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 .

Five-Year Clinical Outcomes after Neoadjuvant Nivolumab in Resectable Non-Small Cell Lung Cancer.

PURPOSE: Neoadjuvant anti-PD-1 therapy has shown promise for resectable non-small cell lung cancer (NSCLC). We reported the first phase I/II trial of neoadjuvant nivolumab in resectable NSCLC, finding it to be safe and feasible with encouraging major pathological responses (MPR). We now present 5-year clinical outcomes from this trial, representing to our knowledge, the longest follow-up data for neoadjuvant anti-PD-1 in any cancer type. PATIENTS AND METHODS: Two doses of nivolumab (3 mg/kg) were administered for 4 weeks before surgery to 21 patients with Stage I-IIIA NSCLC. 5-year recurrence-free survival (RFS), overall survival (OS), and associations with MPR and PD-L1, were evaluated. RESULTS: With a median follow-up of 63 months, 5-year RFS and OS rates were 60% and 80%, respectively. The presence of MPR and pre-treatment tumor PD-L1 positivity (TPS ≥1%) each trended toward favorable RFS; HR, 0.61 [95% confidence interval (CI), 0.15-2.44] and HR, 0.36 (95% CI, 0.07-1.85), respectively. At 5-year follow-up, 8 of 9 (89%) patients with MPR were alive and disease-free. There were no cancer-related deaths among patients with MPR. In contrast, 6/11 patients without MPR experienced tumor relapse, and 3 died. CONCLUSIONS: Five-year clinical outcomes for neoadjuvant nivolumab in resectable NSCLC compare favorably with historical outcomes. MPR and PD-L1 positivity trended toward improved RFS, though definitive conclusions are limited by cohort size.

Plain language summary of the CheckMate 816 study results: nivolumab plus chemotherapy given before surgery for non-small-cell lung cancer.

WHAT IS THIS SUMMARY ABOUT?: In this article, we summarize results from the ongoing phase 3 CheckMate 816 clinical study that were published in The New England Journal of Medicine in 2022. The goal of CheckMate 816 was to find out if nivolumab, an immunotherapy that activates a person's immune system (the body's natural defense system) to fight cancer, plus chemotherapy works better than chemotherapy alone when given before surgery in people with non-small-cell lung cancer (NSCLC) that can be removed surgically (resectable NSCLC). WHAT HAPPENED IN THE STUDY?: Adults who had not previously taken medications to treat NSCLC and whose cancer could be removed with surgery were included in CheckMate 816. During this study, a computer randomly assigned the treatment each person would receive before surgery for NSCLC. In total, 179 people were randomly assigned to receive nivolumab plus chemotherapy, and 179 people were randomly assigned to receive chemotherapy alone. The researchers assessed whether people who received nivolumab plus chemotherapy lived longer without the cancer geting worse or coming back and whether there were any cancer cells left in the tumor and lymph nodes removed by surgery. The researchers also assessed how adding nivolumab to chemotherapy affected the timing and outcomes of surgery and whether the combination of these drugs was safe. WHAT WERE THE RESULTS?: Researchers found that people who took nivolumab plus chemotherapy lived longer without the cancer getting worse or coming back compared with those who took chemotherapy alone. More people in the nivolumab plus chemotherapy group had no cancer cells left in the tumor and lymph nodes removed by surgery. Most people went on to have surgery in both treatment groups; the people who took nivolumab plus chemotherapy instead of chemotherapy alone had less extensive surgeries and were more likely to have good outcomes after less extensive surgeries. Adding nivolumab to chemotherapy did not lead to an increase in the rate of side effects compared with chemotherapy alone, and side effects were generally mild and manageable. WHAT DO THE RESULTS OF THE STUDY MEAN?: Results from CheckMate 816 support the benefit of using nivolumab plus chemotherapy before surgery for people with resectable NSCLC. Clinical Trial Registration: NCT02998528 (ClinicalTrials.gov).

The COVID-19 Era Is Associated With Delays in Esophageal Cancer Diagnosis and Treatment.

INTRODUCTION: The coronavirus disease-2019 (COVID-19) pandemic has substantially affected the delivery of healthcare globally. The purpose of this study was to evaluate the association of this era with the timeline of care in esophageal cancer patients. METHODS: We performed a retrospective chart-review of patients presenting to a single high-volume tertiary care center with the diagnosis of esophageal cancer. COVID era was defined as March 2020-December 2020 and compared with the year before (3/2019-12/2019). RESULTS: In total, 117 patients presented in the COVID-era versus 190 in pre-COVID. Stage 3 + 4 disease was found in 77.8% of the patients in the COVID-era compared to 68.9% in the pre-COVID era (P = 0.34). Diagnoses through emergency department admission were 35.5% in the COVID versus 26.7% in the pre-COVID group (P = 0.15). In the COVID era it took a median of 78 d to visit primary care provider (versus 52 d, P = 0.12 in pre-COVID), 45 d to endoscopy (versus 18 d, P = 0.004) and 38 d to treatment initiation (versus 36 d, P = 0.48). Thirty-five percent of the patients underwent esophagectomy compared to 26% in the pre-COVID-era. Median days of intensive-care-unit (ICU) (2 versus 3, P = 0.16) and hospital stay (14 versus 15, P = 0.28) were similar in both groups as well as postoperative 30-day morbidities (63 versus 63%, P = 0.48). One-year follow-up showed 83.7% (95% confidence interval [CI]: 73.8%-90.1%) survival in the COVID-group compared to 76.4% (95% CI: 66.9%-83.5%) in the pre-COVID-group (P = 0.58). Only three patients had a positive COVID result. CONCLUSIONS: Our institution treated fewer esophageal cancer patients during COVID-19 accompanied by a delay in endoscopic diagnosis. Postoperative outcomes and 1-year survival remained similar.

Spiral Laminar Flow is Associated with a Reduction in Disturbed Shear in Patient-Specific Models of an Arteriovenous Fistula.

PURPOSE: Areas of disturbed shear that arise following arteriovenous fistula (AVF) creation are believed to contribute to the development of intimal hyperplasia (IH). The presence of helical flow can suppress areas of disturbed shear, which may protect the vasculature from IH. Therefore, the aim of this study is to determine if helical flow, specifically spiral laminar flow (SLF), is present in patient-specific AVF models and is associated with a reduction in exposure to disturbed shear. METHODS: Four AVF were imaged using MRI within the first two weeks following fistula creation. Patient-specific boundary conditions were obtained using phase-contrast MRI and applied at the inlet and outlets of each model. Computational fluid dynamics was used to analyse the hemodynamics in each model and compare the helical content of the flow to the distribution of disturbed shear. RESULTS: BC-1 and RC-2 are characterised by the presence of SLF, which coincides with the lowest distribution of disturbed shear. Contrastingly, SLF is absent from BC-2 and RC-1 and experience the largest amount of disturbed shear. Interestingly, BC-2 and RC-1 developed an anastomosis stenosis, while BC-1 and RC-2 remained stenosis free. CONCLUSION: These findings are in agreement with previous clinical studies and further highlight the clinical potential of SLF as a prognostic marker for a healthy AVF, as its presence correlates with an overall reduction in exposure to disturbed shear and a decrease in the incidence of AVF dysfunction, albeit in a small sample size.

Neoadjuvant Nivolumab plus Chemotherapy in Resectable Lung Cancer.

BACKGROUND: Neoadjuvant or adjuvant chemotherapy confers a modest benefit over surgery alone for resectable non-small-cell lung cancer (NSCLC). In early-phase trials, nivolumab-based neoadjuvant regimens have shown promising clinical activity; however, data from phase 3 trials are needed to confirm these findings. METHODS: In this open-label, phase 3 trial, we randomly assigned patients with stage IB to IIIA resectable NSCLC to receive nivolumab plus platinum-based chemotherapy or platinum-based chemotherapy alone, followed by resection. The primary end points were event-free survival and pathological complete response (0% viable tumor in resected lung and lymph nodes), both evaluated by blinded independent review. Overall survival was a key secondary end point. Safety was assessed in all treated patients. RESULTS: The median event-free survival was 31.6 months (95% confidence interval [CI], 30.2 to not reached) with nivolumab plus chemotherapy and 20.8 months (95% CI, 14.0 to 26.7) with chemotherapy alone (hazard ratio for disease progression, disease recurrence, or death, 0.63; 97.38% CI, 0.43 to 0.91; P = 0.005). The percentage of patients with a pathological complete response was 24.0% (95% CI, 18.0 to 31.0) and 2.2% (95% CI, 0.6 to 5.6), respectively (odds ratio, 13.94; 99% CI, 3.49 to 55.75; P<0.001). Results for event-free survival and pathological complete response across most subgroups favored nivolumab plus chemotherapy over chemotherapy alone. At the first prespecified interim analysis, the hazard ratio for death was 0.57 (99.67% CI, 0.30 to 1.07) and did not meet the criterion for significance. Of the patients who underwent randomization, 83.2% of those in the nivolumab-plus-chemotherapy group and 75.4% of those in the chemotherapy-alone group underwent surgery. Grade 3 or 4 treatment-related adverse events occurred in 33.5% of the patients in the nivolumab-plus-chemotherapy group and in 36.9% of those in the chemotherapy-alone group. CONCLUSIONS: In patients with resectable NSCLC, neoadjuvant nivolumab plus chemotherapy resulted in significantly longer event-free survival and a higher percentage of patients with a pathological complete response than chemotherapy alone. The addition of nivolumab to neoadjuvant chemotherapy did not increase the incidence of adverse events or impede the feasibility of surgery. (Funded by Bristol Myers Squibb; CheckMate 816 ClinicalTrials.gov number, NCT02998528.).

Impact of Chest Wall Resection on Mortality After Lung Resection for Non-Small Cell Lung Cancer.

BACKGROUND: Lung cancer invading the chest wall is treated with concomitant en bloc lung and chest wall resection (CWR). It is unclear how CWR affects postoperative outcomes of lung resection. We hypothesized that CWR would be associated with increased risk of adverse outcomes after lung cancer resection. METHODS: We performed a retrospective analysis of The Society of Thoracic Surgeons (STS) General Thoracic Surgery Database from 2016-2019. Patients with superior sulcus tumors were excluded. Patient demographic and operative outcomes were compared between those with and without CWR. Chest wall resection was added to existing STS lung risk models to determine the association with a composite adverse outcome, which included major morbidity and death. RESULTS: Among 41 310 lung resections, 306 (0.74%) occurred with concomitant CWR. Differences between those with and without CWR included demographic and comorbidities. Patients undergoing CWR were more likely to have the composite adverse outcome (64 of 306 [20.9%] vs 3128 of 41 004 [7.6%] for non-CWR resections, P < .001). Mortality was also increased among the CWR cohort (2.9% vs 1.1%, P = .003). CWR was associated with an increased risk of adverse composite outcome among all lung resection patients in a multivariable model (odds ratio 1.74, P = .0003) and the lobectomy subgroup (odds ratio 2.35, P < .0001). Among institutions with ≥10 lung resections, 49.1% performed lung resections with CWR. CONCLUSIONS: Concomitant CWR adds risk of adverse outcomes after lung cancer resection. As a subset of intuitions perform CWR, quality assessments should control for CWR. This variable will be incorporated into the STS lung cancer and lobectomy quality composite measures.

Trimodality therapy for esophageal cancer: The role of surgical and radiation treatment parameters in the development of anastomotic complications.

BACKGROUND: Here, we investigated the relationship between clinical parameters, including the site of surgical anastomosis and radiation dose to the anastomotic region, and anastomotic complications in esophageal cancer patients treated with trimodality therapy. METHODS: Between 2007 and 2016, esophageal cancer patients treated with trimodality therapy at a tertiary academic cancer center were identified. Patient, treatment, and outcome parameters were collected. Radiation dose to the gastric regions were extracted. Anastomotic complication was defined as leak and/or stricture. We used Fisher's exact and Wilcoxon rank-sum tests to compare the association between clinical parameters and anastomotic complications. RESULTS: Of 89 patients identified, the median age was 63 years, 82% (n = 73) were male, and 82% had distal (n = 47) or gastroesophageal junction (n = 26) tumors. Median follow-up was 25.8 months. Esophagectomies were performed with cervical (65%, n = 58) or thoracic anastomoses (35%, n = 31). Anastomotic complications developed in 60% (n = 53). Cervical anastomosis was associated with anastomotic complications (83%, n = 44/53, p < 0.01). Radiation to any gastric substructure was not associated with anastomotic complications (p > 0.05). In the subset of patients with distal/gastroesophageal junction tumors undergoing esophagectomy with cervical anastomosis where radiation was delivered to the future neoesophagus, 80% (n = 35/44) developed anastomotic complications. In this high-risk subgroup, radiation was not associated with anastomotic complications (p > 0.05). CONCLUSIONS: Our analysis did not demonstrate an association between radiation dose to gastric substructures and anastomotic complications. However, it showed an association between esophagectomy with cervical anastomosis and anastomotic complications. Patients with distal/gastroesophageal junction tumors who undergo esophagectomy with cervical anastomosis have higher rates of anastomotic complications unrelated to radiation to gastric substructures.

The Society of Thoracic Surgeons General Thoracic Surgery Database: 2021 Update on Outcomes and Research.

The Society of Thoracic Surgeons General Thoracic Surgery Database (STS GTSD) remains the largest and most robust thoracic surgical database in the world. Participating sites receive risk-adjusted performance reports for benchmarking and quality improvement initiatives. The GTSD also provides several mechanisms for high-quality clinical research using data from 271 participant sites and nearly 720,000 procedures since its inception in 2002. Participant sites are audited at random annually for completeness and accuracy. During the last year and a half, the GTSD Task Force continued to refine the data collection form, ensuring high-quality data while minimizing data entry burden. In addition, the STS Workforce on National Databases has supported robust GTSD-based research program, which led to 10 scholarly publications in 2020. This report provides an update on outcomes, volume trends, and database improvements as well as a summary of research productivity resulting from the GTSD over the preceding year.

Association of severe lymphopenia and disease progression in unresectable locally advanced non-small cell lung cancer treated with definitive chemoradiation and immunotherapy.

BACKGROUND: Definitive chemoradiation with consolidative immunotherapy offers the best chance for cure in patients with unresectable, locally advanced non-small cell lung cancer (NSCLC). However, treatment-related lymphopenia (TRL) may negatively impact outcomes. METHODS: Patients definitively treated with chemoradiation and immunotherapy from 2015 to 2019 at a single tertiary academic center were identified. Severe lymphopenia was defined as <0.5 × 109 cells/L. Progression-free survival (PFS) was calculated by Kaplan Meier methodology. Univariate and multivariate Cox Proportional Hazard modeling was used to correlate clinical variables with disease outcome. Immune-related adverse events (irAEs) were assessed according to CTCAE version 5.0 criteria. RESULTS: Seventy-eight patients were included in the final cohort. The median age was 66 years (IQR: 58-73), 55 % were males, and 88 % had a KPS of >70. At baseline, 90 % (n = 70/78) of patients had a normal ALC and one patient had severe lymphopenia. After chemoradiation, the median ALC decreased from 1.52 × 109cells/L (IQR: 1.23-1.98) to 0.72 × 109cells/L (IQR: 0.52-0.94) (p < 0.001), 22 % (n = 17/78) of patients had a normal ALC, and 23 % (n = 18/78) of patients developed severe lymphopenia. Patients who initiated consolidative immunotherapy with severe lymphopenia had worse PFS than those who did not (median 217 days [IQR: 120-434] vs. 570 days [IQR: 401-NR], p < 0.001). On multivariate modeling, severe lymphopenia at the time of immunotherapy initiation remained an independent predictor of worse PFS (HR 4.90, p < 0.001). CONCLUSIONS: This is the first report to associate severe TRL with disease progression in patients with locally advanced NSCLC receiving consolidative immunotherapy. Factors associated with development of lymphopenia and strategies to mitigate lymphopenic effects should be considered.

Elevated neutrophil to lymphocyte ratio is associated with poor long-term survival and graft failure after lung transplantation.

PURPOSE: We aimed to assess the prognostic value of Neutrophil to Lymphocyte Ratio (NLR) on long-term outcomes and graft dysfunction after lung transplantation. METHODS: We retrospectively reviewed all patients receiving a lung transplant at our institution from 2011 to 2014. The primary exposure was elevated NLR at the time of transplant, defined by NLR>4. The primary outcomes were graft failure and three-year all-cause mortality. Multivariate logistic regression and Kaplan-Meier survival analysis were used to analyze outcomes. RESULTS: 95 patients were included. 40 patients (42%) had an elevated NLR. Elevated NLR was associated with graft failure (OR: 4.7 [1.2-18.8], p = 0.02), and three-year mortality (OR: 5.4 [1.3-23.2], p = 0.03) on multivariate logistic regression. Patients with elevated NLR demonstrated significantly lower survival on Kaplan-Meier analysis (50% versus 74%, p = 0.02). The c-statistic for our multivariate model was 0.91. CONCLUSION: Elevated neutrophil to lymphocyte ratio is associated with poor long-term survival and graft failure after lung transplantation.

Variability in Smoking Status for Lobectomy Among Society of Thoracic Surgeons Database Participants.

BACKGROUND: Current smokers undergoing lobectomy are at greater risk of complications than are former smokers. The Society of Thoracic Surgeons (STS) composite score for rating program performance for lobectomy adjusts for smoking status, a modifiable risk factor. This study examined variability in the proportion of current smokers undergoing lobectomy among STS database participants. Additionally, the study determined whether each participant's rating changed if smoking was excluded from the risk adjustment model. METHODS: This is a retrospective analysis of the STS cohort used to develop the composite score for rating program performance for lobectomy. The study summarized the variability among STS database participants for performing lobectomy on current smokers and compared star ratings developed from models with and without smoking status. RESULTS: There were 24,912 patients with smoking status data: 23% current smokers, 62% former smokers, and 15% never smokers. There was significant variability among participants in the proportion of current smokers undergoing lobectomy (3% to 48.6%; P < .001). Major morbidity or mortality (composite) was greater in current smokers (12.1%) than in former smokers (8.6%) and never smokers (4.2%) (P < .001). Using the current risk adjustment model, participant star ratings were as follows: 1 star, n = 6 (3.2%); 2 stars, n = 170 (91.4%); and 3 stars, n = 10 (5.4%). When smoking status was excluded from the model, 1 participant shifted from a 2-star to a 3-star program. CONCLUSIONS: There is substantial variability among STS database participants with regard to the proportion of current smokers undergoing lobectomy. However, exclusion of smoking status from the model did not significantly affect participant star rating.

Epidemiologic Trends in Pleural Infection. A Nationwide Analysis.

Rationale: Recent trends in the care and outcomes of pleural infection are not well characterized.Objectives: To investigate trends in hospital-based healthcare use, outcomes, and management of pleural infection across the United States.Methods: We identified adult hospitalizations for pleural infection from 2005 through 2014 in the Healthcare Cost and Utilization Project-National Inpatient Sample using International Classification of Diseases, Ninth Edition Clinical Modification diagnosis codes. We calculated weighted estimates of national trends in hospitalization, hospital length of stay, hospital mortality, inflation-adjusted cost, and management practices. We tested trend significance using fitted regression models.Results: Over one decade, there was a significant decline in hospitalizations (54.4 per million to 41.2 per million U.S. adult population), length of stay (13.5 ± 0.2 to 11.2 ± 0.2 d), mortality (4.2-2.6%), and costs ($32,829 to $29,458) (all P < 0.001). Both tube thoracostomy and video-assisted thoracoscopic surgery saw an increase as the procedure of first choice, along with declining use of thoracotomy (all P < 0.001). Most patients who underwent video-assisted thoracoscopic surgery (94%) or tube thoracostomy (64.9%) as the initial procedure did not require a second invasive procedure.Conclusions: Over the 21st century's first decade and a half, inpatient costs, use, and mortality have improved among U.S. adults hospitalized with pleural infection. Simultaneously, there has been a shift toward less invasive interventions upfront.

Defining best practices for tissue procurement in immuno-oncology clinical trials: consensus statement from the Society for Immunotherapy of Cancer Surgery Committee.

Immunotherapy is now a cornerstone for cancer treatment, and much attention has been placed on the identification of prognostic and predictive biomarkers. The success of biomarker development is dependent on accurate and timely collection of biospecimens and high-quality processing, storage and shipping. Tumors are also increasingly used as source material for the generation of therapeutic T cells. There have been few guidelines or consensus statements on how to optimally collect and manage biospecimens and source material being used for immunotherapy and related research. The Society for Immunotherapy of Cancer Surgery Committee has brought together surgical experts from multiple subspecialty disciplines to identify best practices and to provide consensus on how best to access and manage specific tissues for immuno-oncology treatments and clinical investigation. In addition, the committee recommends early integration of surgeons and other interventional physicians with expertise in biospecimen collection, especially in clinical trials, to optimize the quality of tissue and the validity of correlative clinical studies in cancer immunotherapy.