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1.  Long-Term Survival Based on the Surgical Approach to Lobectomy for Clinical Stage I Non-Small Cell Lung Cancer: Comparison of Robotic, Video Assisted Thoracic Surgery, and Thoracotomy Lobectomy 
Annals of surgery  2017;265(2):431-437.
To compare the long-term outcomes among robotic, video-assisted thoracic surgery (VATS), and open lobectomy in stage I non-small cell lung cancer (NSCLC).
Summary Background Data
Survival comparisons between robotic, VATS, and open lobectomy in NSCLC have not yet been reported. Some studies have suggested that survival following VATS is superior, for unclear reasons.
Three cohorts (robotic, VATS, and open) of clinical stage I NSCLC patients were matched by propensity score and compared to assess overall survival (OS) and disease-free survival (DFS). Univariate and multivariate analyses were performed to identify factors associated with the outcomes.
From January 2002 to December 2012, 470 unique patients (172 robotic, 141 VATS, and 157 open) were included in the analysis. The robotic approach harvested a higher number of median stations of lymph nodes (5 for robotic vs 3 for VATS vs 4 for open; P<0.001). Patients undergoing minimally invasive approaches had shorter median length of hospital stay (4 days for robotic vs 4 days for VATS vs 5 days for open; P<0.001). The 5-year OS for the robotic, VATS, and open matched groups were 77.6%, 73.5%, and 77.9%, respectively without a statistically significant difference; corresponding 5-year DFS were 72.7%, 65.5%, and 69.0%, respectively, with a statistically significant difference between the robotic and VATS groups (P=0.047). However, multivariate analysis found that surgical approach was not independently associated with shorter OS and DFS.
Minimally invasive approaches to lobectomy for clinical stage I NSCLC result in similar long-term survival as thoracotomy. Use of VATS and robotics is associated with shorter length of stay, and the robotic approach resulted in greater lymph node assessment.
PMCID: PMC5033685  PMID: 28059973
2.  Spread Through Air Spaces (STAS) is an Independent Predictor of Recurrence and Lung Cancer Specific Death in Squamous Cell Carcinoma 
Spread through air spaces (STAS) is a recently recognized pattern of invasion in lung adenocarcinoma, however, it has not yet been characterized in squamous cell carcinoma (SCC).
We reviewed 445 resected stage I-III lung SCC and investigated the clinical significance of STAS. Cumulative incidence of recurrence (CIR) and lung cancer-specific death (CID) were evaluated by competing risks analyses and overall survival (OS) by Cox models.
Of total 445 patients, 336 (76%) were >65 years old. Among 273 patients who died, 91 (33%) died of lung cancer whereas the remaining died of competing events or unknown cause. STAS was observed in 132 patients (30%) and the frequency increased with stage. The cumulative incidence of any, distant, and locoregional recurrence as well as lung cancer-specific death were significantly higher in patients with STAS compared to those without STAS, whereas there was no statistically significant difference in OS. In multivariable models for any recurrence and lung cancer-specific death, STAS was an independent predictor for both outcomes (p=0.034 and 0.016, respectively).
STAS was present in one third of resected lung SCC. In competing risks analysis in a cohort where three fourths of the patients were elderly, STAS was associated with lung cancer-specific outcomes. Our findings suggest that STAS is one of the most prognostically significant histologic findings in lung SCC.
PMCID: PMC5639476  PMID: 27693541
Lung; competing risks analysis; spread through air spaces; squamous cell carcinoma
3.  Histologic subtype in core lung biopsies of early-stage lung adenocarcinoma is a prognostic factor for treatment response and failure patterns after stereotactic body radiation therapy 
Stereotactic body radiation therapy (SBRT) has emerged as an effective treatment for early-stage lung cancer. Histologic subtyping in surgically resected lung adenocarcinomas is recognized as a prognostic factor, with the presence of solid or micropapillary patterns predicting poor outcomes. Herein, we describe outcomes following SBRT for early-stage lung adenocarcinoma by histologic subtype.
Materials and Methods
We identified 119 consecutive patients (124 lesions) with stage I-IIA lung adenocarcinoma who were treated with definitive SBRT at our institution between August 2008 and August 2015 and had undergone core biopsy. Histologic subtyping was performed according to the 2015 WHO Classification. Thirty-seven tumors (30%) were of high risk subtype, defined as containing a component of solid and/or micropapillary pattern. Cumulative incidences of local, nodal, regional and distant failure were compared between high risk vs. non-high risk adenocarcinoma subtypes with Gray’s test, and multivariable-adjusted hazard ratios were estimated from propensity score-weighted Cox regression models.
Median follow-up for the entire cohort was 17 months and 21 months for surviving patients. The 1-year cumulative incidence and adjusted hazard ratio (HR) of local, nodal, regional and distant failure, respectively, in high risk versus non-high risk lesions were 7.3% vs 2.7% (HR 16.8; 95% CI 3.5–81.4), 14.8% vs 2.6% (HR 3.8; 95% CI 0.95–15.0), 4.0% vs 1.2% (HR 20.9; 95% CI 2.3–192.3) and 22.7% vs 3.6% (HR 6.9; 95% CI 2.2–21.1). No significant difference was seen with regard to overall survival.
Outcomes following SBRT for early-stage adenocarcinoma of the lung are highly correlated with histologic subtype, with micropapillary and solid tumors portending significantly higher rates of locoregional and metastatic progression. In this context, histologic subtype based on core biopsies is a prognostic factor and may have important implications for patient selection, adjuvant treatment, biopsy methods and clinical trial design.
PMCID: PMC5161605  PMID: 27839909
4.  CAR T-cell intrinsic PD-1 checkpoint blockade: A two-in-one approach for solid tumor immunotherapy 
Oncoimmunology  2016;6(2):e1273302.
PD-L1/2 expression in solid tumors inhibits chimeric antigen receptor (CAR) T-cell efficacy. A PD-1 dominant negative receptor expressed in CAR T cells provides cell-intrinsic checkpoint blockade and augments antitumor efficacy. A combinatorial immunotherapeutic strategy of combining CAR T cells with checkpoint blockade is a promising treatment approach for solid tumors.
PMCID: PMC5353939  PMID: 28344886
Adoptive T-cell therapy; breast cancer; immunosuppression; lung cancer; mesothelioma; PD-1 blockade; tumor microenvironment
5.  KRAS Mutation is a Significant Prognostic Factor in Early Stage Lung Adenocarcinoma 
The potential clinical impact of KRAS and epidermal growth factor receptor (EGFR) mutations has been investigated in lung adenocarcinomas; however, their prognostic value remains controversial. In our study, we sought to investigate the prognostic significance of driver mutations using a large cohort of early-stage lung adenocarcinomas.
We reviewed patients with pathologic early-stage, lymph node-negative, solitary lung adenocarcinoma who had undergone surgical resection (1995–2005; stage I/II = 463/19). Tumors were classified according to the IASLC/ATS/ERS classification and genotyped by Sequenom MassARRAY system and polymerase chain reaction-based assays. In stage I disease, the Kaplan-Meier method and cumulative incidence of recurrence (CIR) analyses were used to estimate the probability of overall survival (OS) and recurrence, respectively.
Of all, 129 (27%) patients had mutations in KRAS, 86 (18%) in EGFR, 8 (2%) in BRAF, 8 (2%) in PIK3CA, 4 (1%) in NRAS, and 1 (0.2%) in AKT1. EGFR L858R mutation correlated with lepidic predominant histology (P = 0.006) while exon 19 deletion correlated with acinar predominant histology (P < 0.001). EGFR mutations were not detected in invasive mucinous adenocarcinomas (P = 0.033). The 5-year OS of patients with KRAS mutant tumors was significantly worse (n = 124; 5-year OS, 63%) than those with KRAS wild-type (n = 339; 77%; P < 0.001). In solid predominant tumors, KRAS mutations correlated with worse OS (P = 0.008) and increased risk of recurrence (P = 0.005). On multivariate analysis, KRAS mutation was an independent prognosticator of OS in all patients (hazard ratio, 1.87; P < 0.001) and recurrence in solid predominant tumors (hazard ratio, 4.73; P = 0.012).
In patients with resected stage I lung adenocarcinomas, KRAS mutation was an independent prognostic factor for OS and recurrence, especially in solid predominant tumors.
PMCID: PMC5106330  PMID: 27740967
Adenocarcinoma; lung; KRAS; epidermal growth factor receptor; prognosis
6.  Surgical immune interventions for solid malignancies 
American journal of surgery  2016;212(4):682-690.e5.
The purpose of this study was to systematically review clinically translatable immunotherapeutic agents that are delivered regionally for solid malignancies.
Data Sources
PubMed and were searched for published and registered clinical trials, respectively. The search yielded 334 relevant publications, of which 116 manuscripts were included for review after exclusion criteria were applied.
There has been an increase in the regional administration of cell-based and viral vector-based clinical trials over the last 5 years. Surgical interventions have been developed for intrapleural, intracranial, intraperitoneal, and intratumoral routs of access to enhance the local delivery of there therapies. Multimodality therapies that combine regional immunotherapy with other local and systemic therapies are demonstrating continued growth as the field of immunotherapy continues to expand.
PMCID: PMC5089080  PMID: 27659157
Regional immunotherapy; Surgical immunotherapy; Adoptive cell therapy
7.  Detection of recurrence patterns following wedge resection for early stage lung cancer 
The Annals of thoracic surgery  2016;102(4):1067-1073.
Wedge resection in selected patients with early stage non-small cell lung cancer (NSCLC) is considered to be a valid treatment option. The aim of this study was to evaluate the recurrence patterns after wedge resection, to analyze the survival of patients under routine follow up and to recommend a follow-up regimen.
Retrospective analysis of 446 consecutive patients between May 2000 and December 2012 who underwent a wedge resection for clinical stage I NSCLC. All patients were followed up with a computed tomography (CT) scan with or without contrast. The recurrence was recorded as local (involving the same lobe of wedge resection), local-regional (involving mediastinal or hilar lymph nodes or a different lobe), or distant including distant metastasis and pleural disease.
Median follow-up for survivors (n=283) was 44.6 months. 163 patients died: median overall survival of 82.6 months. 36 patients were diagnosed with new primary NSCLC and 152 with recurrence (79 local, 45 regional, and 28 distant). There was no difference in the incidence of recurrence detection detected by CT scans with vs. without contrast (p=0.18). The cumulative incidence of local recurrences at 1, 2 and 3- years was higher than the cumulative incidence for local, regional and distant recurrences: 5.2, 11.1 and 14.9% vs 3.7, 6.6 and 9.5% vs 2.3, 4.7, and 6.4%, respectively. Primary tumor diameter was associated with local recurrence in univariate analysis.
Wedge resection for early stage NSCLC is associated with a significant risk for local and regional recurrence. A long term follow-up using non-contrast CT scans at consistent intervals is appropriate to monitor for these recurrences.
PMCID: PMC5421376  PMID: 27345095
wedge resection; computed tomography; follow up; recurrence
9.  Cancer antigen profiling for malignant pleural mesothelioma immunotherapy: expression and coexpression of mesothelin, cancer antigen 125, and Wilms tumor 1 
Oncotarget  2017;8(44):77872-77882.
To develop cancer antigen-targeted immunotherapeutic strategies for malignant pleural mesothelioma (MPM), we investigated the individual and coexpressions of the cancer-associated antigens mesothelin (MSLN), cancer antigen 125 (CA125), and Wilms tumor 1 (WT1) in both epithelioid and non-epithelioid MPM.
All available hematoxylin and eosin-stained slides from patients who were diagnosed with MPM (1989-2010) were reviewed. We constructed tissue microarrays from 283 patients (epithelioid = 234; non-epithelioid = 49). Intensity and distribution for each antigen were assessed by immunohistochemistry.
Positive expression of MSLN, CA125, and WT1 were demonstrated in 93%, 75%, and 97% of epithelioid MPM cases, and 57%, 33%, and 98% of non-epithelioid MPM cases, respectively. Triple- and double-positive antigen coexpressions were demonstrated in 72% and 23% of epithelioid MPM cases and 29% and 33% of non-epithelioid MPM cases, respectively. Complete absence of expression for all three antigens was demonstrated in <2% of MPM cases. More than two-thirds of MPM cases had ≥50% distribution of MSLN-positive cells and, among the remaining third, half had ≥50% distribution of WT1-positive cells. CA125/MSLN coexpression was observed in more than two-thirds of epithelioid MPM cases and one-third of non-epithelioid MPM cases.
A limited number of cancer-associated antigens can target almost all MPM tumors for immunotherapy.
PMCID: PMC5652821
mesothelin; CA125; WT1; mesothelioma; chimeric antigen receptor
10.  Impact of Increasing Age on Cause-Specific Mortality and Morbidity in Patients With Stage I Non–Small-Cell Lung Cancer: A Competing Risks Analysis 
Journal of Clinical Oncology  2016;35(3):281-290.
To perform competing risks analysis and determine short- and long-term cancer- and noncancer-specific mortality and morbidity in patients who had undergone resection for stage I non–small-cell lung cancer (NSCLC).
Patients and Methods
Of 5,371 consecutive patients who had undergone curative-intent resection of primary lung cancer at our institution (2000 to 2011), 2,186 with pathologic stage I NSCLC were included in the analysis. All preoperative clinical variables known to affect outcomes were included in the analysis, specifically, Charlson comorbidity index, predicted postoperative (ppo) diffusing capacity of the lung for carbon monoxide, and ppo forced expiratory volume in 1 second. Cause-specific mortality analysis was performed with competing risks analysis.
Of 2,186 patients, 1,532 (70.1%) were ≥ 65 years of age, including 638 (29.2%) ≥ 75 years of age. In patients < 65, 65 to 74, and ≥ 75 years of age, 5-year lung cancer–specific cumulative incidence of death (CID) was 7.5%, 10.7%, and 13.2%, respectively (overall, 10.4%); noncancer-specific CID was 1.8%, 4.9%, and 9.0%, respectively (overall, 5.3%). In patients ≥ 65 years of age, for up to 2.5 years after resection, noncancer-specific CID was higher than lung cancer–specific CID; the higher noncancer-specific, early-phase mortality was enhanced in patients ≥ 75 years of age than in those 65 to 74 years of age. Multivariable analysis showed that low ppo diffusing capacity of lung for carbon monoxide was an independent predictor of severe morbidity (P < .001), 1-year mortality (P < .001), and noncancer-specific mortality (P < .001), whereas low ppo forced expiratory volume in 1 second was an independent predictor of lung cancer–specific mortality (P = .002).
In patients who undergo curative-intent resection of stage I NSCLC, noncancer-specific mortality is a significant competing event, with an increasing impact as patient age increases.
PMCID: PMC5456376  PMID: 28095268
11.  Failure patterns after Hemithoracic Pleural Intensity-Modulated Radiation Therapy for Malignant Pleural Mesothelioma 
We have previously reported on our technique to deliver intensity-modulated radiotherapy (IMRT) to the entire pleura while attempting to spare the lung in patients with malignant pleural mesothelioma (MPM). Herein, we report a detailed pattern-of-failure analysis in patients with MPM who were unresectable or underwent pleurectomy/decortications (P/D), uniformly treated with hemithoracic pleural IMRT.
Sixty-seven patients with MPM were treated with definitive or adjuvant hemithoracic pleural IMRT between 11/2004 and 5/2013. Pretreatment imaging, treatment plans, and post-treatment imaging were retrospectively reviewed to determine failure location(s). Failures were categorized as in-field (within the 90% isodose line), marginal (<90% and ≥50% isodose lines), out-of-field (outside the 50% isodose line), or distant.
The median follow-up was 24 months from diagnosis and the median time to in-field local failure from the end of radiotherapy was 10 months. Forty-three in-field local failures (64%) were found with a 1- and 2-year actuarial failure rate of 56% and 74%, respectively. For patients who underwent P/D versus those who received a partial pleurectomy or were deemed unresectable, the median time to in-field local failure was 14 months versus 6 months, with 1- and 2-year actuarial in-field local failure rates of 43% and 60% versus 66% and 83%, respectively (p=0.03). There were 13 marginal failures (19%). Five of the marginal failures (38%) were located within the costomediastinal recess. Marginal failures decreased with increasing institutional experience (P = .04). Twenty-five patients (37%) had out-of-field failures. Distant failures occurred in 32 patients (48%).
After hemithoracic pleural IMRT, local failure remains the dominant form of failure pattern. Patients treated with adjuvant hemithoracic pleural IMRT after P/D experience a significantly longer time to local and distant failure than patients treated with definitive pleural IMRT. Increasing experience and improvement in target delineation minimize the incidence of avoidable marginal failures.
PMCID: PMC5560169  PMID: 25073664
Mesothelioma; Intensity-Modulated Radiotherapy (IMRT); Patterns of Failure
12.  Phase II Study of Hemithoracic Intensity-Modulated Pleural Radiation Therapy (IMPRINT) As Part of Lung-Sparing Multimodality Therapy in Patients With Malignant Pleural Mesothelioma 
Journal of Clinical Oncology  2016;34(23):2761-2768.
We conducted a two-center phase II study to determine the safety of hemithoracic intensity-modulated pleural radiation therapy (IMPRINT) after chemotherapy and pleurectomy-decortication (P/D) as part of a multimodality lung-sparing treatment.
Patients and Methods
Patients received up to four cycles of pemetrexed plus platinum. If feasible, P/D was performed. Hemithoracic IMPRINT was administered to a planned dose of 50.4 Gy in 28 fractions. The primary end point was the incidence of grade 3 or greater radiation pneumonitis (RP).
A total of 45 patients were enrolled; 18 were not evaluable (because of disease progression before radiation therapy [RT], n = 9; refusal of surgery or RT, n = 5; extrapleural pneumonectomy at time of surgery, n = 2; or chemotherapy complications, n = 2). A total of 26 patients received pemetrexed plus cisplatin, 18 received pemetrexed plus carboplatin, and four received a combination. Thirteen patients (28.9%) had a partial response, 15 patients (33.3%) experienced disease progression, one patient died during chemotherapy, and all others had stable disease. Eight patients underwent P/D or an extended P/D, and 13 underwent a partial P/D. A total of 27 patients started IMPRINT (median dose, 46.8 Gy; range, 28.8 to 50.4 Gy) and were evaluable for the primary end point (median follow-up, 21.6 months). Six patients experienced grade 2 RP, and two patients experienced grade 3 RP; all recovered after corticosteroid initiation. No grade 4 or 5 radiation-related toxicities were observed. The median progression-free survival and overall survival (OS) were 12.4 and 23.7 months, respectively; the 2-year OS was 59% in patients with resectable tumors and was 25% in patients with unresectable tumors.
Hemithoracic IMPRINT for malignant pleural mesothelioma (MPM) is safe and has an acceptable rate of RP. Its incorporation with chemotherapy and P/D forms a new lung-sparing treatment paradigm for patients with locally advanced MPM.
PMCID: PMC5019761  PMID: 27325859
13.  Intraoperative Near-Infrared Fluorescence Imaging as an Adjunct to Robotic Assisted Minimally Invasive Esophagectomy 
Innovations (Philadelphia, Pa.)  2014;9(5):391-393.
During esophagectomy, identification and preservation of the right gastroepiploic vascular arcade are critical and may be challenging with minimally invasive approaches. We assessed the use of near-infrared fluorescence imaging fluorescence angiography (NIFI-FA) during robotic assisted minimally invasive esophagectomy (RAMIE) as an aid to visualize the gastric vasculature with mobilization. After intravenous administration of 10 mg of indocyanine green (ICG), a robotic platform with near-infrared optical fluorescence capability was used to examine the gastric vasculature in patients undergoing RAMIE. Thirty of 42 patients (71%) undergoing RAMIE were assessed NIFI-FA during mobilization of the greater gastric curve and fundus; 11 were excluded because the system was not available and 1 because of documented allergy to iodinated contrast. The median time from ICG administration to detectable fluorescence was 37.5 seconds (range, 20–105 seconds). NIFI-FA identified or confirmed termination of the vascular arcade in all 30 cases. Subjectively, NIFI-FA often identified otherwise unvisualized small transverse vessels between the termination of the vascular arcade and the first short gastric artery, as well as between the short gastric arteries. Identification and/or confirmation of the vascular arcade position during mobilization of the greater curve/omentum were also aided by NIFI-FA. While there are limitations to the current technology, NIFI-FA may be a useful adjunct to confirm and identify the position of gastroepiploic vessels, allow for safer and more confident dissections during gastric mobilization, and potentially decrease serious intraoperative vascular misadventures.
PMCID: PMC5523952  PMID: 25238427
Robotic Surgery; Esophagectomy; Esophageal Cancer; Fluorescence Imaging; Angiography
14.  Improved Outcomes with Modern Lung-Sparing Trimodality Therapy in Patients with Malignant Pleural Mesothelioma 
Higher target conformity and better sparing of organs at risk with modern radiotherapy (RT) may result in higher tumor control and less toxicities. In this study, we compare our institutional multimodality therapy experience of adjuvant chemotherapy and hemithoracic intensity-modulated pleural RT (IMPRINT) to previously used adjuvant conventional RT (CONV) in patients with malignant pleural mesothelioma (MPM) treated with lung-sparing pleurectomy/decortication (P/D).
We analyzed 209 patients who underwent P/D and adjuvant RT (n[CONV]=131, n[IMPRINT]=78) for MPM between 1974 and 2015. The primary endpoint was overall survival (OS). The Kaplan-Meier method and Cox proportional hazards model were used to calculate OS; competing ri sks analysis was performed for local failure-free (LFFS) and progression-free survival (PFS). Univariate (UVA) and multivariate analysis (MVA) was performed with relevant clinical and treatment factors.
The median age was 64 years, 80% were male. Patients receiving IMPRINT had significantly higher rates of epithelial histology, advanced pStage and chemotherapy treatment. OS was significantly higher after IMPRINT (median 20.2 vs 12.3 months, p=0.001). Higher Karnofsky performance score (KPS), epithelioid histology, macroscopically complete resection (MCR), and use of chemotherapy/IMPRINT were found to be significant factors for longer OS upon MVA. No significant predictive factors were identified for local failure or progression. Fewer patients developed grade ≥2 esophagitis after IMPRINT compared to CONV (23% vs 47%).
Trimodality therapy including adjuvant hemithoracic IMPRINT, chemotherapy, and P/D is associated with promising OS rates and decreased toxicities in patients with MPM. Dose constraints should be applied vigilantly to minimize serious adverse events.
PMCID: PMC5499250  PMID: 28341225
Malignant Pleural Mesothelioma; Intensity-Modulated Pleural Radiation Therapy (IMPRINT); conventional RT; Pleurectomy/Decortication
16.  Attaining Proficiency In Robotic-Assisted Minimally Invasive Esophagectomy While Maximizing Safety During Procedure Development 
Innovations (Philadelphia, Pa.)  2016;11(4):268-273.
Robotic-assisted minimally invasive esophagectomy (RAMIE) is an emerging, complex operation with limited reports detailing morbidity, mortality, and requirements for attaining proficiency. Our objective was to develop a standardized RAMIE technique, evaluate procedure safety, and assess outcomes using a dedicated operative team and two surgeon approach.
We conducted a study of sequential patients undergoing RAMIE from January 25, 2011, May 5, 2014. Intermedian demographics and perioperative data were compared between sequential halves of the experience using Wilcoxon rank sum test and Fischer’s exact test. Median operative time was tracked over successive 15-patient cohorts.
100 of 313 esophageal resections performed at our institution underwent RAMIE during the study period. A dedicated team including two attending surgeons, and uniform anesthesia and OR staff was established. Patient demographics and outcomes are summarized in Table 1. There were no significant differences in age, gender, histology, stage, induction therapy, or risk class between the two halves of the study. Estimated blood loss, conversions, operative times, and overall complications significantly decreased. The median resected lymph nodes increased, but was not statistically significant. Median operative time decreased to approximately 370 minutes between the 30th and the 45th cases (Figure 1). There were no emergent intra-operative complications and the anastomotic leak rate was 6% (6/100). 30-day mortality was 0% (0/100) and 90-day mortality was 1% (1/100).
Excellent perioperative and short-term patient outcomes with minimal mortality can be achieved using a standardized RAMIE procedure and dedicated team approach. The structured process described may serve as a model to maximize patient safety during development and assessment of complex novel procedures.
PMCID: PMC5427663  PMID: 27662372
Esophageal Cancer; Surgery Outcomes; Robotic Esophagectomy; Esophagectomy; Learning Curve
17.  New Cancer Immunotherapy Agents in Development: a report from an associated program of the 31stAnnual Meeting of the Society for Immunotherapy of Cancer, 2016 
This report is a summary of ‘New Cancer Immunotherapy Agents in Development’ program, which took place in association with the 31st Annual Meeting of the Society for Immunotherapy of Cancer (SITC), on November 9, 2016 in National Harbor, Maryland. Presenters gave brief overviews of emerging clinical and pre-clinical immune-based agents and combinations, before participating in an extended panel discussion with multidisciplinary leaders, including members of the FDA, leading academic institutions and industrial drug developers, to consider topics relevant to the future of cancer immunotherapy.
PMCID: PMC5477277
Immunotherapy; Cancer; Checkpoint inhibitors; PD-1; Combination therapy
18.  Novel immunotherapy clinical trials in malignant pleural mesothelioma 
In this article, we review ongoing novel clinical trials currently investigating immunotherapeutic approaches for patients with malignant pleural mesothelioma (MPM). There is a dearth of effective therapeutic options for patients diagnosed with MPM and metastatic cancers of the pleura; these diseases have an estimated annual incidence of 150,000. Modulating the immune microenvironment to promote antitumor immune responses by systemically and regionally delivered therapeutic agents is an active area of investigation. We have conducted a review of the clinical trials database for clinical trials actively recruiting MPM patients. We focused on novel therapeutic agents administered either systemically or intrapleurally to modulate the tumor immune microenvironment. Herein, we have summarized the published results of early phase clinical trials. A total of 43 clinical trials met our inclusion criteria. These trials are investigating immunologic agents (n=20) and antibody directed therapies (n=23). The regional intrapleural delivery technique (6 trials) is used to administer chemotherapy agents (3 of 6 trials) and immunotherapy agents (3 of 6 trials), including chimeric antigen receptor T cells (1 of 6 trials). Current clinical trials modulating the MPM immune microenvironment and the combination of these novel agents with standard of care therapy provide a promising area of investigation for MPM therapy.
PMCID: PMC5497103  PMID: 28706913
Chimeric antigen receptors; regional immunotherapy; mesothelin; adoptive T-cell therapy; checkpoint blockade
19.  Immunotherapy for malignant pleural mesothelioma: current status and future directions 
Malignant pleural mesothelioma (MPM) has been marked historically by poor prognosis. Current standard of care for this deadly disease results in sub-optimal improvements in overall survival (OS), which has prompted researchers to explore innovative treatment alternatives. Immunotherapy is an emerging therapeutic modality that harnesses the power of the human immune system. In this review, we summarize the different methods of immunotherapy for malignant pleural mesothelioma. Using we searched the terms “immunotherapy” and “immune therapy” combined with “pleural mesothelioma”. Our search yielded 75 trials, among which 37 trials met our specific criteria. Our search identified immune checkpoint blockade, immunotoxin therapy, anticancer vaccines, oncolytic viral therapy, and adoptive cell therapy as the most common and pertinent methods of immunotherapy currently being assessed in clinical trials. We have reviewed the most up-to-date clinical trials involving immunotherapeutic approaches for the treatment of malignant pleural mesothelioma. In addition to highlighting some of the successes of immunotherapy, we also have identified limitations that must be overcome to improve the efficacy of these therapies.
PMCID: PMC5504119  PMID: 28713676
Immunotherapy; malignant pleural mesothelioma; thoracic malignancies
20.  Immunotherapy for non-small cell lung cancer: current concepts and clinical trials 
Recent successes in immunotherapeutic strategies are being investigated to combat cancers that have less than ideal responses to standard of care treatment, such as non-small-cell lung cancer. In this paper, we summarize concepts and the current status of immunotherapy for non-small cell lung cancer, including salient features of the major categories of immunotherapy—monoclonal antibody therapy, immune checkpoint blockade, immunotoxins, anticancer vaccines, and adoptive cell therapy.
PMCID: PMC4851162  PMID: 26516195
Lung cancer; Antibody therapy; PD-1/PD-L1 blockade; Chimeric antigen receptor; Adoptive cell therapy
21.  CK2α' Drives Lung Cancer Metastasis by Targeting BRMS1 Nuclear Export and Degradation 
Cancer research  2016;76(9):2675-2686.
Breast cancer metastasis suppressor 1 (BRMS1) is decreased in non–small cell lung cancer (NSCLC) and other solid tumors, and its loss correlates with increased metastases. We show that BRMS1 is posttranslationally regulated by tumor necrosis factor–induced casein kinase 2 catalytic subunit (CK2α') phosphorylation of nuclear BRMS1 on serine 30, resulting in 14-3-3ε–mediated nuclear exportation, increased BRMS1 cytosolic expression, and ubiquitin-proteasome–induced BRMS1 degradation. Using our in vivo orthotopic mouse model of lung cancer metastases, we found that mutation of serine 30 in BRMS1 or the use of the CK2-specific small molecule inhibitor CX4945 abrogates CK2α'-induced cell migration and invasion in vitro and decreases NSCLC metastasis by 60-fold. Analysis of 160 human NSCLC specimens confirmed that tumor CK2α' and cytoplasmic BRMS1 expression levels are associated with increased tumor recurrence, metastatic foci, and reduced disease-free survival. Collectively, we identify a therapeutically exploitable post-translational mechanism by which CK2α-mediated degradation of BRMS1 promotes metastases in lung cancer.
PMCID: PMC4873401  PMID: 26980766
RMS1; CK2; Phosphorylation; Degradation; Metastasis
22.  S008 – Real-time intraoperative detection of tissue hypoxia in gastrointestinal surgery by Wireless Pulse Oximetry (WiPOX) 
Surgical endoscopy  2010;25(5):1383-1389.
Dehiscence or leakage following bowel anastomoses is associated with high morbidity and mortality. Perfusion and local tissue oxygenation (StO2), independent of systemic oxygen saturation, are fundamental determinates of anastomotic viability. As current technology is limited for monitoring local StO2 at bowel anastomoses, we aimed to construct a wireless pulse oximeter (WiPOX) to monitor real-time intraoperative tissue oxygenation, permitting identification of compromised anastomotic perfusion.
We have: (a) designed a handheld device capable of real-time monitoring of serosal and mucosal StO2 through endoscopic ports with wireless data transmission to standard intraoperative monitors, (b) constructed the WiPOX using materials meeting FDA regulations for intraoperative use and re-use, (c) performed accuracy testing in humans by comparing the WiPOX to standard pulse oximeters, and (d) tested WiPOX efficacy for detecting early tissue hypoxia in stomach, intestines, and kidneys in anesthetized rats and swine.
In humans, WiPOX demonstrated accuracy within 3% when compared to commercially available pulse oximeters. Application of the WiPOX in rats and swine demonstrated normal serosal and mucosal StO2 and pulse rates in healthy small bowel and stomach. Within 30 seconds of compromised perfusion, the WiPOX detected bowel hypoxia over a wide range of oxygen saturation (p<0.005). A greater degree of hypoxia was detected in mucosal versus serosal measurements during early ischemia, despite normal appearance of tissue. The onboard sensor-processor unit permitted non-invasive pulse oximetry and integration with current intraoperative monitoring. The contact pressure-sensing head allowed for consistent, high quality StO2 waveform readouts despite the presence of body fluids.
We have constructed, validated, and successfully tested a novel wireless pulse oximeter capable of detecting intraoperative tissue hypoxia in open or endoscopic surgery. This device will aid surgeons in detecting anastomotic vascular compromise and facilitate choosing an ideal site for bowel anastomosis by targeting well-perfused tissue with optimal healing capacity.
PMCID: PMC5407085  PMID: 20972585
Anastomotic leak; tissue oxygenation; bowel hypoxia; oximetry
23.  Postinduction PET assessment of N2 nodes is not associated with ypN2 disease or overall survival in stage IIIA non-small cell lung cancer 
Induction therapy is often recommended for patients with clinical stage IIIA–N2 (cIIIA/pN2) lung cancer. We examined whether postinduction positron emission tomography (PET) scans were associated with ypN2 disease and survival of patients with cIIIA/pN2 disease.
We performed a retrospective review of a prospectively maintained database to identify patients with cIIIA/pN2 non-small cell lung cancer treated with induction chemotherapy followed by surgery between January 2007 and December 2012. The primary aim was the association between postinduction PET avidity and ypN2 status; the secondary aims were overall survival (OS), disease-free survival (DFS), and recurrence.
Persistent pathologic N2 disease was present in 61% of patients (61/100). PET N2-negative disease increased from 7% (6/92) before induction therapy to 47% (36/77) afterward. The sensitivity, specificity, and accuracy of postinduction PET for identification of ypN2 disease were 59%, 55%, and 57%, respectively. Logistic regression analysis indicated that postinduction PET N2 status was not associated with ypN2 disease. Of the 39 patients with both pre- and postinduction PET N2-avidity, 25 (64%) had ypN2 disease. The 5-year OS was 40% for ypN2 disease versus 38% for N2-persistent disease (p=0.936); the 5-year OS was 43% for postinduction PET N2-negative disease versus 39% for N2-avid disease (p=0.251). The 5-year DFS was 34% for ypN2-negative disease versus 9% for N2-persistent disease (p=0.079).
Postinduction PET avidity for N2 nodes is not associated with ypN2 disease, OS, or DFS in patients undergoing induction chemotherapy for stage IIIA/pN2 disease.
PMCID: PMC4801676  PMID: 26614420
25.  Pretreatment Dysphagia in Esophageal Cancer Patients May Eliminate the Need for Staging by Endoscopic Ultrasonography 
The Annals of thoracic surgery  2015;101(1):226-230.
Neoadjuvant therapy is typically given to patients with localized disease who have T3-4 esophageal disease by endoscopic ultrasound (EUS). Previously, we noted that patients who present with dysphagia have a higher EUS T stage. We hypothesized that the presence of dysphagia is predictive of EUS T3-4 disease and that staging EUS could be eliminated for esophageal cancer patients with dysphagia.
We performed a prospective, intent-to-treat, single-cohort study in which patients with potentially resectable esophageal cancer completed a standardized 4-tier dysphagia score survey. EUS was performed as part of our standard evaluation. To determine whether presence of dysphagia predicted EUS T3-4 disease, the dysphagia score was compared with EUS T stage.
A total of 114 consecutive patients were enrolled between August 2012 and February 2014: 77% (88/114) received neoadjuvant therapy, 18% (20/114) did not, and 5% (6/114) pursued treatment elsewhere. In total, 70% (80/114) underwent esophagectomy. Fifty-four percent (61/114) had dysphagia; 46% (53/114) did not. Dysphagia scores were as follows: 66% (40/61) grade 1, 25% (15/61) grade 2, and 10% (6/61) grade 3-4. Among patients with dysphagia, 89% (54/61) had T3-4 disease by EUS; among those without dysphagia, only 53% (28/53) had T3-4 disease by EUS (p<0.001).
The presence of dysphagia in patients with esophageal cancer was highly predictive of T3-4 disease by EUS. On the basis of this finding, approximately 50% of patients currently undergoing staging EUS could potentially forgo EUS before neoadjuvant therapy. In contrast, patients without dysphagia should still undergo EUS.
PMCID: PMC4765728  PMID: 26603024
Endoscopic ultrasound; esophageal cancer

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