Diversity of extracellular HSP70 in cancer: advancing from a molecular biomarker to a novel therapeutic target.

Heat shock protein 70 (HSP70) is a highly conserved protein functioning as a "molecular chaperone", which is integral to protein folding and maturation. In addition to its high expression within cells upon stressful challenges, HSP70 can be translocated to the cell membrane or released from cells in free form or within extracellular vesicles (EVs). Such trafficking of HSP70 is also present in cancer cells, as HSP70 is overexpressed in various types of patient samples across a range of common malignancies, signifying that extracellular HSP70 (eHSP70) can serve as a tumor biomarker. eHSP70 is involved in a broad range of cancer-related events, including cell proliferation and apoptosis, extracellular matrix (ECM) remodeling, epithelial-mesenchymal transition (EMT), angiogenesis, and immune response. eHSP70 can also induce cancer cell resistance to various treatments, such as chemotherapy, radiotherapy, and anti-programmed death-1 (PD-1) immunotherapy. Though the role of eHSP70 in tumors is contradictory, characterized by both pro-tumor and anti-tumor effects, eHSP70 serves as a promising target in cancer treatment. In this review, we comprehensively summarized the current knowledge about the role of eHSP70 in cancer progression and treatment resistance and discussed the feasibility of eHSP70 as a cancer biomarker and therapeutic target.

Tet methylcytosine dioxygenase 2 (TET2) deficiency elicits EGFR-TKI (tyrosine kinase inhibitors) resistance in non-small cell lung cancer.

Despite epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) have shown remarkable efficacy in patients with EGFR-mutant non-small cell lung cancer (NSCLC), acquired resistance inevitably develops, limiting clinical efficacy. We found that TET2 was poly-ubiquitinated by E3 ligase CUL7FBXW11 and degraded in EGFR-TKI resistant NSCLC cells. Genetic perturbation of TET2 rendered parental cells more tolerant to TKI treatment. TET2 was stabilized by MEK1 phosphorylation at Ser 1107, while MEK1 inactivation promoted its proteasome degradation by enhancing the recruitment of CUL7FBXW11. Loss of TET2 resulted in the upregulation of TNF/NF-κB signaling that confers the EGFR-TKI resistance. Genetic or pharmacological inhibition of NF-κB attenuate the TKI resistance both in vitro and in vivo. Our findings exemplified how a cell growth controlling kinase MEK1 leveraged the epigenetic homeostasis by regulating TET2, and demonstrated an alternative path of non-mutational acquired EGFR-TKI resistance modulated by TET2 deficiency. Therefore, combined strategy exploiting EGFR-TKI and inhibitors of TET2/NF-κB axis holds therapeutic potential for treating NSCLC patients who suffered from this resistance.

Polyfluorene Conjugated Polyelectrolytes-Covalently Modified Black Phosphorus Nanosheets for Bioinspired Electronics.

As some of the most promising candidates for constituting bioinspired electronics, polymer memristors with analog-type switching behavior exhibit great potential for synaptic mimicking and neuromorphic computing systems. By using highly soluble conjugated polyelectrolyte poly[9,9-bis(6-(3-methyl-1-imidazolium-yl)hexyl)fluorene]-covalently modified black phosphorus (BP) nanomaterial (BP-PF-NMI+Br-) as the active layer, an electronic device with the BP-PF-NMI+Br- film sandwiched between the aluminum and indium tin oxide electrodes is successfully fabricated. This device exhibits an excellent amount of electricity-dependent memristive performance at a small sweep voltage range of ±1 V. With increasing amount of electricity flowing through the device, the device resistance gradually decreased in a linear pattern. The changes in frequency, amplitude, and duration of voltage pulses do not affect the linear relationship between the amount of electricity passing through the device and the resistance value achieved after each state reached equilibrium at different numbers of the same voltage pulse stimulations. Both the synaptic potentiation/depression and learning/memorizing/forgetting functions of biological systems have been emulated. In contrast to BP-PF-NMI+Br-, the pure PF-NMI+Br--based device shows a write-once-read-many-times effect at the same scanning voltage range, while the BP:PF-NMI+Br- blends exhibit very unstable memristive performances.

Complete dissection of right paratracheal lymph nodes (stations 2R and 4R) is critical to improve the prognosis of lung cancer patients: A retrospective cohort study.

BACKGROUND: The optimal extent of mediastinal lymph node dissection is still under debate. This study aimed to investigate the prognostic impact of complete dissection of right paratracheal lymph nodes (LNs) in right-sided non-small cell lung cancer (NSCLC) and evaluate the potential patient population who will particularly benefit from right paratracheal node dissection (RPND). METHODS: Between January 2009 and December 2019, we retrospectively reviewed 2650 patients with primary right-sided NSCLC who underwent pulmonary surgery with lymphadenectomy in the Western China Lung Cancer Database. A total of 2447 patients received both 2R and 4R LNs dissection (complete RPND group), 162 patients received only 2R or 4R LNs dissection (incomplete RPND group), and 41 patients received neither 2R nor 4R LNs dissection (no RPND group). Overall survival (OS) was analyzed. RESULTS: The metastasis rates in stations 2R and 4R were 6.5% and 8.0%, respectively. In stage N2 patients, the frequency of involvement of stations 2R/4R was 74.8%. The complete RPND group had a significantly better survival than the incomplete and no RPND group (5-year OS, 79.5% vs. 72.7% vs. 65.5%; p < 0.001). In the multivariate analysis, status of RPND (incomplete RPND vs. complete RPND: HR 1.45, 95% CI: 1.10-1.90; p = 0.009; no RPND vs. complete RPND: HR 2.25, 95% CI: 1.37 to 3.69; p = 0.001), age, gender, tumor size, histological type, pTNM stage, pT stage, pN stage, and adjuvant treatment were independent factors for OS. CONCLUSIONS: Complete RPND brings survival benefits to patients with right-sided NSCLC. We suggest complete RPND as a standard procedure for patients with right-sided NSCLC.

Immunotherapy for Recurrent Glioma-From Bench to Bedside.

Glioma is the most aggressive malignant tumor of the central nervous system, and most patients suffer from a recurrence. Unfortunately, recurrent glioma often becomes resistant to established chemotherapy and radiotherapy treatments. Immunotherapy, a rapidly developing anti-tumor therapy, has shown a potential value in treating recurrent glioma. Multiple immune strategies have been explored. The most-used ones are immune checkpoint blockade (ICB) antibodies, which are barely effective in monotherapy. However, when combined with other immunotherapy, especially with anti-angiogenesis antibodies, ICB has shown encouraging efficacy and enhanced anti-tumor immune response. Oncolytic viruses and CAR-T therapies have shown promising results in recurrent glioma through multiple mechanisms. Vaccination strategies and immune-cell-based immunotherapies are promising in some subgroups of patients, and multiple new tumor antigenic targets have been discovered. In this review, we discuss current applicable immunotherapies and related mechanisms for recurrent glioma, focusing on multiple preclinical models and clinical trials in the last 5 years. Through reviewing the current combination of immune strategies, we would like to provide substantive thoughts for further novel therapeutic regimes treating recurrent glioma.

Method to Change the Through-Hole Structure to Broaden Grounded Coplanar Waveguide Bandwidth.

A grounded coplanar waveguide (GCPW), as a millimeter wave special transmission line, can be used to calibrate broadband oscilloscope probes. A method to change the through-hole structure to widen the GCPW is investigated in this paper. The effect of the through-hole array on the band-width of the GCPW is investigated and verified using COMSOL Multiphysics simulation software. Finally, the S-parameters of the fabricated GCPWs are measured by a vector network analyzer, and the results show that they have an insertion loss > -3 dB and return loss < -10 dB in the frequency range of DC to 60 GHz, which satisfies the design requirements.

HSP70 Family in Cancer: Signaling Mechanisms and Therapeutic Advances.

The 70 kDa heat shock proteins (HSP70s) are a group of highly conserved and inducible heat shock proteins. One of the main functions of HSP70s is to act as molecular chaperones that are involved in a large variety of cellular protein folding and remodeling processes. HSP70s are found to be over-expressed and may serve as prognostic markers in many types of cancers. HSP70s are also involved in most of the molecular processes of cancer hallmarks as well as the growth and survival of cancer cells. In fact, many effects of HSP70s on cancer cells are not only related to their chaperone activities but rather to their roles in regulating cancer cell signaling. Therefore, a number of drugs directly or indirectly targeting HSP70s, and their co-chaperones have been developed aiming to treat cancer. In this review, we summarized HSP70-related cancer signaling pathways and corresponding key proteins regulated by the family of HSP70s. In addition, we also summarized various treatment approaches and progress of anti-tumor therapy based on targeting HSP70 family proteins.

Heat Shock Proteins in Non-Small-Cell Lung Cancer-Functional Mechanism.

Non-small cell lung cancer (NSCLC) accounts for 80-85% of all lung cancers, which has the highest cancer-related mortality worldwide. Regardless of the therapeutic effects of chemotherapy or targeted therapy, drug resistance will occur after 1 year. Heat shock proteins (HSPs) are a class of molecular chaperones participated in protein stability and multiple intracellular signaling pathways. It has been widely reported that HSPs family is over expressed in non-small cell lung cancer, and these molecules are also associated with protein stability and multiple intracellular signaling pathways. The effect of chemotherapy drugs or targeted drugs on cancer cells is usually to induce apoptosis. It is necessary to explore the interaction between heat shock protein family and apoptosis pathway in NSCLC. Here we provide a brief review of how HSPs affect the apoptotic pathway in NSCLC.

Targeting HSP90 as a Novel Therapy for Cancer: Mechanistic Insights and Translational Relevance.

Heat shock protein (HSP90), a highly conserved molecular chaperon, is indispensable for the maturation of newly synthesized poly-peptides and provides a shelter for the turnover of misfolded or denatured proteins. In cancers, the client proteins of HSP90 extend to the entire process of oncogenesis that are associated with all hallmarks of cancer. Accumulating evidence has demonstrated that the client proteins are guided for proteasomal degradation when their complexes with HSP90 are disrupted. Accordingly, HSP90 and its co-chaperones have emerged as viable targets for the development of cancer therapeutics. Consequently, a number of natural products and their analogs targeting HSP90 have been identified. They have shown a strong inhibitory effect on various cancer types through different mechanisms. The inhibitors act by directly binding to either HSP90 or its co-chaperones/client proteins. Several HSP90 inhibitors-such as geldanamycin and its derivatives, gamitrinib and shepherdin-are under clinical evaluation with promising results. Here, we review the subcellular localization of HSP90, its corresponding mechanism of action in the malignant phenotypes, and the recent progress on the development of HSP90 inhibitors. Hopefully, this comprehensive review will shed light on the translational potential of HSP90 inhibitors as novel cancer therapeutics.

Primary Mediastinal Nonseminomas: A Population-Based Surveillance, Epidemiology, and End Results Analysis.

BACKGROUND: This study aimed to determine the disease characteristics and prognosis of patients with primary mediastinal nonseminomas (PMNS) in a Surveillance, Epidemiology, and End Results (SEER) analysis. MATERIALS AND METHODS: Demographic, treatment, and survival outcome data of cases with PMNS from 1975 to 2016 were retrieved. Cases with unknown variables mentioned in the analysis were excluded. Relative statistical methods were applied to analyze clinical characteristics and prognosis. RESULTS: A total of 587 PMNS patients met the selection criteria, 526 of whom were men. The mean age of patients was 28 (1-85) y. A total of 511 PMNS patients had validated subtypes, including 172 mixed germ cell tumors, 117 yolk sac tumors, 111 malignant teratomas, 70 choriocarcinomas, and 41 embryonal carcinomas. Patients with yolk sac tumors had the highest 3-y cancer-specific survival (CSS) rate (66.9%), while those with choriocarcinoma and embryonal carcinoma showed the worst prognosis. Surgery + chemotherapy (46.2%) was the most common and effective treatment for each subtype of PMNS. Multivariate Cox proportional hazards analysis identified embryonal carcinoma, malignant teratoma, choriocarcinoma, tumor size >15 cm, nodal metastasis, and distant stage as risk factors. In contrast, surgery-based care and younger age were protective factors. Propensity score matching analysis revealed significant improvement in the 5-y CSS rate from 35.8% to 60.3% with surgery (P < 0.001). However, radiotherapy (P = 0.436) and chemotherapy (P = 0.978) showed no survival benefits. CONCLUSIONS: 10 percent of the PMNS patients were female. Choriocarcinomas and embryonal carcinomas had the worst prognosis. Surgery was demonstrated to be the only way to prolong survival time. Chemotherapy and radiotherapy had minimal effects on prognosis.

Identifying the prognostic significance of B3GNT3 with PD-L1 expression in lung adenocarcinoma.

BACKGROUND: As a novel treatment, programmed cell death protein 1 (PD-1) inhibitor appears to be less effective in tumors of lung adenocarcinoma patients with epidermal growth factor receptor (EGFR) mutation. Beta-1,3-N-acetylglucosaminyltransferase 3 (B3GNT3) has reported to be associated with programmed death ligand 1 (PD-L1)/PD-1 interaction. However, the relationship between B3GNT3 and PD-L1 and its prognostic significance in. EGFR: mutant status are still unknown. METHODS: B3GNT3 was identified through transcriptome sequencing and The Cancer Genome Atlas Lung Adenocarcinoma (TCGA-LUAD) database. Flow cytometry and real-time polymerase chain reaction were performed to investigate the association between B3GNT3, PD-L1, and EGFR. Then, B3GNT3 and PD-L1 expression were evaluated by immunohistochemical analysis in 145 surgically resected primary lung adenocarcinomas. The relationships between survival and B3GNT3, PD-L1, and EGFR status were assessed, and the potential prognostic factors in patients with B3GNT3 expression were identified. RESULTS: We found that EGFR activation induced PD-L1 expression, and EGFR tyrosine kinase inhibitor (TKI) could reduce PD-L1 protein in EGFR-TKI-sensitive HCC827 and PC9 cell lines. Subsequent analysis showed that EGFR inhibitor could also lead to both decreased PD-L1 and B3GNT3 mRNA expression. A total of 145 lung adenocarcinoma patients were included. PD-L1 >1% and B3GNT3-positive expression in patients might contribute to worse prognosis in both overall survival (OS) [hazard ratio (HR), 2.63; 95% confidence interval (CI), 0.98-7.06; P=0.048] and disease-free survival (DFS) (HR, 3.04; 95% CI, 1.13-8.14; P=0.019), especially in the PD-L1 ≥50% group. However, when patients were negative for B3GNT3, PD-L1, and EGFR (or "triple negative"), there were significant decreases in OS (HR, 5.44; 95% CI, 0.99-29.83; P=0.029) and DFS (HR, 7.24; 95% CI, 1.32-39.73; P=0.008). Positive B3GNT3 expression was a significant risk factor associated with lower DFS (HR, 3.30; P=0.043). CONCLUSIONS: Our results indicate that the B3GNT3 expression is tightly correlated with PD-L1 expression and EGFR mutation status. B3GNT3 is associated with poor prognosis in lung adenocarcinoma patients. Collectively, these findings may offer new insight into enhancing immune therapy efficacy for lung adenocarcinoma patients.

Spotlight on USP4: Structure, Function, and Regulation.

The deubiquitinating enzyme (DUB)-mediated cleavage of ubiquitin plays a critical role in balancing protein synthesis and degradation. Ubiquitin-specific protease 4 (USP4), a member of the largest subfamily of cysteine protease DUBs, removes monoubiquitinated and polyubiquitinated chains from its target proteins. USP4 contains a DUSP (domain in USP)-UBL (ubiquitin-like) domain and a UBL-insert catalytic domain, sharing a common domain organization with its paralogs USP11 and USP15. USP4 plays a critical role in multiple cellular and biological processes and is tightly regulated under normal physiological conditions. When its expression or activity is aberrant, USP4 is implicated in the progression of a wide range of pathologies, especially cancers. In this review, we comprehensively summarize the current knowledge of USP4 structure, biological functions, pathological roles, and cellular regulation, highlighting the importance of exploring effective therapeutic interventions to target USP4.

Effectiveness of Botulinum Toxin A in Treatment of Hemiplegic Shoulder Pain: A Systematic Review and Meta-analysis.

OBJECTIVE: To evaluate the effectiveness of botulinum toxin A (BTX-A) in the treatment of hemiplegic shoulder pain. DATA SOURCES: PubMed, EMBASE, Elsevier, Springer, Cochrane Library, Physiotherapy Evidence Database, CNKI, and VIP were researched from the earliest records to September 1, 2020. STUDY SELECTION: Randomized controlled trials that compared shoulder BTX-A injections vs a control intervention in patients with a history of hemiplegic shoulder pain after stroke were selected. Among the 620 records screened, 9 trials with 301 eligible patients were included. DATA EXTRACTION: Outcome data were pooled according to follow-up intervals (1, 2, 4, and 12 wk). The primary evaluation indices were pain reduction (visual analog scale [VAS] score) and range of motion (ROM) improvement. The second evaluation indices were upper limb functional improvement, spasticity improvement, and incidence of adverse events. Cochrane risk-of-bias was used to assess the methodological quality of studies independently by 2 evaluators. DATA SYNTHESIS: Meta-analysis revealed a statistically significant decrease in the VAS score in the BTX group vs the control group at 1, 4, and 12 weeks postinjection (wk 1: standardized mean difference [SMD], 0.91; 95% confidence interval [CI], 0.27 to 1.54; wk 4: SMD, 1.63; 95% CI, 0.76 to 2.51; wk 12: SMD, 1.96; 95% CI, 1.44 to 2.47). Furthermore, the meta-analysis demonstrated a statistically significant increase in abduction at 1, 4, and 12 weeks postinjection (wk 1: SMD, 3.71; 95% CI, 0 to 7.41; wk 4: SMD, 8.8; 95% CI, 2.22 to 15.37; wk 12: SMD, 19.59; 95% CI, 9.05 to 30.13) and external rotation at 1, 2, 4 weeks postinjection (wk 1: SMD, 5.67; 95% CI, 0.88 to 10.47; wk 2: SMD, 9.62; 95% CI, 5.57 to 13; wk 4: SMD, 6.89; 95% CI, 2.45 to 11.33) in the BTX group. CONCLUSIONS: BTX-A injection provided greater analgesic effects and increased shoulder abduction and external rotation ROM compared with steroid or placebo injection for the treatment of HSP.

ROS1-fusion protein induces PD-L1 expression via MEK-ERK activation in non-small cell lung cancer.

Introduction: Despite some of the oncogenic driver mutations that have been associated with increased expression of programmed death-ligand 1 (PD-L1), the correlation between PD-L1 expression and ROS1 fusion in NSCLC cells, especially for those with Crizotinib resistance has not been fully addressed. Materials and Methods: The expression of PD-L1 in 30 primary NSCLC tumors with/without ROS1-fusion protein was evaluated by immunohistochemical (IHC) analysis. To assess the correlation between ROS1 fusion and PD-L1 expression, we down-regulated ROS1 with RNA interference or specific inhibitor (Crizotinib) in ROS1-fusion positive NSCLC cell line HCC78; or up-regulate ROS1-fusion gene in an immortalized human bronchial epithelial cell line (HBE). Mouse xenograft models were also used to determine the effect of ROS1 expression on PD-L1 expression in vivo. Crizotinib-resistant cell line was generated for measuring the association between Crizotinib resistance and PD-L1 expression. Results: ROS1-rearrangement in primary NSCLC tumor was significantly associated with up-regulated PD-L1 expression. PD-L1 expression was significantly up-regulated in bronchial epithelial cells after forced expression of ROS1 fusion and was eliminated when HCC78 xenograft mouse models were treated with Crizotinib. We found PD-L1 expression was modulated by MEK-ERK pathway signaling in both parental and Crizotinib-resistant NSCLC cells with ROS1 fusion. Conclusions: The correlation between ROS1-fusion and PD-L1 overexpression suggested that PD-L1/PD-1 blockade could be the second-line treatment option for the Crizotinib-resistant NSCLC with ROS1 rearrangement.

Effect of mesotherapy with nanochip in the treatment of facial rejuvenation.

Objective: To observe the clinical effect of mesotherapy with nanochip for facial rejuvenation.Methods: 24 volunteers with aging skin were treated with a polycomponent formulation - NCTF® BOOST 135 HA for 5 times (once weekly for 3 times and successively biweekly for 2 times). Photographs were taken by VISIA at baseline, and after 1, 4, 10 weeks, while global scores for photoaging (GSP), improvement scores, volunteers' satisfaction, parameters describing the properties of the skin, and adverse effects were assessed during each follow-up period.Results: Total 20 volunteers completed the treatment. Evaluation of the whole face showed that GSP, skin texture (ophthalmic wrinkles, dermal thickness, and intensity of collagen fibers of skin), and skin brightness (Lab value) significantly improved at 4 weeks compared to baseline, while the difference between 4 and 10 weeks was not statistically significant. No evident improvement was observed in pigmented spots, telangiectasia, skin tightening, trans-epidermal water loss (TEWL), and skin hydration. Slight erythema, pain was the most common side effect.Conclusion: Mesotherapy with nanochip can improve skin texture and brightness, but the effect is not permanent. It is recommended that the treatment be used as a complementary method for patients with facial rejuvenation needs.

Thymic Squamous Cell Carcinoma: A Population-Based Surveillance, Epidemiology, and End Result Analysis.

OBJECTIVES: Thymic squamous cell carcinoma (TSCC) is a rare neoplasm that has been sparsely cited in the literature. The aim of this study was to determine disease characteristics and prognostic factors of patients in a Surveillance, Epidemiology, and End Results (SEER) analysis. METHODS: Cases from 1990-2016 were retrieved from the SEER database and demographics, treatments, and survival outcomes were analyzed. RESULTS: The TSCC accounted for 72.4% of the thymic carcinomas and 7.2% of thymic tumors. The 276 patients (165 men) selected for analysis had a median age of 65 (24-85) years, and 201 patients were diagnosed with Masaoka-Koga stage III/IV. The median survival of TSCC was 59 months with a 49.0% 5-year OS rate, a better prognosis than lymphoepithelioma-like carcinoma (32.1%) and undifferentiated carcinoma (33.3%). Multivariate analysis revealed the Masaoka-Koga stage (p = 0.003) and surgical types (complete resection, incomplete resection, and none; p < 0.001) were determinants of survival. Complete resection had the best prognosis with a 72.7% 5-year OS rate. Chemotherapy was an independent protective factor (HR = 0.555, 95% CI 0.347-0.886; p = 0.014) though poor survival was showed in univariate analysis. And the survival benefit of chemotherapy was validated in PSM analysis (3-year OS rate was 77.7% with chemotherapy vs. 52.8% without chemotherapy; p = 0.014). CONCLUSIONS: TSCC was frequently diagnosed in older patients with advanced Masaoka-Koga stage and had more favorable survival than other subtypes of thymic carcinomas. Complete resection is the preferred treatment. Masaoka-Koga stage and chemotherapy had a strong association with prognosis.

Long-term survival outcomes of video-assisted thoracic surgery lobectomy for stage I-II non-small cell lung cancer are more favorable than thoracotomy: a propensity score-matched analysis from a high-volume center in China.

BACKGROUND: Video-assisted thoracic surgery (VATS) has been considered as the better choice for the surgical treatment of resectable non-small cell lung cancer (NSCLC). This study aimed to evaluate the short- and long-term outcomes of VATS versus open thoracotomy lobectomy for patients with pathological stage (p-stage) I-II NSCLC in one of the high-volume center in China. METHODS: Perioperative outcomes and long-term survival of patients who underwent VATS versus open lobectomies for p-stage I-II NSCLC from May 2006 to June 2013 in the Western China Lung Cancer Database (WCLCD) were studied using propensity score matching (PSM). The VATS lobectomy was mainly carried out using the single-direction technique. RESULTS: Of the 3,678 patients who underwent surgery for lung malignancies, 1,485 patients with stage I-II NSCLC were enrolled for the study, including 737 cases of VATS lobectomies and 748 cases of open lobectomies. PSM resulted in 464 cases of VATS lobectomies and 464 cases of open lobectomies who were well matched by ten potential prognostic factors including tumor size, T- and N-stage. VATS lobectomy was associated with less blood loss than open surgery (median: 60 vs. 100 mL, P=0.000), as well as fewer postoperative complications (15.1% vs. 20.3%, P=0.039). In addition, the VATS approach removed more lymph node stations (4.9±1.5 vs. 4.2±1.8, P=0.000). The postoperative hospital stay was shorter in the VATS group (7.7±3.8 vs. 8.3±4.3, P=0.019), but the total hospital costs were more expensive (48.4±11.3 vs. 35.5±9.4 kRMB, P=0.000). The matched cohorts revealed that VATS lobectomy for stage I-II NSCLC had improved 5-year overall survival (OS) than the open approach (71.1% vs. 65.4%, P=0.045). CONCLUSIONS: The VATS lobectomy is associated with less blood loss, fewer postoperative complications, and shorter postoperative hospital stay when comparing with the open approach for stage I-II NSCLC. Despite more hospital costs, VATS lobectomy offer improved 5-year OS than the open approach. It is reasonable to recommend the VATS approach as the preferred option for the surgical treatment of stage I-II NSCLC.

Effect of Vein-First vs Artery-First Surgical Technique on Circulating Tumor Cells and Survival in Patients With Non-Small Cell Lung Cancer: A Randomized Clinical Trial and Registry-Based Propensity Score Matching Analysis.

Importance: It is important to develop a surgical technique to reduce dissemination of tumor cells into the blood during surgery. Objective: To compare the outcomes of different sequences of vessel ligation during surgery on the dissemination of tumor cells and survival in patients with non-small cell lung cancer. Design, Setting, and Participants: This multicenter, randomized clinical trial was conducted from December 2016 to March 2018 with patients with non-small cell lung cancer who received thoracoscopic lobectomy in West China Hospital, Daping Hospital, and Sichuan Cancer Hospital. To further compare survival outcomes of the 2 procedures, we reviewed the Western China Lung Cancer database (2005-2017) using the same inclusion criteria. Interventions: Vein-first procedure vs artery-first procedure. Main Outcomes and Measures: Changes in folate receptor-positive circulating tumor cells (FR+CTCs) after surgery and 5-year overall, disease-free, and lung cancer-specific survival. Results: A total of 86 individuals were randomized; 22 patients (25.6%) were younger and 64 (74.4%) older than 60 years. Of these, 78 patients were analyzed. After surgery, an incremental change in FR+CTCs was observed in 26 of 40 patients (65.0%) in the artery-first group and 12 of 38 (31.6%) in the vein-first group (P = .003) (median change, 0.73 [interquartile range (IQR), -0.86 to 1.58] FU per 3 mL vs -0.50 [IQR, -2.53 to 0.79] FU per 3 mL; P = .006). Multivariate analysis confirmed that the artery-first procedure was a risk factor for FR+CTC increase during surgery (hazard ratio [HR], 4.03 [95% CI, 1.53-10.63]; P = .005). The propensity-matched analysis included 420 patients (210 with vein-first procedures and 210 with artery-first procedures). The vein-first group had significantly better outcomes than the artery-first group for 5-year overall survival (73.6% [95% CI, 64.4%-82.8%] vs 57.6% [95% CI, 48.4%-66.8%]; P = .002), disease-free survival (63.6% [95% CI, 55.4%-73.8%] vs 48.4% [95% CI, 40.0%-56.8%]; P = .001), and lung cancer-specific survival (76.4% [95% CI, 67.6%-85.2%] vs 59.9% [95% CI, 50.5%-69.3%]; P = .002). Multivariate analyses revealed that the artery-first procedure was a prognostic factor of poorer 5-year overall survival (HR, 1.65 [95% CI, 1.07-2.56]; P = .03), disease-free survival (HR, 1.43 [95% CI, 1.01-2.04]; P = .05) and lung cancer-specific survival (HR = 1.65 [95% CI, 1.04-2.61]; P = .03). Conclusions and Relevance: Ligating effluent veins first during surgery may reduce tumor cell dissemination and improve survival outcomes in patients with non-small cell lung cancer. Trial Registration: ClinicalTrials.gov identifier: NCT03436329.

Survival Benefit of Left Lower Paratracheal (4L) Lymph Node Dissection for Patients with Left-Sided Non-small Cell Lung Cancer: Once Neglected But of Great Importance.

OBJECTIVE: The aim of this study was to compare survival outcomes between non-small cell lung cancer (NSCLC) patients with or without 4L node dissection (4LND) and to evaluate the potential patient population who will particularly benefit from 4LND. METHODS: Between January 2009 and December 2015, a total of 2063 patients with primary left-sided NSCLC in the Western China Lung Cancer Database were initially reviewed. After exclusion, 1064 patients were enrolled in this study. A total of 460 patients with 4LND (4LND+ group) were matched with 460 patients without 4LND (4LND- group) using propensity-matched analysis. Disease-free survival (DFS) and overall survival (OS) were analyzed. RESULTS: The metastasis rate of station 4L was 14.6%. Patients with 4LND showed higher DFS (5-year DFS 52.6% vs. 46.7%; hazard ratio [HR] 1.25, 95% confidence interval [CI] 1.03-1.50; p = 0.022) and OS (5-year OS 65.8% vs. 56.3%; HR 1.36, 95% CI 1.10-1.69; p = 0.006) than patients without 4LND. In the multivariate analysis, patients without 4LND (HR 1.33, 95% CI 1.07-1.66; p = 0.011), tumor size > 3 cm, lymph node metastasis, and pathologic stage higher than stage I were independent prognostic factors for poor OS. Subgroup analysis according to pathologic TNM stage and N stage showed that stage II, IIIA, and N2 disease indicated better survival outcomes in the 4LND+ group (p = 0.050, p = 0.016, and p = 0.008, respectively). CONCLUSIONS: Performing 4LND may bring survival benefits to patients with left-sided NSCLC. We suggest 4LND as a standard procedure for left-sided NSCLC patients with stage II or advanced stage disease.

Discovery of lung surface intersegmental landmarks by three-dimensional reconstruction and morphological measurement.

BACKGROUND: The lack of anatomic landmarks between segments on the lung surface makes the identification of intersegmental planes one of the greatest challenges in anatomic segmentectomy. Therefore, with the aim to determine the landmarks of intersegmental planes on the lung surface, we used three-dimensional (3D) reconstruction and morphological measurement techniques to reconstruct stereoscopic models of all pulmonary segments, and measured the length of each segment on the lung surface along the lobe's anatomic landmark lines. METHODS: We downloaded the primary computed tomography (CT) scan data of 619 patients and imported them into a 3D reconstruction system, which could automatically reconstruct the 3D model of the trachea-bronchi system. We manually reconstructed the intersegmental veins to ensure the accuracy of segmental boundary. The 3D models of pulmonary segments could be reconstructed based on the bronchial tree and the pathways of the intersegmental veins. We then measured the length of each segment on the lung surface along the lobe's anatomic landmark lines and calculated the proportions between these lengths. RESULTS: Complete 3D segmental models were successfully reconstructed in 500 patients (241 male and 259 female), and the lengths of every segment on the lung surface along the lobe's anatomic landmark lines were measured. Our data revealed that the length of each segment on lung surface varied among individuals. However, the proportions between these lengths stayed constant, even when stratified by gender, age, height, and weight. CONCLUSIONS: We discovered that the proportion between the lengths of adjacent segments on the lung surface stayed constant. The constant proportion reflected and uncovered the lung surface intersegmental landmarks, which could help direct surgeons to identify intersegmental planes during anatomic segmentectomy in an easy and safe way without additional cost.