P4HA2 activates mTOR via hydroxylation and targeting P4HA2-mTOR inhibits lung adenocarcinoma cell growth.

Mammalian target of rapamycin (mTOR) kinase functions as a central regulator of cell growth and metabolism, and its complexes mTORC1 and mTORC2 phosphorylate distinct substrates. Dysregulation of mTOR signaling is commonly implicated in human diseases, including cancer. Despite three decades of active research in mTOR, much remains to be determined. Here, we demonstrate that prolyl 4-hydroxylase alpha-2 (P4HA2) binds directly to mTOR and hydroxylates one highly conserved proline 2341 (P2341) within a kinase domain of mTOR, thereby activating mTOR kinase and downstream effector proteins (e.g. S6K and AKT). Moreover, the hydroxylation of P2341 strengthens mTOR stability and allows mTOR to accurately recognize its substrates such as S6K and AKT. The growth of lung adenocarcinoma cells overexpressing mTORP2341A is significantly reduced when compared with that of cells overexpressing mTORWT. Interestingly, in vivo cell growth assays show that targeting P4HA2-mTOR significantly suppresses lung adenocarcinoma cell growth. In summary, our study reveals an undiscovered hydroxylation-regulatory mechanism by which P4HA2 directly activates mTOR kinase, providing insights for therapeutically targeting mTOR kinase-driven cancers.

Spatiotemporal distribution of mediastinal neoplasms: A comprehensive multi-center study.

OBJECTIVES: Mediastinal neoplasms are typical but uncommon thoracic diseases with increasing incidence and unfavorable prognoses. A comprehensive understanding of their spatiotemporal distribution is essential for accurate diagnosis and timely treatment. However, previous studies are limited in scale and data coverage. Therefore, this study aims to elucidate the distribution of mediastinal lesions, offering valuable insights into this disease. MATERIALS AND METHODS: This multi-center, hospital-based observational study included 20 nationwide institutions. A retrospective search of electronic medical records from January 1st, 2009, to December 31st, 2020, was conducted, collecting sociodemographic data, computed tomography images, and pathologic diagnoses. Analysis focused on age, sex, time, location, and geographical region. Comparative assessments were made with global data from a multi-center database. RESULTS: Among 7,765 cases, thymomas (30.7%), benign mediastinal cysts (23.4%), and neurogenic tumors (10.0%) were predominant. Distribution varied across mediastinal compartments, with thymomas (39.6%), benign cysts (28.1%), and neurogenic tumors (51.9%) most prevalent in the prevascular, visceral, and paravertebral mediastinum, respectively. Age-specific variations were notable, with germ cell tumors prominent in patients under 18 and aged 18-29, while thymomas were more common in patients over 30. The composition of mediastinal lesions across different regions of China remained relatively consistent, but it differs from that of the global population. CONCLUSION: This study revealed significant heterogeneity in the spatiotemporal distribution of mediastinal neoplasms. These findings provide useful demographic data when considering the differential diagnosis of mediastinal lesions, and would be beneficial for tailoring disease prevention and control strategies.

Impact of CT-guided hookwire localization on tumor spread through air spaces in stage IA lung adenocarcinoma.

Background: It remains undetermined whether preoperative computed tomography (CT)-guided hookwire localization would result in elevated risk of tumor spread through air spaces (STAS) in stage IA lung adenocarcinoma. Methods: A total of 1836 patients who underwent lobectomy were included. To eliminate the potential impact of confounding factors on producing STAS, propensity score-matching (PSM) was used to create two balanced subgroups stratified by implementation of hookwire localization. We also introduced an external cohort including 1486 patients to explore the effect of hookwire localization on the incidence of STAS and patient survival after sublobar resection (SR). For proactive simulation of hookwire localization, 20 consecutive lobectomy specimens of p-stage IA lung adenocarcinoma were selected. Results: Ex vivo tests revealed that mechanical artifacts presenting as spreading through a localizer surface (STALS) could be induced by hookwire localization but be distinguished by CD68 and AE1/3 antibody-based immunohistochemistry. The distance of STALS dissemination tended to be shorter compared with real STAS (P = 0.000). After PSM, implementation of hookwire localization was not associated with elevated STAS incidence, nor worse survival in p-stage IA patients undergoing lobectomy irrespective of STAS. Conclusions: CT-guided hookwire localization might induce mechanical artifacts presenting as STALS which could be distinguished by immunohistochemistry, but would not affect survival in p-stage IA disease. Surgeons can be less apprehensive about performing hookwire localization in relation to STAS on stage IA disease suitable for SR.

Pan-mediastinal neoplasm diagnosis via nationwide federated learning: a multicentre cohort study.

BACKGROUND: Mediastinal neoplasms are typical thoracic diseases with increasing incidence in the general global population and can lead to poor prognosis. In clinical practice, the mediastinum's complex anatomic structures and intertype confusion among different mediastinal neoplasm pathologies severely hinder accurate diagnosis. To solve these difficulties, we organised a multicentre national collaboration on the basis of privacy-secured federated learning and developed CAIMEN, an efficient chest CT-based artificial intelligence (AI) mediastinal neoplasm diagnosis system. METHODS: In this multicentre cohort study, 7825 mediastinal neoplasm cases and 796 normal controls were collected from 24 centres in China to develop CAIMEN. We further enhanced CAIMEN with several novel algorithms in a multiview, knowledge-transferred, multilevel decision-making pattern. CAIMEN was tested by internal (929 cases at 15 centres), external (1216 cases at five centres and a real-world cohort of 11 162 cases), and human-AI (60 positive cases from four centres and radiologists from 15 institutions) test sets to evaluate its detection, segmentation, and classification performance. FINDINGS: In the external test experiments, the area under the receiver operating characteristic curve for detecting mediastinal neoplasms of CAIMEN was 0·973 (95% CI 0·969-0·977). In the real-world cohort, CAIMEN detected 13 false-negative cases confirmed by radiologists. The dice score for segmenting mediastinal neoplasms of CAIMEN was 0·765 (0·738-0·792). The mediastinal neoplasm classification top-1 and top-3 accuracy of CAIMEN were 0·523 (0·497-0·554) and 0·799 (0·778-0·822), respectively. In the human-AI test experiments, CAIMEN outperformed clinicians with top-1 and top-3 accuracy of 0·500 (0·383-0·633) and 0·800 (0·700-0·900), respectively. Meanwhile, with assistance from the computer aided diagnosis software based on CAIMEN, the 46 clinicians improved their average top-1 accuracy by 19·1% (0·345-0·411) and top-3 accuracy by 13·0% (0·545-0·616). INTERPRETATION: For mediastinal neoplasms, CAIMEN can produce high diagnostic accuracy and assist the diagnosis of human experts, showing its potential for clinical practice. FUNDING: National Key R&D Program of China, National Natural Science Foundation of China, and Beijing Natural Science Foundation.

LTF Induces Radioresistance by Promoting Autophagy and Forms an AMPK/SP2/NEAT1/miR-214-5p Feedback Loop in Lung Squamous Cell Carcinoma.

Radiotherapy is the most predominant treatment strategy for lung squamous cell carcinoma (LUSC) patients, but radioresistance is the major obstacle to therapy effectiveness. The mechanisms and regulators of LUSC radioresistance remain unclear. Here, lactotransferrin (LTF) is found to be significantly upregulated in radioresistant LUSC cell lines (H226R and H1703R) and clinical samples and promotes radioresistance of LUSC both in vitro and in vivo. Comprehensive enrichment analyses suggested that LTF potentially modulates autophagy in LUSC. Interestingly, the level of autophagy was raised in the radioresistant cells, and suppression of autophagy sensitized LUSC to irradiation. Functional experiments showed that LTF deficiency inhibits cellular autophagy through the AMPK pathway, ultimately leading to radiosensitization. Mechanistically, LTF can directly interact with AMPK to facilitate its phosphorylation and activate autophagy signaling. Moreover, NEAT1 functions as a ceRNA that targets miR-214-5p resulting in an increased LTF expression. Intriguingly, SP2, a transcription factor regulated by AMPK, induced NEAT1 expression by directly binding to its promoter region and thus forming a LTF/AMPK/SP2/NEAT1/miR-214-5p feedback loop. Our work reveals for the first time that LTF induces radioresistance by promoting autophagy and enhancing its self-expression via forming a positive feedback loop, suggesting that LTF is an appealing radiosensitization target for treating LUSC.

Impact of the extent of recurrent laryngeal nerve lymphadenectomy on thoracic esophageal squamous cell carcinoma: a real-world multicentre study.

OBJECTIVES: To determine the impact of recurrent laryngeal nerve (RLN) lymph node (LN) dissection on survival and postoperative complications in patients with oesophageal squamous cell carcinoma (ESCC). METHODS: Patients with cT1-4N0-3M0 thoracic ESCC who underwent oesophagectomy and two-field lymphadenectomy from three institutions were included. The entire cohort was divided into three groups that underwent the total two-field lymphadenectomy (T-2FL), standard two-field lymphadenectomy (S-2FL) or unilateral RLN-LN dissection plus S-2FL (U-2FL) based on the extent of RLN-LN dissection. Subgroup analyses were also performed and were stratified by treatment modality. RESULTS: Both the U-2FL and T-2FL groups had significantly superior outcomes compared with the S-2FL group (overall survival: U-2FL versus S-2FL: P = 0.002; T-2FL versus S-2FL: P < 0.001; recurrence-free survival: U-2FL versus S-2FL: P = 0.01; T-2FL versus S-2FL: P < 0.001). Moreover, no significant differences were observed between U-2FL and T-2FL regarding overall survival (P > 0.05) and recurrence-free survival (P > 0.05), irrespective of administration of neoadjuvant therapy plus oesophagectomy or upfront oesophagectomy. Additionally, the extent of RLN-LN dissection was not an independent predictor of stage migration (P = 0.14) but was for postoperative nodal upstaging (P = 0.02). Notably, S-2FL brought significantly lowered risk in postoperative complications, especially for RLN palsy, when compared with T-2FL (P = 0.002) but not U-2FL (P = 0.72). CONCLUSIONS: Adequacy of RLN-LN dissection is an important prognosticator for improved overall survival and recurrence-free survival in patients with thoracic ESCC. U-2FL may serve as an alternative to T-2FL in selected populations.

Clinical implications and molecular features of tertiary lymphoid structures in stage I lung adenocarcinoma.

AIMS: We investigated the clinical implications and molecular features of TLS in stage I lung adenocarcinoma (LUAD). METHODS: We retrospectively reviewed the clinicopathological characteristics of 540 patients with p-stage I LUAD. Logistic regression analysis was applied to determining the relationships between clinicopathological features and the presence of TLS. TLS-associated immune infiltration pattern and signature genes were characterized using the transcriptomic profiles of 511 LUADs from The Cancer Genome Atlas (TCGA) database. RESULTS: The presence of TLS was associated with a higher pT stage, low- and middle-grade patterns, and the absence of tumor spreading through air spaces (STAS) and subsolid nodules. Multivariate Cox regression analysis identified that the presence of TLS was associated with favorable overall survival (OS) (p < 0.001) and recurrence-free survival (RFS) (p < 0.001). Subgroup analysis showed that the most favorable OS (p < 0.001) and RFS (p < 0.001) favored the TLS + PD-1- subgroup. The presence of TLS was characterized by abundance in antitumor immunocytes including activated CD8+ T and B cells as well as dentritic cells in TCGA cohort. CONCLUSION: The presence of TLS was an independent favorable factor for patients with stage I LUAD. The presence TLS was featured by special immune profiles which might aid oncologists in determining personalized adjuvant treatment.

Clinical profiles and intraoperative identification of complex glands in stage I lung adenocarcinoma.

OBJECTIVES: This study aimed to investigate the potential of complex glandular patterns (CGP) in lymph node micrometastasis (LNMM) and to determine the clinical beneficiaries in stage I lung adenocarcinoma (LUAD) with CGP. Meanwhile, the feasibility of detecting CGP on frozen section was also evaluated. METHODS: We retrospectively analysed the clinicopathological characteristics of 848 pathologic-stage I LUADs. A logistic regression model and a Cox proportional-hazards model were conducted to define the risk factors for LNMM and survival respectively. Furthermore, 5 pathologists reviewed frozen sections of 100 LUADs independently. RESULTS: The logistic regression model indicated that CGP [odds ratio 3.89, 95% confidence interval (CI) 2.46-6.15; P < 0.001] was an independent predictor of the presence of LNMM. Subgroup analysis revealed that CGP-present/LNMM-positive LUAD had the highest risk of both loco-regional and distant recurrence. Moreover, adequate lymphadenectomy [recurrence-free survival: hazard ratio (HR) 0.61, 95% CI 0.40-0.95; P = 0.028; overall survival: HR 0.64, 95% CI 0.41-0.99; P = 0.043] and adjuvant chemotherapy (recurrence-free survival: HR 0.30, 95% CI 0.18-0.52; P < 0.001; overall survival: HR 0.33, 95% CI 0.19-0.57; P < 0.001) brought survival benefits to CGP-present patients, especially to CGP-present/LNMM-positive subgroup. Across the 5 pathologists, sensitivity ranged from 59 to 68% and specificity ranged from 79 to 83%, with moderate diagnostic agreement and high interobserver agreement for detecting CGP on frozen section. CONCLUSIONS: LNMM was more frequently observed in stage I LUAD with CGP. Adequate lymphadenectomy and adjuvant chemotherapy were associated with improved survival in CGP-present patients, especially in CGP-present/LNMM-positive subgroup. Additionally, it is feasible to identify CGP on frozen section intraoperatively.

Log odds of positive lymph nodes is a robust predictor of survival and benefits from postoperative radiotherapy in stage IIIA-N2 resected non-small cell lung cancer.

BACKGROUND: The significance of postoperative adjuvant radiotherapy (PORT) on the survival of resected IIIA-N2 non-small cell lung cancer (NSCLC) remains controversial. Here, we aimed to determine the predictive value of the three nodal classifications which might aid in PORT decision-making. METHODS: A total of 4797 patients with stage IIIA-N2 resected NSCLC were identified in the Surveillance, Epidemiology and End Results (SEER) database and were grouped by whether PORT was administered. Survival analysis was used to identify the patient groups who can benefit from PORT. Multivariate analysis was performed to confirm the independent risk factors for lung cancer-specific survival (LCSS) and overall survival (OS). A validation cohort of 1184 patients from three medical centers in China were also included. RESULTS: PORT was not associated with better LCSS and OS in the entire cohort after propensity score matching (PSM). However, in the subgroups of positive lymph nodes 4 (PLN4), lymph node ratio 4 (LNR4), and log odds of positive lymph nodes 4 (LODDS4), PORT exhibited its role in improving LCSS (p < 0.05). Although the three nodal classifications were all identified as independent predictors of LCSS and OS, LODDS classification had the best discriminatory ability and prognostic accuracy for stage IIIA-N2 patients. Similar results were also obtained in the validation cohort. CONCLUSIONS: The LODDS classification not only exhibited the best prognostic performance in predicting LCSS and OS in stage IIIA-N2 disease, but also could help tailor individualized PORT.

Prognostic and predictive value of the newly proposed grading system of invasive pulmonary adenocarcinoma in Chinese patients: a retrospective multicohort study.

Our aim was to validate and analyze the prognostic impact of the novel International Association for the Study of Lung Cancer (IASLC) Pathology Committee grading system for invasive pulmonary adenocarcinomas (IPAs) in Chinese patients and to evaluate its utility in predicting a survival benefit from adjuvant chemotherapy (ACT). In this multicenter, retrospective, cohort study, we included 926 Chinese patients with completely resected stage I IPAs and classified them into three groups (Grade 1, n = 119; Grade 2, n = 431; Grade 3, n = 376) according to the new grading system proposed by the IASLC. Recurrence-free survival (RFS) and overall survival (OS) were estimated by the Kaplan-Meier method, and prognostic factors were assessed using univariable and multivariable Cox proportional hazards models. All included cohorts were well stratified in terms of RFS and OS by the novel grading system. Furthermore, the proposed grading system was found to be independently associated with recurrence and death in the multivariable analysis. Among patients with stage IB IPA (N = 490), the proposed grading system identified patients who could benefit from ACT but who were undergraded by the adenocarcinoma (ADC) classification. The novel grading system not only demonstrated prognostic significance in stage I IPA in a multicenter Chinese cohort but also offered clinical value for directing therapeutic decisions regarding adjuvant chemotherapy.

Benefit of adjuvant chemotherapy for patients with stage IB non-small cell lung cancer: a systematic review and meta-analysis.

BACKGROUND: Adjuvant chemotherapy (ACT) is routinely the recommended treatment for patients with advanced non-small cell lung cancer (NSCLC) but remains a controversial option in stage IB patients. We therefore pooled the current evidence to determine the prognostic impact of ACT in stage IB NSCLC patients in the context of the eighth tumor, node, metastasis (TNM) staging system. METHODS: Five electronic databases were searched for eligible studies up to December 2020 without language restrictions. The primary and secondary outcomes were overall survival (OS) and disease-free survival (DFS). Search results were filtered by a set of eligibility criteria and analyzed in line with PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. The risk of bias was assessed independently using a modified set. Stata 16.0 was used for general data analysis and meta-analysis, and subgroup analyses were performed to investigate the source of interstudy heterogeneity. RESULTS: In all, 12 eligible studies were identified and 15,678 patients included. Our results demonstrated that ACT was associated with improved OS [n=11; hazard ratio (HR) =0.65; 95% confidence interval (CI): 0.60-0.70; P<0.001; I2=33.4%, P=0.131] and DFS (n=9; HR =0.73; 95% CI: 0.63-0.83; P<0.001; I2=66.7%, P=0.002) in stage IB NSCLC patients. Subgroup analysis by histology indicated that administration of ACT conferred more favorable survival to both stage IB squamous cell carcinoma (n=1; HR =0.56; 95% CI: 0.28-0.84; P<0.001) and adenocarcinoma (n=6; HR =0.59; 95% CI: 0.47-0.71; P<0.001; I2=31.0%, P=0.203). Meanwhile, both platinum-based ACT (n=7; HR =0.62; 95% CI: 0.51-0.74; P<0.001; I2=44.8%, P=0.093) and other regimens (n=2; HR =0.66; 95% CI: 0.61-0.72; P<0.001; I2=0.7%, P=0.316) could benefit patients with stage IB disease. DISCUSSION: ACT might provide survival benefits to patients with stage IB NSCLC irrespective of histology or regimens. Patient selection and time trend biases were inevitable due to the limitation of retrospective studies. More prospective studies should be initiated to investigate the optimal ACT regimens in different histologic types in stage IB NSCLC patients.

Comprehensive analysis of prognostic value of lymph node classifications in esophageal squamous cell carcinoma: a large real-world multicenter study.

BACKGROUND: We aim to assess the prognostic ability of three common lymph node-based staging algorithms, namely, the number of positive lymph nodes (pN), the lymph node ratio (LNR), and log odds of positive lymph nodes (LODDS) in patients with esophageal squamous cell carcinoma (ESCC). METHODS: A total of 3902 ESCC patients treated at 10 Chinese institutions between 2003 and 2013 were included, along with 2465 patients from the Surveillance, Epidemiology, and End Results (SEER) database. The prognostic ability of the aforementioned algorithms was evaluated using time-dependent receiver operating characteristic (tdROC) curves, R 2, Harrell's concordance index (C-index), and the likelihood ratio chi-square score. The primary outcomes included cancer-specific survival (CSS), overall survival (OS), and CSS with a competing risk of death by non-ESCC causes. RESULTS: LODDS had better prognostic performance than pN or LNR in both continuous and stratified patterns. In the multicenter cohort, the multivariate analysis showed that the model based on LODDS classification was superior to the others in predictive accuracy and discriminatory capacity. Two nomograms integrating LODDS classification and other clinicopathological risk factors associated with OS as well as cancer-specific mortality were constructed and validated in the SEER database. Finally, a novel TNLODDS classification which incorporates the LODDS classification was built and categorized patients in to three new stages. CONCLUSION: Among the three lymph node-based staging algorithms, LODDS demonstrated the highest discriminative capacity and prognostic accuracy for ESCC patients. The nomograms and novel TNLODDS classification based on LODDS classification could serve as precise evaluation tools to assist clinicians in estimating the survival time of individual patients and improving clinical outcomes postoperatively in the future.

Potentiated lung adenocarcinoma (LUAD) cell growth, migration and invasion by lncRNA DARS-AS1 via miR-188-5p/ KLF12 axis.

Lung adenocarcinoma (LUAD) is the most common histological type of non-small cell lung cancer (NSCLC). Due to the nonspecific early symptoms, the majority of the diagnosed LUAD patients are in the middle and late stages, with multiple metastases, and have missed the optimal period for treatment. Current studies have reported lncRNA DARS-AS1 as a cancer-promoting gene that expedites tumorigenesis. This is the first study demonstrating that DARS-AS1 is involved in the mediating process of LUAD. Cell functional experiments revealed that lncRNA DARS-AS1 participated in enhancing LUAD proliferation, invasion, and migration by inhibiting miR-188-5p. The investigation on DARS-AS1/miR-188-5p led to the discovery of KLF12 as a downstream target of miR-188-5p, and the regulatory pathway was established as DARS-AS1/miR-188-5p/KLF12. According to western blot results, DARS-AS1 promoted LUAD cell growth, migration, and invasion via stimulation of the PI3K/AKT pathway, activating the EMT process, and up-regulating the CyclinD1 and Bcl-2 proteins. This was the first report on the DARS-AS1/miR-188-5p/KLF12 axis and offered a novel strategy for early diagnosis, a new therapeutic method, and an improved prognosis for LUAD.

[Progress in Single-cell RNA Sequencing of Lung Adenocarcinoma].

Lung adenocarcinoma (LUAD) is the most common subtype of lung cancer and one of the main causes of cancer-related deaths. In the past decade, with the widespread use of computed tomography (CT) in routine screening for lung cancer, the incidence of LUAD presenting as small pulmonary nodules radiologically, has increased remarkably. The mechanisms of the occurrence and progression of LUADs are complex, and the prognoses of patients with LUAD vary significantly. Although significant progress has been made in targeted therapy and immunotherapy for LUADs in recent years, the drug resistance of tumor cells has not been effectively overcome, which limits the benefits of patients. With the accomplishment of the Human Genome Project, sequencing-based genomic and transcriptomics have come into the field of clinical and scientific researches. Single-cell sequencing, as a new type of sequencing method that has captured increasing attention recently, can perform specific analysis of cell populations at single-cell level, which can reveal the unique changes of each cell type. Single-cell sequencing can also provide accurate assessment on heterogeneous stromal cells and cancer cells, which is helpful to reveal the complexity of molecular compositions and differences between non- and malignant tissues. To sum up, it is an urgent need for clinicians and basic scientists to deeply understand the pathogenesis and development of LUAD, the heterogeneity of tumor microenvironment (TME) and the mechanism of drug resistance formation through single-cell sequencing, so as to discover new therapeutic targets. In this paper, we reviewed and summarized the application and progress in single-cell sequencing of LUADs.
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M2 macrophage-derived exosomal long non-coding RNA AGAP2-AS1 enhances radiotherapy immunity in lung cancer by reducing microRNA-296 and elevating NOTCH2.

Long noncoding RNAs (lncRNAs) and microRNAs (miRNAs) play vital roles in human diseases. We aimed to identify the effect of the lncRNA AGAP2 antisense RNA 1 (AGAP2-AS1)/miR-296/notch homolog protein 2 (NOTCH2) axis on the progression and radioresistance of lung cancer. Expression of AGAP2-AS1, miR-296, and NOTCH2 in lung cancer cells and tissues from radiosensitive and radioresistant patients was determined, and the predictive role of AGAP2-AS1 in the prognosis of patients was identified. THP-1 cells were induced and exosomes were extracted, and the lung cancer cells were respectively treated with silenced AGAP2-AS1, exosomes, and exosomes upregulating AGAP2-AS1 or downregulating miR-296. The cells were radiated under different doses, and the biological processes of cells were assessed. Moreover, the natural killing cell-mediated cytotoxicity on lung cancer cells was determined. The relationships between AGAP2-AS1 and miR-296, and between miR-296 and NOTCH2 were verified. AGAP2-AS1 and NOTCH2 increased while miR-296 decreased in radioresistant patients and lung cancer cells. The malignant behaviors of radioresistant cells were promoted compared with the parent cells. Inhibited AGAP2-AS1, macrophage-derived exosomes, and exosomes overexpressing AGAP2-AS1 or inhibiting miR-296 facilitated the malignant phenotypes of radioresistant lung cancer cells. Furthermore, AGAP2-AS1 negatively regulated miR-296, and NOTCH2 was targeted by miR-296. M2 macrophage-derived exosomal AGAP2-AS1 enhances radiotherapy immunity in lung cancer by reducing miR-296 and elevating NOTCH2. This study may be helpful for the investigation of radiotherapy of lung cancer.

Simultaneous Vascular Reconstruction and Cervical Anastomosis in McKeown Esophagectomy.

A stomach was considered ineligible to be an ideal conduit conventionally if its right gastroepiploic artery (RGEA) were injured. However, both sufficient blood flow and good venous return are crucial to the success of reconstruction. And there lacks robust evidence regarding the surgical techniques of reconstructing RGEA and right gastroepiploic vein (RGEV) and performing cervical anastomosis with gastric conduit simultaneously. Herein, we summarized the key surgical techniques for simultaneous vascular reconstruction and gastric conduit anastomosis in McKeown esophagectomy.

Concurrent use of metformin enhances the efficacy of EGFR-TKIs in patients with advanced EGFR-mutant non-small cell lung cancer-an option for overcoming EGFR-TKI resistance.

BACKGROUND: Resistance is almost inevitable and is still a major obstacle in epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) therapy. Only limited relevant clinical studies evaluated the therapeutic effects by combing metformin and EGFR-TKIs in non-small cell lung cancer (NSCLC) patients. Therefore, we evaluated the efficacy of concurrent use of metformin with EGFR-TKIs, and assessed whether the addition of metformin may improve clinical outcomes and delay the occurrence of EGFR-TKI resistance. METHODS: We conducted cell proliferation and apoptosis assay for investigation of metformin in combination with EGFR-TKIs to overcome EGFR-TKI resistance in vitro. Furthermore, we retrospectively reviewed clinicopathological characteristics and therapeutic outcomes of EGFR-mutant advanced NSCLC diabetic patients who received EGFR-TKIs with or without concurrent use of metformin. RESULTS: In vitro experiment, metformin showed synergistic interaction both with gefitinib in PC9R (CI =0.77) and with osimertinib in PC9R/OR (CI =0.77) in proliferation inhibition assay. Metformin can also augment apoptosis effect of these TKI-resistant cells to EGFR-TKIs. In retrospective cohort, a total of 85 patients were identified (cohort A), in which 28 patients had concurrent use of metformin. The objective response rate in metformin use group was significantly higher (85.7% vs. 47.4%, P=0.001). The median progression-free survival (PFS) and overall survival (OS) in metformin use group were significantly longer (21.6 vs. 9.2 months, P=0.000; 48.4 vs. 36.6 months, P=0.049). Further analysis revealed that metformin obviously prolonged the median PFS2 of osimertinib treatment among patients who progressed to prior line EGFR-TKIs due to secondary EGFR T790M mutation (cohort B). CONCLUSIONS: Our study suggest that concurrent use of metformin could be beneficial to EGFR-mutant NSCLC patients treated with either first-line EGFR-TKIs or second-line osimertinib.

Extracapsular lymph node involvement is a robust survival predictor in esophageal cancer patients: A pooled analysis.

BACKGROUND: Although extracapsular lymph node involvement (EC-LNI) has been proposed to be incorporated into the staging system of esophageal cancer, the prognostic value of EC-LNI remains controversial with conflicting data available, especially in the era of neoadjuvant therapy. METHODS: An electronic literature search was undertaken using four public databases. Studies investigating the effects of EC-LNI on survival were included. In addition to analysis of the entire cohort, subset analyses were also performed to assess the impact of EC-LNI on patients receiving different treatment modalities. RESULTS: A total of 20 studies were included in this meta-analysis. Pooling 13 studies on overall survival (OS), we observed that presence of EC-LNI was associated with significantly worse OS (HR = 2.09, 95%CI: 1.63-2.68; p < 0.01). Nine studies describing disease-free survival (DFS) included, the pooled data revealed that presence of EC-LNI was associated with significantly worse DFS (HR = 1.89, 95%CI: 1.63-2.20; p < 0.001). Subset analyses of patients receiving neoadjuvant therapy demonstrated a survival disadvantage of EC-LNI on OS (HR = 1.928, 95%CI: 1.196-3.107; p = 0.007) and DFS (HR = 1.985, 95%CI: 1.585-2.487; p < 0.001). Similar result was also seen in patients receiving primary surgery (OS: HR = 2.219, 95%CI: 1.720-2.864; p < 0.001; DFS: HR = 1.659, 95%CI: 1.285-2.141; p < 0.001). CONCLUSION: EC-LNI is a strong prognostic predictor of inferior survival in patients with esophageal cancer irrespective of treatment modality. The currently pooled evidence indicates that EC-LNI has great potential to be incorporated into the future staging system.