Bryan M. Burt

Allogeneic IgG combined with dendritic cell stimuli induce antitumour T-cell immunity

Whereas cancers grow within host tissues and evade host immunity through immune-editing and immunosuppression, tumours are rarely transmissible between individuals. Much like transplanted allogeneic organs, allogeneic tumours are reliably rejected by host T cells, even when the tumour and host share the same major histocompatibility complex alleles, the most potent determinants of transplant rejection. How such tumour-eradicating immunity is initiated remains unknown, although elucidating this process could provide the basis for inducing similar responses against naturally arising tumours. Here we find that allogeneic tumour rejection is initiated in mice by naturally occurring tumour-binding IgG antibodies, which enable dendritic cells (DCs) to internalize tumour antigens and subsequently activate tumour-reactive T cells. We exploited this mechanism to treat autologous and autochthonous tumours successfully. Either systemic administration of DCs loaded with allogeneic-IgG-coated tumour cells or intratumoral injection of allogeneic IgG in combination with DC stimuli induced potent T-cell-mediated antitumour immune responses, resulting in tumour eradication in mouse models of melanoma, pancreas, lung and breast cancer. Moreover, this strategy led to eradication of distant tumours and metastases, as well as the injected primary tumours. To assess the clinical relevance of these findings, we studied antibodies and cells from patients with lung cancer. T cells from these patients responded vigorously to autologous tumour antigens after culture with allogeneic-IgG-loaded DCs, recapitulating our findings in mice. These results reveal that tumour-binding allogeneic IgG can induce powerful antitumour immunity that can be exploited for cancer immunotherapy.

Thoracoscopic lobectomy is associated with acceptable morbidity and mortality in patients with predicted postoperative forced expiratory volume in 1 second or diffusing capacity for carbon monoxide less than 40% of normal

OBJECTIVEnA predicted postoperative (ppo) forced expiratory volume in 1 second (FEV1%) or diffusing capacity of the lung for carbon monoxide (DLCO%) of <40% has traditionally been considered to convey a high risk of lobectomy owing to elevated postoperative morbidity and mortality. These recommendations, however, were largely derived from the pre-video-assisted thoracoscopic surgical (VATS) era. We hypothesized that VATS lobectomy would be associated with acceptable morbidity and mortality at ppoFEV1% and ppoDLCO% valuesxa0<xa040%.nnnMETHODSnPpoFEV1% and ppoDLCO% were calculated for patients undergoing open or VATS lobectomy for lung cancer in the Society of Thoracic Surgeons General Thoracic database from 2009 to 2011. Univariate comparisons, multivariate analyses, and 1:1 propensity matching were performed.nnnRESULTSnA total of 13,376 patients underwent lobectomy (50.9% open, 49.1% VATS). A decreased ppoFEV1% and ppoDLCO% were each independent predictors for both cardiopulmonary complications and mortality in the open group (all P ≤ .008). In the VATS group, ppoFEV1% was an independent predictor of complications (Pxa0=xa0.001) but not mortality (Pxa0=xa0.77), and ppoDLCO% was an independent predictor of complications (Pxa0=xa0.046) and mortality (Pxa0=xa0.008). With decreasing ppoFEV1% or ppoDLCO%, complications and mortality increased at a greater rate in the open lobectomy than in a propensity-matched VATS group (nxa0=xa04215 each). For patients with ppoFEV1%xa0<xa040%, mortality was greater in the open (4.8%) than in the matched VATS group (0.7%, Pxa0=xa0.003). Similar results were seen for ppoDLCO%xa0<xa040% (5.2% open, 2.0% VATS, Pxa0=xa0.003). The rate of complications was significantly greater at ppoFEV1%xa0<xa040% in the open (21.9%) than in the matched VATS (12.8%, Pxa0=xa0.005) group and similar results were seen with ppoDLCO%xa0<xa040% (14.9% open, 10.4% VATS, Pxa0=xa0.016).nnnCONCLUSIONSnVATS lobectomy can be performed with acceptable rates of morbidity and mortality in patients with reduced ppoFEV1% or ppoDLCO%.

Circulating and Tumor-Infiltrating Myeloid Cells Predict Survival in Human Pleural Mesothelioma

Malignant pleural mesothelioma (MPM) tumor cells produce copious amounts of myeloid cell‐stimulating factors. The current study examined the prognostic significance of circulating monocytes and tumor‐infiltrating macrophages on overall survival in patients with MPM.

Malignant pleural mesothelioma and the Society of Thoracic Surgeons Database: An analysis of surgical morbidity and mortality

BACKGROUNDnTo date, reported surgical morbidity and mortality for pleurectomy/decortication and extrapleural pneumonectomy performed for malignant pleural mesothelioma primarily represent the experience of a few specialized centers. For comparison, we examined early outcomes of pleurectomy/decortication and extrapleural pneumonectomy from a broader group of centers/surgeons participating in the Society of Thoracic Surgeons-General Thoracic Database.nnnMETHODSnAll patients in the Society of Thoracic Surgeons-General Thoracic Database (version 2.081, representing 2009-2011) who underwent pleurectomy/decortication or extrapleural pneumonectomy for malignant pleural mesothelioma were identified. Patient characteristics, morbidity, mortality, center volume, and procedure were examined using univariable and multivariable analyses.nnnRESULTSnA total of 225 patients underwent pleurectomy/decortication (nxa0=xa0130) or extrapleural pneumonectomy (nxa0=xa095) for malignant pleural mesothelioma at 48 centers. Higher volumes of procedures (≥5/y) were performed at 3 pleurectomy/decortication and 2 extrapleural pneumonectomy centers. Patient characteristics were statistically equivalent between pleurectomy/decortication and extrapleural pneumonectomy groups, except those undergoing extrapleural pneumonectomy were younger (63.2 ± 7.8 years vs 68.3 ± 9.5 years; Pxa0<xa0.001) and more likely to have received preoperative chemotherapy (30.1% vs 17.8%; Pxa0=xa0.036). Majorxa0morbidity was greater after extrapleural pneumonectomy, including acute respiratory distress syndrome (8.4% vs 0.8%; Pxa0=xa0.005), reintubation (14.7% vs 2.3%; Pxa0=xa0.001), unexpected reoperation (9.5% vs 1.5%; Pxa0=xa0.01), and sepsis (4.2% vs 0%; Pxa0=xa0.03), as was mortality (10.5% vs 3.1%; Pxa0=xa0.03). Multivariate analyses revealed that extrapleural pneumonectomy was an independent predictor of major morbidity or mortality (oddsxa0ratio, 6.51; Pxa0=xa0.001). Compared with high-volume centers, increased acute respiratory distress syndrome was seen in low-volume centers performing extrapleural pneumonectomy (0% vs 12.5%; Pxa0=xa0.05).nnnCONCLUSIONSnExtrapleural pneumonectomy is associated with greater morbidity and mortality compared withxa0pleurectomy/decortication when performed by participating surgeons of the Society of Thoracic Surgeons-General Thoracic Database. Effects of center volume require further study.

Repeated and Aggressive Pulmonary Resections for Leiomyosarcoma Metastases Extends Survival

BACKGROUNDnSarcoma frequently metastasizes to the lungs, and pulmonary metastasectomy is the only treatment modality that can provide a cure for these patients. We attempted to determine the clinicopathologic features and survival determinants of a common subset of patients who undergo pulmonary metastasectomy for leiomyosarcoma.nnnMETHODSnAll patients undergoing pulmonary metastasectomy at The Brigham and Womens Hospital from 1989 to 2004 were reviewed retrospectively. Analyzed variables included number, size, pathology, and location of metastases, age, gender, location of primary tumor, disease-free interval (DFI), surgical approach, margin status, adjuvant therapy, recurrence, number of metastasectomies, and disease-free and overall survival.nnnRESULTSnEighty-two patients underwent pulmonary metastasectomy for metastases from sarcoma. Leiomyosarcoma was the most common histologic finding (n = 31; 38%). Fifteen patients with leiomyosarcoma (48%) underwent repeated pulmonary metastasectomy. Patients with leiomyosarcoma were more commonly female (77% versus 43%; p = 0.031), less frequently received chemotherapy for their primary tumor (48% versus 71%, p = 0.041), and presented with fewer number of pulmonary metastases than did patients with nonleiomyosarcoma metastases (1.9 ± 1.5 standard deviation [SD] versus 3.6 ± 4.4; p = 0.033). Although there was no difference in disease-free survival, patients with leiomyosarcoma demonstrated improved overall survival compared with those with nonleiomyosarcoma metastases (70 versus 24 months; p = 0.049). In multivariate analyses, the DFI from primary tumor resection to pulmonary metastases and the DFI from pulmonary metastasectomy to second pulmonary recurrence were identified as independent predictors of survival.nnnCONCLUSIONSnLeiomyosarcoma is a common subset of sarcomatous pulmonary metastases that behave more indolently compared with other pulmonary metastases from sarcoma. Long-term survival is achievable with an aggressive approach toward pulmonary metastasectomy and repeated pulmonary metastasectomy.

A Dominant Adenocarcinoma With Multifocal Ground Glass Lesions Does Not Behave as Advanced Disease

BACKGROUNDnInvasive lung adenocarcinomas increasingly present with synchronous, multifocal, in situ lesions that appear as ground glass opacities (GGOs). The optimal approach in this circumstance (often nonsmokers) remains unclear. We evaluated a general strategy of anatomic resection of the dominant tumor (DT) and wedge resection of accessible ipsilateral GGOs.nnnMETHODSnThis is a retrospective review of 39 patients with suspected multifocal in situ adenocarcinomas and 1 DT in a predominantly Caucasian population. Mean follow-up is 30.7 months.nnnRESULTSnForty-nine percent of patients had no or minimal smoking history; 21% were Asian. The resected DT was pathologically bronchioloalveolar carcinoma (26%), minimally invasive adenocarcinoma (5%), adenocarcinoma with bronchioloalveolar features (41%), or moderate well-differentiated adenocarcinoma (28%). The p stage of the DT was IA in 20, IB in 15, and IIA in 4, with mean diameter of 2.6 cm. Thirty-two patients (82%) underwent anatomic resection of the DT; 7 (18%) underwent wedge resection. The mean number of GGOs present initially was 2.7 (range, 1 to 7) with a 5.2-mm mean diameter. An unresected nodule increased in size during follow-up in only 9 patients (23%). The mean diameter growth among these was 3.2 mm, with mean doubling time of 49 months. New GGOs (range, 1 to 8) developed in 16 patients (41%), all of which remained at 7 mm or less. Distant metastasis developed in 2 patients (5.2%); only 1 patient has required intervention for progression of a GGO. The overall survival is 100%.nnnCONCLUSIONSnPatients with limited, multifocal, in situ adenocarcinomas and a clinical N0 DT enjoy prolonged survival with generally anatomic resection of the DT and wedge resection of accessible GGOs. These patients should not be considered to harbor T4 or M1a disease.

Early-Stage Non-Small Cell Lung Cancer: Surgery, Stereotactic Radiosurgery, and Individualized Adjuvant Therapy

Despite cures in early stage (IA-IIB) non-small cell lung cancer (NSCLC), the 5-year survival rate is only 36%-73%. Surgical resection via lobectomy is the treatment of choice in early-stage NSCLC, with the goal being complete anatomic resection of the tumor and mediastinal lymph node evaluation. Newer technologies, including the minimally invasive thoracoscopic approach and the many techniques available to stage the mediastinum, have introduced advantages over traditional approaches in achieving this goal. The advent of stereotactic ablative radiotherapy (SABR) has changed how we treat those patients who cannot undergo surgery secondary to comorbidities or patient preference. SABR allows for precise radiation delivery in a short course and at high doses. Adjuvant cisplatin-based chemotherapy is the standard of care for completely resected high-risk stage IB and stage II NSCLC based on a ~5% improvement in 5-year overall survival. The concept of customized adjuvant chemotherapy is emerging, and we will explore the potential value of targeting tumor mutations with available drugs (ie, epidermal growth factor receptor [EGFR] mutations with erlotinib), a strategy that for the moment should be restricted to clinical trials.

Expression of Interleukin-4 Receptor Alpha in Human Pleural Mesothelioma Is Associated with Poor Survival and Promotion of Tumor Inflammation

Purpose: The origin and pathogenesis of malignant pleural mesothelioma (MPM) are closely aligned with inflammation. MPM tumors express interleukin-4 receptor α (IL-4Rα), the principal subunit of the IL-4 receptor. We set out to determine the biologic function and clinical relevance of IL-4Rα in human MPM. Experimental Design: Expression of IL-4Rα by human MPM tumors was determined by quantitative real-time PCR (n = 37) and immunohistochemistry (n = 52). Intracellular cytokine analysis of T-cell–derived IL-4 was carried out on matched tumor and blood samples from eight patients with MPM. Four human MPM cell lines were used to determine the direct effects of IL-4 on MPM tumor cells. Results: High tumor mRNA expression of IL-4Rα was an independent predictor of poor survival in patients with epithelial MPM [HR, 3.13, 95% confidence interval (CI), 1.68–7.15; P = <0.0001]. Ninety-seven percent of epithelial MPM tumors and 95% of nonepithelial MPM tumors expressed IL-4Rα protein by immunohistochemistry, and strong IL-4Rα staining correlated with worse survival in patients with epithelial histology (P = 0.04). A greater percentage of tumor-infiltrating T cells produced IL-4 compared with matched blood T cells (21% ± 7% vs. 4% ± 2%, P = 0.0002). In response to IL-4, human MPM cells showed increased STAT-6 phosphorylation and increased production of IL-6, IL-8, and VEGF, without effect on proliferation or apoptosis. Conclusions: Tumor expression of IL-4Rα is inversely correlated with survival in patients undergoing surgical resection for epithelial MPM. Tumor-infiltrating T cells in MPMs are polarized to produce IL-4 and may provide endogenous activation signals to MPM tumor cells in situ. The IL-4/IL-4 receptor axis is a potential therapeutic target in human MPM. Clin Cancer Res; 18(6); 1568–77. ©2012 AACR.

Influence of experience and the surgical learning curve on long-term patient outcomes in cardiac surgery

OBJECTIVEnWe hypothesized that increased postgraduate surgical experience correlates with improved operative efficiency and long-term survival in standard cardiac surgery procedures.nnnMETHODSnUtilizing a prospectively collected retrospective database, we identified patients who underwent isolated coronary artery bypass grafting (CABG) (nxa0=xa03726), aortic valve replacement (AVR) (nxa0=xa01626), mitral valve repair (nxa0=xa0731), mitral valve replacement (MVR) (nxa0=xa0324), and MVRxa0+xa0AVR (nxa0=xa0184) from January 2002 through June 2012. After adjusting for patient risk and surgeon variability, we evaluated the influence of surgeon experience on cardiopulmonary bypass and crossclamp times, and long-term survival.nnnRESULTSnMean surgeon experience after fellowship graduation was 16.0xa0±xa011.7xa0years (range, 1.0-35.2xa0years). After adjusting for patient risk and surgeon-level fixed effects, learning curve analyses demonstrated improvements in cardiopulmonary bypass and crossclamp times with increased surgeon experience. There was marginal improvement in the predictability (R(2) value) of cardiopulmonary bypass and crossclamp time for CABG with the addition of surgeon experience; however, all other procedures had marked increases in the R(2) following addition of surgeon experience. Cox proportional hazard models revealed that increased surgeon experience was associated with improved long-term survival in AVR (hazard ratio [HR], 0.85; Pxa0<xa0.0001), mitral valve repair (HR, 0.73; Pxa0<xa0.0001), and MVRxa0+xa0AVR (HR, 0.95; Pxa0=xa0.006) but not in CABG (HR, 0.80; Pxa0=xa0.15), and a trend toward significance in MVR (HR, 0.87; Pxa0=xa0.09).nnnCONCLUSIONSnIn cardiac surgery, not including CABG, surgeon experience is an important determinant of operative efficiency and of long-term survival.

A meta-analysis of surgical versus nonsurgical management of recurrent thymoma.

This meta-analysis was designed to determine the effect of surgical and nonsurgical approaches on 5-year and 10-year overall survival (OS) in patients with recurrent thymoma. PubMed, Scopus, and the Journal of Japanese Association for Chest Surgery were queried, and 11 studies were eligible. Our meta-analysis using a random-effect model revealed significant differences in the rates of 5- and 10-year OS after thymectomy and in 5-year OS after recurrence, favoring surgically managed patients. Surgical resection may be associated with improved long-term survival and should be considered for patients with recurrent thymoma.