Objective The study objective was to compare endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) with mediastinoscopy for mediastinal lymph node staging of potentially ...resectable non–small cell lung cancer. Methods Patients with confirmed or suspected non–small cell lung cancer who required mediastinoscopy to determine suitability for lung cancer resection were entered into the trial. All patients underwent EBUS-TBNA followed by mediastinoscopy under general anesthesia. If both were negative for N2 or N3 disease, the patient underwent pulmonary resection and mediastinal lymphadenectomy. Results Between July 2006 and August 2010, 190 patients were registered in the study, 159 enrolled, and 153 were eligible for analysis. EBUS-TBNA and mediastinoscopy sampled an average of 3 and 4 lymph node stations per patient, respectively. The mean short axis of the lymph node biopsied by EBUS-TBNA was 6.9 ± 2.9 mm. The prevalence of N2/N3 disease was 35% (53/153). There was excellent agreement between EBUS-TBNA and mediastinoscopy for mediastinal staging in 136 patients (91%; Kappa, 0.8; 95% confidence interval, 0.7–0.9). Specificity and positive predictive value for both techniques were 100%. The sensitivity, negative predictive value, and diagnostic accuracy for mediastinal lymph node staging for EBUS-TBNA and mediastinoscopy were 81%, 91%, 93%, and 79%, 90%, 93%, respectively. No significant differences were found between EBUS-TBNA and mediastinoscopy in determining the true pathologic N stage (McNemar’s test, P = .78). There were no complications from EBUS-TBNA. Minor complications from mediastinoscopy were observed in 4 patients (2.6%). Conclusions EBUS-TBNA and mediastinoscopy achieve similar results for the mediastinal staging of lung cancer. As performed in this study, EBUS-TBNA can replace mediastinoscopy in patients with potentially resectable non–small cell lung cancer.
How best to sequence and integrate immunotherapy into standard of care is currently unknown. Clinical protocols with accelerated nonablative hypofractionated radiation followed by surgery could ...provide an opportunity to implement immune checkpoint blockade.
We therefore assessed the impact of nonablative hypofractionated radiation on the immune system in combination with surgery in a mouse mesothelioma model. Blunt surgery (R1 resection) was used to analyze the short-term effect, and radical surgery (R0 resection) was used to analyze the long-term effect of this radiation protocol before surgery.
Nonablative hypofractionated radiation led to a specific immune activation against the tumor associated with significant upregulation of CD8
T cells, limiting the negative effect of an incomplete resection. The same radiation protocol performed 7 days before radical surgery led to a long-term antitumor immune protection that was primarily driven by CD4
T cells. Radical surgery alone or with a short course of nonablative radiation completed 24 hours before radical surgery did not provide this vaccination effect. Combining this radiation protocol with CTLA-4 blockade provided better results than radiation alone. The effect of PD-1 or PD-L1 blockade with this radiation protocol was less effective than the combination with CTLA-4 blockade.
A specific activation of the immune system against the tumor contributes to the benefit of accelerated, hypofractionated radiation before surgery. Nonablative hypofractionated radiation combined with surgery provides an opportunity to introduce immune checkpoint blockades in the clinical setting.
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Ex-vivo lung perfusion (EVLP) can be used to extend overall lung preservation time by splitting one long cold ischaemic time into two shorter ones and interposing an additional EVLP time. We assessed ...the outcomes after clinical transplantation of lungs with more than 12 h of preservation time.
For this retrospective study, we searched the Toronto Lung Transplant Program database for patients who had received at least one lung transplant between Jan 1, 2006, and April 30, 2015, at a single hospital in Toronto, Canada. We split the identified patients into those with a total preservation time of more than 12 h and those with a total preservation time of less than 12 h to act as the control group. Total preservation time was defined as the sum of first cold ischaemic time, EVLP time, and second cold ischaemic time. We excluded patients if they had received a heart-lung transplant or were younger than 18 years. In bilateral lung transplantations, we used the longer preservation time of the two lungs for analysis. Lung preservation was done according to present standards of care and EVLP was done according to the Toronto EVLP technique. The primary outcomes were survival and International Society for Heart and Lung Transplantation Primary Graft Dysfunction (PGD) grade at 72 h post-transplantation. We compared outcomes with our control group using univariable and multivariable models.
We identified 906 patients who met eligibility criteria and had sufficient data for analysis (<12 h group n=809; mean lung preservation time 400·8 min SD 121·8 vs >12 h group n=97; 875·7 min 109·0). Median hospital and intensive-care unit length of stay were similar between the less than 12 h group and the more than 12 h group (hospital stay: 23 days 16-42 vs 25·5 days 17-50·25, p=0·60; intensive-care unit stay: 4 days 2-14 vs 4 days 2-16, p=0·53). PGD grade was also not different between the two groups at 72 h post-transplantation (p=0·85). There was also no difference in survival between the two groups as shown on Kaplan-Meier survival curves (p=0·61). Multivariable survival analysis using Cox's model showed increasing recipient age to be a significant variable affecting survival.
Extension of graft preservation time beyond 12 h with EVLP does not negatively affect early lung transplantation outcomes. Extension of clinical lung preservation times might allow for more transplantations to be done as a result of improved facilitation and increased flexibility around timing of lung transplantation operations.
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Malignant pleural mesothelioma (MPM) is a rare but aggressive disease with few therapeutic options. The tumor-stromal interface is important in MPM, but this is lost in cell lines, the main model ...used for preclinical studies. We sought to characterize MPM patient-derived xenografts (PDX) to determine their suitability as preclinical models and whether tumors that engraft reflect a more aggressive biological phenotype.
Fresh tumors were harvested from extrapleural pneumonectomy, decortication, or biopsy samples of 50 MPM patients and implanted subcutaneously into immunodeficient mice and serially passaged for up to five generations. We correlated selected mesothelioma biomarkers between PDX and patient tumors, and PDX establishment with the clinical pathologic features of the patients, including their survival. DNA of nine PDXs was profiled using the OncoScan FFPE Express platform. Ten PDXs were treated with cisplatin and pemetrexed.
A PDX was formed in 20 of 50 (40%) tumors implanted. Histologically, PDX models closely resembled the parent tumor. PDX models formed despite preoperative chemotherapy and radiotherapy. In multivariable analysis, patients whose tumors formed a PDX had significantly poorer survival when the model was adjusted for preoperative treatment (HR, 2.46; 95% confidence interval, 1.1-5.52;
= 0.028). Among 10 models treated with cisplatin, seven demonstrated growth inhibition. Genomic abnormalities seen in nine PDX models were similar to that previously reported.
Patients whose tumors form PDX models have poorer clinical outcomes. MPM PDX tumors closely resemble the genotype and phenotype of parent tumors, making them valuable models for preclinical studies.
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Background Standard imaging modalities are inaccurate in staging malignant pleural mesothelioma (MPM). Single-institution studies suggest that volumetric computed tomography (CT) is more accurate but ...labor intensive. We established a multicenter network to test interobserver variability, accuracy (relative to pathologic stage), and the prognostic significance of semiautomated volumetric CT. Methods Six institutions electronically submitted to an established multicenter database clinical and pathologic data for patients with MPM who had operations. Institutional radiologists reviewed preoperative CT scans for quality and then submitted by electronic network (AG Mednet, www.agmednet.com ) to the biostatistical center. Two reference radiologists blinded to clinical data performed semiautomated tumor volume calculations using Vitrea Enterprise 6.0 software (Vital Images, Minnetonka, MN) and then submitted readings to the biostatistical center. Study end points included feasibility of the network, interobserver variability for volumetric CT, correlation of tumor volume to pTN stages, and overall survival (OS). Results Of 164 patients, the CT scans for 129 were analyzable and read by reference radiologists. Most tumors were less than 500 cm3 . A small bias was observed between readers because one provided consistently larger measurements than the other (mean difference, 47.9; p = .0027), but for 80%, the absolute difference was 200 cm3 or less. Spearman correlation between readers was 0.822. Volume correlated with pTN stages and OS, best defined by three groups with average volumes of 91.2, 245.3, and 511.3 cm3 associated with median OS of 37, 18, and 8 months, respectively. Conclusions For the first time, a multicenter network was established and initial correlations of tumor volume with pTN stages and OS are shown. A larger multicenter international study is planned to confirm the results and refine correlations.
Abstract Thymectomy is part of the therapeutic armamentarium for myasthenia gravis (MG). During the past 80 years, multiple observational studies have shown that thymectomy can potentially fasten ...stabilization of the disease, reduce the need for corticosteroids, and in some patients lead to complete remission. The benefit from thymectomy in MG is supported by propensity score analysis. A randomized control trial looking at the role of thymectomy in nonthymomatous MG patients was recently completed, but the results are not yet available. The approach and extent of thymectomy remain a topic of intense discussion, particularly with the development of minimally invasive surgery. Although the presence of extracapsular thymic tissue is frequent and well described, the accessibility of these ectopic thymic foci as well as their function and impact on outcome after surgery have been unclear, leading to divergent views between proponents of a maximal cervicomediastinal thymectomy with en bloc resection of all fatty tissue between the thyroid grand and the diaphragm and those of a less extensive approach. In the future, better definition of the type of thymectomy will be important, particularly if prospective studies and randomized trials are performed to compare different surgical approaches. One possibility would be to reserve the term “extended thymectomy” to resection of the thymus with the anterior mediastinal fat between both pleura, the pericardium and diaphragm. More extensive surgery should be specified when it encompasses sites such as the right and left pericardiophrenic angles, the aortopulmonary window, the aortocaval groove and retro-innominate space, and the perithyroid area.
Objective Normothermic ex vivo lung perfusion is a novel method to evaluate and improve the function of injured donor lungs. We reviewed our experience with 50 consecutive transplants after ex vivo ...lung perfusion. Methods A retrospective study using prospectively collected data was performed. High-risk brain death donor lungs (defined as Pa o2 /F io2 <300 mm Hg or lungs with radiographic or clinical findings of pulmonary edema) and lungs from cardiac death donors were subjected to 4 to 6 hours of ex vivo lung perfusion. Lungs that achieved stable airway and vascular pressures and Pa o2 /F io2 greater than 400 mm Hg during ex vivo lung perfusion were transplanted. The primary end point was the incidence of primary graft dysfunction grade 3 at 72 hours after transplantation. End points were compared with lung transplants not treated with ex vivo lung perfusion (controls). Results A total of 317 lung transplants were performed during the study period (39 months). Fifty-eight ex vivo lung perfusion procedures were performed, resulting in 50 transplants (86% use). Of these, 22 were from cardiac death donors and 28 were from brain death donors. The mean donor Pa o2 /F io2 was 334 mm Hg in the ex vivo lung perfusion group and 452 mm Hg in the control group ( P = .0001). The incidence of primary graft dysfunction grade 3 at 72 hours was 2% in the ex vivo lung perfusion group and 8.5% in the control group ( P = .14). One patient (2%) in the ex vivo lung perfusion group and 7 patients (2.7%) in the control group required extracorporeal lung support for primary graft dysfunction ( P = 1.00). The median time to extubation, intensive care unit stay, and hospital length of stay were 2, 4, and 20 days, respectively, in the ex vivo lung perfusion group and 2, 4, and 23 days, respectively, in the control group ( P > .05). Thirty-day mortality (4% in the ex vivo lung perfusion group and 3.5% in the control group, P = 1.00) and 1-year survival (87% in the ex vivo lung perfusion group and 86% in the control group, P = 1.00) were similar in both groups. Conclusions Transplantation of high-risk donor lungs after 4 to 6 hours of ex vivo lung perfusion is safe, and outcomes are similar to those of conventional transplants. Ex vivo lung perfusion improved our center use of donor lungs, accounting for 20% of our current lung transplant activity.
Ex vivo lung perfusion (EVLP) is an effective method to assess and improve the function of otherwise unacceptable lungs, alleviating the shortage of donor lungs. The early results with EVLP have been ...encouraging, but longer-term results, including functional and patient-reported outcomes, are not well characterized.
This retrospective single-center study included all lung transplants performed between September 2008 and December 2012. We investigated whether survival or rate of chronic lung allograft dysfunction (CLAD) differed in recipients of EVLP-treated lungs compared with contemporaneous recipients of conventional donor lungs. We also studied functional (highest forced expiratory volume in 1 second predicted, change in 6-minute walk distance, number of acute rejection episodes) and quality of life outcomes.
Of 403 lung transplants that were performed, 63 patients (15.6%) received EVLP-treated allografts. Allograft survival for EVLP and conventional donor lung recipients was 79% vs 85%, 71% vs 73%, and 58% vs 57% at 1, 3, and 5 years after transplant, respectively (log-rank p = not significant). Freedom from CLAD was also similar (log-rank p = 0.53). There were no significant differences in functional outcomes such as highest forced expiratory volume in 1 second predicted (76.5% ± 23.8% vs 75.8% ± 22.8%, p = 0.85), change in 6-minute walk distance (194 ± 108 meters vs 183 ± 126 meters, p = 0.57), or the number of acute rejection episodes (1.5 ± 1.4 vs 1.3 ± 1.3, p = 0.36). The EVLP and conventional donor groups both reported a significantly improved quality of life after transplantation, but there was no intergroup difference.
EVLP is a safe and effective method of assessing and using high-risk donor lungs before transplantation and leads to acceptable long-term survival, graft function, and improvements of quality of life that are comparable with conventionally selected donor lungs.
Localized malignant mesotheliomas (LMM) is an uncommon and poorly recognized neoplasm. Its pathologic diagnosis is often surprising in patients with serosal/subserosal based localized tumors that are ...clinically suspicious for metastatic lesions or primary sarcomas. Once a tumor is diagnosed as "mesothelioma", LMM is often mistaken for diffuse malignant mesothelioma (DMM). Best currently available evidence about LMM was collected from the literature and cases diagnosed by members of the International Mesothelioma Panel (IMP). One hundred and one (101) LMM have been reported in the English literature. Patients had localized tumors with identical histopathologic features to DMM. Patients ranged in age from 6 to 82 years; 75% were men. Most (82%) of the tumors were intrathoracic. Others presented as intrahepatic, mesenteric, gastric, pancreatic, umbilical, splenic, and abdominal wall lesions. Tumors varied in size from 0.6 to 15 cm. Most patients underwent surgical resection and/or chemotherapy or radiation therapy. Median survival in a subset of patients was 29 months. Seventy two additional LMM from IMP institutions ranged in age from 28 to 95 years; 58.3% were men. Sixty tumors (83.3%) were intrathoracic, others presented in intraabdominal sites. Tumors varied in size from 1.2 to 19 cm. Median survival for 51 cases was 134 months. Best evidence was used to formulate guidelines for the diagnosis of LMM. It is important to distinguish LMM from DMM as their treatment and prognosis is different. A multidisciplinary approach is needed for the diagnosis of LMM as it shows identical histopathology and immunophenotype to DMM.
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