Impact of treatment interval between neoadjuvant immunochemotherapy and surgery in lung squamous cell carcinoma.

OBJECTIVE: The optimal timing for surgery following neoadjuvant immunochemotherapy for lung squamous cell carcinoma appears to be a topic of limited data. Many clinical studies lack stringent guidelines regarding this timing. The objective of this study is to explore the effect of the interval between neoadjuvant immunochemotherapy and surgery on survival outcomes in patients with lung squamous cell carcinoma. METHODS: This study conducted a retrospective analysis of patients with lung squamous cell carcinoma who underwent neoadjuvant immunochemotherapy between January 2019 and October 2022 at The First Affiliated Hospital, Zhejiang University School of Medicine. Patients were divided into two groups based on the treatment interval: ≤33 days and > 33 days. The primary observational endpoints of the study were Disease-Free Survival (DFS) and Overall Survival (OS). Secondary observational endpoints included Objective response rate (ORR), Major Pathological Response (MPR), and Pathological Complete Remission (pCR). RESULTS: Using the Kaplan-Meier methods, the ≤ 33d group demonstrated a superior DFS curve compared to the > 33d group (p = 0.0015). The median DFS for the two groups was 952 days and 590 days, respectively. There was no statistical difference in the OS curves between the groups (p = 0.66), and the median OS was not reached for either group. The treatment interval did not influence the pathologic response of the tumor or lymph nodes. CONCLUSIONS: The study observed that shorter treatment intervals were associated with improved DFS, without influencing OS, pathologic response, or surgical safety. Patients should avoid having a prolonged treatment interval between neoadjuvant immunochemotherapy and surgery.

A survival nomogram model for patients with resectable non-small cell lung cancer and lymph node metastasis (N1 or N2) based on the Surveillance, Epidemiology, and End Results Database and single-center data.

Background: The ability to predict survival in patients with lymph node metastasis has long been elusive. After surgery, the basis for decision-making on the combination treatment of patients is not clear. The purpose of this study was thus to build a survival nomogram model to effectively predict the overall survival (OS) of patients with non-small cell lung cancer (NSCLC) and lymph node metastasis. The number of dissected lymph nodes (NDLN), number of positive lymph nodes (NPLN), lymph node ratio (LNR), and log odds of positive lymph nodes (LODDS) were included in this study to determine the risk factors in patients with advanced NSCLC. Methods: The data of 5,132 patients with NSCLC and lymph node metastasis (N1 or N2) were extracted from the Surveillance, Epidemiology, and End Results (SEER) database according to inclusion and exclusion criteria and used as the training cohort. We enrolled 117 patients from the First Affiliated Hospital, Zhejiang University School of Medicine as the external validation cohort. Receiver operating characteristic (ROC) analyses were performed to determine the best cutoff values for predicting the prognosis of patients with NSCLC. Based on the risk factors affecting prognosis, a nomogram was constructed using univariate and multivariate Cox proportional hazard regression models. The discrimination ability of the nomogram was evaluated with the concordance index (C-index) and calibration curves. For the independent risk factors, survival curves were drawn using Kaplan-Meier analysis. Results: ROC curve analysis showed that the optimal NPLN cut-off value was 4, LNR was 0.26, and LODDS was -0.25, respectively. However, LNR was nonsignificant in multivariate analysis, with a P value of 0.274. The novel survival nomogram model included seven independent risk factors, among which were NPLN, LODDS, and chemotherapy. Model 4, which included N stage, NPLN, and LODDS, had a higher likelihood ratio (LR) and C-index than did the other models. The C-index was 0.648 [95% confidence interval (CI): 0.636-0.659] in the training cohort and 0.807 (95% CI: 0.751-0.863) in the external validation cohort, showing good prognostic accuracy and discrimination ability. According to the median risk score, the patients in the training cohort and external validation cohort were divided into high-risk and low-risk groups, between which significant differences in OS were found. In the training cohort, age, sex, T stage, N stage, NPLN, LODDS, and chemotherapy were significantly associated with OS (P<0.001). In the external validation cohort, T stage, NPLN, LODDS, and chemotherapy were found to be correlated with OS. Conclusions: The NPLN and LODDS nomogram is an accurate survival prediction tool for patients with N1 or N2 NSCLC. Patients with lymph node metastasis can benefit from chemotherapy, but no evidence shows that radiotherapy is necessary for patients with resectable NSCLC.

Comparisons of short-term outcomes between robot-assisted, video-assisted, and open esophagectomy for resectable esophageal cancer after neoadjuvant treatment: a retrospective study.

Background: Robot-assisted esophagectomy (RAE), video-assisted minimally invasive esophagectomy (VAMIE), and open esophagectomy (OE) all have significant roles in the management of esophageal cancer (EC). Few studies have compared efficacy and safety between RAE, VAMIE, and OE for resectable EC after neoadjuvant treatment. Therefore, this study aimed to explore the short-term outcomes between RAE, VAMIE, and OE for resectable EC after neoadjuvant treatment. Methods: Ninety-eight patients were consecutively enrolled who underwent esophagectomy. A retrospective study was performed including 98 consecutive patients treated from January 2021 to August 2022 who received neoadjuvant treatment (including immunochemotherapy and chemoradiotherapy) followed by RAE, VAMIE or OE. Evaluated endpoints in the present study consisted of pathological outcomes, intraoperative and postoperative outcomes, as well as postoperative complications. Results: No significant differences were seen in the operating time, blood loss, length of intensive care unit (ICU) stay, R0 resection, and number of dissected lymph nodes between the three RAE, VAMIE, or OE groups. The achievement rate of right recurrent laryngeal nerve (RLN) lymph node removal (P=0.01) and the total cost (P<0.001) were higher in RAE. The postoperative hospital stay of OE was longer than the other two groups (P<0.05). There were no significant differences in postoperative complications. Conclusions: Compared to VAMIE, no clear benefit exists for RAE in the treatment of resectable EC after neoadjuvant therapy. OE resulted in a longer hospital stay. Although the rate of successful right RLN node removal was higher with RAE, the clinical relevance for this is yet unclear.

Does the time interval from neoadjuvant camrelizumab combined with chemotherapy to surgery affect outcomes for locally advanced esophageal squamous cell carcinoma?

BACKGROUND: There is currently no consensus on the optimal interval time between neoadjuvant therapy and surgery, and whether prolonged time interval from neoadjuvant therapy to surgery results in bad outcomes for locally advanced esophageal squamous cell carcinoma (ESCC). In this study, we aim to evaluate outcomes of time intervals ≤ 8 weeks and > 8 weeks in locally advanced ESCC. METHODS: This retrospective study consecutively included ESCC patients who received esophagectomy after neoadjuvant camrelizumab combined with chemotherapy at the Department of Thoracic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine. The primary endpoints were disease-free survival (DFS) and overall survival (OS), while the secondary endpoints were pathological response, surgical outcomes, and postoperative complications. RESULTS: From 2019 to 2021, a total of 80 patients were included in our study and were divided into two groups according to the time interval from neoadjuvant immunochemotherapy to surgery: ≤ 8 weeks group (n = 44) and > 8 weeks group (n = 36). The rate of MPR in the ≤ 8 weeks group was 25.0% and 27.8% in the > 8 weeks group (P = 0.779). The rate of pCR in the ≤ 8 weeks group was 11.4%, with 16.7% in the > 8 weeks group (P = 0.493). The incidence of postoperative complications in the ≤ 8 weeks group was 27.3% and 19.4% in the > 8 weeks group (P = 0.413). The median DFS in the two groups had not yet reached (hazard ratio [HR], 3.153; 95% confidence interval [CI] 1.383 to 6.851; P = 0.004). The median OS of ≤ 8 weeks group was not achieved (HR, 3.703; 95% CI 1.584 to 8.657; P = 0.0012), with the > 8 weeks group 31.6 months (95% CI 21.1 to 42.1). In multivariable analysis, inferior DFS and OS were observed in patients with interval time > 8 weeks (HR, 2.992; 95% CI 1.306 to 6.851; and HR, 3.478; 95% CI 1.481 to 8.170, respectively). CONCLUSIONS: Locally advanced ESCC patients with time interval from neoadjuvant camrelizumab combined with chemotherapy to surgery > 8 weeks were associated with worse long-term survival.

Efficacy of neoadjuvant immunochemotherapy and survival surrogate analysis of neoadjuvant treatment in IB-IIIB lung squamous cell carcinoma.

Until now, there are still few comparisons between neoadjuvant immunochemotherapy and chemotherapy as first-line treatment for patients with stage IB-IIIB lung squamous cell carcinoma (LUSC). In addition, the ability of pathologic response to predict long-term survival has still not been established. In this retrospective, controlled clinical trial, we ultimately enrolled 231 patients with stage IB to IIIB LUSC who received 2-4 cycles perioperative immunochemotherapy or chemotherapy alone, followed by resection. The primary endpoint of this study was pathological response. Secondary endpoints were disease-free survival (DFS), overall survival (OS), objective response rate (ORR), surgical resection rate and adverse events (AEs). The rates of major pathologic response (MPR) and pathologic complete response (pCR) in the immunochemotherapy group were 66.7% and 41.9%, respectively, which were both higher than that in the other group (MPR: 25.0%, pCR: 20.8%) (P < 0.001). The median DFS in the chemotherapy group was 33.1 months (95% CI 8.4 to 57.8) and not reached in the immunochemotherapy group (hazard ratio [HR] for disease progression, disease recurrence, or death, 0.543; 95% CI 0.303 to 0.974; P = 0.038). The median OS of the immunochemotherapy group was not achieved (HR for death, 0.747; 95% CI 0.373 to 1.495; P = 0.41), with the chemotherapy group 64.8 months (95% CI not reached to not reached). The objective response rate (ORR) of immunochemotherapy regimen was higher than that of the chemotherapy regimen (immunochemotherapy: 74.5%, chemotherapy: 42.3%, P < 0.001). About 60.8% in the immunochemotherapy group and 61.5% in the chemotherapy group eventually underwent surgery. The incidence of grade3 and 4 adverse events was 18.3% in the immunochemotherapy group and 2.6% in the chemotherapy group. MPR was significantly associated with DFS and OS (HR, 0.325; 95% CI 0.127 to 0.833; P = 0.019; and HR, 0. 906; 95% CI 0.092 to 1.008; P = 0.051, respectively). The C-index of MPR (0.730 for DFS, 0.722 for OS) was higher than the C-index of cPR (0.672 for DFS, 0.659 for OS) and clinical response (0.426 for DFS, 0.542 for OS). Therapeutic regimen (P < 0.001; OR = 7.406; 95% CI 3.054 to 17.960) was significantly correlated with MPR. In patients with stage IB to IIIB LUSC, neoadjuvant treatment with immunochemotherapy can produce a higher percentage of patients with a MPR and longer survival than chemotherapy alone. MPR may serve as a surrogate endpoint of survival to evaluate neoadjuvant therapy.

The efficacy and safety of percutaneous CT-guided iodine-125 brachytherapy combined with standard chemotherapy and brachytherapy alone for lung malignant nodule: a retrospective comparative cohort study.

Background: Lung metastasis nodules and advanced-stage tumors are often considered inoperable conditions for thoracic surgery and remain major challenges to clinical decision-making. Brachytherapy has its advantages in treating localized solid tumors, which can be used in combination with other treatments to achieve good safety and efficacy. In this study, we aimed to determine the outcomes of patients who received a combination of standard chemotherapy and computed tomography (CT)-guided percutaneous brachytherapy treatment for advanced-stage lung malignant lesions. Methods: We retrospectively collected data on patients with advanced lung cancer or lung metastasis nodules who underwent percutaneous CT-guided iodine-125 (125I) brachytherapy treatment. Patients were divided into two groups: Group A (brachytherapy with chemotherapy) and Group B (brachytherapy-only). Patients were reevaluated 1 month after the operation and then followed up every 3 months. The primary endpoint of this study was overall survival. Results: Our results showed that the mean age in Group B was higher (62.32±8.79 years) than that of Group A (68.59±11.46 years; P=0.018). Patients receiving a combination of chemotherapy and brachytherapy had a median survival time of 20.5 months [95% confidence interval (CI), 16.5-24.5], while those receiving brachytherapy alone had a median survival time of 16.4 months (95% CI, 11.7-21.1) (P=0.026). Patients who received additional thermal ablation treatment and those who did not have median survival times of 16.4 (95% CI, 10.2-22.7) and 17.0 months (95% CI, 13.3-20.8) (P=0.607). The median survival time for patients with oligo lesions was 19.8 months (95% CI, 15.7-23.9), while it was 10.5 months (95% CI, 7.5-13.4) for those who had multiple lesions. Conclusions: The combination of percutaneous CT-guided 125I brachytherapy and standard chemotherapy was superior to brachytherapy alone in terms of overall survival for patients with inoperable pulmonary lesions. Our results showed no benefit from additional adjuvant thermal ablation treatment. Patients with a single oligo nodule seem to have a better prognosis than those with multiple lesions.

Clinical evaluation of the impact of mediastinal tumour size on the subxiphoid approach video-assisted thoracoscopic surgery.

OBJECTIVES: The application of video-assisted thoracoscopic surgery (VATS) for relatively large mediastinal tumours (≥5.0 cm) has been a subject of debate, and few studies have investigated the subxiphoid approach VATS in different tumour size categories. The study aims to compare the efficacy of the subxiphoid approach VATS for achieving curative outcomes based on tumour size categories (<3.0, 3.0-4.9 and 5.0-10.0 cm). METHODS: A total of 165 patients with anterior mediastinal tumours who underwent surgery at our hospital between January 2018 and July 2022 were consecutively enrolled, categorized according to tumour size-group A (<3.0 cm): 58, group B (3.0-4.9 cm): 70 and group C (5.0-10.0 cm): 37. Clinical baseline data, intraoperative and postoperative outcomes, and postoperative complications were analysed. RESULTS: The study revealed significant differences in operation time among the 3 groups (group A: 103.4 ± 36.1, group B: 106.4 ± 35.2, group C: 127.4 ± 44.8; P < 0.05) as well as in the volume of drainage (group A: 273.3 ± 162.0, group B: 411.9 ± 342.6, group C: 509.7 ± 543.7; P < 0.05). However, no differences were seen in blood loss, drainage duration, postoperative hospital stay and duration of postoperative oral analgesics. Additionally, the incidence of postoperative complications did not exhibit significant differences across these groups. CONCLUSIONS: Subxiphoid approach VATS is considered a feasible and safe surgical method for large-sized anterior mediastinal tumours (5.0-10.0 cm) with no invasion to the surrounding tissues and organs.

Safety and efficacy of tislelizumab plus chemotherapy as preoperative treatment in potentially resectable locally advanced non-small-cell lung cancer patients.

OBJECTIVES: Locally advanced non-small-cell lung cancer (LA-NSCLC) requires more preoperative regiments in the era of immunotherapy. Tislelizumab was approved for first-line treatment for advanced lung cancer, bringing hope for preoperative therapy in LA-NSCLC. The aim of this study was to investigate the safety and efficacy of preoperative tislelizumab plus chemotherapy in LA-NSCLC. METHODS: The medical records at the First Affiliated Hospital of Zhejiang University were examined retrospectively from September 2019 to June 2022 for this descriptive single-arm cohort study. Patients with LA-NSCLC were treated with tislelizumab plus platinum-based dual-drug regimens for 2-6 cycles and regular imaging assessments were performed every 1-2 cycles. Data including demographic characteristics, clinicopathological staging, adverse events and surgery-related details were recorded in specifically designed forms. RESULTS: Forty patients met the inclusion criteria of the study and 23 patients underwent curative intent surgeries. Significantly clinical and pathological downstaging was observed, with the objective response rate being 65.00%, leading to a major pathological remission (MPR) rate of 56.52% and a pathological complete remission (pCR) rate of 34.78%. Grade 3-4 treatment-related adverse events occurred in 4 patients and no perioperative death occurred. The 1-year progress-free survival rate and the 1-year overall survival rate were 85.0% and 90.0%, respectively. CONCLUSIONS: Tislelizumab plus chemotherapy as preoperative therapy demonstrates promising antitumour activity for potentially resectable LA-NSCLC with high MPR, pCR and acceptable toxicity and survival.

Development of predictive models for assessing the progression and invasiveness of satellite lesions in patients with multiple pulmonary ground glass nodules.

Background: Currently, the appropriate treatment of satellite lesions is still controversial. With this study, we aimed to construct a set of nomograms to determine the characteristics of satellite lesions in patients with multiple pulmonary ground glass nodules (MPGGNs) and propose a reference for the management of satellite lesions. Methods: We retrospectively analyzed patients with MPGGNs who had undergone multiple rounds of surgical resection of primary and satellite lesions, including pathologic examinations after surgical resection. Results: A total of 125 lesions from 105 patients were included in the analysis; 85 lesions were advanced and 40 lesions were not advanced. Among them, 55 invasive pulmonary adenocarcinomas (IPA) and 70 noninvasive pulmonary adenocarcinomas were identified. After the final regression analysis, the patients' age, satellite lesion location, consolidation tumor ratio (CTR), lesion border clarity, and lesion diameter were used to predict satellite lesion progression. Patients' gender, satellite lesion location, lesion diameter, and computed tomography (CT) attenuation values were used to predict the invasiveness of the satellite lesion. The constructed nomograms showed strong discrimination with concordance indices (C indices) of 0.816 and 0.823, respectively. Conclusions: We developed a set of nomograms that can predict the risk of advanced or invasive satellite lesions in patients with MPGGNs. The area under the receiver operating characteristic (ROC) curve (AUC), the C-index, and the calibration curve suggest that the nomogram may be useful in the clinical setting. This model has the potential to help clinicians make treatment recommendations for the remaining lesions while treating the primary lesion in patients with MPGGNs.

The implications of N6-methyladenosine (m6A) modification in esophageal carcinoma.

Esophageal carcinoma (EC) is always diagnosed at advanced stage and its the mortality rate remains high. The patients usually miss the best opportunity for treatment because of non-specific symptoms and the survival rates are low. N6-methyladenosine (m6A) the predominant modification in eukaryotic messenger RNA(mRNA), serves vital roles in numerous bioprocess. This chemical modification is dynamic, reversible and consists of three regulators: m6A methyltransferases (writers), demethylases (erasers) and m6A-binding proteins (readers). Recently, a growing number of evidences have indicated relationships between m6A and EC. Whereas, lacking of cognition about the molecular mechanism of m6A modification in esophageal carcinoma. We will focus on the biological function roles of m6A modification in the tumorigenesis and development of EC. Recent studies showed that immunotherapy had a positive impact on EC. The relationship between m6A and immunotherapy in EC deserves further research and discussion. We will also discuss the potential clinical applications regarding diagnosis, treatment and prognosis of m6A modification for EC and provide perspectives for further studies.

Comparison of Carotid Blood Flow Measured by Ultrasound and Cardiac Output in Patients Undergoing Cardiac Surgery.

BACKGROUND: In general, cerebral blood flow accounts for 10-15% of cardiac output (CO), of which about 75% is delivered through the carotid arteries. Hence, if carotid blood flow (CBF) is constantly proportional to CO with high reproducibility and reliability, it would be of great value to measure CBF as an alternative to CO. The aim of this study was to investigate the direct correlation between CBF and CO. We hypothesized that measurement of CBF could be a good substitute for CO, even under more extreme hemodynamic conditions, for a wider range of critically ill patients. METHODS: Patients aged 65-80 years, undergoing elective cardiac surgery were included in this study. CBF in different cardiac cycles were measured by ultrasound: systolic carotid blood flow (SCF), diastolic carotid blood flow (DCF), and total (systolic and diastolic) carotid blood flow (TCF). CO simultaneously was measured by transesophageal echocardiography. RESULTS: For all patients, the correlation coefficients between SCF and CO, TCF and CO were 0.45 and 0.30, respectively, which were statistically significant, but not between DCF and CO. There was no significant correlation between either SCF, TCF or DCF and CO, when CO was <3.5 L/min. CONCLUSIONS: Systolic carotid blood flow may be used as a better index to replace CO. However, the method of direct measurement of CO is essential when the patient's heart function is poor.

Minimally invasive surgery for pleuroperitoneal communication complicating peritoneal dialysis.

OBJECTIVE: Pleuroperitoneal communication (PPC) is an uncommon but serious complication of continuous ambulatory peritoneal dialysis (CAPD). At present, there are many kinds of treatment options, with different effects. We describe our single-institutional experiences in the minimally invasive surgery of pleuroperitoneal communication complicating continuous ambulatory peritoneal dialysis in detail. METHODS: Our study consecutively enrolled 12 pleuroperitoneal communication patients complicating CAPD. All patients underwent direct closure of the defective diaphragm and mechanical rub pleurodesis under video-assisted thoracoscopy. What is more, pseudomonas aeruginosa injection was infused into the thoracic cavity postoperatively to further promote pleural adhesion, which was the innovation of our study. RESULTS: After 1.0-8.3 months of CAPD, all 12 patients presented hydrothorax in the right side. All these patients received surgery 7-179 days (18.0 ± 49.5 days) after onset. Bleb-like lesions situated on the diaphragm were discovered in all patients and three patients also had obvious hole on the surface of diaphragm. Pseudomonas aeruginosa injection was infused into the thoracic cavity postoperatively, and three cases showed fever with remission after 2-3 days of symptomatic treatment. The time from surgery to restarting CAPD ranged from 14 to 47 days, with a median of 20 days. There was no recurrence of hydrothorax and transformation to hemodialysis during the follow-up period (median: 7.5 months). CONCLUSIONS: Video-assisted thoracoscopic direct closure of the defective diaphragm and mechanical rub pleurodesis plus chemical pleurodesis using pseudomonas aeruginosa injection postoperatively is a safe and effective option for the treatment of pleuroperitoneal communication complicating continuous ambulatory peritoneal dialysis with 100% success rate.

Oxidant-Induced Bioconjugation for Protein Labeling in Live Cells.

Chemical proteomics is a powerful technology that can be used in the studies of the functions of uncharacterized proteins in the human proteome. It relies on a suitable bioconjugation strategy for protein labeling. This could be either a UV-responsive photo-crosslinker or an electrophilic warhead embedded in chemical probes that can form covalent bonds with target proteins. Here, we report a new protein-labeling strategy in which a nitrile oxide, a highly reactive intermediate that reacts with proteins, can be efficiently generated by the treatment of oximes with a water-soluble and a minimally toxic oxidant, phenyliodine bis (trifluoroacetate) (PIFA). The resulting intermediate can rapidly bioconjugate with amino acid residues of target proteins, thus enabling target identification of oxime-containing bioactive molecules. Excellent chemoselectivity of cysteine residues by the nitrile oxide was observed, and over 4000 reactive and/or accessible cysteines, including KRAS G12C, have been successfully characterized by quantitative chemical proteomics. Some of these residues could not be detected by conventional cysteine reagents, thus demonstrating the complementary utility of this method.

The Safety and Efficacy of Preoperative Immunotherapy Combined with Chemotherapy in Patients with Stage IIIA-IIIB Lung Squamous Cell Carcinoma.

OBJECTIVE: Data on preoperative immunotherapy combined with chemotherapy in potentially resectable lung squamous cell carcinoma (LUSC) remain scarce. This study was designed to investigate the safety and efficacy of preoperative immunotherapy and chemotherapy for stage IIIA-IIIB LUSC. METHODS: This study consecutively enrolled stage IIIA-IIIB LUSC who received preoperative immunotherapy combined with chemotherapy between January 2019 and July 2021. Patients received two to four cycles of immunotherapy combined with platinum-based doublet chemotherapy (platinum + paclitaxel) before surgery. Patients were assessed radiographically every one to two cycles until surgery. Postoperative pathological evaluation was also performed. Follow-up was performed until at least 3 months after surgery. RESULTS: Sixty-five patients with stage IIIA-IIIB LUSC were enrolled. The objective response rate was 78.46% (51/65), and no patients had progressive disease. Fifty-seven patients underwent surgery, and 55 patients achieved R0 resection. There were no perioperative deaths. The rate of pathological complete response (pCR) was 31.58% (18/57) and major pathological response was 68.42% (39/57). The incidence of grade 3 and 4 adverse reactions was 21.21 and 1.54%, respectively. CONCLUSION: Perioperative immunotherapy combined with chemotherapy followed by surgical resection for male patients with stage IIIA-IIIB LUSC was effective with a tolerable toxicity profile.

Safety and effectiveness of neoadjuvant immunotherapy combined with chemotherapy followed by surgical resection in patients with stage I-IIIA small-cell lung cancer: a retrospective single-arm clinical trial.

Background: Immunotherapy, chemotherapy and surgery all have significant roles in the management of small-cell lung cancer (SCLC). Neoadjuvant immunotherapy combined with chemotherapy followed by surgery has shown encouraging efficacy for resectable SCLC with a good tolerability and considerable survival benefit. However, there are still few data on whether surgery for stage I-IIIA SCLC can be performed after immunotherapy with chemotherapy. Therefore, we investigated the safety and effectiveness of neoadjuvant immunotherapy combined with chemotherapy followed by surgery in patients with stage I-IIIA SCLC in the hope of adding new ideas to the treatment of SCLC. Methods: The study group comprised 19 patients with stage I-IIIA SCLC who received neoadjuvant immunotherapy and chemotherapy between 2019 and 2021. Patients received 2-4 cycles of immunotherapy combined with platinum-containing dual-drug chemotherapy (platinum + paclitaxel) before surgery. Imaging evaluation was performed every two cycles until surgery. Tumor response to neoadjuvant therapy, neoadjuvant treatment related adverse events, perioperative and postoperative complications, surgical resection rate, and degree of tumor regression were evaluated. We obtained follow-up data from the patients' regular examination or treatment in hospital. If we can't complete it, contacting patients by telephone or WeChat would be adopted by us. The follow-up was not terminated until 3 months after surgery. Results: The objective response rate (ORR) was 84.2% (16/19), and no patients had progressive disease (PD). Of the 10 patients who underwent surgery, and approximately 9 (90.0%) had R0 resection. There were no perioperative deaths, and 1 case of pyothorax. The rate of pathological complete remission (pCR) and major pathological response (MPR) was 30.0% (3/10), and 40.0% (4/10) respectively. Grade 3-4 adverse reactions comprised 1 case of anemia and 1 case of constipation. Conclusions: Neoadjuvant immunotherapy combined with chemotherapy followed by surgical resection for patients with stage I-IIIA SCLC is effective and safe with a high ORR and MPR rate, as well as a high R0 resection rate and a tolerable toxicity profile. Whether this regimen gives a survival benefit should be confirmed by further follow-up and larger, randomized controlled trials are required to confirm our findings.

Prevalence of ground glass nodules in preschool children: a cross-sectional study.

Background: Following increased screening efforts and the use of thin-slice computed tomography (CT), there has been a considerable increase in the incidence of ground-glass nodules (GGNs) in adults. As a result, we have more and more treatments for ground-glass nodules in adults, but few in children. Most think development pattern of pulmonary GGNs is lung inflammation, tumor, or tuberculosis that are more related to acquired or environmental factors. By studying the incidence of pulmonary GGNs in preschool children, we sought to determine whether we had ground glass nodules in the lung before we were teenagers, but we didn't pay attention to them until later. If the hypothesis holds, we may change the cognition and treatment strategies of ground glass nodules. Even not, there are few epidemiological studies with big data that can fill this gap. Methods: We retrospectively collected the data of all preschool children who had undergone CT at the Children's Hospital of Zhejiang University School of Medicine from 2013 to 2020. These data were filtered according to the following exclusion criteria: severe artifacts, data with identical names to the original data; and patients without follow-up records (≥3 months). Inclusion criteria: must have undergone thin-slice CT (≤1.25 mm) at the first and last follow-up. Two thoracic radiologists with 5 years of experience and another senior one assessed the images. Results: There were a total of 13,361 cases after relevant exclusions, 311 patients were finally enrolled. Clinical features: age at diagnosis (year): 3.56±1.84, female: 147, male: 164, follow-up interval (month): 6.90±4.74, leukemia: 99, pneumonia: 21, lung cyst: 8, space-occupying lesions outside the lungs: 69, foreign body in respiratory tract: 6. After manual screening and reading, only 1 patient meets all requirements. The results showed that between 2013 and 2020, the incidence of GGNs that could be basically determined in the Children's Hospital of Zhejiang University School of Medicine was 0.32%. Conclusions: There have been few previous studies of GGNs in children, and based on our study, we found that there is still some associated morbidity for preschool children, it is rarely found when they are young.

A toxin-deformation dependent inhibition mechanism in the T7SS toxin-antitoxin system of Gram-positive bacteria.

Toxin EsaD secreted by some S. aureus strains through the type VII secretion system (T7SS) specifically kills those strains lacking the antitoxin EsaG. Here we report the structures of EsaG, the nuclease domain of EsaD and their complex, which together reveal an inhibition mechanism that relies on significant conformational change of the toxin. To inhibit EsaD, EsaG breaks the nuclease domain of EsaD protein into two independent fragments that, in turn, sandwich EsaG. The originally well-folded ßßα-metal finger connecting the two fragments is stretched to become a disordered loop, leading to disruption of the catalytic site of EsaD and loss of nuclease activity. This mechanism is distinct from that of the other Type II toxin-antitoxin systems, which utilize an intrinsically disordered region on the antitoxins to cover the active site of the toxins. This study paves the way for developing therapeutic approaches targeting this antagonism.

The microbiome of lower respiratory tract and tumor tissue in lung cancer manifested as radiological ground-glass opacity.

Recent studies have confirmed the existence of microbiota in the lungs. The relationship between lung ground-glass opacity (GGO) and microbiota in the lung microenvironment is not clear. In this study, we investigated the microbial composition and diversity in bronchoalveolar lavage fluid (BALF) of diseased lung segments and paired contralateral healthy lung segments from 11 GGO patients. Furthermore, lung GGO and paired normal tissues of 26 GGO patients were explored whether there are microbial characteristics related to GGO. Compared with the control group, the community richness of GGO tissue and BALF of GGO lung segment (α-diversity) and overall microbiome difference (ß-diversity) had no significant difference. The microbiome composition of BALF of GGO segments is distinct from that of paired healthy lung segments [genus (Rothia), order (Lachnospiraceae), family (Lachnospiraceae), genus (Lachnospiraceae_NK4A136_group, Faecalibacterium), and species (Faecalibacterium prausnitzii, Bacteroides uniforms)]. GGO tissue and adjacent lung tissue had more significant differences at the levels of class, order, family, genus, and species level, and most of them are enriched in normal lung tissue. The area under the curve (AUC) using 10 genera-based biomarkers to predict GGO was 91.05% (95% CI: 81.93-100%). In conclusion, this study demonstrates there are significant differences in the lower respiratory tract and lung microbiome between GGO and the non-malignant control group through the BALF and lung tissues. Furthermore, some potential bacterial biomarkers showed good performance to predict GGO.

Ynamide Electrophile for the Profiling of Ligandable Carboxyl Residues in Live Cells and the Development of New Covalent Inhibitors.

Covalent inhibitors with an electrophilic warhead have received considerable attention due to their remarkable pharmacological properties. However, the electrophilic warhead in covalent drugs is often an α, ß-unsaturated amide, and the targets are mainly cysteine or lysine residues. Thus, the development of novel electrophiles that can target other amino acids is highly desirable. Ynamide, a useful and versatile building block, is commonly employed in the construction of various compounds in organic synthesis. The performance of this functional group in a proteome-wide environment has been studied here for the first time, and it has been shown that it can efficiently modify carboxyl residues in situ and in vitro. Upon incorporation of this ynamide warhead into the pharmacophores of kinase inhibitors, the resulting compound showed moderate inhibition against the EGFR L858R mutant but not against EGFR WT. This novel electrophilic group can be used in the development of new types of covalent inhibitors.