Neoadjuvant durvalumab plus radiation versus durvalumab alone in stages I-III non-small cell lung cancer: survival outcomes and molecular correlates of a randomized phase II trial.

We previously reported the results of a randomized phase II trial (NCT02904954) in patients with early-stage non-small cell lung cancer (NSCLC) who were treated with either two preoperative cycles of the anti-PD-L1 antibody durvalumab alone or combined with immunomodulatory doses of stereotactic radiation (DRT). The trial met its primary endpoint of major pathological response, which was significantly higher following DRT with no new safety signals. Here, we report on the prespecified secondary endpoint of disease-free survival (DFS) regardless of treatment assignment and the prespecified exploratory analysis of DFS in each arm of the trial. DFS at 2 and 3 years across patients in both arms of the trial were 73% (95% CI: 62.1-84.5) and 65% (95% CI: 52.5-76.9) respectively. For the exploratory endpoint of DFS in each arm of the trial, three-year DFS was 63% (95% CI: 46.0-80.4) in the durvalumab monotherapy arm compared to 67% (95% CI: 49.6-83.4) in the dual therapy arm. In addition, we report post hoc exploratory analysis of progression-free survival as well as molecular correlates of response and recurrence through high-plex immunophenotyping of sequentially collected peripheral blood and gene expression profiles from resected tumors in both treatment arms. Together, our results contribute to the evolving landscape of neoadjuvant treatment regimens for NSCLC and identify easily measurable potential biomarkers of response and recurrence.

Sub-Lobar Resection: The New Standard of Care for Early-Stage Lung Cancer.

The Lung Cancer Study Group previously established lobectomy as the standard of care for treatment of clinical T1N0 NSCLC. Advances in imaging technology and refinements in staging have prompted a re-investigation to determine the non-inferiority of sub-lobar resections to lobectomies. Two recent randomized studies, JCOG 0802 and CALGB 140503, are reviewed here in the context of LCSG 0821. The studies confirm non-inferiority for sub-lobar resection (wedge or segmentectomy) compared to lobectomy for peripheral T1N0 NSCLC less than or equal to 2 cm. Sub-lobar resection should therefore be considered the new standard of care in this sub-set of patients with NSCLC.

Neoadjuvant durvalumab with or without stereotactic body radiotherapy in patients with early-stage non-small-cell lung cancer: a single-centre, randomised phase 2 trial.

BACKGROUND: Previous phase 2 trials of neoadjuvant anti-PD-1 or anti-PD-L1 monotherapy in patients with early-stage non-small-cell lung cancer have reported major pathological response rates in the range of 15-45%. Evidence suggests that stereotactic body radiotherapy might be a potent immunomodulator in advanced non-small-cell lung cancer (NSCLC). In this trial, we aimed to evaluate the use of stereotactic body radiotherapy in patients with early-stage NSCLC as an immunomodulator to enhance the anti-tumour immune response associated with the anti-PD-L1 antibody durvalumab. METHODS: We did a single-centre, open-label, randomised, controlled, phase 2 trial, comparing neoadjuvant durvalumab alone with neoadjuvant durvalumab plus stereotactic radiotherapy in patients with early-stage NSCLC, at NewYork-Presbyterian and Weill Cornell Medical Center (New York, NY, USA). We enrolled patients with potentially resectable early-stage NSCLC (clinical stages I-IIIA as per the 7th edition of the American Joint Committee on Cancer) who were aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0 or 1. Eligible patients were randomly assigned (1:1) to either neoadjuvant durvalumab monotherapy or neoadjuvant durvalumab plus stereotactic body radiotherapy (8 Gy × 3 fractions), using permuted blocks with varied sizes and no stratification for clinical or molecular variables. Patients, treating physicians, and all study personnel were unmasked to treatment assignment after all patients were randomly assigned. All patients received two cycles of durvalumab 3 weeks apart at a dose of 1·12 g by intravenous infusion over 60 min. Those in the durvalumab plus radiotherapy group also received three consecutive daily fractions of 8 Gy stereotactic body radiotherapy delivered to the primary tumour immediately before the first cycle of durvalumab. Patients without systemic disease progression proceeded to surgical resection. The primary endpoint was major pathological response in the primary tumour. All analyses were done on an intention-to-treat basis. This trial is registered with ClinicalTrial.gov, NCT02904954, and is ongoing but closed to accrual. FINDINGS: Between Jan 25, 2017, and Sept 15, 2020, 96 patients were screened and 60 were enrolled and randomly assigned to either the durvalumab monotherapy group (n=30) or the durvalumab plus radiotherapy group (n=30). 26 (87%) of 30 patients in each group had their tumours surgically resected. Major pathological response was observed in two (6·7% [95% CI 0·8-22·1]) of 30 patients in the durvalumab monotherapy group and 16 (53·3% [34·3-71·7]) of 30 patients in the durvalumab plus radiotherapy group. The difference in the major pathological response rates between both groups was significant (crude odds ratio 16·0 [95% CI 3·2-79·6]; p<0·0001). In the 16 patients in the dual therapy group with a major pathological response, eight (50%) had a complete pathological response. The second cycle of durvalumab was withheld in three (10%) of 30 patients in the dual therapy group due to immune-related adverse events (grade 3 hepatitis, grade 2 pancreatitis, and grade 3 fatigue and thrombocytopaenia). Grade 3-4 adverse events occurred in five (17%) of 30 patients in the durvalumab monotherapy group and six (20%) of 30 patients in the durvalumab plus radiotherapy group. The most frequent grade 3-4 events were hyponatraemia (three [10%] patients in the durvalumab monotherapy group) and hyperlipasaemia (three [10%] patients in the durvalumab plus radiotherapy group). Two patients in each group had serious adverse events (pulmonary embolism [n=1] and stroke [n=1] in the durvalumab monotherapy group, and pancreatitis [n=1] and fatigue [n=1] in the durvalumab plus radiotherapy group). No treatment-related deaths or deaths within 30 days of surgery were reported. INTERPRETATION: Neoadjuvant durvalumab combined with stereotactic body radiotherapy is well tolerated, safe, and associated with a high major pathological response rate. This neoadjuvant strategy should be validated in a larger trial. FUNDING: AstraZeneca.

The Use of Standardized Measures to Predict and Assess Quality of Life after Laparoscopic Hiatal Hernia Repair.

The literature regarding laparoscopic hiatal hernia repair is difficult to interpret because of inconsistencies in describing hernia characteristics and outcome measures. This study was performed to evaluate risk factors for an unsatisfactory outcome after repair using objective definitions of hernia size and a clinically relevant outcome instrument. A retrospective review of a prospectively maintained database was conducted over a seven-year period. Data collected included patient demographics and hernia-related variables. Outcomes were defined using a validated quality of life (QOL) instrument. Postoperatively, the mean total QOL score decreased from 22.9 to 5.8 (P < 0.001). In all, 13.8 per cent of patients had unsatisfactory QOL scores postoperatively. Multivariate analysis showed that high gastroesophageal (GE) junction position (P = 0.03) and female gender (P = 0.02) were the only significant factors associated with an unsatisfactory postoperative QOL. Laparoscopic hiatal hernia repair significantly improves QOL. With respect to predicting clinically relevant outcomes, hernias are best characterized by the position of the GE junction. Females with high GE junction position are at the highest risk for an unsatisfactory outcome.

Incidence and Prognostic Significance of Carcinoid Lymph Node Metastases.

BACKGROUND: Pulmonary carcinoid tumors are often considered indolent tumors. The prognostic significance of lymph node (LN) metastases and the need for mediastinal dissection is controversial. We sought to determine the incidence, risk factors, and prognosis of LN metastases in resected carcinoid patients. METHODS: Patients undergoing lung resection for carcinoid and removal of ≥10 LNs were identified in the National Cancer Database from 2004 to 2014. Typical (TCs) and atypical carcinoids (ACs) were included. Clinical and pathologic LN status was assessed. Overall survival (OS) was analyzed using log-rank test and Cox hazard regression analysis. RESULTS: A total of 3,335 patients (TC 2,893; AC 442), underwent resection (lobectomy/bilobectomy 84%, pneumonectomy 8%, sublobar resection 8%). LN involvement was present in 21% of patients (N1 15%, N2 6%) and increased with tumor size and AC histology. Tumor size was an independent predictor of LN disease. The rate of nodal upstaging was 13% (TC 11%, AC 24%). Independent predictors of OS were AC type (HR 3.25 [95% CI 2.19-4.78]) and LN metastases (HR 2.3 [1.49-3.58]). LN disease was associated with worse survival for TC > 2 cm (5-year OS 87% versus 94%, p = 0.005) and AC (58% versus 88%, p = 0.001), but not for small (≤ 2 cm) TC patients (5-year OS 93% versus 92%, p = 0.67). CONCLUSIONS: A substantial number of well-staged carcinoid patients had LN metastases. Large tumor size is a valuable predictor of carcinoid nodal disease. LN involvement was an independent predictor of worse survival. Nodal dissection in tumors > 2 cm and in atypical subtype can yield important prognostic information.

Robotic Thymectomy Is Feasible for Large Thymomas: A Propensity-Matched Comparison.

BACKGROUND: Robotic-assisted thymectomy (RAT) is increasingly performed for resection of thymomas. Its application for large tumors remains controversial. In this study, we evaluated the safety and feasibility of RAT for large thymomas in comparison with transsternal thymectomy (ST). METHODS: A single institution database was reviewed for patients who underwent RAT for thymoma of 4 cm or larger between 2004 and 2016. Propensity scores were applied to match RAT with ST patients, based on age, sex, tumor size, and Masaoka stage. Perioperative outcomes were compared. RESULTS: Twenty patients (15 women and 5 men, median age 59 years) underwent RAT for a large thymoma (median size 6.0 cm). A right-sided approach was used in 14 patients (70%). A control group of 34 ST patients (median size 6.7 cm) had similar Masaoka staging (p = 0.64). Combined resection of adjacent structures, including pericardium, lung, and phrenic nerve, were frequently performed in both groups (50% RAT versus 47% ST, p = 0.83). RAT patients had lower blood loss (25 mL versus 150 mL, p = 0.001), were more frequently managed with a single chest tube (85% versus 56%, p = 0.027), and had a shorter median length of stay (3 days versus 4 days, p = 0.034). There were no perioperative deaths and no major vascular injuries. Three RAT patients (15%) were converted to open approach. Overall complication rates were similar between RAT and ST patients (15% versus 24%, p = 0.45). No difference was seen in R0 resection rates (90% versus 85%, p = 0.62). CONCLUSIONS: RAT can be performed safely and effectively in a radical fashion for large thymomas. Future studies are necessary to determine long-term oncologic outcomes.

Survival Following Gastro-Left Ventricular Fistula in a Patient Post Roux-en-Y Gastric Bypass.

We report a case of a 55-year old woman with a prior roux-en-Y gastric bypass who survived after surgical repair of a gastro-left ventricular fistula.

Successful Treatment of an Iatrogenic Tracheal Laceration With a Temporary Polyurethane-Coated Nitinol Stent.

We report the case of a 63-year-old woman who required emergent intubation after a choking episode at home. It resulted in a 5-cm tear in the membranous trachea. She was treated by placement of a temporary tracheal stent, which was successfully removed 3 months later.

Nodal Upstaging in Robotic and Video Assisted Thoracic Surgery Lobectomy for Clinical N0 Lung Cancer.

BACKGROUND: Recent multiinstitutional published data have demonstrated increased pathologic nodal upstaging by robotic lobectomy compared with historical video-assisted thoracic surgery (VATS) lobectomy data. To eliminate potential variability from multiple surgical techniques, we compared the rate of nodal upstaging at a single institution where robotic and VATS lobectomy are both performed. METHODS: We retrospectively reviewed clinically node-negative patients with lung cancer undergoing VATS or robotic lobectomy. Clinical data were recorded in concordance with The Society of Thoracic Surgeons database elements. The rates of pathologic nodal upstaging as well as disease-free and overall survival were calculated. RESULTS: A total of 211 patients underwent anatomic lobectomy by VATS (n = 158) or robotics (n = 53) from 2009 to 2014. The two groups were statistically similar in their clinical stage, tumor size, location, and histologic evaluation. Within the VATS group, 24 patients experienced nodal upstaging (15.2%), with 13 patients having pN1 disease, and 11 patients having pN2 disease. The robotics group contained 7 patients (13.2%) with nodal upstaging, with 5 patients exhibiting pN1 disease and 2 patients with pN2 disease. When VATS and robotics were compared, there was no significant difference in pathologic upstaging (p = 0.72), 2-year overall survival (88% vs 95%, respectively; p = 0.40), or 2-year disease-free survival (83% vs 93%, respectively; p = 0.48). CONCLUSIONS: In this comparison of robotic and VATS lobectomy for clinically node-negative lung cancer that was managed with consistent surgical technique and pathologic evaluation, the rate of nodal upstaging achieved by robotics appears similar to VATS. In addition, there were no appreciable differences in disease-free or overall survival.

Right pneumonectomy for resection of a posterior mediastinal follicular dendritic cell sarcoma arising from Castleman's disease.

Follicular dendritic cell sarcoma is a rare malignant neoplasm of immune accessory follicular dendritic cells and may be associated with Castleman's disease which is a known precursor to follicular dendritic cell sarcomas. We report a case of a follicular dendritic cell sarcoma arising in Castleman's disease in a 63-year-old man who presented with a large posterior mediastinal mass, which required a radical pneumonectomy for complete resection.

Transitioning from video-assisted thoracic surgical lobectomy to robotics for lung cancer: are there outcomes advantages?

OBJECTIVES: To determine if there are advantages to transitioning to robotics by a surgeon who is already proficient in performing video-assisted thoracic surgical (VATS) lobectomy. METHODS: A single surgeon proficient in VATS lobectomy initiated a robotic lobectomy program, and a retrospective review was conducted of his patients undergoing minimally invasive lobectomy (robotics or VATS) for lung cancer between 2011 and 2012. Data collected included patient/tumor characteristics, morbidity, mortality, operative times, and length of hospital stay. RESULTS: Over a 24-month period, a total of 69 patients underwent minimally invasive lobectomy (35 robotic, 34 VATS). Patients in each group were similar in age and clinical stage. Robotic upper lobectomy operative times were longer than VATS (172 vs 134 minutes; P = .001), with no significant difference in lower lobectomies noted (140 vs 123 minutes; P = .1). Median length of stay was 3 days in both groups, and the median number of lymph nodes harvested was 18 (robotic) versus 16 (VATS; P = .42). Morbidity and mortality for robotic versus VATS were 11% versus 18% (P = .46) and 0% versus 3% (P = .49), respectively. CONCLUSIONS: There does not seem to be a significant advantage for an established VATS lobectomy surgeon to transition to robotics based on clinical outcomes. The learning curve for robotic upper lobectomies seems to be more significant than that for lower lobectomies.

Patterns of recurrent and persistent intestinal metaplasia after successful radiofrequency ablation of Barrett's esophagus.

OBJECTIVE: Radiofrequency ablation can eradicate Barrett's esophagus successfully in the majority of cases. We sought to determine (1) how often intestinal metaplasia is detected during follow-up endoscopy after successful ablation and (2) patterns of persistent/recurrent intestinal metaplasia. METHODS: Patients ablated successfully during a phase II clinical trial of radiofrequency ablation for Barrett's esophagus were followed using endoscopic surveillance according to a defined protocol. Systematic biopsies were performed in all patients throughout the neosquamous epithelium as well as at the gastroesophageal junction, and patterns of recurrent or persistent intestinal metaplasia were documented. RESULTS: Fifty-three patients were ablated successfully during this single-institution clinical trial. A total of 151 follow-up endoscopies were performed (range, 1-5 endoscopies per patient) and 2492 biopsies were obtained, of which 604 (24%) were from the gastroesophageal junction. The median follow-up period was 18 months (range, 3-50 months). Recurrent/persistent intestinal metaplasia was detected in 14 patients (26%) in 3 distinct patterns: endoscopically invisible intestinal metaplasia underneath the neosquamous epithelium (buried glands) in 3 patients, visible recurrence in the tubular esophagus in 3 patients, and intestinal metaplasia of the gastroesophageal junction (with a squamous-lined tubular esophagus) in 10 patients. Dysplasia or cancer was not detected in any patient during the follow-up period. CONCLUSIONS: Recurrent/persistent intestinal metaplasia after successful radiofrequency ablation of Barrett's esophagus is relatively common. This finding has implications for the continued surveillance of patients who are ablated successfully.

Utility of endobronchial ultrasound-guided mediastinal lymph node biopsy in patients with non-small cell lung cancer.

OBJECTIVE: Invasive mediastinal biopsy is often necessary in the evaluation of non-small cell lung cancer (NSCLC), and mediastinoscopy has long been considered the reference standard. However, the emergence of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) has resulted in controversy regarding it represents a suitable replacement for mediastinoscopy. We chose to determine the utility of EBUS-TBNA in evaluating the mediastinum in patients with NSCLC. METHODS: The present study was a retrospective review of a prospective database of consecutive patients with NSCLC who underwent EBUS-TBNA for mediastinal evaluation from 2009 to 2011. The sensitivity, specificity, negative predictive value, and accuracy of EBUS-TBNA are reported. Also reported are the size of the lymph nodes biopsied and the number of instances in which EBUS-TBNA obviated the need for cervical mediastinoscopy. RESULTS: A total of 73 patients had a total of 140 mediastinal stations biopsied using EBUS-TBNA. Of the 73 patients, 30 had benign findings and underwent surgical resection, 1 of whom was found to have stage N2 disease. Of the remaining patients, 42 had a positive result and 1 had nondiagnostic biopsy findings for which malignancy was confirmed by mediastinoscopy. Mediastinoscopy would have changed the tumor stage and treatment planning in only 2 (2.7%) of the 73 patients. Overall, EBUS-TBNA had a sensitivity of 95%, a specificity of 100%, a negative predictive value of 94%, and an accuracy of 97%. CONCLUSIONS: EBUS-TBNA might be a feasible option for most patients with NSCLC for whom histologic assessment of the mediastinum is necessary. The rates of nondiagnostic and false-negative biopsy findings using EBUS-TBNA were low, small subcentimeter nodes could be routinely biopsied, and most patients with a radiographically positive mediastinum had their disease pathologically confirmed.

Effect of hiatal hernia size and columnar segment length on the success of radiofrequency ablation for Barrett's esophagus: a single-center, phase II clinical trial.

OBJECTIVE: Hiatal hernia is common in patients with Barrett's esophagus. We sought to evaluate the effect of hiatal hernia size and initial columnar segment length on the success of radiofrequency ablation of Barrett's esophagus. METHODS: A phase II clinical trial was conducted aimed at evaluating the success of radiofrequency ablation in eradicating Barrett's esophagus. Success was defined as complete replacement of the columnar lining with squamous mucosa and lack of intestinal metaplasia using light microscopy. Hiatal hernia size and columnar segment length were measured endoscopically. RESULTS: Sixty-seven patients were accrued to the protocol. In the 55 patients who completed radiofrequency ablation (43 successes, 12 failures), the mean hiatal hernia size was 3.3 cm (range, 0-10 cm), and the mean columnar segment length was 5.4 cm (range, 1-18 cm). The median length of the columnar segment was 3 cm in the successful cases and 8.5 cm in the failed cases (P = .002). Although the median hiatal hernia size was identical in the successful and failed cases (3 cm, P = .38), the median hiatal hernia size was 7 cm (P = .001) in the 6 patients who experienced nonhealing after the initial ablation. Patients who were successfully ablated but had larger hiatal hernias and longer columnar segment lengths required significantly more radiofrequency ablation sessions than those with smaller hernias and shorter segments (P = .003 and P = .007, respectively). CONCLUSIONS: Patients with larger hiatal hernias and longer columnar segments are more likely to experience failure or nonhealing after radiofrequency ablation. These patients also require more radiofrequency ablation treatments to achieve successful eradication of Barrett's esophagus.

The utility of automated volumetric growth analysis in a dedicated pulmonary nodule clinic.

OBJECTIVE: Our objectives were 3-fold: to define the correlation between automated volumetric and 2-dimensional measurements of pulmonary nodule growth and prospectively; to determine whether volumetric growth analysis represents a useful addition to 2-dimensional measurements; and to evaluate growth rates over time of biopsy-proven lung cancers using automated volumetric software. METHODS: Nodule growth on consecutive 2-dimensional computed tomographic scans was measured, and a decision regarding nodule biopsy was made. Automated volumetric software was then used to determine nodule growth, growth rates obtained from the 2 techniques were correlated, and the decision to perform a biopsy was reassessed. Biopsy-proven lung cancer growth rates were then documented over time. RESULTS: Growth rates measured using volumetric software were highly correlated with 2-dimensional measurements (r = 0.69; P < .00001). This correlation was affected by nodule type (irregular [r = .63] versus smooth [r = 0.84]; P = .02) as well as the interval between scans (<100 days [r = .5] versus >100 days [r = 0.76]; P = .02). The addition of volumetric growth analysis changed the decision to perform a biopsy after only a minority (6.2%) of scan comparisons; however, lung cancer was diagnosed in 43% of these cases. Growth curves for individual cancers were highly variable, with 45% of tumors showing at least 1 period of shrinkage. CONCLUSIONS: Automated volumetric software influences biopsy decisions in only a minority of cases in a dedicated pulmonary nodule clinic, but seems to be useful in detecting lung cancer in this minority. Radiographically determined nodule growth rates, in general, need to be questioned as the sole determinate of the need to perform a biopsy.

An unusual case of dysphagia from intrathoracic liver.

We report an unusual case of heterotopic intrathoracic liver resulting in severe dysphagia and esophageal obstruction.

TNM stage is the most important determinant of survival in metachronous lung cancer.

BACKGROUND: Distinguishing a metachronous lung cancer from a metastatic or recurrent lesion in patients with a prior history of non-small cell lung cancer is a challenging task. Previous studies have suggested histologic type and disease-free interval as criteria for diagnosing metachronous lung cancer. These factors may not be as relevant now that current imaging allows for earlier detection of tumors and with the rising incidence of adenocarcinoma. The purpose of this study was to reexamine the factors that determine outcomes in patients with a second primary lung cancer. METHODS: A retrospective review of a prospective lung cancer database was performed to identify patients with metachronous lung cancer. Metachronous lung cancer was defined as any non-small cell lung cancer occurring after a prior resection regardless of disease-free interval or histologic type. The Kaplan-Meier method was used for survival analysis. The Mantel-Cox method was used to compare overall survival. Cox regression was used for multivariate analysis. RESULTS: Fifty-eight patients had metachronous lung cancer. Overall survival at 5 years was 66% (stage IA, 74%; IB, 59%; all other stages, 0%; p = 0.01). Seventy-two percent (42 of 58 patients) had similar histologic type. There was no difference in overall survival based on similar versus different histologic type (65% versus 73%; p = 0.77). Median disease-free interval was 42 months (range, 8 to 312 months). Disease-free interval was not a significant predictor of overall survival (p = 0.24). The extent of resection included wedge (36%, 21 of 58 patients), segmentectomy (24%, 14 of 58 patients), and lobectomy (40%, 23 of 58 patients), with no difference in overall survival (58% versus 60% versus 75%, respectively; p = 0.32). CONCLUSIONS: These data suggest that early tumor stage is the only significant determinant of survival after surgical treatment of metachronous lung cancer. Neither histologic type nor disease-free interval was of prognostic value. Limited resections may be adequate treatment.