputation-based regression analyses of the individual roles of BMI on overall survival of patients with NSCLC, similar results were observed between overall and EGFR-mutation-negative cohort analyses of patients of all ancestries. However, our approach identified some differences: EGFR-mutated Asian patients did not incur a survival benefit from being obese, as observed in EGFR-wildtype Asian patients. CONCLUSIONS: We introduce a pragmatic method to evaluate the potential impact of EGFR-status on epidemiological analyses of NSCLC. IMPACT: The proposed method is generalizable in the common occurrence in which EGFR-status data are missing.

The relationship between body-mass index and overall survival in non-small cell lung cancer by sex, smoking status, and race: A pooled analysis of 20,937 International lung Cancer consortium (ILCCO) patients.

INTRODUCTION: The relationship between Body-Mass-Index (BMI) and lung cancer prognosis is heterogeneous. We evaluated the impact of sex, smoking and race on the relationship between BMI and overall survival (OS) in non-small-cell-lung-cancer (NSCLC). METHODS: Data from 16 individual ILCCO studies were pooled to assess interactions between BMI and the following factors on OS: self-reported race, smoking status and sex, using Cox models (adjusted hazard ratios; aHR) with interaction terms and adjusted penalized smoothing spline plots in stratified analyses. RESULTS: Among 20,937 NSCLC patients with BMI values, females = 47 %; never-smokers = 14 %; White-patients = 76 %. BMI showed differential survival according to race whereby compared to normal-BMI patients, being underweight was associated with poor survival among white patients (OS, aHR = 1.66) but not among black patients (aHR = 1.06; pinteraction = 0.02). Comparing overweight/obese to normal weight patients, Black NSCLC patients who were overweight/obese also had relatively better OS (pinteraction = 0.06) when compared to White-patients. BMI was least associated with survival in Asian-patients and never-smokers. The outcomes of female ever-smokers at the extremes of BMI were associated with worse outcomes in both the underweight (pinteraction<0.001) and obese categories (pinteraction = 0.004) relative to the normal-BMI category, when compared to male ever-smokers. CONCLUSION: Underweight and obese female ever-smokers were associated with worse outcomes in White-patients. These BMI associations were not observed in Asian-patients and never-smokers. Black-patients had more favorable outcomes in the extremes of BMI when compared to White-patients. Body composition in Black-patients, and NSCLC subtypes more commonly seen in Asian-patients and never-smokers, may account for differences in these BMI-OS relationships.

Immunoscore Signature Predicts Postoperative Survival and Adjuvant Chemotherapeutic Benefits in Esophageal Squamous Cell Carcinoma.

OBJECTIVE: The aim of this study was to construct the immunoscore (IS) to facilitate the prediction of postoperative survival and benefit from adjuvant chemotherapy (ACT) in esophageal squamous cell carcinoma (ESCC). METHODS: A total of 249 patients who received radical esophagectomy at Fudan University Shanghai Cancer Center were divided into training set and testing set. Eighty-nine patients with ESCC from TCGA database were enrolled into the validation set. Myeloid cells in tumor microenvironment were evaluated by immunohistochemistry or CIBERSORT, and then were included into a LASSO Cox regression model to construct the immunoscore. The predictive value of the immunoscore for prognosis after surgery or ACT was analyzed. RESULTS: The immunoscore was constructed by four types of myeloid cells including macrophages, neutrophils, mast cells, and dendritic cells and was demonstrated as IS=2^(0.527719*Mφ -0.2604269*MC-0.4812935*DC-0.4519706*Neu). The overall survival was significantly different between two immunotypes, which were divided according to the immunoscore, in all sets (P<0.001, P=0.005, and P=0.002, respectively). Immunotype A was identified as an independent predictor for survival benefit in all three sets (HR=2.068, P=0.005; HR=2.028, P=0.007; HR=6.474, P=0.007; respectively). In patients who received ACT, immunotype A was significantly related to longer overall survival both in the training set (P<0.001) and in the testing set (P=0.011). The nomogram based on immunotype and other clinicopathological factors showed good efficiency of predicting response to ACT. Finally, several important cytokines and pathways were highly enriched in immunoscore A subgroup. CONCLUSION: The immunoscore was an effective prognostic predictor in ESCC for patients undergoing surgical resection and receiving ACT.

Body Mass Index (BMI), BMI Change, and Overall Survival in Patients With SCLC and NSCLC: A Pooled Analysis of the International Lung Cancer Consortium.

INTRODUCTION: The relationships between morbid obesity, changes in body mass index (BMI) before cancer diagnosis, and lung cancer outcomes by histology (SCLC and NSCLC) have not been well studied. METHODS: Individual level data analysis was performed on 25,430 patients with NSCLC and 2787 patients with SCLC from 16 studies of the International Lung Cancer Consortium evaluating the association between various BMI variables and lung cancer overall survival, reported as adjusted hazard ratios (aHRs) from Cox proportional hazards models and adjusted penalized smoothing spline plots. RESULTS: Overall survival of NSCLC had putative U-shaped hazard ratio relationships with BMI based on spline plots: being underweight (BMI < 18.5 kg/m2; aHR = 1.56; 95% confidence interval [CI]:1.43-1.70) or morbidly overweight (BMI > 40 kg/m2; aHR = 1.09; 95% CI: 0.95-1.26) at the time of diagnosis was associated with worse stage-specific prognosis, whereas being overweight (25 kg/m2 ≤ BMI < 30 kg/m2; aHR = 0.89; 95% CI: 0.85-0.95) or obese (30 kg/m2 ≤ BMI ≤ 40 kg/m2; aHR = 0.86; 95% CI: 0.82-0.91) was associated with improved survival. Although not significant, a similar pattern was seen with SCLC. Compared with an increased or stable BMI from the period between young adulthood until date of diagnosis, a decreased BMI was associated with worse outcomes in NSCLC (aHR = 1.24; 95% CI: 1.2-1.3) and SCLC patients (aHR=1.26 (95% CI: 1.0-1.6). Decreased BMI was consistently associated with worse outcome, across clinicodemographic subsets. CONCLUSIONS: Both being underweight or morbidly obese at time of diagnosis is associated with lower stage-specific survival in independent assessments of NSCLC and SCLC patients. In addition, a decrease in BMI at lung cancer diagnosis relative to early adulthood is a consistent marker of poor survival.

NLGN3 promotes neuroblastoma cell proliferation and growth through activating PI3K/AKT pathway.

Neuroblastoma is the most common extracranial solid tumor of childhood, previous studies show synaptic protein neuroligin-3 (NLGN3) promotes glioma proliferation and growth, However, no investigation about the role of NLGN3 in neuroblastoma was reported. Here, we found NGLGN3 was significantly upregulated in neuroblastoma cells and tissues, its overexpression significantly promoted neuroblastoma cell proliferation and growth determined by MTT analysis, colony formation assay, cell cycle progression analysis, BrdU incorporation assay and animal model, while its knockdown inhibited cell proliferation and growth. Then we found NLGN3 could increase the phosphorylation level of AKT and the transcription activity of FOXO family, suggesting NLGN3 activated PI3K/AKT pathway, inhibition of PI3K/AKT pathway in NLGN3 overexpressing cells inhibited cell proliferation, confirming NLGN3 promoted neuroblastoma proliferation through activating PI3K/AKT pathway. In summary, we found NLGN3 promoted neuroblastoma cell proliferation and growth through activating PI3K/AKT pathway and providing a new target for neuroblastoma therapy.

GDNF family receptor alpha 2 promotes neuroblastoma cell proliferation by interacting with PTEN.

Neuroblastoma is a childhood tumor, and high-stage neuroblastoma has a poor prognosis. The regulatory mechanisms for neuroblastoma progression are poorly understood. In present study, we found that GDNF family receptor alpha 2 (GFRA2) was upregulated in neuroblastoma cells and tissues, and its overexpression promoted neuroblastoma cell proliferation, as revealed using colony formation, soft agar growth, and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays Tumor suppressor phosphatase and tensin homolog (PTEN) is an inhibitor of the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/AKT serine/threonine kinase (AKT) pathway that interacts with GFRA2. A luciferase activity assay showed GFRA2 inhibits the transcriptional activity of the forkhead box O (FOXO) family proteins, which suggested that GFRA2 activated the PI3K/AKT pathway. Inhibition of the PI3K/AKT pathway in GFRA2 overexpressing cells decreased cell proliferation, confirming that GFRA2 promoted neuroblastoma cell proliferation by activating the PI3K/AKT pathway. In summary, cell proliferation via the GFRA2-PTEN-PI3K/AKT axis may represent new target to develop treatments for neuroblastoma.

Preoperative brain MRI for clinical stage IA lung cancer: is routine scanning rational?

PURPOSE: Early detection and control of lung cancer brain metastases (BMs) are important. However, several guideline recommendations are inconsistent with regard to routine preoperative brain MRI, especially in patients with clinical stage IA lung cancer. Our study evaluated the value of preoperative brain MRI in patients with clinical stage IA lung cancer. METHODS: A retrospective analysis of patients with lung cancer was performed using a prospectively collected database. Clinical data and the results of brain MRI were collected and analyzed. RESULTS: Patients with pathologically proved primary lung cancer who underwent an MRI at initial diagnosis were identified (3392 patients). In total, 170 patients (5.0%) were diagnosed with BMs. The increased frequency of BMs was significantly associated with advanced clinical stage (P = 0.000) and pathological type (P = 0.011). BMs were detected in 11 out of 1595 patients with clinical stage IA lung cancer (0.7%). BMs were more common in patients with clinical stage cT1c lung cancer (1.9%) than those with clinical stage cT1a or cT1b (0.1%, odds ratio = 21.30, 95% confidence interval: 2.7-166.9, P = 0.000). All patients with stage IA lung cancer and BMs had solid lung lesions (P = 0.002). CONCLUSIONS: Preoperative brain MRI might help identify BMs in patients with lung cancer that has progressed beyond stage IA. In patients with clinical stage IA lung cancer, we do not recommend preoperative brain MRI, but it may potentially be beneficial in those with solid T1c cancers.

A B7-CD28 family based signature demonstrates significantly different prognoses and tumor immune landscapes in lung adenocarcinoma.

B7 family ligands and CD28 family receptors have complicated interaction for modulating immune functions. They play a central role in response to immunotherapy and outcome of patients with lung adenocarcinoma (LUAD). Thus, we analyzed B7-CD28 family gene expression profiles in LUAD and generated a signature to predict prognosis and immune host status. B7-CD28 family gene expression profiles and clinical data of LUAD from The Cancer Genome Atlas (TCGA) were analyzed. In the training cohort, prognostic association was assessed and then a prognostic signature was built with stepwise multivariable Cox analysis. The signature was validated by Kaplan-Meier and multivariable Cox analysis in several published gene expression datasets and a Fudan University cohort. Expression of immune cell populations and other immunotherapy predictors was further investigated. In TCGA LUAD cohort, eight B7-CD28 family genes had prognostic association with p values <0.05. Stepwise regression generated a gene signature including two genes, CD28 and CD276. Signature high-risk cases had worse overall survival (OS) and disease-free survival (DFS) in three published gene expression datasets and a Fudan University validation cohort. The B7-CD28 family based signature also significantly stratified OS and DFS in important clinical subsets, including stage I-II and EGFR mutant subsets. Signature high- and low-risk tumor had significantly different expressions of PD-L1 and tumor infiltrating leukocytes. The B7-CD28 family based signature demonstrates significantly different prognoses and tumor immune landscapes in LUAD. Whether it could serve as potential biomarkers for immunotherapy needs further investigation.

Development and Validation of Web-Based Nomograms to Precisely Predict Conditional Risk of Site-Specific Recurrence for Patients With Completely Resected Non-small Cell Lung Cancer: A Multiinstitutional Study.

BACKGROUND: There is currently no consensus regarding the optimal postoperative follow-up strategy for patients with completely resected non-small cell lung cancer (NSCLC). We aimed to develop web-based nomograms to precisely predict site-specific postoperative recurrence in patients with NSCLC and to guide individual surveillance strategies including when to follow up and what diagnostic tests to perform. METHODS: We investigated the pattern of recurrence in a series of 2,017 patients with NSCLC (squamous cell carcinoma and nonlepidic invasive adenocarcinoma) who underwent complete surgical resection at Fudan University Shanghai Cancer Center (development cohort), and developed web-based clinicopathologic prediction models for conditional risk of site-specific recurrence based on Cox regression. The variables used in the analysis included sex, age, smoking history, tumor size, tumor histology, lymphovascular invasion, visceral pleural invasion, and pathologic TNM stage. A separate cohort of 3,308 patients with NSCLC from Shanghai Chest Hospital was used for external validation. RESULTS: In the development cohort and the external validation cohort for the established nomograms to predict overall recurrence, thorax recurrence, abdomen recurrence, neck recurrence, brain recurrence, and bone recurrence, the C-statistics of Harrell et al were 0.743 and 0.748, 0.728 and 0.703, 0.760 and 0.749, 0.779 and 0.757, 0.787 and 0.784, and 0.777 and 0.739, respectively. The calibration plots showed optimal agreement between nomogram-predicted 3-year recurrence-free survival and actual 3-year recurrence-free survival. CONCLUSIONS: These user-friendly nomograms can precisely predict site-specific recurrence in patients with completely resected NSCLC, based on clinicopathologic features. They may help physicians to make individual postoperative follow-up plans.

Does delayed esophagectomy after endoscopic resection affect outcomes in patients with stage T1 esophageal cancer? A propensity score-based analysis.

BACKGROUND: Although endoscopic resection (ER) may be sufficient treatment for early-stage esophageal cancer, additional treatment is recommended when there is a high risk of cancer recurrence. It is unclear whether delaying esophagectomy by performing and assessing the success of ER affects outcomes as compared with immediate esophagectomy without ER. Additionally, long-term survival after sequential ER and esophagectomy required further investigation. METHODS: Between 2011 and 2015, 48 patients with stage T1 esophageal cancer underwent esophagectomy after ER with curative intent at our institution. Two-to-one propensity score methods were used to identify 96 matched-control patients who were treated with esophagectomy only using baseline patient, tumor characteristics and surgical approach. Time from initial evaluation to esophagectomy, relapse-free survival, overall survival, and postoperative complications were compared between the propensity-matched groups. RESULTS: In the ER + esophagectomy group, the time from initial evaluation to esophagectomy was significantly longer than in the esophagectomy only group (114 vs. 8 days, p < 0.001). The incidence of dense adhesion (p = 0.347), operative time (p = 0.867), postoperative surgical complications (p = 0.966), and postoperative length of hospital stay (p = 0.125) were not significantly different between the groups. Moreover, recurrence-free survival and overall survival were also similar between the two groups (p = 0.411 and p = 0.817, respectively). CONCLUSIONS: Treatment of stage T1 esophageal cancer with ER prior to esophagectomy did not increase the difficulty of performing esophagectomy or the incidence of postoperative complications and did not affect survival after esophagectomy. These results suggest that ER can be recommended for patients with stage T1 cancer even if esophagectomy is warranted eventually.