Treatment patterns and clinical outcomes of patients with resectable non-small cell lung cancer receiving neoadjuvant immunochemotherapy: A large-scale, multicenter, real-world study (NeoR-World).

BACKGROUND: Neoadjuvant immunotherapy has ushered in a new era of perioperative treatment for resectable non-small cell lung cancer (NSCLC). However, large-scale data for verifying the efficacy and optimizing the therapeutic strategies of neoadjuvant immunochemotherapy in routine clinical practice are scarce. METHODS: NeoR-World (NCT05974007) was a multicenter, retrospective cohort study involving patients who received neoadjuvant immunotherapy plus chemotherapy or chemotherapy alone in routine clinical practice from 11 medical centers in China between January 2010 and March 2022. Propensity score matching was performed to address indication bias. RESULTS: A total of 408 patients receiving neoadjuvant immunochemotherapy and 684 patients receiving neoadjuvant chemotherapy were included. The pathologic complete response (pCR) and major pathologic response (MPR) rates of the real-world neoadjuvant immunochemotherapy cohort were 32.8% and 58.1%, respectively. Notably, patients with squamous cell carcinoma exhibited significantly higher pCR and MPR rates than those with adenocarcinoma (pCR, 39.2% vs 16.5% [P < .001]; MPR, 66.6% vs 36.5% [P < .001]), whereas pCR and MPR rates were comparable among patients receiving different neoadjuvant cycles. In addition, the 2-year rates of disease-free survival (DFS) and overall survival (OS) rate were 82.0% and 93.1%, respectively. Multivariate analyses identified adjuvant therapy as an independent prognostic factor for DFS (hazard ratio [HR], 0.51; 95% confidence interval [CI], 0.29-0.89; P = .018) and OS (HR, 0.28; 95% CI, 0.13-0.58; P < .001). A significantly longer DFS with adjuvant therapy was observed in patients with non-pCR or 2 neoadjuvant cycles. We observed significant benefits in pCR rate (32.4% vs 6.4%; P < .001), DFS (HR, 0.50; 95% CI, 0.38-0.68; P < .001) and OS (HR, 0.61; 95% CI, 0.40-0.94; P = .024) with immunotherapy plus chemotherapy compared to chemotherapy alone both in the primary propensity-matched cohort and across most key subgroups. CONCLUSIONS: The study validates the superior efficacy of neoadjuvant immunochemotherapy over chemotherapy alone for NSCLC. Adjuvant therapy could prolong DFS in patients receiving neoadjuvant immunochemotherapy, and patients with non-pCR or those who underwent 2 neoadjuvant cycles were identified as potential beneficiaries of adjuvant therapy.

Clinical implications of myeloid malignancy­related somatic mutations in aplastic anemia.

Aplastic anemia (AA) is a potentially fatal bone marrow failure syndrome characterized by a paucity of hematopoietic stem cells and progenitor cells with varying degrees of cytopenia and fatty infiltration of the bone marrow space. Recent advances in genomics have uncovered a link between somatic mutations and myeloid cancer in AA patients. At present, the impact of these mutations on AA patients remains uncertain. We retrospectively investigated 279 AA patients and 174 patients with myelodysplastic syndromes (MDS) and performed targeted sequencing of 22 genes on their bone marrow cells using next-generation sequencing (NGS). Associations of somatic mutations with prognostic relevance and response to treatment were analyzed. Of 279 AA patients, 25 (9.0%) patients had somatic mutations, and 20 (7.2%) patients had one mutation. The most frequently mutated genes were ASXL1(3.2% of the patients), DNMT3A (1.8%) and TET2 (1.8%). In the MDS group, somatic mutations were detected in 120 of 174 (69.0%) patients, and 81 patients (46.6%) had more than one mutation. The most frequently mutated genes were U2AF1 (24.7% of the patients), ASXL1 (18.4%) and TP53 (13.2%). Compared with MDS patients, AA patients had a significantly lower frequency of somatic mutations and mostly one mutation. Similarly, the median variant allele frequency was lower in AA patients than in MDS patients (6.9% vs. 28.4%). The overall response of 3 and 6 months in the somatic mutation (SM) group was 37.5% and 66.7%, respectively. Moreover, there was no significant difference compared with the no somatic mutation (N-SM) group. During the 2-years follow-up period, four (20%) deaths occurred in the SM group and 40 (18.1%) in the N-SM group, with no significant difference in overall survival and event-free survival between the two groups. Our data indicated that myeloid tumor-associated somatic mutations in AA patients were detected in only a minority of patients by NGS. AA and MDS patients had different gene mutation patterns. The somatic mutations in patients with AA were characterized by lower mutation frequency, mostly one mutation, and lower median allelic burden of mutations than MDS. Somatic mutations were a common finding in the elderly, and the frequency of mutations increases with age. The platelet count affected the treatment response at 3 months, and ferritin level affected the outcome at 6 months, while somatic mutations were not associated with treatment response or long-term survival. However, our cohort of patients with the mutation was small; this result needs to be further confirmed with large patient sample.

Prognostic value of different N1 lymph node zones in pN1M0 non-small cell lung cancer: a systematic review and meta-analysis.

The IASLC lymph node map grouped the lymph node stations into "zones" for prognostic analyses. In the N1 lymph nodes group, N1 nodes are divided into the Hilar/Interlobar zone (N1h) and Peripheral zone (N1p). There is no consensus on the different prognostic values of N1 lymph nodes in N1h and N1p. Therefore, we conducted a systematic review and meta-analysis to assess the survival difference between N1h and N1p in patients of pN1M0 NSCLC. Medline, the Cochrane Library, Embase, and the Web of science were systematically searched to identify relevant studies published up to April 4th, 2020. A retrospective and prospective cohort study comparing N1h versus N1p to the pN1M0 NSCLC was included. Hazard ratios (HRs) for OS were aggregated according to a fixed or random-effect model. Ten publications for 1946 patients of pN1M0 NSCLC were included for the meta-analysis.The 5-year OS was lower for patients with N1h (HR: 1.67, 95% CI 1.44-1.94; P < 0.001). The pooled 5-year OS in N1h and N1p were 40% and 56%, respectively. The patients in pN1M0 NSCLC have different survival according to different N1 lymph node zones involvement: patients with N1p metastasis have a better prognosis than those with N1h metastasis.

ESRP1 as a prognostic factor of non-small-cell lung cancer is related to the EMT transcription factor of Twist.

OBJECTIVE: Non-small-cell lung cancer (NSCLC) is one of the most common fatal cancers in the world. Although the treatment of NSCLC has been significantly improved, there is still an unmet need to identify novel targets for developing therapeutic agents and diagnostic/prognostic markers. The aim of this study is explore the role and underlying mechanism of the epithelial splicing regulatory protein (ESRP1) in the development and progression of NSCLC. METHODS: A total of 115 participants, 65 cases of NSCLC, 20 cases of precancerous lesions, and 30 cases of benign lung nodules, were included in this study. The expressions of ESRP1 and related transcription factor Twist in enrolled lung tissues were evaluated by histochemistry and immunohistochemistry assay. The survival analysis and related prognosis factors were evaluated by the Kaplan-Meier curve and Cox regression. In addition, the expression of ESRP1 and epithelial-mesenchymal transition (EMT)related transcription factor Twist and EMT markers E-cadherin and N-cadherin were ascertained by immunohistochemical and immunoblotting assay on A549 lung adenocarcinoma cell lines that were exposed to transforming growth factor ß1 (TGFß1). RESULTS: Compared with normal lung tissues, the abundance of ESRP1 protein was significantly increased in precancerous lesions and lung cancer. Correlation analysis demonstrated that ESRP1 was an independent prognostic factor in NSCLC. The expression of ESRP1 and Twist was positively correlated in lung tissues (r = 0.285, p < 0.001). In vitro analysis further showed that TGFß1 could upregulate the expression of EMT transcription factor Twist while downregulating ESRP1. CONCLUSIONS: Our data suggest that the aberrant expression of ESRP1 is an early event in the development of NSCLC. The ESRP1 could serve as a prognostic biomarker for NSCLC, particularly when combined with Twist. The Twist negatively regulated the expression of ESRP1, emphasizing the role of the TGFß/ESRP1 pathway in the development of NSCLC, which warrants further investigation.

The role of EGFR-TKIs as adjuvant therapy in EGFR mutation-positive early-stage NSCLC: A meta-analysis.

BACKGROUND: The role of adjuvant epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) is not clear in early-stage nonsmall-cell lung cancer (NSCLC) patients. This meta-analysis aims to compare the efficacy and safety of EGFR-TKIs as adjuvant therapy with chemotherapy or placebo in NSCLC patients harboring EGFR mutations. PATIENTS AND METHODS: Pubmed, Embase, and Cochrane databases were searched for randomized controlled trials. The hazard ratio (HR) of disease-free survival (DFS) and overall survival (OS) as well as the risk ratio (RR) of severe adverse events were merged. RESULTS: Seven articles from five studies from 1843 records, a total of 1227 patients, were included in the analysis. The HR for DFS was 0.38 (95% confidence interval [CI] 0.22-0.63), in favor of EGFR-TKIs. However, no significant benefit of OS was seen (HR = 0.61, 95% CI 0.31-1.22). Treatment benefit was more pronounced in patients with advanced disease stage and longer duration of medication, EGFR exon 19 deletion mutation, and treatment with third-generation EGFR-TKIs. Adjuvant targeted therapy may cause few adverse events compared with chemotherapy (RR = 0.28, 95% CI 0.09-0.94). The possibility of severe adverse events for the first-generation drugs was significantly lower than for third-generation drugs. CONCLUSION: In EGFR mutation-positive patients with stage IB-IIIA NSCLC, compared with adjuvant chemotherapy or placebo, adjuvant EGFR-TKIs should effectively improve the patient's DFS, but not effectively improve OS. Disease stage, treatment duration, mutation types, and therapeutic drugs could affect the degree of benefit. Adjuvant EGFR-TKIs had more favorable tolerability than chemotherapy, especially with the usage of first-generation drugs.

[The Initial Experience of Video-assisted Thoracic Surgery Segmentectomy for Early Stage Lung Cancer].

BACKGROUND: Segmentectomy can retains more healthy lung tissue than lobectomy, but it remains controversial in oncology for early stage lung cancer. The aim of this study is to discuss the problems of video-assisted thoracic surgery (VATS) segmentectomy in early stage lung cancer, by analyzing the clinical and pathological data of 35 cases and reviewing the literature. METHODS: There were 35 patients who received segmentectomy by complete video-assisted thoracic surgery, from May 2013 to July 2017, in single operation group in the Third Hospital of Peking University. We analyzed the patient's clinical and pathological data, intraoperative and postoperative complications, lymph node number and metastasis its situation, and compared postoperative pathology and preoperative computed tomography (CT) imaging type. In 35 cases of segmentectomy, there were 11 males and 24 females, with an average age of 57.7 years old. The lesions located in the right upper lobe were 8 cases, in the right lower lobe were 8 cases, in the left upper lobe were 13 cases, in the left lower lobe were 6 cases. The mean maximum diameter of CT imaging was 12.7 mm, and the largest diameter of hilar and mediastinal lymph nodes was less than 10 mm. 23 of them were ground glass predominating and 12 were solid components predominating. RESULTS: All 35 cases were successfully completed VATS anatomical segmentectomy. The average operation time was 153 minutes, the amount of bleeding was 51 mL. There were 10 cases of air leakage after operation, all of which were not more than 3 days. There was contralateral atelectasis in 1 case, chylothorax in 1 case. The average length of hospitalization was 6.1 days. There was no other complications outpatient related to surgery, in 30 days after discharge. The pathological changes were as follow, 2 cases of metastatic tumor, 8 cases of benign lung disease and 25 cases of primary lung cancer. In the 25 cases of primary lung cancer, there were 14 cases of invasive lung adenocarcinoma (7 cases were groundglassopacity (GGO) predominating in CT imaging), 4 cases of micro-invasive adenocarcinoma (3 cases were GGO predominating in CT imaging), 6 cases of adenocarcinoma in situ (all were pure GGO in CT imaging), 1 case of lung squamous cell carcinoma (mainly composed of solid in CT imaging). An average of 7.2 lymph nodes were removed in 25 cases of lung cancer, and all lymph nodes had no metastasis. CONCLUSIONS: VATS anatomical segmentectomy is technically safe and reliable, and the indications for lung cancer need to be strictly controlled. Its advantages still need to be confirmed by prospective randomized controlled trials.

Neoadjuvant chemotherapy followed by minimally invasive esophagectomy is safe and feasible for treatment of esophageal squamous cell carcinoma.

BACKGROUND: The advantage of neoadjuvant chemotherapy (NAC) followed by open esophagectomy for treatment of esophageal squamous cell carcinoma has been widely recognized. However, the safety and feasibility of NAC for patients receiving minimally invasive esophagectomy (MIE) remain controversial. The purpose of this study was to evaluate the potential impact of prior neoadjuvant chemotherapy on the clinical outcome of MIE by comparing two groups of patients, MIE alone and NAC plus MIE. METHODS: From May 2013 to July 2017, 124 patients with esophageal squamous cell carcinoma underwent MIE in our department, with 57 cases receiving NAC plus MIE and 67 cases receiving MIE alone. Perioperative parameters and short-term postoperative survival were compared between these two groups to evaluate the safety and feasibility of NAC given before MIE. RESULTS: The group with NAC plus MIE had slightly longer operating time, more blood loss, higher morbidity, increased chance of surgical intensive care unit stay, and longer surgical intensive care unit stay time than the group with MIE alone. However, there was no statistically significant difference between these two groups (P > 0.05). The number of lymph nodes harvested was similar in the two groups without significant difference (P > 0.05). The overall survival was not significantly different between these two groups either (P > 0.05), although before surgery the clinical stage of the group with NAC plus MIE was more advanced than the group with MIE alone. CONCLUSIONS: NAC followed by MIE is safe and feasible for treatment of esophageal squamous cell carcinoma. NAC does not negatively impact the therapeutic outcome of MIE.

Minimally invasive esophagectomy in the lateral-prone position: Experience of 124 cases in a single center.

BACKGROUND: Minimally invasive esophagectomy was first introduced as a new technique for esophageal cancer treatment 20 years ago. Performing this procedure in the lateral-prone position is the most appropriate method. Since May 2013, our center has performed 124 esophageal cancer operations using this procedure. Herein, we share our experience. METHODS: We retrospectively reviewed 124 consecutive patients who had received minimally invasive esophagectomy in the lateral-prone position from May 2013 to June 2017. The procedure, operative variables, postoperative complications, and oncology outcomes were assessed. RESULTS: The surgery was successful in all 124 patients; three cases converted to an abdominal opening procedure during surgery. The mean total lymph node harvest was 19.2: 12.9 in the thoracic cavity and 6.0 in the abdominal cavity. The average total operation duration was 376 minutes and blood loss was 156 mL. No mortality occurred within 30 postoperative days. Forty-three cases of postoperative morbidity occurred in 38 patients (30.6%), including 11 anastomotic leakages (8.9%), 1 chyle leak (0.8%), 12 lateral recurrent nerve palsies (9.7%), 11 pulmonary complications (8.9%), and 8 other complications (6.5%). A learning curve indicated that blood loss, operation duration, and the number of lymph nodes harvested would improve with time. CONCLUSIONS: Surgical and oncological outcomes following minimally invasive esophagectomy for esophageal cancer were acceptable. There are some advantages to this technique compared to previous reports of opening procedures.

Initial experience of sleeve lobectomy under complete video-assisted thoracic surgery.

PURPOSE: Review the initial results of a single-center complete video-assisted thoracoscopic surgery (VATS) sleeve lobectomy and discuss the key procedure of this operation, in addition to its safety and feasibility. METHODS: Retrospectively analyze the perioperative data of 11 patients who accepted complete VATS sleeve lobectomy between May 2013 and Jun 2017 in Peking University Third Hospital, try to evaluate the safety of this procedure. All the patients were followed up and their oncological recurrence and metastasis were observed, and feasibility of VATS sleeve lobectomy for lung cancer was evaluated. RESULTS: All of the 11 cases underwent complete VATS sleeve lobectomy successfully and there is no conversion to thoracotomy. The mean operative time was 338 min (range from 243 to 511 min), the mean time of bronchial anastomotic was 63 min (range from 40 to 96 min), the mean blood loss was 205 mL (range from 50 to 400 mL), and the mean number of lymph nodes dissected is 22.1. There was no other complication except one patient suffered from high-risk pulmonary embolism, and no anastomotic leakage and stricture was found. The mean hospital stay postoperation was 8.7 days. The time of follow-up was between 2 and 38 months, only one out of the 11 cases died of bone metastasis, and the other 10 survived till now. One of these 10 patients had local recurrence 24 months after operation, and one suffered adenocarcinoma of esophageal-gastric junction at 15 months postoperation. The rest of eight patients all survived to June 2017 and no local recurrence and metastasis was found. The mean survival time was 14.8 months. CONCLUSION: Complete VATS sleeve lobectomy is a safe and feasible procedure, but the advantage of perioperative and long-term survival need prospective randomized controlled large sample trial to be confirmed.

[Surgical Treatment of Small Pulmonary Nodules Under Video-assisted Thoracoscopy 
(A Report of 129 Cases)].

BACKGROUND: The development of image technology has led to increasing detection of pulmonary small nodules year by year, but the determination of their nature before operation is difficult. This clinical study aimed to investigate the necessity and feasibility of surgical resection of pulmonary small nodules through a minimally invasive approach and the operational manner of non-small cell lung cancer (NSCLC). METHODS: The clinical data of 129 cases with pulmonary small nodule of 10 mm or less in diameter were retrospectively analyzed in our hospital from December 2013 to November 2016. Thin-section computed tomography (CT) was performed on all cases with 129 pulmonary small nodules. CT-guided hook-wire precise localization was performed on 21 cases. Lobectomy, wedge resection, and segmentectomy with lymph node dissection might be performed in patients according to physical condition. RESULTS: Results of the pathological examination of 37 solid pulmonary nodules (SPNs) revealed 3 primary squamous cell lung cancers, 3 invasive adenocarcinomas (IAs), 2 metastatic cancers, 2 small cell lung cancers (SCLCs), 16 hamartomas, and 12 nonspecific chronic inflammations. The results of pathological examination of 49 mixed ground glass opacities revealed 19 IAs, 6 micro invasive adenocarcinomas (MIAs), 4 adenocarcinomas in situ (AIS), 1 atypical adenomatous hyperplasia (AAH), 1 SCLC, and 18 nonspecific chronic inflammations. The results of pathological examination of 43 pure ground glass opacities revealed 19 AIS, 6 MIAs, 6 IA, 6 AAHs, and 6 nonspecific chronic inflammations. Wedge resection under video-assisted thoracoscopic surgery (VATS) was performed in patients with 52 benign pulmonary small nodules. Lobectomy and systematic lymph node dissection under VATS were performed in 33 patients with NSCLC. Segmentectomy with selective lymph node dissection, wedge resection, and selective lymph node dissection under VATS were performed in six patients with NSCLC. Two patients received secondary lobectomy and systematic lymph node dissection under VATS because of intraoperative frozen pathologic error that happened in six cases. Two cases of N2 lymph node metastasis were found in patients with SPN of IA. CONCLUSIONS: Positive surgical treatment should be taken on patients with persistent pulmonary small nodules, especially ground glass opacity, because they have a high rate of malignant lesions. During the perioperative period, surgeons should fully inform the patients and family members that error exist in frozen pathologic results to avoid medical disputes.