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.

Impact of the Number of Harvested Lymph Nodes on Long-Term Survival in Node-Negative Non-Small-Cell Lung Cancer: Based on Clinical Stage But Not Pathological Stage.

BACKGROUND: We aimed to investigate the impact of the number of harvested lymph nodes (LNs) on the overall survival (OS) and disease-free survival (DFS) of patients with clinical node-negative (cN0) non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: A total of 2247 patients with cN0 NSCLC between 2001 and 2014 were included. Scatter plots of hazard ratios from Cox proportional hazards models against the number of harvested LNs were created, and curves were fitted using a LOWESS smoother. Chow test was used to determine the cut-off points for the optimal number of harvested LNs. Long-term survival was compared between groups divided by the cut-off points. RESULTS: The increasing numbers of harvested LNs and N2 level LNs were independent factors favoring OS and DFS. Seventeen LNs and 10 N2 level LNs were determined as the optimal cut-off points. The patients with ≥17 harvested LNs had a better OS (P = .001) and DFS (P = .002), while the patients with ≥10 harvested N2 level LNs also had a better OS (P < .001) and DFS (P = .001). The increasing numbers of harvested LNs and N2 level LNs were independent prognostic factors associated with prolonged OS and DFS only in patients with clinical T2 (cT2) NSCLC. CONCLUSIONS: The increasing numbers of harvested LNs and N2 level LNs were associated with better OS and DFS in cN0 NSCLC patients that were suitable for lobectomies. At least 17 LNs and 10 N2 level LNs were required to be harvested, especially in cT2 patients.

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.

Station 3A lymph node dissection does not improve long-term survival in right-side operable non-small-cell lung cancer patients: A propensity score matching study.

BACKGROUND: To investigate the impact of station 3A lymph node dissection (LND) on overall survival (OS) and disease-free survival (DFS) in completely resected right-side non-small-cell lung cancer (NSCLC) patients. METHODS: A total of 1661 cases with completely resected right-side NSCLC were included. Propensity score matching (PSM) was performed to minimize selection bias, and a logistic regression model was conducted to investigate the risk factors associated with station 3A lymph node metastasis (LNM). The Kaplan-Meier method and Cox proportional hazards model were used to evaluate the impact of station 3A LND on survival. RESULTS: For the entire cohort, 503 patients (30.3%) underwent station 3A LND. Of those, 11.3% (57/503) presented station 3A LNM. Univariate and multivariate logistic analyses showed that station 10 LNM, tumor location, and the number of resected lymph nodes were independent risk factors associated with station 3A LNM. Before PSM, patients with station 3A LND had worse 5-year OS (p = 0.002) and DFS (p = 0.011), and more drainage on postoperative day 1 (p = 0.041) than those without. After PSM, however, station 3A LND was not associated with the 5-year OS (65.7% vs. 63.6%, p = 0.432) or DFS (57.4% vs. 56.0%, p = 0.437). The multivariate analysis further confirmed that station 3A LND was not a prognostic factor (OS, p = 0.361; DFS, p = 0.447). CONCLUSIONS: Station 3A LND could not improve long-term outcomes and it was unnecessary to dissect station 3A lymph nodes during surgery of right-side NSCLC.

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.

Modification of Pathologic T Classification for Non-small Cell Lung Cancer With Visceral Pleural Invasion: Data From 1,055 Cases of Cancers ≤ 3 cm.

BACKGROUND: Visceral pleural invasion (VPI) with PL1 or PL2 increases the T classification from T1 to T2 in non-small cell lung cancers (NSCLCs) ≤ 3 cm. We proposed a modified T classification based on VPI to guide adjuvant therapy. RESEARCH QUESTION: Is it reasonable to upstage PL1-positive cases from T1 to T2 for NSCLCs ≤ 3 cm? STUDY DESIGN AND METHODS: In total, 1,055 patients with resected NSCLC were retrospectively included. Tumor sections were restained with hematoxylin and eosin stain and Victoria blue elastic stain for the elastic layer. Disease-free survival (DFS) and overall survival (OS) were calculated by the Kaplan-Meier method. Subgroup analysis and a Cox proportional hazards model were used to further determine the impact of VPI on survival. RESULTS: The extent of VPI was diagnosed as PL0 in 824 patients, PL1 in 133 patients, and PL2 in 98 patients. The 5-year DFS rates of patients with PL0, PL1, and PL2 were 62.6%, 60.2%, and 28.8% (P < .01), whereas the corresponding 5-year OS rates were 78.6%, 74.4%, and 50.0% (P < .01), respectively. As predicted, the DFS and OS of patients with PL2 were much worse than those of patients with PL0 (P < .01) and PL1 (P < .01). However, both the DFS and OS of patients with PL0 and PL1 were comparable (DFS: P = .198; OS: P = .150). For node-negative cases, the DFS and OS of patients with PL0 and PL1 were also comparable (DFS: P = .468; OS: P = .388), but patients with PL2 had much worse DFS and OS than patients with PL0 (P < .01) and PL1 (P < .01). Multivariable analyses suggested that PL2, together with node positivity and poor cell differentiation, was an independent adverse prognostic factor. INTERPRETATION: In NSCLCs ≤ 3 cm, tumors with PL1 should remain defined as T1, not T2. Overtreatment by adjuvant chemotherapy in node-negative NSCLCs ≤ 3 cm might be avoided in PL1 cases.

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.

Learning curve of robotic portal lobectomy for pulmonary neoplasms: A prospective observational study.

BACKGROUND: We aim to assess the learning curve of robotic portal lobectomy with four arms (RPL-4) in patients with pulmonary neoplasms using prospectively collected data. METHODS: Data from 100 consecutive cases with lung neoplasms undergoing RPL-4 were prospectively accumulated into a database between June 2018 and August 2019. The Da Vinci Si system was used to perform RPL-4. Regression curves of cumulative sum analysis (CUSUM) and risk-adjusted CUSUM (RA-CUSUM) were fit to identify different phases of the learning curve. Clinical indicators and patient characteristics were compared between different phases. RESULTS: The mean operative time, console time, and docking time for the entire cohort were 130.6 ± 53.8, 95.5 ± 52.3, and 6.4 ± 3.0 min, respectively. Based on CUSUM analysis of console time, the surgical experience can be divided into three different phases: 1-10 cases (learning phase), 11-51 cases (plateau phase), and >51 cases (mastery phase). RA-CUSUM analysis revealed that experience based on 56 cases was required to truly master this technique. Total operative time (p < 0.001), console time (p < 0.001), and docking time (p = 0.026) were reduced as experience increased. However, other indicators were not significantly different among these three phases. CONCLUSIONS: The RPL-4 learning curve can be divided into three phases. Ten cases were required to pass the learning curve, but the mastery of RPL-4 for satisfactory surgical outcomes requires experience with at least 56 cases.

Complete portal robotic resection of a giant mediastinal parathyroid cyst; A case report.

Parathyroid cysts (PCs) are rare, benign, cystic lesions, and PCs that occur in the mediastinum (mediastinal parathyroid cysts [MPCs]) are even more rare. Surgical resection is recommended as the first choice of treatment for MPCs. Sternotomy, thoracotomy, and thoracoscopic approaches are the most common methods for resection of MPCs. Herein, we report a case of robotic right portal minimally invasive resection of a giant nonfunctional MPC in the right anterosuperior mediastinum.

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.

Impact of L4 lymph node dissection on long-term survival in left-side operable non-small-cell lung cancer: a propensity score matching study.

OBJECTIVES: We investigated the impact of level 4 (L4) lymph node dissection (LND) on overall survival (OS) in left-side resectable non-small-cell lung cancer (NSCLC), with the aim of guiding lymphadenectomy. METHODS: A total of 1929 patients with left-side NSCLC who underwent R0 resection between 2001 and 2014 were included in the study. The patients were divided into a group with L4 LND (L4 LND+) and a group without L4 LND (L4 LND-). Propensity score matching was applied to minimize selection bias. The Kaplan-Meier method and Cox proportional hazards model were used to assess the impact of L4 LND on OS. RESULTS: A total of 317 pairs were matched. Of the cohort of patients, 20.3% (391/1929) had L4 LND. Of these patients, 11.8% (46/391) presented with L4 lymph node metastasis. L4 lymph node metastasis was not associated with the primary tumour lobes (P = 0.61). Before propensity score matching, the 5-year OS was comparable between the L4 LND+ and L4 LND- groups (69.0% vs 65.2%, P = 0.091). However, after propensity score matching, the 5-year OS of the L4 LND+ group was much improved compared to that of the L4 LND- group (72.9% vs 62.3%, P = 0.002) and L4 LND was an independent factor favouring OS (hazard ratio 0.678, 95% confidence interval 0.513-0.897; P = 0.006). Subgroup analysis suggested that L4 LND was an independent factor favouring OS in left upper lobe tumours. CONCLUSIONS: In patients with left-side operable NSCLC, L4 lymph node metastasis was not rare and L4 LND should be routinely performed.

The incidence and distribution of mediastinal lymph node metastasis and its impact on survival in patients with non-small-cell lung cancers 3 cm or less: data from 2292 cases.

OBJECTIVES: Our goal was to investigate the incidence and distribution of mediastinal lymph node metastases (MLNM) in non-small-cell lung cancers (NSCLC) 3 cm or less, with the purpose of guiding mediastinal lymph node dissection. METHODS: A total of 2292 cases seen between January 2001 and December 2014 were included. These patients were grouped according to the lobes with the primary tumours. The incidence and distribution of pathological MLNM were compared among the groups. The impact of MLNM on overall survival was also compared. RESULTS: The most common mediastinal metastatic sites for different primary tumour lobes were as follows: right upper lobe, 17.7% (87/492) for level 4R; right middle lobe, 14.9% (28/188) for level 7; right lower lobe, 19.8% (82/414) for level 7; left upper lobe, 18.2% (96/528) for level 5; and left lower lobe, 16.6% (42/253) for level 7. For patients with tumours in the upper lobe, the median survival time was 32 months for those with MLNM in the subcarinal zone or lower zone compared with 83 months for those with MLNM only in the upper zone (P < 0.01). When the tumours were 1 cm or less, the incidence of MLNM to the lower zone for upper lobe tumours and of MLNM to the upper zone for lower lobe tumours was zero. CONCLUSIONS: Different primary NSCLC lobe locations have a different propensity to be sites of MLNM for those tumours that are 3 cm or less. For tumours no larger than 1 cm, a lower zone mediastinal lymph node dissection might be unnecessary for upper lobe tumours and an upper zone mediastinal lymph node dissection might be unnecessary for lower lobe tumours.

Incidence and Distribution of Lobe-Specific Mediastinal Lymph Node Metastasis in Non-small Cell Lung Cancer: Data from 4511 Resected Cases.

OBJECTIVE: We aimed to investigate the incidence and distribution of mediastinal lymph node metastases (MLNM) in operable non-small cell lung cancer (NSCLC) with the purpose of guiding mediastinal lymph node dissection (MLND). METHODS: A total of 4511 NSCLC patients who underwent resection between January 2001 and December 2014 were included. These patients were preoperatively untreated and grouped according to the primary tumor lobes. The incidence and distribution of pathologic MLNM were compared among groups, and multivariate analysis was conducted to find the independent factors impacting MLNM. RESULTS: Lymph node involvement was observed in 1784 patients (39.5%). A total of 628 cases (13.9%) were N1-positive only, 752 cases (16.7%) were both N1- and N2-positive, and 404 cases (9.0%) were N2-positive only. The most common sites of mediastinal metastasis for different primary tumor lobes were the right upper lobe, station 4R (21.5%, 192/893); right middle lobe, station 7 (21.1%, 69/327); right lower lobe, station 7 (24.1%, 212/878); left upper lobe, station 5 (22.2%, 224/1008); and left lower lobe, station 7 (21.7%, 136/628). However, when only N2 cases were considered, each mediastinal lymph node zone can be involved with metastasis to a high proportion (> 5%). Multivariable analyses showed that poor cell differentiation, adenocarcinoma, larger tumor size, central type, and younger age were independent factors favoring MLNM. CONCLUSIONS: Different primary tumor locations have a different propensity to be sites of MLNM; however, once MLNM occurs, each zone can be involved and should not be neglected. Systematic MLND is the preferred procedure for operable NSCLC.