tRNA-based prognostic score in predicting survival outcomes of lung adenocarcinomas.

As the most abundant noncoding RNA in cells, tRNA plays an important role in tumorigenesis and development. The report of tRNA on the pathogenesis of lung adenocarcinoma is rare. It is of great clinical significance to explore the relationship between tRNA expression and prognosis of lung adenocarcinoma. The expression level of tRNAs in lung adenocarcinoma tissues and paracarcinoma tissues was detected using a tRNA RT-qPCR array. A total of 104 lung adenocarcinomas were included in the analysis of the correlation between candidate tRNAs expression and prognosis. A tRNA-based prognostic model was constructed and validated using Cox proportional hazards regression. A nomogram was built to help clinicians develop treatment strategies. We screened a series of differentially expressed tRNAs between lung adenocarcinoma tissues and paracarcinoma tissues. Among these tRNAs, tRNAAsnATT , tRNAIleAAT , tRNALeuTAA , mt-tRNATrpTCA , mt-tRNALeuTAA , tRNAProAGG , tRNALysCTT-1 and tRNALeuAAG were associated with the clinicopathological characteristics of lung adenocarcinoma. tRNALysCTT-1 , mt-tRNASerGCT and tRNATyrATA were associated with cancer-specific survival. We constructed a prognostic model for lung adenocarcinoma using specific tRNA expression levels as reference factors. Multivariate analyses showed that tRNA-based prognostic score was a significant and important prognostic factor. The prognostic model based on the tRNAs expression signatures can help predict the prognosis of patients with lung adenocarcinoma.

Frequency and clinical significance of NF1 mutation in lung adenocarcinomas from East Asian patients.

NF1 is a tumor suppressor gene that negatively regulates Ras signaling. NF1 deficiency plays an important role in carcinogenesis. To investigate the frequency and clinical significance of NF1 mutation, we examined mutation status of NF1, TP53, LKB1 and RB1 in 704 surgically resected lung adenocarcinomas from East Asian patients using semiconductor-based Ion Torrent sequencing platform. Common driver events, including mutations in EGFR, KRAS, HER2, BRAF, MET, and fusions affecting ALK, RET and ROS1, were also concurrently detected. The correlation between NF1 mutations and clinicomolecular features of patients was further evaluated. Among 704 patients, 42 NF1 mutations were found in 33 patients (33/704, 4.7%), including 14 patients harboring EGFR/NF1 comutations (14/33, 42.4%). Comparing with EGFR-mutant patients, patients harboring NF1 mutations were closely associated with solid component subtype (p = 0.028). Comparing with KRAS mutations, NF1 mutations were found more common in female and never smokers (p = 0.003 and p = 0.004, respectively). Kaplan-Meier survival analysis revealed that patients harboring NF1 mutation had similar disease-free survival (DFS) and overall survival (OS) with patients with KRAS mutation. Although frequently overlapped with EGFR mutation, patients harboring NF1 mutation had significantly shorter DFS (p = 0.019) and OS (p = 0.004) than patients with EGFR mutation. During follow-up, one female patient with EGFR exon 19 deletion and NF1 Q1815X comutation showed poor response to EGFR TKIs (Gefitinib and Osimertinib) after disease relapse. In conclusion, NF1 mutations define a unique molecular and clinicopathologic subtype of lung adenocarcinoma. Examination of NF1 mutation may contribute to molecular subtyping and therapeutic intervention of lung adenocarcinoma.

The lymph node status and histologic subtypes influenced the effect of postoperative radiotherapy on patients with N2 positive IIIA non-small cell lung cancer.

BACKGROUND AND OBJECTIVE: To investigate the role of postoperative radiotherapy (PORT) in IIIA-N2 non-small cell lung cancer (NSCLC) patients and subgroups which derived benefit from PORT. METHODS: A total of 576 patients with pathological IIIA-N2 NSCLC, who underwent complete resection, were identified. Propensity score matching (PSM) methods were used to balance the patients' characteristics between two groups. Overall survival (OS) and relapse-free survival (RFS) were compared between PORT and non-PORT patients. RESULTS: On multivariable analysis, improved OS remained correlated with younger age, single N2 station involvement, less positive lymph nodes, and chemotherapy. After PSM, 121 PROT patients and 242 non-PORT patients were matched. PORT was not associated improved patients' OS (P = 0.735) or RFS ( P = 0.483). For patients who underwent postoperative chemotherapy (POCT), PORT could improve OS in single N2 station involved patients (HR: 0.572, 95%CI: 0.312 to 1.05, P = 0.040). Patients with papillary predominant adenocarcinoma also benefited from PORT with an increase in OS (HR: 0.350, 95%CI: 0.126 to 0.972, P = 0.033). CONCLUSIONS: For patients with completely resected IIIA-N2 NSCLC, mediastinal lymph node metastasis and histologic subtypes could influence the effect of PORT. Single N2 station involvement and papillary predominant subtype were predictors of benefit from PORT.

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.

Minor Components of Micropapillary and Solid Subtypes in Lung Adenocarcinoma are Predictors of Lymph Node Metastasis and Poor Prognosis.

BACKGROUND: Lung adenocarcinoma with micropapillary and solid predominant subtypes was reported to be associated with poor prognosis; however, whether minor components (non-predominant) of micropapillary and solid subtypes predict poor prognosis remains unknown. In this study, we investigated the predictive and prognostic value of lymph node metastasis of minor micropapillary and solid components. METHODS: Specimens of resected tumors of 1244 patients were reclassified to determine the predominant subtype and minor components (>5 %, but not predominant). Of these specimens, 105 contained a micropapillary component and 210 contained a solid component. The correlation between each subtype and lymph node metastasis was analyzed, and survival analyses were used to determine the association between each subtype and patient survival. RESULTS: Adenocarcinomas harboring micropapillary and/or solid components held higher rates of metastatic lymph node stations (25.2 % vs. 15.6 %, p = 0.002; and 24.0 % vs. 14.9 %, p < 0.001, respectively) and lymph nodes (17.3 % vs. 10.1 %, p = 0.004; and 15.5 % vs. 9.7 %, p = 0.001, respectively). Patients with micropapillary and solid components in their tumors showed a shorter median recurrence-free survival (15.8 vs. 62.8 months, p < 0.001; and 20.8 months vs. not reached, p < 0.001) and overall survival (47.0 months vs. not reached, p < 0.001; and 69.0 months vs. not reached, p < 0.001). CONCLUSIONS: Minor components of micropapillary and/or solid subtypes of lung adenocarcinoma are correlated with lymph node metastasis and poor prognosis. Thus, it is beneficial to focus not only on predominant subtypes but also minor components to predict prognoses and make therapeutic strategies more comprehensively.

Prevalence and Clinicopathological Characteristics of BRAF Mutations in Chinese Patients with Lung Adenocarcinoma.

BACKGROUND: This study was designed to identify the prevalence of BRAF mutations in Chinese patients with lung adenocarcinoma, and to reveal the association between BRAF mutations and clinicopathological characteristics in these patients. METHODS: From October 2007 to February 2013, patients with newly diagnosed primary lung adenocarcinoma were detected for mutations in BRAF, EGFR, KRAS, HER2 and ALK. Clinicopathological characteristics, including sex, age, TNM stage, tumor differentiation, smoking status, histological subtypes, and survival information were analyzed. RESULTS: Of 1358 patients with lung adenocarcinoma, 20 patients were harboring BRAF mutations, including five BRAF V600E mutations and 15 BRAF non-V600E mutations. Among these, BRAF N581I and BRAF G593S were newly reported. BRAF mutations were associated with smoking status (odds ratio 3.28; 95 % CI 1.33-8.08; p = 0.008). In patients less than 60 years of age, BRAF mutations tended to have poor differentiation in tumor samples (70.0 vs. 35.1 %; p = 0.014), and were more likely to relapse (70 vs. 28 %; p = 0.008). A significant difference was found in relapse-free survival (RFS) between BRAF mutations and other mutations, but not in overall survival. CONCLUSIONS: The prevalence of BRAF mutations in Chinese patients with lung adenocarcinoma was approximately 1.5 %. BRAF mutations were more frequent in current smokers. Patients harboring BRAF mutations had a higher rate of recurrence and worse RFS compared with other patients.

Increased Tumor Intrinsic Growth Potential and Decreased Immune Function Orchestrate the Progression of Lung Adenocarcinoma.

Background: The overall 5-year survival of lung cancer was reported to be only ~15%, with lung adenocarcinoma (LUAD) as the main pathological subtype. Before developing into invasive stages, LUAD undergoes pre-invasive stages of adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma (MIA), where surgical resection gives an excellent 5-year survival rate. Given the dramatic decline of prognosis from pre-invasive to invasive stages, a deeper understanding of key molecular changes driving the progression of LUAD is highly needed. Methods: In this study, we performed whole-exome sequencing and RNA sequencing on surgically resected 24 AIS, 74 MIA, 99 LUAD specimens, and their adjacent paired normal tissues. Survival data were obtained by follow-up after surgery. Key molecular events were found by comparing the gene expression profiles of tumors with different stages. Finally, to measure the level of imbalance between tumor intrinsic growth potential and immune microenvironment, a tumor progressive (TP) index was developed to predict tumor progression and patients' survival outcome and validated by external datasets. Results: As tumors progressed to more invasive stages, they acquired higher growth potential, mutational frequency of tumor suppressor genes, somatic copy number alterations, and tumor mutation burden, along with suppressed immune function. To better predict tumor progression and patients' outcome, TP index were built to measure the imbalance between tumor intrinsic growth potential and immune microenvironment. Patients with a higher TP index had significantly worse recurrence-free survival [Hazard ratio (HR), 10.47; 95% CI, 3.21-34.14; p < 0.0001] and overall survival (OS) [Hazard ratio (HR), 4.83e8; 95% CI, 0-Inf; p = 0.0013]. We used The Cancer Genome Atlas (TCGA)-LUAD dataset for validation and found that patients with a higher TP index had significantly worse OS (HR, 1.10; 95% CI, 0.83-1.45; p = 0.048), demonstrating the prognostic value of the TP index for patients with LUAD. Conclusions: The imbalance of tumor intrinsic growth potential and immune function orchestrate the progression of LUAD, which can be measured by TP index. Our study provided new insights into predicting survival of patients with LUAD and new target discovery for LUAD through assessing the imbalance between tumor intrinsic growth potential and immune function.

Impact of post-operative serum albumin level on anastomotic leakage after transthoracic oesophagectomy for oesophageal squamous cell carcinoma.

BACKGROUND: The correlation of post-operative serum albumin level with the occurrence of anastomotic leakage (AL) in oesophageal squamous cell carcinoma (ESCC) remains unclear. The aim of this study was to evaluate the impact of post-operative serum albumin level on AL after transthoracic oesophagectomy. METHODS: Patients with ESCC who underwent transthoracic oesophagectomy between 2013 and 2017 in Fudan University Shanghai Cancer Center were included. The correlation of post-operative serum albumin level with the occurrence and short-term outcomes of AL was analysed. RESULTS: Patients with serum albumin level of <35 g/L on the first post-operative day were identified with higher frequency of AL in the whole study population (10.3% versus 6.1%; P < 0.001), intrathoracic anastomosis subgroup (7.1% versus 3.9%; P = 0.002) and cervical anastomosis subgroup (24.1% versus 16.0%; P = 0.042). Multivariate analysis showed that low albumin level was an independent risk factor of AL in the overall population (odds ratio (OR) 1.842; P < 0.001), intrathoracic anastomosis subgroup (OR 1.815; P = 0.006) and cervical anastomosis subgroup (OR 1.946; P = 0.013). In patients with AL, low albumin level was associated with poorer short-term outcomes. For patients with low albumin level on the first post-operative day, the probability of AL was significantly reduced if the level in the first post-operative week was improved to the normal range (5.9% versus 14.9%; P < 0.001). CONCLUSION: Serum albumin level on the first post-operative day was an independent predictor of AL in patients with ESCC receiving transthoracic oesophagectomy. Increase of albumin level to the normal range post-operatively could reduce the risk of AL.

Comparison of perioperative and survival outcomes between sublobar resection and lobectomy of patients who underwent a second pulmonary resection.

BACKGROUND: Repeat pulmonary resection is widely accepted in clinical practice. This study aimed to compare sublobar resection (segmentectomy or wedge resection) with lobectomy in the treatment of patients who underwent a second pulmonary resection. METHODS: This study retrospectively included patients who underwent lobectomy or sublobar resection for second pulmonary resection. 1:1 propensity score matching (PSM) was performed to balance selection bias. Clinicopathological features, perioperative and survival outcomes of lobectomy and sublobar resection were compared. RESULTS: A total of 308 patients who underwent second pulmonary resection were identified: 71 (23.1%) who underwent lobectomy and 237 (76.9%) who underwent sublobar resection. After PSM, 58 patients for each group were selected with well-balanced clinicopathological characteristics. In patients who underwent sublobar resection, significantly shorter chest tube duration (days) (median, 4 vs. 2, p < 0.001) and postoperative hospital stay (days) (median, 6 vs. 4, p < 0.001) were observed. There was no significant difference in overall survival between these two groups after the second and first surgery (p = 0.65, p = 0.98), respectively. Subgroup analysis according to the type of the first resection showed consistent results. CONCLUSIONS: Sublobar resection may be considered as an alternative option for second pulmonary resection due to its perioperative advantages and similar survival outcomes compared with lobectomy.

Gender Differences and Influencing Factors in Specialty Choices: Findings From One Medical School in China.

Background: Gender plays a significant role in the selection of medical specialty. Few studies have been conducted to explore the impact of gender differences on specialty choosing among Chinese medical students. Methods: The specialty choices of 648 students from six consecutive classes in an 8-year MD program were collected and compared between male and female students. A total of 110 students from one graduating class were surveyed by a questionnaire covering 22 career influencing factors. Each factor has a scale of zero to three (zero = no influence, one = mild influence, two = moderate influence, and three = strong influence). Results: Statistically significant gender differences were observed in 10 out of 16 specialties. Most male students limited their specialty choices to surgery (64%), internal medicine (12%), and orthopedics (12%), compared with a relatively diversified pattern in female students. For male students, the top three influencing factors were personal interest, future job prospects for the chosen specialty, and job opportunity in academic medicine. The strongest influencing factors of females were personal interest, specialty-specific knowledge and skills, and the sense of achievement. The expected salary was ranked among the top 10 influencing factors in male but not in females, while the work-life balance was ranked among the top 10 factors in females but not in males. Conclusion: There is a significant gender difference regarding specialty choices among Chinese medical students. Career coaching is needed to help students in their specialty choosing process.

Risk stratification model for patients with stage I invasive lung adenocarcinoma based on clinical and pathological predictors.

BACKGROUND: The aim of this study was to propose a new kind of pathological classification and further establish a prognostic model for resected stage I invasive adenocarcinoma (IADC). METHODS: Clinicopathological data were collected from 2 hospitals. The new proposed pathological reclassification was defined according to certain subtype instead of a predominant one. Survival curves were plotted by Kaplan-Meier analysis. Cox regressions were analyzed for recurrence-free survival (RFS) and overall survival (OS), through which prognostic scores and stratification models were established. The comparison between risk models and the eighth edition of tumor, node, metastasis (TNM) classification was conducted through receiver operating characteristic curves (ROC), as identified by the area under the curve (AUC) and z test. RESULTS: In all, 1,196 patients were enrolled. At multivariable analysis, solid and micropapillary of the new pathological reclassification, along with stage IA3 and IB were independent predictors for poorer RFS. Stage IB and smoking status significantly indicated worse OS. After normalization and standardization of log-hazard ratio (HR), personalized scores were calculated and the risk stratifications with 3 risk groups were generated. Compared with TNM classification, the risk model of RFS showed advantage over early-recurrence prediction (1-year: 0.653 vs. 0.556, P=0.033; 3-year: 0.663 vs. 0.076, P=0.008). No marked difference was observed in long-term RFS or OS. CONCLUSIONS: Considering the harboring of certain patterns may be a new concept in adenocarcinoma classification. The risk stratification model based on this pathological classification and the eighth TNM classification showed remarkable superiority over TNM alone in predicting early recurrence of stage I adenocarcinoma. However, TNM classification remained valuable for long-term recurrence and survival prediction.

Is flexible bronchoscopy necessary in the preoperative workup of patients with peripheral cT1N0 subsolid lung cancer? -a prospective multi-center cohort study.

BACKGROUND: Necessity of flexible bronchoscopy (FB) examination as a routine preoperative work-up for peripheral clinical T1N0 subsolid lung cancer was unknown. METHODS: This was a prospective, multi-center clinical trial (NCT03591445). Patients with peripheral GGO nodules (GGNs) who were candidates for surgical resection were enrolled. FB examination was performed preoperatively. Surgical plan could be changed if any aberrant histologic and anatomic findings were detected by FB examination. Primary endpoint was the rate that surgical plan was changed by positive FB findings. Secondary endpoints were rate of positive FB findings and rate of procedural complications. RESULTS: Six hundred and fifteen patients with peripheral subsolid nodules detected by thoracic CT were enrolled. There were 187 (30.4%) male and 428 (69.6%) female patients, mean age was 54.85±10.41 y (range, 26-78). 262 (42.6%) patients had pure GGNs and 353 (57.4%) patients had part-solid nodules. Mean size of nodules was 13.87±6.37 mm (range, 5-30). FB examinations confirmed one (0.16%) adenocarcinoma, seven (1.14%) bronchial variations, one (0.16%) segmental bronchostenosis, one (0.16%) segmental bronchial occlusion and one (0.16%) bronchial inflammation. No complications of FB examinations occurred. 568 (92.35%) thoracoscopic and 47 (7.65%) open surgeries were performed. No established surgical plan was changed by positive FB findings. Final pathologies revealed 26 (4.2%) adenocarcinoma in situ (AIS), 240 (39%) minimal invasive adenocarcinomas (MIAs), 343 (55.8%) invasive adenocarcinomas (IADs), one (0.2%) adenosquamous cell carcinoma, one (0.2%) squamous cell carcinoma, two (0.3%) atypical adenoid hyperplasia and two (0.3%) inflammations. CONCLUSIONS: FB examination was unnecessary in the preoperative assessment of peripheral clinical T1N0 subsolid lung cancer.

Survival Prediction and Adjuvant Chemotherapy Based on Tumor Marker for Stage IB Lung Adenocarcinoma.

BACKGROUND: We aimed to find out the prognosis of stage IB invasive lung adenocarcinoma according to perioperative tumor markers (TMs), especially carcinoembryonic antigen (CEA), and to determine whether TMs could guide adjuvant chemotherapy. METHODS: Stage IB adenocarcinoma patients were selected from 2 medical centers in Shanghai between January 2007 and December 2013. Perioperative TMs, including preoperative and postoperative TMs, were stratified into normal level, CEA normal, and CEA elevated. Propensity score matching was analyzed for eliminating variable differences between chemotherapy and observation groups. Univariable and multivariable Cox regression analyses were conducted to discover the prognostic independent risk factors. Kaplan-Meier curves were plotted and assessed by the log-rank test. Subgroup analysis was performed to investigate chemotherapy benefit according to postoperative TMs. RESULTS: Postoperative CEA elevated (hazard ratio [HR], 6.783, 95% confidence interval [CI], 2.534-18.162; P < .001), CEA normal (HR, 3.332; 95% CI, 1.553-7.147; P = .002), and older age were independently correlated with worse recurrence; however, only postoperative CEA elevated (HR, 11.546; 95% CI, 3.854-34.588; P < .001) and CEA normal (HR, 4.389; 95% CI, 1.566-12.300; P = .005) independently influenced survival outcome. Chemotherapy showed limited recurrence and survival benefit among the primary cohort. In subgroup analysis, chemotherapy even shortened survival outcome when postoperative TMs were normal (HR, 8.870; 95% CI, 1.134-69.381; P = .038). CONCLUSIONS: Postoperative rather than preoperative CEA normal and CEA elevated were 2 independent risk indicators for poorer clinical outcome. Chemotherapy failed to improve clinical outcomes when postoperative TMs were elevated. Importantly, chemotherapy could not be recommended when postoperative TMs were at a normal level.

Marital status independently predicts non-small cell lung cancer survival: a propensity-adjusted SEER database analysis.

PURPOSE: Marital status has been demonstrated as an independent prognostic factor in many cancer types. The impact of marital status on non-small cell lung cancer (NSCLC) survival has not been assessed at the population level. Here, we used the surveillance, epidemiology and end results (SEER) database, a US national cancer registry, to address this issue. METHODS: All patients diagnosed with NSCLC from 2004 to 2009 were identified in the SEER database (version 8.3.2, updated at April 14, 2016). Those with incomplete clinicopathological information were excluded. The tumor, node, metastasis (TNM) staging was based on the criteria of the American Joint Committee on Cancer (AJCC) 6th edition. We used propensity-score matching analysis to balance baseline characteristics between the patients who were married and those who were not married. The impact of marital status on cancer-specific survival was analyzed with Cox proportional-hazards regression. RESULT: A total of 72, 984 NSCLC patients (41, 095 married patients, 56.3%) were enrolled in this study. After propensity-score matching, 25, 617 patients in the married group were 1:1 matched with patients in the unmarried group. Being unmarried was found to be associated with significantly decreased cancer-specific survival (hazard ratio (HR): 1.142, 95% CI: 1.119-1.166, p < 0.001). Among the unmarried group, patients who were single had worse cancer-specific survival (median survival 12 months, 95% CI: 11.37-12.63 months) than those who were divorced (median survival 15 months, 95% CI: 14.24-15.76 months, p < 0.001) or widowed (median survival 15 months, 95% CI: 14.25-15.76 months, p < 0.001). CONCLUSION: This study shows that marital status is an independent prognostic factor for cancer-specific survival in NSCLC patients. Patients who were married had better cancer-specific survival compared to the unmarried ones.

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.

EGFR-mutant lung adenocarcinoma harboring co-mutational tumor suppressor genes predicts poor prognosis.

INTRODUCTION: EGFR mutations occur most frequently in patients with lung adenocarcinoma in East Asia. However, the prognostic and therapeutic impact of co-mutational status of EGFR and tumor suppressor genes is not fully understood. This study aims to provide a deeper understanding of lung adenocarcinoma patients with co-mutation of EGFR and tumor suppressor genes. METHODS: From November 2009 to May 2016, 675 patients with lung adenocarcinoma who underwent complete surgery were included in this study. Samples were collected and pathologically examined. Whole-exome sequencing was performed on 197 samples, while direct sequencing of major driver genes, including EGFR, KRAS, ERBB2 and BRAF and Ion-torrent targeted sequencing of tumor suppressor genes, including TP53, KEAP1, MGA, NF1, RB1, SMARCA4 and STK11, were performed on 478 samples. Tumor mutational burden was calculated and survival analyses were performed. RESULTS: The frequency of EGFR and TP53 mutation was 409 (60.6%) and 215 (31.9%), respectively. Co-mutation of EGFR and TP53 occured in 151 patients (22.4%), while co-mutation of EGFR and at least one tumor suppressor gene occured in 184 patients (27.3%). Compared with patients with only EGFR mutations, patients with co-mutations of EGFR and TP53 had a higher tumor mutational burden (p = 0.007) and worse recurrence-free survival (p = 0.010), while patients with co-mutations of EGFR and at least one tumor suppressor gene had a higher tumor mutational burden (p = 0.007), worse recurrence-free survival (p = 0.016) and worse overall survival (p = 0.018). CONCLUSIONS: Lung adenocarcinoma patients harboring EGFR and co-mutational tumor suppressor genes should be regarded as a unique subgroup.

Outcomes comparison between neoadjuvant chemotherapy and adjuvant chemotherapy in stage IIIA non-small cell lung cancer patients.

BACKGROUND: A neoadjuvant chemotherapy (NCT) is a feasible second-option other than an adjuvant chemotherapy (ACT); however, no definite conclusions have been drawn about whether or not a NCT is associated with better clinical outcomes for IIIA non-small cell lung cancer (NSCLC) patients. METHODS: We reviewed 68 clinical IIIA NSCLC patients who received preoperative chemotherapy (NCT group), and 535 pathological IIIA NSCLC patients who received ACT after surgery (ACT group). After a 1:1 propensity score matching (PSM), we compared the relapse-free survival (RFS) and overall survival (OS) rates as the long-term clinical outcomes, and hospital stay, surgery duration, postoperative complications as the short-term clinical outcomes. To evaluate the predictive value of the NCT response, we also assessed the response evaluation criteria in solid tumors (RECIST) response to NCT. RESULTS: There was no significant difference in RFS or OS between the NCT group and ACT group (RFS: P=0.1138; OS: P=0.4234). On multivariate analysis, large cell lung carcinoma (P=0.0264), bilobectomy (P=0.0039) and clinical N2 stage (P=0.0309) were independent predictive factors of a worse OS. Short-term clinical outcomes including the hospital stay and postoperative complications had no statistically distinct difference between the ACT and NCT groups. Meanwhile, the OS of the partial response (PR) patients group was better than the stable disease/progressive disease (SD/PD) (P=0.0205) and ACT (P=0.0442) group, but none of the clinical features we tested was found to be a predictive factor for a PR response. CONCLUSIONS: There was a non-significant difference between the long-term and short-term clinical outcomes of both NCT and ACT. The OS of PR patients was better than SD/PD and ACT, indicating that NCT response acts as a predictor for a higher long-term survival rate.

A prognostic score system with lymph node ratio in stage IIIA-N2 NSCLC patients after surgery and adjuvant chemotherapy.

PURPOSE: The survival of patients with IIIA-N2 non-small cell lung cancer after surgery followed by adjuvant chemotherapy is heterogeneous. The aim of this study is to form a prognostic system and a heat map method to visualize the overall survival rates in those patients. METHODS: Univariate and multivariate Cox hazards regression models and the associated Wald Chi square coefficient were used to form the prognostic score system. Recursive partitioning analysis was used to determine the cutoff values of lymph node ratio and prognostic score in SEER cohort and validated in FDUSCC cohort. Meanwhile, a heat map method was used to visualize the overall survival probabilities of 3, 5 and 10 years for individual patient of both cohorts. RESULTS: Lymph node ratio (with cutoff of 0.36) significantly correlates with overall survival of these patients. In addition, in patients with the same level of N2 disease, lymph node ratio still significantly affects survival. Also, after the multivariate analysis in SEER cohort, six factors were independent prognostic factors including age, sex, type of surgery, size, lymph node ratio and differentiation. A prognostic sore system with these factors (with cutoff of 12) was validated as a predictor for overall survival in FDUSCC cohort. CONCLUSIONS: This prognostic score system including lymph node ratio can predict the survival rates of IIIA-N2 patient after surgery and post-operative chemotherapy. Lymph node ratio could be a useful supplementation in TNM stage classification for IIIA-N2 patients. The heat map method can visualize the predicted overall survival of an individual patient.

Detection of Novel NRG1, EGFR, and MET Fusions in Lung Adenocarcinomas in the Chinese Population.

INTRODUCTION: Multiple oncogene fusions beyond ALK receptor tyrosine kinase (ALK), RET, and ROS1 fusion has been described in lung cancer, especially in lung adenocarcinomas without common oncogenic mutations. Molecular inhibitors have been developed and proved effective for patients whose tumors harbor these novel alterations. METHODS: A consecutive series of surgically resected lung adenocarcinomas were collected and profiled using an enrichment strategy to detect nine common oncogenic driver mutations and fusions concerning EGFR, KRAS, HER2, BRAF, MET, ALK, RET, ROS1, and FGFR. Driver-negative cases were further analyzed by a comprehensive RNA-based next-generation sequencing (NGS) fusion assay for novel fusions. RESULTS: In total, we profiled 1681 lung adenocarcinomas, among which 255 cases were common driver-negative. One hundred seventy-seven cases had sufficient tissue for NGS fusions screening, which identified eight novel fusions. NRG1 fusions occurred in 0.36% of all lung adenocarcinoma cases (6 of 1681 cases), including 4 CD74-NRG1-positive cases, 1 RBPMS-NRG1-positive case, and 1 novel ITGB1-NRG1-positive case. Furthermore, another 2 novel fusions were also detected, including 1 EGFR-SHC1 fusion and 1 CD47-MET fusion, both of which were in-frame and retained the functional domain of the corresponding kinases. No fusion event was detected for NTRK, KRAS, BRAF or HER2 genes in this cohort. Detailed clinicopathologic data showed that invasive mucous adenocarcinoma (three of eight cases) and acinar-predominant adenocarcinoma (three of eight cases) were the most prevalent pathologic subtypes among novel fusions. CONCLUSIONS: Fusions affecting NRG1, EGFR, and MET were detected in 0.48% of unselected lung adenocarcinomas, and NRG1 fusions ranked the most prevalent fusions in common driver-negative lung adenocarcinomas from Chinese population. RNA-based NGS fusion assay was an optional method for screening actionable fusions in common driver-negative cases.