Surgical results of the Lung Cancer Mutation Consortium 3 trial: A phase II multicenter single-arm study to investigate the efficacy and safety of atezolizumab as neoadjuvant therapy in patients with stages IB-select IIIB resectable non-small cell lung cancer

OBJECTIVE: Multimodality treatment for resectable non-small cell lung cancer has long remained at a therapeutic plateau. Immune checkpoint inhibitors are highly effective in advanced non-small cell lung cancer and promising preoperatively in small clinical trials for resectable non-small cell lung cancer. This large multicenter trial tested the safety and efficacy of neoadjuvant atezolizumab and surgery. METHODS: Patients with stage IB to select IIIB resectable non-small cell lung cancer and Eastern Cooperative Oncology Group performance status 0/1 were eligible. Patients received atezolizumab 1200 mg intravenously every 3 weeks for 2 cycles or less followed by resection. The primary end point was major pathological response in patients without EGFR/ALK+ alterations. Pre- and post-treatment computed tomography, positron emission tomography, pulmonary function tests, and biospecimens were obtained. Adverse events were recorded by Common Terminology Criteria for Adverse Events v.4.0. RESULTS: From April 2017 to February 2020, 181 patients were entered in the study. Baseline characteristics were mean age, 65.1 years; female, 93 of 181 (51%); nonsquamous histology, 112 of 181 (62%); and clinical stages IIB to IIIB, 147 of 181 (81%). In patients without EGFR/ALK alterations who underwent surgery, the major pathological response rate was 20% (29/143; 95% confidence interval, 14-28) and the pathological complete response rate was 6% (8/143; 95% confidence interval, 2-11). There were no grade 4/5 treatment-related adverse events preoperatively. Of 159 patients (87.8%) undergoing surgery, 145 (91%) had pathologic complete resection. There were 5 (3%) intraoperative complications, no intraoperative deaths, and 2 postoperative deaths within 90 days, 1 treatment related. Median disease-free and overall survival have not been reached. CONCLUSIONS: Neoadjuvant atezolizumab in resectable stage IB to IIIB non-small cell lung cancer was well tolerated, yielded a 20% major pathological response rate, and allowed safe, complete surgical resection. These results strongly support the further development of immune checkpoint inhibitors as preoperative therapy in locally advanced non-small cell lung cancer

Acupuncture is a feasible treatment for post-thoracotomy pain: results of a prospective pilot trial

BACKGROUND: Thoracotomy is associated with severe pain that may persist for years. Acupuncture is a complementary therapy with a proven role in pain control. A randomized trial showed that acupuncture was effective in controlling pain after abdominal surgery, but the efficacy of this technique for the treatment of thoracotomy pain has not been established. We developed a novel technique for convenient application of acupuncture to patients undergoing thoracotomy, and in a Phase II trial evaluated the safety of this intervention and the feasibility of doing a randomized trial. METHODS: Adult patients scheduled for unilateral thoracotomy with preoperative epidural catheter placement received acupuncture immediately prior to surgery. Eighteen semi-permanent intradermal needles were inserted on either side of the spine, and four were inserted in the legs and auricles. Needles were removed after four weeks. Using a numerical rating scale, pain was measured on the first five postoperative days. After discharge, pain was assessed using the Brief Pain Inventory at 7, 30, 60 and 90 days. RESULTS: Thirty-six patients were treated with acupuncture. Of these, 25, 23, and 22 patients provided data at 30, 60, and 90 days, respectively. The intervention was well tolerated by patients with only one minor and transient adverse event of skin ulceration. CONCLUSION: The rate of data completion met our predefined criterion for determining a randomized trial to be feasible (at least 75% of patients tolerated the intervention and provided evaluable data). This novel intervention is acceptable to patients undergoing thoracotomy and does not interfere with standard preoperative care. There was no evidence of important adverse events. We are now testing the hypothesis that acupuncture significantly adds to standard perioperative pain management in a randomized trial

Intraoperative localization of lymph node metastases with a replication-competent herpes simplex virus

ObjectivesLymph node status is the most important prognostic factor determining recurrence and survival in patients with mesothelioma and other thoracic malignancies. Accurate localization of lymph node metastases is therefore necessary to improve selection of resectable and curable patients for surgical intervention. This study investigates the potential to identify lymph node metastases intraoperatively by using herpes-guided cancer cell–specific expression of green fluorescent protein.MethodsAfter infection with NV1066, a herpes simplex virus carrying green fluorescent protein transgene, human mesothelioma cancer cell lines were assessed for cancer cell–specific infection, green fluorescent protein expression, viral replication, and cytotoxicity. Murine models of lymphatic metastasis were established by means of surgical implantation of cancer cells into the preauricular (drainage to cervical lymph nodes) and pleural (mediastinal and retroperitoneal lymph nodes) spaces of athymic mice. Fluorescent thoracoscopy, laparoscopy, and stereomicroscopy were used to localize lymph node metastases that were confirmed by means of immunohistochemistry.ResultsIn vitro NV1066 infected, replicated (5- to 17,000-fold), and expressed green fluorescent protein in all cancer cells, even when infected at a low ratio of one viral plaque-forming unit per 100 tumor cells. In vivo NV1066 injected into primary tumors was able to locate and infect lymph node metastases producing green fluorescent protein that was visualized by means of fluorescent imaging. Histology confirmed lymphatic metastases, and immunohistochemistry confirmed viral presence in regions that expressed green fluorescent protein.ConclusionsHerpes virus–guided cancer cell–specific production of green fluorescent protein can facilitate accurate localization of lymph node metastases. Fluorescent filters that detect green fluorescent protein can be incorporated into operative scopes to precisely localize and biopsy lymph node metastases

Esophageal Cancer Recurrence Patterns and Implications for Surveillance

Introduction:After definitive treatment of esophageal cancer, patients are at high risk for recurrence. Consistent follow-up is important for detection and treatment of recurrence. The optimal surveillance regimen remains undefined. We investigated posttreatment recurrence patterns and methods of detection in survivors of esophageal cancer.Methods:We retrospectively studied a cohort of patients who had undergone surgical resection for esophageal cancer at our institution between 1996 and 2010. Routine computed tomography scan and upper endoscopy were performed for surveillance.Results:In total, 1147 patients with resected esophageal adenocarcinoma or squamous cell carcinoma were included (median follow-up, 46 months). Of these, 723 patients (63%) had received neoadjuvant therapy before surgery. During follow-up, there were 595 deaths (52%) and 435 recurrences (38%) (distant [55%], locoregional [28%], or both [17%]). Half of recurrences were detected as a result of symptoms (n = 217), 45% by routine chest and abdominal computed tomography scan (n = 194), and 1% by surveillance upper endoscopy (n = 6). The recurrence rate decreased from 27 per 100 person-years in posttreatment year 1 to 4 per 100 person-years in year 6. In the first 2 years, the rate of recurrence was higher among patients who had received neoadjuvant therapy (35 per 100 person-years) than among those who had not (14 per 100 person-years) (p < 0.001).Conclusions:The incidence of recurrence is high after esophagectomy for cancer. Surveillance endoscopy has limited value for detection of asymptomatic local recurrence. The yield from follow-up scans diminishes significantly after the sixth year; surveillance scans after that point are likely unnecessary

An In Vivo Platform for Tumor Biomarker Assessment

Tumor biomarkers provide a quantitative tool for following tumor progression and response to therapy. However, investigations of clinically useful tumor biomarkers are time-consuming, costly, and limited by patient and tumor heterogeneity. In addition, assessment of biomarkers as indicators of therapy response is confounded by the concomitant use of multiple therapeutic interventions. Herein we report our use of a clinically relevant orthotopic animal model of malignant pleural mesothelioma for investigating tumor biomarkers. Utilizing multi-modality imaging with correlative histopathology, we demonstrate the utility and accuracy of the mouse model in investigating tumor biomarkers – serum soluble mesothelin-related peptide (SMRP) and osteopontin (OPN). This model revealed percentage change in SMRP level to be an accurate biomarker of tumor progression and therapeutic response – a finding consistent with recent clinical studies. This in vivo platform demonstrates the advantages of a validated mouse model for the timely and cost-effective acceleration of human biomarker translational research

Predictive Value of Initial PET-SUVmax in Patients with Locally Advanced Esophageal and Gastroesophageal Junction Adenocarcinoma

Introduction:We have previously shown that in early clinical stage esophageal adenocarcinoma, a positron emission tomography standardized uptake values (PET SUVmax) of <4.5 is associated with earlier pathologic stage and predicts better survival. In this study, we analyze the impact of the pretreatment PET SUVmax in patients with locally advanced esophageal adenocarcinoma who undergo preoperative chemoradiotherapy.Methods:We performed a retrospective analysis, selecting patients with adenocarcinoma of the esophagus who had a pretreatment PET scan and who received chemoradiotherapy before esophagectomy. Data recorded included demographics, PET SUVmax, treatment details, pathologic details, and survival data. Comparison of categorical variables was done by χ2 analysis, continuous variables by t test, survival analysis by the Kaplan-Meier method, and comparisons of survival using the log-rank test.Results:Between January 1996 and September 2007, 189 patients were appropriate for this analysis. The initial PET SUVmax was <4.5 in 28 patients and ≥4.5 in 161 patients. The two groups were similar with regards to demographics and treatment details. Patients in the low SUV group were less likely to show evidence of treatment response after chemoradiotherapy, including a higher likelihood of residual nodal disease and a lower likelihood of a pathologic complete response and estimated treatment response. However, both groups had similar survival.Conclusions:Although the initial PET SUVmax does not predict survival in patients with locally advanced esophageal adenocarcinoma who receive preoperative chemoradiotherapy, patients with a high initial SUVmax respond better to preoperative therapy. These results can be used to better select esophageal cancer patients for combined modality treatment

Extrapleural pneumonectomy versus pleurectomy/decortication in the surgical management of malignant pleural mesothelioma: Results in 663 patients

ObjectiveThe optimal procedure for resection of malignant pleural mesothelioma is controversial, partly because previous analyses include small numbers of patients. We performed a multi-institutional study to increase statistical power to detect significant differences in outcome between extrapleural pneumonectomy and pleurectomy/decortication.MethodsPatients with malignant pleural mesothelioma who underwent extrapleural pneumonectomy or pleurectomy/decortication at 3 institutions were identified. Survival and prognostic factors were analyzed by the Kaplan–Meier method, log-rank test, and Cox proportional hazards analysis.ResultsFrom 1990 to 2006, 663 consecutive patients (538 men and 125 women) underwent resection. The median age was 63 years (range, 26–93 years). The operative mortality was 7% for extrapleural pneumonectomy (n = 27/385) and 4% for pleurectomy/decortication (n = 13/278). Significant survival differences were seen for American Joint Committee on Cancer stages 1 to 4 (P < .001), epithelioid versus non-epithelioid histology (P < .001), extrapleural pneumonectomy versus pleurectomy/decortication (P < .001), multimodality therapy versus surgery alone (P < .001), and gender (P < .001). Multivariate analysis demonstrated a hazard rate of 1.4 for extrapleural pneumonectomy (P < .001) controlling for stage, histology, gender, and multimodality therapy.ConclusionPatients who underwent pleurectomy/decortication had a better survival than those who underwent extrapleural pneumonectomy; however, the reasons are multifactorial and subject to selection bias. At present, the choice of resection should be tailored to the extent of disease, patient comorbidities, and type of multimodality therapy planned

Predictors of survival in malignant tumors of the sternum

AbstractFrom 1930 to 1994, 54 patients with primary malignant tumors of the sternum were seen. Fifty patients were first seen with a mass, and one half of them also had pain in the sternal region. Two patients had no symptoms at presentation. Among 39 solid tumors were 26 chondrosarcomas, 10 osteosarcomas, 1 fibrosarcoma, 1 angiosarcoma, and 1 malignant fibrous histiocytoma. Of these, 25 were low-grade and 14 were high-grade tumors. Among 15 small cell tumors were 8 plasmacytomas, 6 malignant lymphomas, and 1 Ewing's sarcoma. Partial or subtotal sternectomy was done in 37 patients and total sternectomy in 3. Of the remaining 14 patients, 3 had local excision; 10 had external radiation or chemotherapy without operation, or both; and 1 had no treatment. All but one patient treated by wide resection ( N = 40) had some form of skeletal reconstruction of the chest wall defect. Thirty-one (78%) underwent repair with Marlex mesh, and in 25 this was combined with methyl methacrylate. The skin edges were closed per primum in 32 patients; 8 required muscle, omentum, or skin flaps. Resection in chondrosarcomas yielded a 5-year survival (Kaplan-Meier) of 80% (median follow-up, 17 years). The 5-year survival in osteosarcomas was 14%. Resection was curative in 64% of low-grade sarcomas but in only 7% of high-grade sarcomas. In small cell tumors, resection and radiation were helpful for local control; all failures were a result of distant metastases. We conclude that primary sarcomas of the sternum though uncommon are potentially curable by wide surgical excision. With rigid prostheses to repair the skeletal defects, the surgical complication rates are low. Overall survival after complete surgical resection is related to tumor histologic type and grade. (J THORAC CARDIOVASC SURG 1996;111:96-106