Robot-Assisted Bronchoscopy for Identification of Lung Nodules During Minimally Invasive Pulmonary Resection.

OBJECTIVE: Small pulmonary nodules can be difficult to identify during minimally invasive surgical (MIS) resection. Previous investigators have reported using standard bronchoscopy with electromagnetic navigation to identify small pulmonary nodules. Robot-assisted bronchoscopy has been introduced into clinical practice and has shown utility for the biopsy of small lesions. We report our experience using robot-assisted bronchoscopy with dye marking to aid in minimally invasive pulmonary resection. METHODS: Patients with peripheral pulmonary nodules underwent robot-assisted bronchoscopy before a planned minimally invasive resection. Indocyanine green or methylene blue was injected directly into the targeted lesion. Surgical resection was then immediately performed. Success was defined as dye visualization leading to sublobar resection of the target nodule without the need for lobectomy or thoracotomy. RESULTS: Thirty patients with a single targeted nodule underwent robot-assisted bronchoscopy followed by MIS resection. The median lesion size was 9 mm (4 to 25 mm), and the median distance from the pleura was 5 mm (1 to 32 mm). The success rate was 83.3% (25 of 30). There were 3 cases in which the dye was not visualized, and in 2 cases there was free extravasation of dye. The targeted nodule was identified in these 5 patients without the need for thoracotomy or lobectomy. Pathology revealed non-small cell lung cancer (n = 13, 43.3%), metastatic disease (n = 11, 36.7%), and benign disease (n = 6, 20%). There were no complications related to the use of robot-assisted bronchoscopy. CONCLUSIONS: Robot-assisted bronchoscopy with dye marking is safe and effective for guiding minimally invasive resection of small peripheral pulmonary nodules.

Neoadjuvant nivolumab or nivolumab plus LAG-3 inhibitor relatlimab in resectable esophageal/gastroesophageal junction cancer: a phase Ib trial and ctDNA analyses.

Gastroesophageal cancer dynamics and drivers of clinical responses with immune checkpoint inhibitors (ICI) remain poorly understood. Potential synergistic activity of dual programmed cell death protein 1 (PD-1) and lymphocyte-activation gene 3 (LAG-3) inhibition may help improve immunotherapy responses for these tumors. We report a phase Ib trial that evaluated neoadjuvant nivolumab (Arm A, n = 16) or nivolumab-relatlimab (Arm B, n = 16) in combination with chemoradiotherapy in 32 patients with resectable stage II/stage III gastroesophageal cancer together with an in-depth evaluation of pathological, molecular and functional immune responses. Primary endpoint was safety; the secondary endpoint was feasibility; exploratory endpoints included pathological complete (pCR) and major pathological response (MPR), recurrence-free survival (RFS) and overall survival (OS). The study met its primary safety endpoint in Arm A, although Arm B required modification to mitigate toxicity. pCR and MPR rates were 40% and 53.5% for Arm A and 21.4% and 57.1% for Arm B. Most common adverse events were fatigue, nausea, thrombocytopenia and dermatitis. Overall, 2-year RFS and OS rates were 72.5% and 82.6%, respectively. Higher baseline programmed cell death ligand 1 (PD-L1) and LAG-3 expression were associated with deeper pathological responses. Exploratory analyses of circulating tumor DNA (ctDNA) showed that patients with undetectable ctDNA post-ICI induction, preoperatively and postoperatively had a significantly longer RFS and OS; ctDNA clearance was reflective of neoantigen-specific T cell responses. Our findings provide insights into the safety profile of combined PD-1 and LAG-3 blockade in gastroesophageal cancer and highlight the potential of ctDNA analysis to dynamically assess systemic tumor burden during neoadjuvant ICI that may open a therapeutic window for future intervention. ClinicalTrials.gov registration: NCT03044613 .

Elucidating the Heterogeneity of Immunotherapy Response and Immune-Related Toxicities by Longitudinal ctDNA and Immune Cell Compartment Tracking in Lung Cancer.

PURPOSE: Although immunotherapy is the mainstay of therapy for advanced non-small cell lung cancer (NSCLC), robust biomarkers of clinical response are lacking. The heterogeneity of clinical responses together with the limited value of radiographic response assessments to timely and accurately predict therapeutic effect-especially in the setting of stable disease-calls for the development of molecularly informed real-time minimally invasive approaches. In addition to capturing tumor regression, liquid biopsies may be informative in capturing immune-related adverse events (irAE). EXPERIMENTAL DESIGN: We investigated longitudinal changes in circulating tumor DNA (ctDNA) in patients with metastatic NSCLC who received immunotherapy-based regimens. Using ctDNA targeted error-correction sequencing together with matched sequencing of white blood cells and tumor tissue, we tracked serial changes in cell-free tumor load (cfTL) and determined molecular response. Peripheral T-cell repertoire dynamics were serially assessed and evaluated together with plasma protein expression profiles. RESULTS: Molecular response, defined as complete clearance of cfTL, was significantly associated with progression-free (log-rank P = 0.0003) and overall survival (log-rank P = 0.01) and was particularly informative in capturing differential survival outcomes among patients with radiographically stable disease. For patients who developed irAEs, on-treatment peripheral blood T-cell repertoire reshaping, assessed by significant T-cell receptor (TCR) clonotypic expansions and regressions, was identified on average 5 months prior to clinical diagnosis of an irAE. CONCLUSIONS: Molecular responses assist with the interpretation of heterogeneous clinical responses, especially for patients with stable disease. Our complementary assessment of the peripheral tumor and immune compartments provides an approach for monitoring of clinical benefits and irAEs during immunotherapy.

Intercostal Cryoablation During Video-Assisted Lung Resection Can Decrease Postoperative Opioid Use.

OBJECTIVE: Pain requiring opioid use remains an issue even with minimally invasive thoracic surgery. The objective of this study was to investigate the effectiveness of intercostal nerve cryoablation (CRYO) for pain control in adult patients undergoing pulmonary resection. METHODS: A retrospective analysis of patients undergoing pulmonary resection by uniportal video-assisted thoracic (uVATS) approach was undertaken. Patients treated with our usual pain regimen (STANDARD) were compared with those who additionally received CRYO. STANDARD includes intercostal bupivacaine, patient-controlled analgesia (24 h), ketorolac (48 to 72 h), and tramadol. Intraoperative CRYO was performed on 5 intercostal levels. The primary aim was to compare pain scores (range, 0 to 10) and morphine equivalent dosages (MED). Secondary outcomes included length of stay, chest tube duration, presence of an air leak, and adverse events. A p value <0.05 was considered significant. RESULTS: There were 49 patients (34 female, 15 male). The median age was 74 (37 to 90) years. Procedures included lobectomy (n = 32), segmentectomy (n = 7), and wedge resections (n = 10). There were 23 (46.9%) CRYO and 26 (53.1%) STANDARD patients. Baseline characteristics were similar. Mean length of stay (2.9 vs 3.5 days), chest tube duration (2.2 vs 1.8 days), and adverse events (9 of 23 vs 7 of 26) were similar. There were no complications attributable to CRYO. Pain scores were not significantly different on postoperative days (POD) 1 to 4. MED was significantly reduced after CRYO on POD 1 (5 vs 47.24), POD 2 (10.93 vs 25.04), POD 3 (8.13 vs 21.7), and POD 4 (7.08 vs 19.17). CONCLUSIONS: CRYO can be performed safely during pulmonary resection and can decrease in-hospital opioid use. The results from this retrospective study will need to be validated in future prospective studies.

Safety of adjuvant atezolizumab after pneumonectomy/bilobectomy in stage II-IIIA non-small cell lung cancer in the randomized phase III IMpower010 trial.

OBJECTIVE: Adjuvant atezolizumab is a standard of care after chemotherapy in completely resected stage II-IIIA programmed death ligand-1 tumor cell 1% or greater non-small cell lung cancer based on results from the phase III IMpower010 study. We explored the safety and tolerability of adjuvant atezolizumab by surgery type in IMpower010. METHODS: Patients had completely resected stage IB-IIIA non-small cell lung cancer (Union Internationale Contre le Cancer/American Joint Committee on Cancer, 7th Ed), received up to four 21-day cycles of cisplatin-based chemotherapy, and were randomized 1:1 to receive atezolizumab 1200 mg every 3 weeks (≤16 cycles or 1 year) or best supportive care. Adverse events and clinical characteristics were investigated by surgery type (pneumonectomy/bilobectomy or lobectomy/sleeve lobectomy) in the randomized stage II-IIIA population who received 1 or more atezolizumab dose or with 1 or more postbaseline assessment (safety evaluable) for best supportive care. RESULTS: Overall, 871 patients comprised the safety-evaluable randomized stage II-IIIA population. In the atezolizumab arm, 23% (100/433) received pneumonectomy/bilobectomy and 77% (332/433) received lobectomy/sleeve lobectomy. Atezolizumab discontinuation occurred in 32% (n = 32) and 35% (n = 115) of the pneumonectomy/bilobectomy and lobectomy/sleeve lobectomy groups, respectively. Grade 3/4 adverse events were reported in 21% (n = 21) and 23% (n = 76) of patients in the atezolizumab arms in the pneumonectomy/bilobectomy and lobectomy/sleeve lobectomy groups, respectively. In the atezolizumab arms of the surgery groups, 13% (n = 13) and 17% (n = 55) had an adverse event leading to hospitalization. Atezolizumab-related adverse events leading to hospitalization occurred in 5% (n = 5) and 7% (n = 23) of the surgery groups. CONCLUSIONS: These exploratory findings support use of adjuvant atezolizumab after platinum-based chemotherapy in patients with completely resected stage II-IIIA programmed death ligand-1 tumor cell 1% or more non-small cell lung cancer, regardless of surgery type.

Factors associated with access and approach to esophagectomy for cancer: a National Cancer Database study.

BACKGROUND: Minimally invasive esophagectomy (MIE) for esophageal cancer has been associated with decreased pain, less blood loss, and shorter hospital stay with comparable survival to open surgery. To date, there is minimal information regarding what factors are associated with access to MIE. METHODS: The National Cancer Database (NCDB) was used to compare rates of MIE (either robotic or laparoscopic) and open esophagectomy (OE) by demographic and clinical factors. Continuous variables were compared using a linear trend test, and categorical variables were compared using Mantel-Haenszel tests. Binomial regression was performed to examine significant factors after adjusting for confounding variables. RESULTS: There were 18,366 patients included in the analysis. Of all esophagectomies performed in the US, 49% were performed by OE and 51% were performed by MIE. Patients who had undergone MIE were more likely to live in the Eastern US as compared with the Midwest [odds ratio (OR) 1.72; 95% confidence interval (CI) 1.58, 1.88] or the South (OR 1.31; 95% CI 1.19, 1.44). They were also more likely to be treated at an academic center (OR 1.64; 95% CI 1.53, 1.75) rather than a community hospital, and to be of White race as compared with Asian race (OR 1.46; 95% CI 1.10, 1.92). There was not a significant difference in the rates of MIE between White and Black patients (OR 1.12; 95% CI 0.96, 1.32). MIE was more likely with each passing year, and higher TNM stages of cancer were less likely to be treated with MIE (P < 0.001 for all). CONCLUSION: While MIE is evolving, OE is still considered standard of care with robotic approaches representing a minority of MIE. While there are several factors associated with access to MIE, including race, facility type and geographic location, these factors should be further explored to help increase access to MIE.

Randomized trial of bupivacaine with epinephrine versus bupivacaine liposome suspension in patients undergoing minimally invasive lung resection.

OBJECTIVES: Thoracic surgery can cause significant pain, and multiple strategies have been developed to control pain after surgery. We compared 2 bupivacaine formulations given intraoperatively: bupivacaine with epinephrine (1,200,000) or liposomal bupivacaine. METHODS: This was a randomized, open-label study (NCT03560362). Eligible patients were adults scheduled for a minimally invasive lung procedure. Incision sites were injected with bupivacaine with epinephrine or liposomal bupivacaine before incision, and each intercostal space was injected with 1 mL of bupivacaine with epinephrine or liposomal bupivacaine entering the thoracic cavity. Patient-controlled analgesia was initiated in the recovery room. Pain was recorded using a visual analog scale. The primary outcome was the amount of narcotics taken during the postoperative hospital stay. RESULTS: We recruited 50 patients; 25 received bupivacaine with epinephrine, and 25 received liposomal bupivacaine. The treatment groups were similar in age, histology, and procedure performed. There were no statistical differences between the treatment groups in the amount of narcotics required during the hospital stay (36.3 mg for bupivacaine and 38 mg for liposomal bupivacaine) or in pain assessed the day of surgery (5 and 5), the first day (3.5 and 2.3), second day (3 and 2.6), 2 weeks (0 and 1), or 3 months (0 and 0) postoperatively. Hospital length of stay and complications were also similar. CONCLUSIONS: In a small, randomized study, we did not find significant differences between bupivacaine with epinephrine or liposomal bupivacaine in mitigating pain after minimally invasive lung resection. We currently favor using the less expensive nonliposomal bupivacaine preparations until additional data are available.