The single cell immunogenomic landscape after neoadjuvant immunotherapy combined chemotherapy in esophageal squamous cell carcinoma.

Neoadjuvant immunotherapy represents promising strategy in the treatment of esophageal squamous cell carcinoma (ESCC). However, the mechanisms underlying its impact on treatment sensitivity or resistance remain a subject of controversy. In this study, we conducted single-cell RNA and T/B cell receptor (scTCR/scBCR) sequencing of CD45+ immune cells on samples from 10 patients who received neoadjuvant immunotherapy and chemotherapy. We also validated our findings using multiplexed immunofluorescence and analyzed bulk RNA-seq from other cohorts in public database. By integrating analysis of 87357 CD45+ cells, we found GZMK + effector memory T cells (Tem) were relatively enriched and CXCL13+ exhausted T cells (Tex) and regulator T cells (Treg) decreased among responders, indicating a persistent anti-tumor memory process. Additionally, the enhanced presence of BCR expansion and somatic hypermutation process within TNFRSF13B + memory B cells (Bmem) suggested their roles in antigen presentation. This was further corroborated by the evidence of the T-B co-stimulation pattern and CXCL13-CXCR5 axis. The complexity of myeloid cell heterogeneity was also particularly pronounced. The elevated expression of S100A7 in ESCC, as detected by bulk RNA-seq, was associated with an exhausted and immunosuppressive tumor microenvironment. In summary, this study has unveiled a potential regulatory network among immune cells and the clonal dynamics of their functions, and the mechanisms of exhaustion and memory conversion between GZMK + Tem and TNFRSF13B + Bmem from antigen presentation and co-stimulation perspectives during neoadjuvant PD-1 blockade treatment in ESCC.

Frontline combination of dasatinib and low-intensity chemotherapy in adults with de novo Philadelphia chromosome-positive acute lymphoblastic leukemia.

BACKGROUND: Studies on dasatinib-based low-intensity induction regimens and post-remission strategies are limited in China. Therefore, we conducted a single-center phase 2 trial in newly diagnosed adult patients with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) to establish the efficacy and safety of this treatment approach. RESEARCH DESIGN AND METHODS: Patients received one month of dasatinib plus low-intensity chemotherapy and two months of dasatinib monotherapy for induction, followed by a single course of high-dose methotrexate for consolidation. Subsequently, they underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) or tyrosine kinase inhibitor (TKI)-based treatment for maintenance therapy between October 2015 and August 2022. RESULTS: Twenty-two patients were enrolled. Median age was 45 years (range, 20-71). The rates of major and complete molecular responses in the third month were 18.2% and 40.9% respectively. With a median follow-up of 15 months (range, 5-89), the estimated 3-year disease-free survival (DFS) and overall survival (OS) were 52.4% and 73.2%, respectively. The TKI-based cohort had a significantly poorer DFS (p = 0.014) and OS (p = 0.008) than the allo-HSCT cohort. CONCLUSIONS: Our results suggest that dasatinib-based low-intensity chemotherapy is safe and effective as an induction strategy in the Chinese population. Allo-HSCT plays a crucial role in the long-term outcomes of patients with Ph+ ALL. CLINICAL TRIAL REGISTRATION: The trial was registered at ClinicalTrials.gov as NCT02690922.

Recombinant Human Thrombopoietin Promotes Platelet Engraftment in Severe Aplastic Anemia Patients Following Treatment With Haploid Hematopoietic Stem Cell Transplantation using Modified Post-Transplantation Cyclophosphamide.

BACKGROUND: Recombinant human TPO (rhTPO) promotes platelet engraftment in patients after allogeneic HSCT (allo-HSCT). However, the effects of rhTPO on platelet recovery after Haplo-HSCT in patients with severe aplastic anemia (SAA) have not been intensively studied. OBJECTIVE: We aimed to evaluate the efficacy of rhTPO on platelet engraftment in patients with SAA who were treated with Haplo-HSCT using post-transplantation cyclophosphamide (PTCy). STUDY DESIGN: SAA patients who received Haplo-HSCT plus PTCy regimen were divided into the rhTPO group (with subcutaneous injection of rhTPO, n = 28) and Control group (no rhTPO administration, n = 27). The engraftment of platelet/neutrophil, platelet infusion amount, and transplant-related complications between the 2 groups were compared. RESULTS: All 55 patients showed successful hematopoietic reconstitution. The median time of platelet engraftment was 11 (9 to 29) days in the rhTPO group and 14 (9 to 28) days in the Control group (P = .003). The rhTPO group had a significantly reduced amount of infused platelets compared to the Control group (2 (1 to 11.5) versus 3 (1 to 14) therapeutic doses; P = .004). There was no significant difference between the 2 groups regarding median time of neutrophil engraftment, incidence of acute graft-versus-host disease (aGVHD) and chronic GVHD (cGVHD), incidence of cytomegalovirus or Epstein-Barr virus reactivation, 3-yr overall survival rate, and failure-free-survival rate. No obvious adverse reactions were observed in the rhTPO group. CONCLUSION: rhTPO promoted platelet engraftment, reduced the amount of transfused platelets, and demonstrated good safety profiles without evidence of adverse reactions in patients with SAA who received Haplo-HSCT using PTCy regimen.

Real-world experience with selinexor-containing chemotherapy-free or low-dose chemotherapy regimens for patients with relapsed/refractory acute myeloid leukemia and myeloid sarcoma.

Introduction: Treatment of relapsed or refractory acute myeloid leukemia (R/R AML) and myeloid sarcoma (MS) has presented challenges for decades. Studies on selinexor in combination with various standard or intensive chemotherapy regimens for the treatment of R/R AML have demonstrated promising results. This study aimed to evaluate the efficacy and safety of chemotherapy-free or low-dose chemotherapy regimens with selinexor for R/R AML and MS patients. Methods: Ten patients with R/R AML or MS who received chemotherapy-free or low-dose chemotherapy regimens in combination with selinexor at Tongji Hospital from October 2021 to August 2022 were included in this study. The primary endpoint was overall response rate (ORR) and secondary endpoints included complete remission (CR), CR with incomplete hematological recovery (CRi), partial remission (PR), transplantation rate, and safety. Results: All patients were evaluable for response, achieving CR in four (40.0%) patients and CRi in two (20.0%) patients for a total CR/CRi of 60.0%. The ORR was 80.0% when patients with PR were included. Five (50.0%) patients underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) after treatment with selinexor-containing regimens. At the end of the follow-up, seven (70.0%) patients were alive, and three patients died of transplant-related complications or disease progression. The most frequently reported nonhematologic adverse events (AEs) in patients were grade 1 or 2 asymptomatic hyponatremia. Conclusion: The chemotherapy-free or low-dose chemotherapy regimens in combination with selinexor for R/R AML are feasible and tolerable and provide an opportunity for patients to receive transplantation.

Identified optimal candidates for pulmonary resection in octogenarians with non-small cell lung cancer: a web-based predictive model.

Background: A survival benefit from pulmonary resection was observed in octogenarians with non-small cell lung cancer (NSCLC). Meanwhile, the identification of patients who can indeed benefit can be difficult. Therefore, we aimed to establish a web-based predictive model to identify optimal candidates for pulmonary resection. Methods: Octogenarians with NSCLC in Surveillance, Epidemiology and End Results (SEER) database were enrolled and split into the surgery and non-surgery groups based on whether they received pulmonary resection. Propensity-score matching (PSM) was utilized to eliminate the imbalance. Independent prognostic factors were identified. Patients in the surgery group who lived longer than the median cancer-specific survival (CSS) time of the non-surgery group were assumed to benefit from the surgery. The surgery group was further divided into the beneficial group and the non-beneficial group based on the median CSS time of the non-surgery group. Among the surgery group, a nomogram was established through a logistic regression model. Results: A total of 14,264 eligible patients were extracted, with 4,475 (31.37%) patients receiving pulmonary resection. Surgery was an independent favorable factor of prognosis after PSM (median CSS time: 58 vs. 14 months, P<0.001). A total of 750 (70.4%) patients lived longer than 14 months (beneficial group) in the surgery group. Factors including age, gender, race, histologic type, differentiation grade, and tumor-node-metastasis (TNM) stage were used to formulate the web-based nomogram. The precise discrimination and predictive capability of the model were validated through receiver operating characteristic curves, calibration plots, and decision curve analyses. Conclusions: A web-based predicted model was constructed to distinguish specific patients who can indeed benefit from pulmonary resection among octogenarians with NSCLC.

Lobe-Specific Lymph Node Dissection May be Feasible for Clinical N0 Solid-Predominant Part-Solid Lung Adenocarcinoma With Solid Component Diameter ≤ 2 cm.

BACKGROUND: Lymph node (LN) involvement was not rare in patients with radiological solid-predominant part-solid nodules (PSNs). The lymph node dissection (LND) strategy remained unclear. MATERIALS AND METHODS: Six hundred seventy-two patients with clinical N0 solid-predominant PSNs (0.5 < consolidation-to-tumor ratio < 1) receiving systematic LND (development cohort, n = 598) or limited LND (validation cohort A, n = 74) at 2 Chinese institutions from 2008 to 2016 were collected. The development cohort was utilized to investigate the incidence and pattern of LN metastasis. Lobe-specific LN metastasis pattern was defined as superior mediastinal LN involvement from upper-lobe tumor or inferior mediastinal LN involvement from lower-lobe tumor. To further validate the LN metastasis pattern observed in the development cohort, validation cohort B consisting of 7273 patients with primary lung adenocarcinomas who received surgery from 2016 to 2021 was identified. The clinical outcomes between the development cohort and validation cohort A were compared in order to assess the feasibility of limited LND. RESULTS: LN involvement rate for solid-predominant PSNs was 10.0%. Larger solid component diameter (P = .005) was independently associated with increased risk of LN involvement. In upper/lower lobes solid-predominant PSNs with solid component diameter ≤ 2 cm, a lobe-specific LN involvement pattern was identified. Further validation indicated that the observed mediastinal LN involvement pattern was generalizable, and the oncologic outcomes did not vary by the extent of LND in solid-predominant PSNs with solid component diameter ≤ 2 cm. CONCLUSION: Lobe-specific LND might be feasible for solid-predominant PSNs with solid component diameter ≤ 2 cm. For other solid-predominant PSNs, systematic LND should be recommended.

Individualized prediction of survival benefit from postoperative radiotherapy for patients with malignant pleural mesothelioma.

OBJECTIVES: The role of postoperative radiotherapy (PORT) in malignant pleural mesothelioma (MPM) remains controversial and the eighth edition TNM staging scheme for MPM has not been fully verified. We aimed to develop an individualized prediction model for identifying optimal candidates for PORT among MPM patients who received surgery plus chemotherapy and externally validate the performance of the new TNM staging scheme. MATERIALS AND METHODS: Detailed characteristics of MPM patients during 2004-2015 were retrieved from SEER registries. Propensity score matching (PSM) was conducted to reduce disparities of baseline characteristics (age, sex, histologic type, stage, and type of surgery) between the PORT group and no-PORT group. A novel nomogram was constructed based on independent prognosticators identified by multivariate Cox regression model. The discriminatory performance and degree of calibration were evaluated. We stratified patients into different risk groups according to nomogram total scores and estimated the survival benefit of PORT in different subgroups in order to identify the optimal candidates. RESULTS: We identified 596 MPM patients, among which 190 patients (31.9%) received PORT. PORT conferred significant survival benefit in the unmatched population, while there was no significant survival difference favoring PORT in the matched population. The C-index of the new TNM staging scheme was closed to 0.5, which represented a poor discriminatory ability. A novel nomogram was constructed based on clinicopathological factors, including age, sex, histology, and N stage. We stratified patients into three risk groups. Subgroup analyses indicated that PORT was beneficial for high-risk group (p = 0.003) rather than low-risk group (p = 0.965) and intermediate-risk group (p = 0.661). CONCLUSION: We established a novel predictive model, which could make individualized prediction of survival benefit of PORT for MPM and could compensate for weakness in TNM staging system.

Cladribine- and decitabine-containing conditioning regimen has a low post-transplant relapse rate in patients with relapsed or refractory acute myeloid leukemia and high-risk myelodysplastic syndrome.

To reduce the risk of relapse after allogeneic hematopoietic stem cell transplantation (allo-HSCT), there have been continuing efforts to optimize the conditioning regimens. Our study aimed to analyze the risk factors associated with the relapse of relapsed/refractory (R/R), high-risk acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS) post-transplant and the efficacy of a new conditioning regimen involving decitabine and cladribine. Clinical data of 125 patients with R/R AML, high-risk AML and high-risk MDS who underwent allo-HSCT were collected. In addition, 35 patients with R/R AML, high-risk AML and high-risk MDS received treatment with a new conditioning regimen including decitabine and cladribine. Cox regression analysis was used to identify risk factors associated with OS, RFS and relapse. Among 125 patients who underwent allo-HSCT, CR before allo-HSCT and matched sibling donors were independent protective factors for OS. DNMT3A abnormality was an independent risk factor for both relapse and RFS. Among 35 patients who received a new conditioning regimen containing decitabine and cladribine, only six patients relapsed and 1-year cumulative incidence of relapse was 11.7%. Moreover, this new regimen showed efficient MRD clearance early after allo-HSCT. The combined decitabine- and cladribine-based conditioning regimen showed a low relapse rate and a high survival without an increased incidence of GVHD or adverse effects and thus has potential for use in allo-HSCT for R/R AML, high-risk AML and high-risk MDS.

The impact of station 4L lymph node dissection on short-term and long-term outcomes in non-small cell lung cancer.

OBJECTIVE: The optimal extent of lymph node dissection (LND) remains controversial. We aimed to investigate whether the addition of station 4L lymph node dissection (S4L-LND) was beneficial for non-small cell lung cancer (NSCLC). METHODS: Data on 1040 left-sided NSCLC patients undergoing rigorous systematic LND were retrospectively reviewed. Multivariate logistic regression analysis determined risk factors of station 4L (S4L) nodal involvement to facilitate risk stratified analysis of the significance of S4L-LND. Propensity score matching (PSM) was conducted to reduce disparities of baseline characteristics between S4L-LND group and no-S4L-LND group. Recurrence-free survival (RFS), overall survival (OS), and postoperative complications were compared. RESULTS: S4L-LND was performed in 586 (56.3%) patients. The S4L nodal involvement rate was 15.5% (91/586). Aortopulmonary zone nodes involvement (P < 0.001), N1 nodes involvement (P < 0.001), and advanced T stage (P = 0.015) were independent risk factors of S4L nodal involvement. Patients with ≥ 2 risk factors of S4L nodal involvement were classified as high risk group, and the others were classified as low risk group. Among patients with negative aortopulmonary zone nodes and inferior mediastinal nodes (n = 425), only 28 (6.6%) patients had S4L involvement. After PSM, a total of 416 pairs were well matched. There was no significant survival difference between S4L-LND group and no-S4L-LND group (OS, P = 0.247; RFS, P = 0.569). When stratified by risk subgroup, S4L-LND group did not demonstrate superior survival than no-S4L-LND group in the high risk group (OS, P = 0.273; RFS, P = 0.754) or the low risk group (OS, P = 0.558; RFS, P = 0.319). S4L-LND group demonstrated significantly greater risk of postoperative complications than no-S4L-LND group (9.6% vs. 5.8%; P = 0.037). CONCLUSIONS: S4L involvement was not rare and usually occurred with multiple nodal stations involvement. Routine dissection of aortopulmonary zone and inferior mediastinal nodes was sufficient to ensure staging accuracy. The addition of S4L-LND did not improve survival, but might increase the risk of postoperative complications.

Efficacy and safety of neoadjuvant chemotherapy and immunotherapy in locally resectable advanced esophageal squamous cell carcinoma.

BACKGROUND: Esophageal squamous cell cancer (ESCC) patients with the potentially resectable disease most would experience relapse after surgery. Immunotherapy has been reported to improve the prognosis of advanced esophageal cancer and may be a new strategy to prevent this urgent condition's recurrence. We first evaluated the efficacy and safety of neoadjuvant chemotherapy combined with immunotherapy in patients with resectable ESCC. METHODS: All patients with resectable locally advanced ESCC (clinical stage III-IVB). Received at least 1 cycle of neoadjuvant chemotherapy combined with immunotherapy (NACI), and the interval between each cycle and the operation should be at least 3 weeks. All patients were treated with standard surgery. The tumor imaginations were obtained at baseline and within a week before surgery. The efficacy endpoint was the rate of major pathologic response (MPR, 10% viable tumor cells). Expression of immunohistochemical-related molecules was investigated in surgical samples. RESULTS: A total of 38 patients with ESCC were included (36 males, median age 61 years), and most of them used Pembrolizumab (55.26%) and Camrelizumab (31.58%). We analyzed 19 patients and found that 13 patients (68.42%) achieved radiological partial response (PR) by CT images. R0 resection was performed in 35 patients (92.11%), and 10 patients (26.32%) developed postoperative complications. Through postoperative pathology, we found 13 (34.21%) patients had complete pathologic response (cPR), and 16 (42.11%) patients achieved MPR. We also found that none of the factors had a statistically significant impact on MPR. Still, the regression rate of Sum of lesion diameter (SLD) was significantly positively correlated with the pathological remission rate (P=0.012, r=0.565). CONCLUSIONS: The rate of MPR in ESCC patients reached 42.11%. The use of the NACI regimen did not increase the occurrence of complications in neoadjuvant treatment and operation, and the SLD regression rate has a certain guiding significance for the effect of immunotherapy.

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.

A systematic dissection of the epigenomic heterogeneity of lung adenocarcinoma reveals two different subclasses with distinct prognosis and core regulatory networks.

BACKGROUND: Lung adenocarcinoma (LUAD) is a highly malignant and heterogeneous tumor that involves various oncogenic genetic alterations. Epigenetic processes play important roles in lung cancer development. However, the variation in enhancer and super-enhancer landscapes of LUAD patients remains largely unknown. To provide an in-depth understanding of the epigenomic heterogeneity of LUAD, we investigate the H3K27ac histone modification profiles of tumors and adjacent normal lung tissues from 42 LUAD patients and explore the role of epigenetic alterations in LUAD progression. RESULTS: A high intertumoral epigenetic heterogeneity is observed across the LUAD H3K27ac profiles. We quantitatively model the intertumoral variability of H3K27ac levels at proximal gene promoters and distal enhancers and propose a new epigenetic classification of LUAD patients. Our classification defines two LUAD subgroups which are highly related to histological subtypes. Group II patients have significantly worse prognosis than group I, which is further confirmed in the public TCGA-LUAD cohort. Differential RNA-seq analysis between group I and group II groups reveals that those genes upregulated in group II group tend to promote cell proliferation and induce cell de-differentiation. We construct the gene co-expression networks and identify group-specific core regulators. Most of these core regulators are linked with group-specific regulatory elements, such as super-enhancers. We further show that CLU is regulated by 3 group I-specific core regulators and works as a novel tumor suppressor in LUAD. CONCLUSIONS: Our study systematically characterizes the epigenetic alterations during LUAD progression and provides a new classification model that is helpful for predicting patient prognosis.

Tuberculosis in Patients with Primary Myelofibrosis During Ruxolitinib Therapy: Case Series and Literature Review.

BACKGROUND: The selective Janus-activated kinase inhibitor ruxolitinib (rux) is now widely used to treat myelofibrosis and polycythemia vera due to its remarkable effect of reducing splenomegaly and improving constitutional symptoms. With opportunistic infections secondary to rux constantly reported; however, an increasing number of studies have begun to investigate the mechanism and underlying immunosuppressive effect of rux. CASE PRESENTATION: We report two cases of tuberculosis (TB) in primary myelofibrosis patients during rux therapy. The first patient received rux soon after diagnosis, and tracheobronchial TB (TBTB) and bronchoesophageal fistula were found after 4 months. After discontinuation of rux, antituberculosis therapy (ATT) was introduced. The second patient initiated rux due to progressive splenomegaly after 7.5 years of interferon therapy and was diagnosed with disseminated TB after 2 months. He received ATT as well. His rux was maintained due to the high burden of systematic symptoms and splenomegaly. Both myelofibrosis and TB were well controlled in these patients. CONCLUSION: This is the first case report that describes rux-related TBTB accompanied by a bronchoesophageal fistula. Through a review of the literature, we provide supporting evidence to the finding that intrinsic disorders of myeloproliferative neoplasms and rux-induced immunologic deregulation together lead to TB. We highlight the importance of screening for latent TB infection and timely chemoprophylaxis before rux therapy. Once TB is diagnosed during treatment, rux is recommended to be stopped and active ATT should begin quickly.

Integrated analysis of optical mapping and whole-genome sequencing reveals intratumoral genetic heterogeneity in metastatic lung squamous cell carcinoma.

BACKGROUND: Intratumoral heterogeneity is a crucial factor to the outcome of patients and resistance to therapies, in which structural variants play an indispensable but undiscovered role. METHODS: We performed an integrated analysis of optical mapping and whole-genome sequencing on a primary tumor (PT) and matched metastases including lymph node metastasis (LNM) and tumor thrombus in the pulmonary vein (TPV). Single nucleotide variants, indels and structural variants were analyzed to reveal intratumoral genetic heterogeneity among tumor cells in different sites. RESULTS: Our results demonstrated there were less nonsynonymous somatic variants shared with PT in LNM than in TPV, while there were more structural variants shared with PT in LNM than in TPV. More private variants and its affected genes associated with tumorigenesis and progression were identified in TPV than in LNM. It should be noticed that optical mapping detected an average of 77.1% (74.5-78.5%) large structural variants (>5,000 bp) not detected by whole-genome sequencing and identified several structural variants private to metastases. CONCLUSIONS: Our study does demonstrate structural variants, especially large structural variants play a crucial role in intratumoral genetic heterogeneity and optical mapping could make up for the deficiency of whole-genome sequencing to identify structural variants.

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.

Development and validation of nomograms for predicting overall and cancer-specific survival in young patients with non-small cell lung cancer.

BACKGROUND: Young patients with non-small cell lung cancer (NSCLC) represent a distinct subgroup of patients with this disease. This study aimed to construct nomograms to predict the overall survival (OS) and cancer-specific survival (CSS) of young patients with NSCLC. METHODS: NSCLC patients under 50 years old diagnosed between 2010 and 2016 were selected from the Surveillance, Epidemiology, and End Results (SEER) database and randomly divided into training (n=1,357) and validation (n=678) cohorts at a ratio of 2:1. Independent prognostic factors for OS or CSS were identified through the log-rank test, Cox proportional hazards models or competing risk model and further integrated to construct nomograms. The predictive capability of the nomogram was assessed by Harrell's concordance index (C-index), the calibration curve and risk group stratification. RESULTS: A total of 2,035 patients were enrolled. In the training cohort, insurance, marital status, histological type, grade, T stage, N stage and surgery were identified as independent prognostic for OS and CSS. The C-index value were 0.759 [95% confidence interval (CI): 0.731-0.787] for OS and 0.810 (95% CI: 0.803-0.818) for BCSS in the training cohort and 0.751 (95% CI: 0.711-0.790) for OS and 0.807 (95% CI: 0.795-0.819) for CSS in the validation cohort. The calibration curves showed optimal agreement between the predicted and actual survival both in internal and external validation. In addition, patients in the validation cohort within different risk groups exhibited significantly different survival even in each TNM stage. CONCLUSIONS: Nomograms were developed and validated to predict OS and CSS of young patients with NSCLC in our study. A prospective study with more potential prognostic factors and the latest TNM classification is required to ameliorate this model.

FGB and FGG derived from plasma exosomes as potential biomarkers to distinguish benign from malignant pulmonary nodules.

Previous proteomic analysis (label-free) of plasma exosomes revealed that the expression of FGG and FGB was significantly higher in the malignant pulmonary nodules group, compared to the benign pulmonary nodules group. The present study was performed to evaluate the role of plasma exosomal proteins FGB and FGG in the diagnosis of benign and malignant pulmonary nodules. We examined the expression levels of FGB and FGG in plasma exosomes from 63 patients before surgery. Postoperative pathological diagnosis confirmed that 43 cases were malignant and 20 cases were benign. The ROC curve was used to describe the sensitivity, specificity, area under the curve (AUC) of the biomarker and the corresponding 95% confidence interval. We confirmed that the expression levels of FGB and FGG were higher in the plasma exosomes of malignant group than in the benign group. The sensitivity and AUC of FGB combined with FGG detection to determine the nature of pulmonary nodules are superior to single FGB or FGG detection. FGB and FGG might represent novel and sensitive biomarker to distinguish benign from malignant pulmonary nodules.

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.

Proteomic analysis of plasma exosomes to differentiate malignant from benign pulmonary nodules.

BACKGROUND: It is difficult to distinguish benign pulmonary nodules (PNs) from malignant PNs by conventional examination. Therefore, novel biomarkers that can identify the nature of PNs are needed. Exosomes have recently been identified as an attractive alternative approach since tumor-specific molecules can be found in exosomes isolated from biological fluids. METHODS: Plasma exosomes were extracted via the exoEasy reagent method. The major proteins from plasma exosomes in patients with PNs were identified via labelfree analysis and screened for differentially expressed proteins. A GO classification analysis and KEGG pathway analysis were performed on plasma exosomal protein from patients with benign and malignant PNs. RESULTS: Western blot confirmed that protein expression of CD63 and CD9 could be detected in the exosome extract. Via a search of the human Uniprot database, 736 plasma exosome proteins from patients with PNs were detected using high-confidence peptides. There were 33 differentially expressed proteins in the benign and malignant PNs. Of these, 12 proteins were only expressed in the benign PNs group, while 9 proteins were only expressed in the malignant PNs group. We further obtained important information on signaling pathways and nodal proteins related to differential benign and malignant PNs via bioinformatic analysis methods such as GO, KEGG, and String. CONCLUSIONS: This study provides a new perspective on the identification of novel detection strategies for benign and malignant PNs. We hope our findings can provide clues for the identification of benign and malignant PNs.