Tyrosine hydroxylase inhibits HCC progression by downregulating TGFß/Smad signaling.

The alteration of metabolic processes has been found to have significant impacts on the development of hepatocellular carcinoma (HCC). Nevertheless, the effects of dysfunction of tyrosine metabolism on the development of HCC remains to be discovered. This research demonstrated that tyrosine hydroxylase (TH), which responsible for the initial and limiting step in the bio-generation of the neuro-transmitters dopamine and adrenaline, et al. was shown to be reduced in HCC. Increased expression of TH was found facilitates the survival of HCC patients. In addition, decreased TH indicated larger tumor size, much more numbers of tumor, higher level of AFP, and the presence of cirrhosis. TH effectively impairs the growth and metastasis of HCC cells, a process dependent on the phosphorylation of serine residues (S19/S40). TH directly binds to Smad2 and hinders the cascade activation of TGFß/Smad signaling with the treatment of TGFß1. In summary, our study uncovered the non-metabolic functions of TH in the development of HCC and proposes that TH might be a promising biomarker for diagnosis as well as an innovative target for metastatic HCC.

Structural Biochemistry of Muscle Contraction.

Muscles are essential for movement and heart function. Contraction and relaxation of muscles rely on the sliding of two types of filaments-the thin filament and the thick myosin filament. The thin filament is composed mainly of filamentous actin (F-actin), tropomyosin, and troponin. Additionally, several other proteins are involved in the contraction mechanism, and their malfunction can lead to diverse muscle diseases, such as cardiomyopathies. We review recent high-resolution structural data that explain the mechanism of action of muscle proteins at an unprecedented level of molecular detail. We focus on the molecular structures of the components of the thin and thick filaments and highlight the mechanisms underlying force generation through actin-myosin interactions, as well as Ca2+-dependent regulation via the dihydropyridine receptor, the ryanodine receptor, and troponin. We particularly emphasize the impact of cryo-electron microscopy and cryo-electron tomography in leading muscle research into a new era.

Trustworthy learning with (un)sure annotation for lung nodule diagnosis with CT.

Recent evolution in deep learning has proven its value for CT-based lung nodule classification. Most current techniques are intrinsically black-box systems, suffering from two generalizability issues in clinical practice. First, benign-malignant discrimination is often assessed by human observers without pathologic diagnoses at the nodule level. We termed these data as "unsure-annotation data". Second, a classifier does not necessarily acquire reliable nodule features for stable learning and robust prediction with patch-level labels during learning. In this study, we construct a sure-annotation dataset with pathologically-confirmed labels and propose a collaborative learning framework to facilitate sure nodule classification by integrating unsure-annotation data knowledge through nodule segmentation and malignancy score regression. A loss function is designed to learn reliable features by introducing interpretability constraints regulated with nodule segmentation maps. Furthermore, based on model inference results that reflect the understanding from both machine and experts, we explore a new nodule analysis method for similar historical nodule retrieval and interpretable diagnosis. Detailed experimental results demonstrate that our approach is beneficial for achieving improved performance coupled with trustworthy model reasoning for lung cancer prediction with limited data. Extensive cross-evaluation results further illustrate the effect of unsure-annotation data for deep-learning based methods in lung nodule classification.

Impact of Lymph Node Dissection on Survival After Neoadjuvant Chemoradiotherapy for Locally Advanced Esophageal Squamous Cell Carcinoma: From the Results of NEOCRTEC5010, a Randomized Multicenter Study.

OBJECTIVE: To clarify whether systemic LND influences the safety of surgery and the survival of patients with locally advanced esophageal squamous cell carcinoma (ESCC) after neoadjuvant chemoradiotherapy (nCRT). SUMMARY OF BACKGROUND DATA: Prognostic impact of systemic lymphadenectomy during surgery after nCRT for ESCC is still uncertain and requires clarification. METHODS: This is a secondary analysis of NEOCRTEC5010 trial which compared nCRT followed by surgery versus surgery alone for locally advanced ESCC. Relationship between number of LND and perioperative, recurrence, and survival outcomes were analyzed in the nCRT group. RESULTS: Three-year overall survival was significantly better in the nCRT group than the S group (75.2% vs 61.5%; P = 0.011). In the nCRT group, greater number of LND was associated with significantly better overall survival (hazard ratio, 0.358; P < 0.001) and disease-free survival (hazard ratio, 0.415; P = 0.001), but without any negative impact on postoperative complications. Less LND (<20 vs ≥20) was significantly associated with increased local recurrence (18.8% vs 5.2%, P = 0.004) and total recurrence rates (41.2% vs 25.8%, P = 0.027). Compared to patients with persistent nodal disease, significantly better survival was seen in patients with complete response and with LND ≥20, but not in those with LND <20. CONCLUSIONS: Systemic LND does not increase surgical risks after nCRT in ESCC patients. And it is associated with better survival and local diseasecontrol. Therefore, systemic lymphadenectomy should still be considered as an integrated part of surgery after nCRT for ESCC.

Case report: Complete resection of invasive thymoma invading the superior vena cava and right atrium under cardiopulmonary bypass support.

Here we describe an uncommon case of a 48-year-old male patient with an invasive thymoma invading the superior vena cava, bilateral innominate veins, right internal jugular vein, right subclavian vein, right atrium, azygos vein, and part of the lung tissues. The tumor was resected entirely under cardiopulmonary bypass support, and the venous bypass using a vascular graft was successfully established between the left innominate vein and the right atrium. The postoperative course was uneventful, and the patient was discharged 15 days after surgery without complications.

Multi-scale characterization of tumor-draining lymph nodes in resectable lung cancer treated with neoadjuvant immune checkpoint inhibitors.

BACKGROUND: Regional lymph node (LN) acts as a pivotal organ for antitumor immunity. Paradoxically, tumor-draining LNs (TDLNs) are usually the first site of tumor metastasis in lung cancer. It is largely unknown about the association between the status of TDLNs and the response of primary tumor beds to immune checkpoint inhibitors (ICIs) in lung cancer patients. Also, studies characterizing the TDLNs in response to ICIs are scarce. METHODS: We characterized and compared the radiological, metabolic (18F-FDG) and pathologic responses between primary tumor beds and paired TDLNs (invaded/non-invaded) from 68 lung cancer patients who underwent neoadjuvant ICIs plus surgery. Additionally, we performed the spatial profiling of immune and non-immune cells within TDLNs using multiplexed immunofluorescence. Therapy responses (e.g., pathologic complete (pCR) or major response (MPR)) of primary lung tumor beds and paired TDLNs were investigated separately. FINDINGS: We observed that responses of TDLNs to ICIs markedly differ from their paired primary lung tumors regarding the radiological, metabolic (18F-FDG uptake), and pathologic alterations. Neoadjuvant ICIs therapy specifically decreased 18F-FDG-reflected metabolic activity in the primary tumor beds with pCR/MPR but not their TDLNs counterparts. Furthermore, the presence of invaded TDLNs was associated with poor pathologic responses in the matched primary tumor beds and predictive of rapid post-treatment tumor relapse. Spatial profiling demonstrated exclusion of T cell infiltrates within the metastatic lesions of invaded TDLNs, and diminished multiple immune and non-immune compositions in non-involved regions surrounding the metastatic lesions. INTERPRETATION: These results provide the first clinically-relevant evidence demonstrating unique response patterns of TDLNs under ICIs treatment and revealing the underappreciated association of TDLNs status with the response of their paired primary tumors to ICIs in lung cancer. FUNDING: This work was supported by the National Natural Science Foundation of China (82072570 to F. Yao; 82002941 to B. Sun), the excellent talent program of Shanghai Chest Hospital (to F.Y), the Basic Foundation Program for Youth of Shanghai Chest Hospital (2021YNJCQ2 to H.Yang), and the Innovative Research Team of High-level Local Universities in Shanghai (SHSMU-ZLCX20212302 to F. Yao).

The improved success rate and reduced complications of a novel localization device vs. hookwire for thoracoscopic resection of small pulmonary nodules: a single-center, open-label, randomized clinical trial.

Background: In our previous study, we developed a 4-hook claw-suture localization device for pulmonary nodule resection, which acheived satifisfactory results. Following this, we conducted this single-center, open-label, randomized clinical trial to compare the success rate and complication rate of this novel localization device and currently widely-used hookwire. Methods: Patients with small pulmonary nodules (0.4-1 cm) who received preoperative localization and thoracoscopic resection at Shanghai Chest Hospital were randomly assigned (1:2 ratio, via computer-generated randomized numbers) to undergo localization using either a novel claw-suture system (claw group) or classical (hookwire group) localization device. The primary endpoint of this study was localization success rate, and the secondary endpoints included complications, localization-related time, and pain. Results: A total of 411 patients were randomly assigned to the claw group (n=136) or the hookwire group (n=275) before thoracoscopic resection of small pulmonary nodules and analyzed. Compared with the hookwire group, the claw group had a significantly higher success rate (133/136, 97.8% vs. 254/275, 92.4%, P=0.027), less asymptomatic hemorrhage (16.9% vs. 37.5%, P=0.003) and pleural reaction (0% vs. 5.1%, P=0.017), as well as better pain alleviation 10 min after localization (measured using the difference between two visual analog scale scores, 0.84±0.98 vs. 0.35±0.79, P<0.001). In contrast, the hookwire group was associated with a shorter localization procedure duration than the claw group (7.2±2.9 vs. 14.4±6.6 min, P<0.001). In the multiple localization subgroup, the claw group compared to the hookwire group also achieved higher success (32/33, 97.0% vs. 70/86, 81.4%) and less pleural reaction (0% vs. 16.3%). Conclusions: The new claw-suture localization device is superior to traditional hookwire, with a higher success rate, fewer complications, and better patient tolerance for preoperative localization of small pulmonary nodules. Trial Registration: Chinese Clinical Trial Registry ChiCTR1900027346.

Primary pulmonary choriocarcinoma in male: report a case with genetic testing and review of the literature.

Background: Primary pulmonary choriocarcinoma is an extremely rare malignant trophoblastic tumor with a poor prognosis. Most choriocarcinomas originated from gonads, such as the ovaries and testes. Review the previous literature, only 41 cases were reported. Case Description: We reported that a 65-year-old man found shadows in the lungs when undergoing the X-ray examination. Positron emission tomography (PET) was performed to exclude metastatic disease before surgery. The patient underwent three-dimension uniportal thoracoscopic left upper lung resection and lymph node dissection. The operation was uneventful, and he was discharged on the fourth day postoperatively. Postoperative pathology: malignant trophoblastic tumors (choriocarcinoma). After the operation, the patient has genetically tested, the mutations in tumor protein p53 (TP53), NRAS proto-oncogene (NRAS), and fibroblast growth factor receptor 1 (FGFR1) were found. Conclusions: Primary pulmonary choriocarcinoma is an extremely rare and highly malignant tumor difficult to detect in the early stage. By analyzing the previous literature, the patients with active treatment have more extended survival periods than the patients without treatment (P=0.0051). Patients, including surgery, had better survival than patients without surgery (P=0.027) depending on the different treatment regimens. Hence, once the diagnosis was confirmed, the comprehensive treatment of surgical resection combined with chemotherapy and radiotherapy is of great significance to improve the prognosis of patients.

Multi-scale integrative analyses identify THBS2+ cancer-associated fibroblasts as a key orchestrator promoting aggressiveness in early-stage lung adenocarcinoma.

Rationale: Subsets of patients with early-stage lung adenocarcinoma (LUAD) have a poor post-surgical course after curative surgery. However, biomarkers stratifying this high-risk subset and molecular underpinnings underlying the aggressive phenotype remain unclear. Methods: We integrated bulk and single-cell transcriptomics, proteomics, secretome and spatial profiling of clinical early-stage LUAD samples to identify molecular underpinnings that promote the aggressive phenotype. Results: We identified and validated THBS2, at multi-omic levels, as a tumor size-independent biomarker that robustly predicted post-surgical survival in multiple independent clinical cohorts of early-stage LUAD. Furthermore, scRNA-seq data revealed that THBS2 is exclusively derived from a specific cancer-associated fibroblast (CAF) subset that is distinct from CAFs defined by classical markers. Interestingly, our data demonstrated that THBS2 was preferentially secreted via exosomes in early-stage LUAD tumors with high aggressiveness, and its levels in the peripheral plasma associated with short recurrence-free survival. Further characterization showed that THBS2-high early-stage LUAD was characterized by suppressed antitumor immunity. Specifically, beyond tumor cells, THBS2+ CAFs mainly interact with B and CD8+ T lymphocytes as well as macrophages within tumor microenvironment of early-stage LUAD, and THBS2-high LUAD was associated with decreased immune cell infiltrates but increased immune exhaustion marker. Clinically, high THBS2 expression predicted poor response to immunotherapies and short post-treatment survival of patients. Finally, THBS2 recombinant protein suppressed ex vivo T cells proliferation and promoted in vivo LUAD tumor growth and distant micro-metastasis. Conclusions: Our multi-level analyses uncovered tumor-specific THBS2+ CAFs as a key orchestrator promoting aggressiveness in early-stage LUAD.

Limited airway resection and reconstruction for paediatric tracheobronchial inflammatory myofibroblastic tumour.

OBJECTIVES: The paediatric tracheobronchial inflammatory myofibroblastic tumour (IMT) is a rare disease. Whether limited surgical resection is a feasible surgical approach for these patients remains controversial. The objectives of this study were to report the long-term prognosis after limited surgical resections on paediatric tracheobronchial IMT and provide a surgical management strategy for this rare disease. METHODS: Paediatric tracheobronchial IMT patients who underwent limited surgical resection from 2012 to 2020 were enrolled in this study. The clinical characteristics, course of treatment and long-term outcomes of all participants were collated. We presented the accumulated data and analysed the feasibility of limited surgical resection on the paediatric tracheobronchial IMT. RESULTS: A total of 9 children with tracheobronchial IMTs were enrolled in our study. Cough and shortness of breath were the most common symptoms. All 9 participants underwent surgical treatment, including 2 tracheal reconstructions, 4 carinal reconstructions and 3 bronchial sleeve resections. Among the participants, 6/9 (66%) were positive for the anaplastic lymphoma receptor tyrosine kinase gene in terms of immunohistochemistry. None of the participants died of short-term complications. The follow-up period was 5.4 (range, 1.1-9.3) years, during which all participants remained well. CONCLUSIONS: Limited surgical resection is preferred for paediatrics with tracheobronchial IMTs. Meanwhile, patients with complete resection have an excellent long-term prognosis.

Indocyanine green fluorescence-navigated thoracoscopy versus traditional inflation-deflation approach in precise uniportal segmentectomy: a short-term outcome comparative study.

Background: Uniportal video-assisted thoracoscopic surgery (VATS) segmentectomy is widely used in the field of thoracic surgery. However, anatomical variations in the bronchi and lung vessels may be critical obstacles during precise pulmonary segmentectomy. Thus, it is necessary to optimize uniportal VATS segmentectomy and to accurately identify the plane between lung segments by precisely transecting the bronchi and blood vessels of the lung segments. The indocyanine green fluorescence (ICGF)-based method has the potential to be a feasible and effective technique to facilitate the uniportal VATS segmentectomy. The present study aims at comparing the short-term outcomes of ICGF versus the traditional inflation-deflation method for uniportal VATS segmentectomy. Methods: The perioperative clinical data in 200 consecutive patients undergoing uniportal VATS segmentectomy from December 2018 to August 2020 at Shanghai Chest Hospital were analyzed retrospectively. The targeted segment structures were identified and dissected precisely by using ICGF-based (N=100) or the traditional inflation-deflation (N=100) methods. The parameters of intraoperative blood loss and operation time, postoperative drainage volume, air leakage time, drainage tube retention time, length of hospital stay, and complications in the ICGF group were collected. Further, the operation time between the ICGF and the inflation-deflation groups was compared. The data summary and statistical analysis were performed by SPSS 19.0. P value <0.05 was considered statistically significant. Results: No massive hemorrhage, hypoxemia, allergy, conversion to lobectomy, or wedge resection was noted during the surgery. ICGF groups resulted in a shorter operative time (90±11.46 vs. 118±10.59 min, P<0.001). No postoperative complications were observed, e.g., bronchopleural fistula, hemoptysis, or atelectasis. All patients were discharged as routinely scheduled. No disease recurrence or metastasis was found during the follow-ups. Conclusions: Our study indicated that the ICGF-based navigation approach is a simple, effective, and reliable technique that can greatly facilitate the uniportal VATS segmentectomy.

Establishment and validation of a novel immune-related prognostic signature in malignant pleural mesothelioma.

Background: Immune-related genes (IRGs) play an important role in the tumor immune microenvironment and affect tumor prognosis. This study aimed to establish a prognostic signature for malignant pleural mesothelioma (MPM) patients. Methods: We obtained the relevant data of MPM patients in The Cancer Genome Atlas (TCGA), and univariate and multivariate Cox regression were used to construct the prediction signature and verify it with the external validation dataset GSE2549. A nomogram was then constructed, and its predictive ability was evaluated and analyzed the level of immune cell infiltration in different groups in the signature. Results: An IRG-related prognostic signature composed of INHBA, CAT, SORT1, TNFSF13B, and BIRC5 was constructed, with patients divided into high-risk and low-risk groups according to the risk score. The survival time of overall survival (OS), progression-free survival (PFS), disease-free interval (DFI), and relapse-free survival (RFS) in low-risk groups was longer than in high-risk groups. Furthermore, the signature had high predictive performance, and the receiver operating characteristic (ROC) of 1, 2, and 3 years could reach 0.853, 0.881, and 0.914, respectively. The predictive accuracy of the signature was verified by using the independent GSE2549 dataset. The levels of activated CD4 T cells, immature dendritic cells, and type 2 T helper cells were higher in high-risk patients. The gene set enrichment analysis (GSEA) analysis showed that a high concentration and P53 signal pathways were found in high-risk groups. Conclusions: This research developed and verified a new type of immune prognostic signature based on five IRGs, which can predict the prognosis of tumor patients and provide new ideas for individualized treatment.

Structures from intact myofibrils reveal mechanism of thin filament regulation through nebulin.

In skeletal muscle, nebulin stabilizes and regulates the length of thin filaments, but the underlying mechanism remains nebulous. In this work, we used cryo-electron tomography and subtomogram averaging to reveal structures of native nebulin bound to thin filaments within intact sarcomeres. This in situ reconstruction provided high-resolution details of the interaction between nebulin and actin, demonstrating the stabilizing role of nebulin. Myosin bound to the thin filaments exhibited different conformations of the neck domain, highlighting its inherent structural variability in muscle. Unexpectedly, nebulin did not interact with myosin or tropomyosin, but it did interact with a troponin T linker through two potential binding motifs on nebulin, explaining its regulatory role. Our structures support the role of nebulin as a thin filament "molecular ruler" and provide a molecular basis for studying nemaline myopathies.

Smoking signature is superior to programmed death-ligand 1 expression in predicting pathological response to neoadjuvant immunotherapy in lung cancer patients.

BACKGROUND: There is a paucity of biomarkers that can predict the degree of pathological response [e.g., pathological complete response (pCR) or major response (pMR)] to immunotherapy. Neoadjuvant immunotherapy provides an ideal setting for exploring responsive biomarkers because the pathological responses can be directly and accurately evaluated. METHODS: We retrospectively collected the clinicopathological characteristics and treatment outcomes of non-small cell lung cancer (NSCLC) patients who received neoadjuvant immunotherapy or chemo-immunotherapy followed by surgery between 2018 and 2020 at a large academic thoracic cancer center. Clinicopathological factors associated with pathological response were analyzed. RESULTS: A total of 39 patients (35 males and 4 females) were included. The most common histological subtype was lung squamous cell carcinoma (LUSC) (n=28, 71.8%), followed by lung adenocarcinoma (LUAD) (n=11, 28.2%). After neoadjuvant treatment, computed tomography (CT) scan-based evaluation showed poor agreement with the postoperatively pathological examination (weighted kappa =0.0225; P=0.795), suggesting the poor performance of CT scans in evaluating the response to immunotherapy. Importantly, we found that the smoking signature displayed a better performance than programmed death-ligand 1 (PD-L1) expression in predicting the pathological response (area under the curve: 0.690 vs. 0.456; P=0.0259), which might have resulted from increased tumor mutational burden (TMB) and/or microsatellite instability (MSI) relating to smoking exposure. CONCLUSIONS: These findings suggest that CT scan-based evaluation is not able to accurately reflect the pathological response to immunotherapy and that smoking signature is a superior marker to PD-L1 expression in predicting the benefit of immunotherapy in NSCLC patients.

Left secondary carinal resection and reconstruction for low-grade bronchial malignancies.

OBJECTIVES: A rare and complex procedure, total lung sparing left secondary carinal resection and reconstruction is only performed in a few specialized centers in a restricted group of patients. We reviewed our experience to evaluate its safety. METHODS: Patients who underwent left secondary carinal resection and reconstruction with complete lung parenchymal preservation for low-grade bronchial malignancies at the Shanghai Chest Hospital and the Padua University Hospital were retrospectively reviewed. Clinicopathologic factors and perioperative outcomes were analyzed. RESULTS: Thirty patients underwent the procedure between July 2012 and July 2019 (mean age, 42.9 years). No operative mortality occurred and postoperative complications developed in 4 patients (13.3%), including pneumonia (n = 3 [10.0%]), subcutaneous emphysema (n = 2 [6.7%]), and prolonged air leak (n = 2 [6.7%]). Pathologies included adenoid cystic carcinoma (n = 11), mucoepidermoid carcinoma (n = 6), carcinoid tumors (n = 9 [8 typical and 1 atypical subtypes]), inflammatory myofibroblastic tumor (n = 3), and myoepithelioma (n = 1). The margins were positive in 8 patients (26.7%), whereas 2 patients (6.7%) had positive lymph nodes. Adjuvant therapies were performed postoperatively, including chemoradiotherapy for positive lymph nodes and radiotherapy for positive margins. CONCLUSIONS: Total lung sparing left secondary carinal resection and reconstruction can be performed safely in well-selected and oncologically appropriate patients with low-grade bronchial malignancies.

Lung sparing left secondary carina resection for low-grade tumors: a single-center study.

Left-side secondary carina resection and reconstruction is a rare, complex procedure, performed just in a few specialized centers in a restricted group of patients. Few studies describe this technique and report its short and long-term results. We reviewed our experience to evaluate the perioperative and short-term outcomes of a very demanding surgery. We retrospectively collected the information of all the patients who underwent secondary carina resection and reconstruction for low-grade malignant bronchial tumors at our center. Between January 2012 and September 2018, 23 patients received surgery for low-grade malignant bronchial tumors. In all patients, a secondary carina resection and reconstruction with total lung parenchymal preservation was performed. The mean age was 44.5 ± 12.2 years. Pathologies included adenoid cystic carcinoma in ten patients, carcinoid in 7 (6 typical and 1 atypical), mucoepidermoid carcinoma in 4, myoepithelioma in 1 and inflammatory myofibroblastic tumor in 1. The median length of the resected bronchus was 25 mm (range 15-50 mm). Three patients (13%) had, at least, one postoperative complication with no deaths. Two patients had lymph node metastases and eight had positive margins. Nine patients received adjuvant therapy. Follow-up ranged from 13 to 96 months, all patients are currently alive and free of recurrence. Resection and reconstruction of the left secondary carina with preservation of the lung parenchyma can be performed safely in anatomically and oncologically appropriate patients, providing good short-term results when combined with adjuvant therapies.

Targeting histone deacetylase enhances the therapeutic effect of Erastin-induced ferroptosis in EGFR-activating mutant lung adenocarcinoma.

BACKGROUND: Intrinsic or acquired resistance to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) is common, thus strategies for the management of EGFR-TKIs resistance are urgently required. Ferroptosis is a recently discovered form of cell death that has been implicated in tumorigenesis and resistance treatment. Accumulating evidence suggests that ferroptosis can be therapeutically exploited for the treatment of solid tumors; however, whether ferroptosis can be targeted to treat EGFR mutant lung cancer and/or overcome the resistance to EGFR-TKIs is still unknown. METHODS: The effect of ferroptosis inducers on a panel of EGFR mutant lung cancer cell lines, including those with EGFR-TKI intrinsic and acquired (generated by long-term exposure to the third-generation EGFR-TKI osimertinib), was determined using cytotoxicity assays. Further, drug candidates to enhance the effect of ferroptosis inducers were screened through implementing WGCNA (weighted gene co-expression network analysis) and CMAP (connectivity map) analysis. Flow cytometry-based apoptosis and lipid hydroperoxides measurement were used to evaluate the cell fates after treatment. RESULTS: Compared with EGFR-TKI-sensitive cells, those with intrinsic or acquired resistance to EGFR-TKI display high sensitivity to ferroptosis inducers. In addition, Vorinostat, a clinically used inhibitor targeting histone deacetylase, can robustly enhance the efficacy of ferroptosis inducers, leading to a dramatic increase of hydroperoxides in EGFR mutant lung cancer cells with intrinsic or acquired resistance to EGFR-TKI. Mechanistically, Vorinostat promotes ferroptosis via xCT downregulation. CONCLUSIONS: Ferroptosis-inducing therapy shows promise in EGFR-activating mutant lung cancer cells that display intrinsic or acquired resistance to EGFR-TKI. Histone deacetylase inhibitor (HDACi) Vorinostat can further promote ferroptosis by inhibiting xCT expression.

Postoperative atrial fibrillation in pneumonectomy for primary lung cancer.

BACKGROUND: This study assessed the incidence and risk factors (RFs) of postoperative atrial fibrillation (POAF) and its impact on clinical outcomes in patients undergoing pneumonectomy for lung cancer. METHODS: Between 2013 and 2018, this monocentric retrospective study enrolled 324 consecutive pneumonectomy patients for primary lung cancer from our institution and 350 lobectomy and 349 segmentectomy cases matched by age, sex and body mass index (BMI). RF for POAF and postoperative death in pneumonectomy patients were assessed by logistic regression, and long-term outcomes after a median follow-up of 30 (range, 2-61) months by Cox proportional hazard model. Electrophysiology study (EPS) files of 30 AF patients with lung resection history were reviewed. RESULTS: POAF developed more often after pneumonectomy than lobectomy and segmentectomy (23.2% vs. 6.6% vs. 1.4%, respectively; P<0.001). Among 75 pneumonectomy patients with POAF, POAF was solitary in 55 patients (73.3%) and concurrent with other complications in 3 patients (4%). POAF risk after pneumonectomy was 4 and 22 times that after lobectomy and segmentectomy, respectively, with age >60 years and left atrial diameter (LAd) ≥35 mm as independent predictors. POAF, infection and hemorrhage were independent RFs for perioperative death after pneumonectomy; however, POAF was not RF for long-term death. Pulmonary vein (PV) trigger was identified in 60% (18/30) of AF patients with lung resection history, with stump PVs being more active than non-stump PVs (38.2% vs. 10.5%, P<0.001). CONCLUSIONS: Post-pneumonectomy AF, with remarkable incidence, risk and independent predictors including age >60 years and LAd ≥35 mm, was mostly solitary and possibly secondary to stump and non-stump PV triggers. POAF, along with infection and hemorrhage, was a RF for perioperative death.

Neoadjuvant immunotherapy facilitates resection of surgically-challenging lung squamous cell cancer.

BACKGROUND: Locally-advanced lung squamous cell carcinoma represents a special subset that is challenging to resect completely with surgery alone. Immunotherapy has achieved great success in treating late-stage lung cancer. However, whether neoadjuvant immunotherapy can facilitate resection of initially locally-advanced and surgically-difficult locally-advanced lung squamous cell carcinoma remains to be investigated. METHODS: We retrospectively collected clinical records of locally-advanced lung squamous cell carcinoma patients who received neoadjuvant immunotherapy followed by surgery between 2018 and 2020 at a large academic thoracic cancer center. RESULTS: A total of 23 patients (22 males, 1 female) with locally-advanced locally-advanced lung squamous cell carcinoma were included, initially clinically staged at IIIA (16, 69.6%), IIIB (n=4, 17.4%), IIB (n=2, 8.7%) and IIIC (n=1, 4.3%). The median interval between final treatment to surgery was 36 days (range, 25-93 days), without treatment-related delay in surgery. The neoadjuvant treatment resulted in a high rate of radical resection (n=20, 87.0%). The final histopathological examination demonstrated 6 (26.1%) cases with pathological complete response and 8 (34.8%) with pathological major response. Comparing with the computed tomography scan-based response, we observed a very low consistency (weighted kappa =0.122, P=0.315) between the computed tomography scan-based and final pathological evaluation. The median follow-up time was 510 days (range, 217-920 days). At the end of the follow-up, 1 patient died. CONCLUSIONS: Our findings showed the clinical promise of neoadjuvant immunotherapy plus surgery for locally-advanced lung squamous cell carcinoma. Computed tomography scan displays a poor role in assessing the resectability after neoadjuvant immunotherapy.

Carinal resection and reconstruction with complete pulmonary parenchyma preservation: a single-institution analysis of 36 cases.

BACKGROUND: Carinal resection, performed in only a few high-volume centers, remains one of the most complicated and technically demanding surgeries. Few studies have examined the outcomes of carinal resection and reconstruction with complete pulmonary parenchyma preservation. METHODS: Patients who underwent isolated carinal resection and reconstruction at the Shanghai Chest Hospital between 2006 and 2020 were retrospectively reviewed. Clinicopathological, perioperative, and follow-up outcomes were analyzed. RESULTS: A total of 36 patients were included, including 19 men and 17 women. The average age was 50.7±14.8 years. Right posterolateral thoracotomy (n=33, 91.7%) and cross-field intubation during anastomosis (n=31, 86.1%) were selected for the majority of the carinal surgeries. The average intraoperative blood loss was 225.0 mL, and the mean operation duration was 196.1 minutes. Postoperative complications were observed in 14 patients (38.9%), including cicatricial stenosis (n=8, 22.2%), anastomotic fistula (n=3, 8.3%), air leak (n=1, 2.8%), cardiac arrhythmia (n=4, 11.1%), pneumonia (n=2, 5.6%), respiratory failure (n=1, 2.8%), and pulmonary embolism (n=1, 2.8%). There were 2 perioperative deaths (5.6%). Multivariate analysis revealed that being overweight was an independent favorable factor for postoperative complications [P=0.042, odds ratio (OR) =0.092, 95%, confidence interval (CI): 0.009-0.922]. Pathological diagnoses included squamous cell carcinoma (SCC) (n=12, 33.3%), adenoid cystic carcinoma (ACC) (n=15, 41.7%), mucoepidermoid carcinoma (MEC) (n=2, 5.6%), stricture (n=1, 2.8%), and other rare histological types. An R0 resection was achieved in 14 patients, while 21 patients (60.0%) had microscopically positive margins. Lymph node metastasis was confirmed in 6 patients (17.1%). Overall survival (OS) was 94.4% at 1 year and 79.4% at 5 years, with 107 months as the median survival time (95% CI: 64.0-150.0 months). All patients with negative margins remained alive during the follow-up period, while those who received R1 resections had much poorer survival rates due to tumor recurrence [P=0.042, hazard ratio (HR) =4.938, 95% CI: 1.062-22.950]. CONCLUSIONS: In selected patients, carinal resection and reconstruction with complete pulmonary parenchyma preservation was a feasible option to achieve an appreciable long-term survival at the risk of acceptable operative mortality and morbidity, particularly when complete resection with negative margins could be realized.