Targeting pyruvate dehydrogenase kinase 1 overcomes EGFR C797S mutation-driven osimertinib resistance in non-small cell lung cancer.

Osimertinib, a selective third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), effectively targets the EGFR T790M mutant in non-small cell lung cancer (NSCLC). However, the newly identified EGFR C797S mutation confers resistance to osimertinib. In this study, we explored the role of pyruvate dehydrogenase kinase 1 (PDK1) in osimertinib resistance. Patients exhibiting osimertinib resistance initially displayed elevated PDK1 expression. Osimertinib-resistant cell lines with the EGFR C797S mutation were established using A549, NCI-H292, PC-9, and NCI-H1975 NSCLC cells for both in vitro and in vivo investigations. These EGFR C797S mutant cells exhibited heightened phosphorylation of EGFR, leading to the activation of downstream oncogenic pathways. The EGFR C797S mutation appeared to increase PDK1-driven glycolysis through the EGFR/AKT/HIF-1α axis. Combining osimertinib with the PDK1 inhibitor leelamine helped successfully overcome osimertinib resistance in allograft models. CRISPR-mediated PDK1 knockout effectively inhibited tumor formation in xenograft models. Our study established a clear link between the EGFR C797S mutation and elevated PDK1 expression, opening new avenues for the discovery of targeted therapies and improving our understanding of the roles of EGFR mutations in cancer progression.

Robotic portal resection for mediastinal tumours: a prospective observational study.

BACKGROUND: To demonstrate the effectiveness and feasibility of robotic portal resection (RPR) for mediastinal tumour using a prospectively collected database. METHODS: Data from 73 consecutive patients with mediastinal tumours who underwent RPRs were prospectively collected from August 2018 to April 2023. All patients underwent chest and abdominal enhanced computed tomography (CT) and preoperative multidisciplinary team (MDT) discussion. The patients were stratified into two groups based on tumour size: Group A (tumour size < 4 cm) and Group B (tumour size ≥ 4 cm). General clinical characteristics, surgical procedures, and short outcomes were promptly recorded. RESULTS: All of the cases were scheduled for RPRs. One patient (1/73, 1.4%) was switched to a small utility incision approach because of extensive pleural adhesion. Two patients (2.8%) converted to sternotomy, however, no perioperative deaths occurred. Most of the tumours were located in the anterior mediastinum (51/73, 69.9%). Thymoma (27/73, 37.0%) and thymic cyst (16/73, 21.9%) were the most common diagnoses. The median diameter of tumours was 3.2 cm (IQR, 2.4-4.5 cm). The median total operative time was 61.0 min (IQR, 50.0-90.0 min). The median intraoperative blood loss was 20 mL (IQR, 5.0-30.0 ml), and only one patient (1.4%) experienced an intraoperative complication. The median length of hospital stay was 3 days (IQR, 2-4 days). Compared with Group A, the median total operative time and console time of Group B were significantly longer (P = 0.006 and P = 0.003, respectively). The volume of drainage on the first postoperative day was greater in group B than in group A (P = 0.013). CONCLUSION: RPR is a safe and effective technique for mediastinal tumour treatment, which can expand the application of minimally invasive surgery for the removal of complicated mediastinal tumours.

Short-term outcomes of robotic lobectomy versus video-assisted lobectomy in patients with pulmonary neoplasms.

BACKGROUND: To explore whether robotic lobectomy (RL) is superior to video-assisted lobectomy (VAL) in terms of short-term outcomes in patients with pulmonary neoplasms. METHODS: From January 30, 2019 to February 28, 2022, a series of consecutive minimally invasive lobectomies were performed for patients with pulmonary neoplasms. Perioperative outcomes such as operation time, blood loss, dissected lymph nodes (LNs), surgical complications, postoperative pain control, length of postoperative stay in hospital, and total cost of hospitalization were compared. RESULTS: A total of 336 cases including 173 RLs and 163 VALs were enrolled. Baseline characteristics were comparable between groups. RLs were associated with shorter operation time (median [interquadrant range, IQR], 107 min [90-130] vs. 120 min [100-149], p < 0.001), less blood loss (median [IQR], 50 mL [30-60] vs. 50 mL [50-80], p = 0.02), and lower blood transfusion rate (3.5% vs. 9.8%, p = 0.02) compared with VALs. More LNs were harvested by the robotic approach (median [IQR], 29 [20-41] vs. 22 [15-45], p = 0.04). The incidences of conversion, major postoperative complications, extra analgesic usage, and postoperative length of stay were all comparable between the RL and VAL groups. As predicted, the total cost of hospitalization was greater in the RL group (median [IQR], $16728.35 [15682.16-17872.15] vs. $10713.47 [9662.13-11742.15], p < 0.001). CONCLUSION: RL improved surgical efficacy with shortened operative time, less blood loss, and more thorough LN dissection compared with VAL, compromised by higher cost.

Comparison of Short-Term Outcomes Between Robot-Assisted and Video-Assisted Segmentectomy for Small Pulmonary Nodules: A Propensity Score-Matching Study.

BACKGROUND: Our study aimed to compare the short-term outcomes between robot-assisted segmentectomy (RAS) and video-assisted segmentectomy (VAS) for small pulmonary nodules. METHODS: The study included of 299 segmentectomies (132 RAS and 167 VAS procedures) for small pulmonary nodules between June 2018 and November 2021. The patients were divided into two groups: the RAS group and the VAS group. Propensity score-matching (PSM) analysis was performed to minimize bias. A logistic regression model was performed to identify the independent risk factors associated with complications. RESULTS: Before PSM, the following clinical variables were not balanced: age (P = 0.004), tumor size (P < 0.001), forced expiratory volume for 1 s (FEV1), and FEV1 percentage (P < 0.001). The patients with RAS had a shorter operative time (P = 0.014), less blood loss, a shorter postoperative hospital stay, less use of strong opioids, less drainage on postoperative day 1, and less postoperative total drainage, but more cost (all P < 0.001). Conversion to open surgery was performed for two patients in the VAS group but none in the RAS group. After PSM, 53 pairs were successfully matched. The data again suggested that the patients with RAS had less blood loss, a shorter postoperative hospital stay, and less use of strong opioids, but more cost (all P < 0.001). The operation time also was shorter in the RAS group, with a borderline statistically significant P value (0.053). CONCLUSIONS: In our study, RAS had better short-term outcomes than VAS, indicating a safer and more efficient technique than VAS.

Defining the learning curve of robotic portal segmentectomy in small pulmonary lesions: a prospective observational study.

Although robotic segmentectomy has been applied for the treatment of small pulmonary lesions for many years, studies on the learning curve of robotic segmentectomy are quite limited. Thus, we aim to investigate the learning curve of robotic portal segmentectomy with 4 arms (RPS-4) using prospectively collected data in patients with small pulmonary lesions. One hundred consecutive patients with small pulmonary lesions who underwent RPS-4 between June 2018 and April 2021 were included in the study. Da Vinci Si/Xi systems were used to perform RPS-4. The mean operative time, console time, and docking time for the entire cohort were 119.2 ± 41.6, 85.0 ± 39.6, and 6.6 ± 2.8 min, respectively. The learning curve of RPS-4 can be divided into three different phases: 1-37 cases (learning phase), 38-78 cases (plateau phase), and > 78 cases (mastery phase). Moreover, 64 cases were required to ensure acceptable surgical outcomes. The total operative time (P < 0.001), console time (P < 0.001), blood loss (P < 0.001), and chest tube duration (P = 0.014) were reduced as experience increased. In conclusion, the learning curve of RPS-4 could be divided into three phases. 37 cases were required to pass the learning phase, and 78 cases were needed to truly master this technique.

Nomogram to Predict Cancer Specific Survival in Patients with Pathological Stage IA Non-small Cell Lung Cancer.

We identified the prognostic factors of resected stage IA non-small cell lung cancer (NSCLC) and developed a nomogram, with purpose of defining the high-risk population who may need closer follow-up or more intensive care. Eligible stage IA NSCLC cases from the Surveillance, Epidemiology, and End Results (SEER) database and the Sun Yat-sen University Cancer Center (SYSUCC) were included. Stage IB NSCLCs were also included for evaluating the risk stratification efficacy. Cancer specific survival (CSS) was compared between groups. Statistically significant factors from multivariate analysis were entered into the nomogram. The performance of the nomogram was evaluated by concordance index (C-index) and calibration plots. A total of 23,112 NSCLC cases (SEER stage IA training cohort, N=7,777; SEER stage IA validation cohort, N=7,776; SEER stage IB cohort, N=7,559) from the SEER database were included. 1,304 NSCLC cases (SYSUCC stage IA validation cohort, N=684; SYSUCC stage IB cohort, N=620) from the SYSUCC were also included. Younger age, female, lobectomy, well differentiated, smaller size and more examined lymph nodes were identified as favorable prognostic factors. A nomogram was established. The C-index was 0.68 (95%CI, 0.67-0.69), 0.66 (95% CI, 0.64-0.68) and 0.66 (95% CI, 0.61-0.71) for the SEER training cohort, SEER validation cohort and SYSUCC validation cohort. A risk classification system was constructed to stratify stage IA NSCLC into low-risk subgroup and high-risk subgroup. The CSS curves of these two subgroups showed statistically significant distinctions. This nomogram delivered a prognostic prediction for stage IA NSCLC and may aid individual clinical practice.

Is major pathologic response sufficient to predict survival in resectable nonsmall-cell lung cancer patients receiving neoadjuvant chemotherapy?

BACKGROUND: Major pathologic response (MPR) is mainly focused on residual viable tumor in the tumor bed regardless of lymph node. Herein, we investigated the predictive value of MPR and node status on survival in nonsmall-cell lung cancer (NSCLC) patients receiving neoadjuvant chemotherapy (NAC) and surgery. METHODS: A total of 194 eligible cases were included. Tumor pathologic response and node status were assessed. Based on these evaluations, patients were divided into the MPR group and the non-MPR group, the nodal downstaging (ND) group and non-ND group. Furthermore, patients were assigned into four subgroups (MPR + ND, MPR + non-ND, non-MPR + ND, and non-MPR + non-ND). Overall survival (OS) and disease-free survival (DFS) were compared between groups. Multivariate analyses were performed to identify prognostic factors. RESULTS: MPR was identified in 32 patients and ND was present in 108 patients. OS and DFS were better in the MPR group than in the non-MPR group, but with no statistical significance (OS, p = 0.158; DFS, p = 0.126). The ND group had better OS than the non-ND group (p = 0.031). However, the DFS between these two groups was comparable (p = 0.103). Further analyses suggested that both OS and DFS were better in the MPR + ND group than in the non-MPR + non-ND group (OS, p = 0.017; DFS, p = 0.029). Multivariate analyses confirmed that MPR + ND was an independent favorable predictor. CONCLUSIONS: MPR combined with ND could improve the predictive value on survival in NSCLC patients receiving NAC.

Total minimally invasive McKeown esophagectomy in an esophageal cancer patient with situs inversus totalis: A case report.

Situs inversus totalis (SIT) is an extremely rare anomaly characterized by a left-to-right reversal of all the thoracic and abdominal organs. Only 11 cases of esophageal cancer with SIT have been reported worldwide, most of which underwent hybrid minimally invasive esophagectomy (MIE) but not total MIE. Here, we report a case of esophageal cancer with SIT successfully treated by total MIE, with a right lateral-prone position adopted during the thoracic procedure. The relevant literature is also discussed and reviewed.