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Two successful regional gene therapies have emerged in recent years: chimeric antigen receptor (CAR) T-cell therapy and oncolytic virus therapy. Coupled with the recent advances in the understanding of solid tumor immunology, the success of these therapies illustrates how regional therapy can be combined with efficient gene transfer and immune stimulation to treat solid tumors. CAR T cells and oncolytic viruses leverage the fundamental advantages of regional delivery to accomplish the following three objectives: 1. Enhance delivery of therapeutics to the tumor. Cancer-targeted gene therapy can be inefficient when infused intravenously, owing to the increased volume of distribution, sequestration in other organs, and poor or altered vascularity, which limit drug perfusion into tumor tissue. Regional CAR T-cell administration can bypass these limitations. Oncolytic viruses can be regionally infused or intralesionally injected. 2. Enhance targeting of cancer cells, thereby limiting normal-tissue toxicity. CAR T cells and oncolytic viruses are genetically modified to optimize cancer-specific targeting. The flexibility afforded by genetic engineering allows preferential targeting, infection of cancer cells, and sparing of normal tissues. 3. Generate both a local and a systemic immune response that can target metastatic disease and prevent tumor recurrence. Perhaps, the most impressive feature of these local therapies is their ability to generate an immune response that extends beyond the primary tumor to establish systemic immune surveillance. This immune response follows the tenets of the adaptive immune system: it establishes circulating immune memory that is capable of self-renewal and is long-lasting. Regional delivery of CAR T cells elicits a robust local immune response and establishes systemic immunity. Oncolytic viruses not only target tumors via local cancer cell destruction but also generate a local and systemic immune response. The regression of metastatic lesions following local delivery of oncolytic virus exemplifies the potential to generate systemic immune responses.

Although opioids are frequently prescribed in the postoperative setting, the call for increased opioid stewardship among surgeons has only recently become more urgent. Recent studies have shown that opioids are overprescribed postoperatively (1,2). Given that the risk of chronic opioid use and consequently, misuse and abuse, has been demonstrated to increase with longer duration and higher dosage prescriptions, it is time for surgeons to have a proactive role in mitigating the opioid crisis (3,4). Most of the current literature to date on postoperative opioid prescribing has focused on general, gynecologic, and orthopedic surgery (1-3,5,6). Opioid prescribing patterns and implications for thoracic surgery remain mostly undefined.

Currently, there is no established guidance on how to process and evaluate resected lung cancer specimens after neoadjuvant therapy in the setting of clinical trials and clinical practice. There is also a lack of precise definitions on the degree of pathologic response, including major pathologic response or complete pathologic response. For other cancers such as osteosarcoma and colorectal, breast, and esophageal carcinomas, there have been multiple studies investigating pathologic assessment of the effects of neoadjuvant therapy, including some detailed recommendations on how to handle these specimens. A comprehensive mapping approach to gross and histologic processing of osteosarcomas after induction therapy has been used for over 40 years. The purpose of this article is to outline detailed recommendations on how to process lung cancer resection specimens and to define pathologic response, including major pathologic response or complete pathologic response after neoadjuvant therapy. A standardized approach is recommended to assess the percentages of (1) viable tumor, (2) necrosis, and (3) stroma (including inflammation and fibrosis) with a total adding up to 100%. This is recommended for all systemic therapies, including chemotherapy, chemoradiation, molecular-targeted therapy, immunotherapy, or any future novel therapies yet to be discovered, whether administered alone or in combination. Specific issues may differ for certain therapies such as immunotherapy, but the grossing process should be similar, and the histologic evaluation should contain these basic elements. Standard pathologic response assessment should allow for comparisons between different therapies and correlations with disease-free survival and overall survival in ongoing and future trials. The International Association for the Study of Lung Cancer has an effort to collect such data from existing and future clinical trials. These recommendations are intended as guidance for clinical trials, although it is hoped they can be viewed as suggestion for good clinical practice outside of clinical trials, to improve consistency of pathologic assessment of treatment response.

Introduction: Globular C1q receptor (gC1qR/p32/HABP1) is overexpressed in a variety of cancers, particularly adenocarcinomas. This study investigated gC1qR expression in malignant pleural mesothelioma (MPM) and its pathophysiologic correlates in a surgical patient cohort. Methods: Tissue microarrays comprising 6 tumoral and 3 stromal cores from 265 patients with MPM (216 epithelioid, 26 biphasic, and 23 sarcomatoid; 1989-2010) were investigated by immunohistochemistry for gC1qR expression (intensity and distribution by H-score, range 0-300), and immune cell infiltration. Overall survival (OS) was analyzed by the Kaplan-Meier method (high vs. low gC1qR expression delineated by median score) in the whole cohort and by neoadjuvant chemotherapy (NAC) status. Multivariable Cox analysis included stage, chemotherapy, and immune cell infiltration. Results: gC1qR was overexpressed in all histological types of MPMs (263/265, 99.2%) compared to normal pleura. In epithelioid MPM, high gC1qR expression was associated with better OS (median 25 vs. 11 months; p = 0.020) among NAC patients, and among patients without NAC (No-NAC) but who received post-operative chemotherapy (median OS 38 vs. 19 months; p = 0.0007). In multivariable analysis, high gC1qR expression was an independent factor for improved OS in patients treated with NAC. In the No-NAC cohort, high gC1qR expression correlated with lower tumor stage. Moreover, the influence of Ki67 and CD4 T-cell infiltration on OS were more pronounced among patients with high gC1qR expression. Conclusion: This is the first description of gC1qR expression in MPM. The data identify gC1qR as a potential new prognostic factor in patients treated with surgery and chemotherapy.

Kay See Tan,1 Takashi Eguchi,2 Prasad S Adusumilli21Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY 10017, USA; 2Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USACorrespondence: Kay See TanDepartment of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, 485 Lexington Avenue, New York, NY 10017, USATel +1 646 888 8257Email tank@mskcc.orgBackground: Net survival is commonly quantified as relative survival (observed survival among lung cancer patients versus expected survival among the general population) and cause-specific survival (lung cancer–specific survival among lung cancer patients). These approaches have drastically different assumptions; hence, failure to distinguish between them results in significant implications for study findings. We quantified the differences between relative and cause-specific survival when reporting net survival of patients with non-small cell lung cancer (NSCLC).Methods: Cases of NSCLC diagnosed between 2004 and 2014 were extracted from the Surveillance, Epidemiology, and End Results database. The net survival of each stage-by-age stratum was expressed as cause-specific survival (Kaplan-Meier approach) and relative survival (Ederer II approach); percentage-point (pp) differences between the survival estimates were quantified up to 10years postdiagnosis.Results: Analyses included 263,894 cases. Cause-specific survival estimates were higher than relative survival estimates across all strata. Although the differences were negligible at 1year postdiagnosis, they increased with increasing years of follow-up, up to 9.3pp at 10years (eg, aged 60–74 with stage I disease: 53.0% vs 43.7%). Differences in survival estimates between the methods also increased by increasing age groups (eg, at 10years postdiagnosis: 5.1pp for ages 18–44, 8.8pp for ages 45–59, and 9.3pp for ages 60–74) but decreased drastically for those aged ≥75 (3.1pp).Conclusion: Relative survival and cause-specific survival are not interchangeable. The type of survival estimate used in cancer studies should be specified, particularly for long-term survival.Keywords: biostatistics, cancer epidemiology, epidemiological methods, mortality, lung cancer

V-domain Ig-containing suppressor of T-cell activation (VISTA) is an immune checkpoint gene that inhibits anti-tumor immune responses. Since most malignant pleural mesotheliomas do not respond to anti-programmed cell death(-ligand)1 (PD-(L)1)/cytotoxic T-lymphocyte-associated protein 4 (CTLA4) therapy and given the recent finding of The Cancer Genome Atlas Study that pleural mesothelioma displays the highest expression of VISTA among all cancers studied, we examined VISTA expression in a large pleural mesothelioma cohort. VISTA and PD-L1 immunohistochemistry were performed on tissue microarray of immunotherapy-naive pleural mesotheliomas (254 epithelioid, 24 biphasic and 41 sarcomatoid) and ten whole-tissue sections of benign pleura (VISTA only). Percentages of tumor and inflammatory cells with positive staining were assessed. Optimal prognostic cutoff percentages were determined using maximally selected rank statistics. Overall survival was evaluated using Kaplan–Meier methods and Cox proportional hazard analysis. All benign mesothelium expressed VISTA. Eighty-five percent of 319 and 38% of 304 mesotheliomas expressed VISTA and PD-L1 (88% and 33% of epithelioid, 90% and 43% of biphasic, and 42% and 75% of sarcomatoid), respectively. Median VISTA score was significantly higher in epithelioid (50%) (vs. biphasic [20%] and sarcomatoid [0]) (p

Trimodality therapy may prolong survival for patients with resectable malignant pleural mesothelioma. However, many patients are unable to complete therapy. We sought to identify risk factors for failing to complete adjuvant intensity-modulated radiation therapy after cytoreduction for malignant pleural mesothelioma.We performed a single-institution review of those who received an extrapleural pneumonectomy or pleurectomy/decortication for malignant pleural mesothelioma from 2004 to 2017. Multivariable logistic regression was used to assess preoperative or intraoperative risk factors associated with failing to complete adjuvant intensity-modulated radiation therapy.A total of 160 patients were identified, among whom 94 (59%) received an extrapleural pneumonectomy and 66 (41%) received a pleurectomy/decortication. Adjuvant intensity-modulated radiation therapy was completed among 105 patients (66%). Reasons for failing to complete adjuvant intensity-modulated radiation therapy included mortality (19), dose constraints (21), postoperative morbidity or delayed recovery (11), and refused or unknown status (4). On multivariable analysis, American Society of Anesthesiologists 3+ classification (P = .002) and smoking history (P = .022) were associated with failure to complete adjuvant intensity-modulated radiation therapy, whereas forced expiratory volume in 1 second 70% or less of predicted and pStage 4 (T4) were significant on univariable analysis only. Other factors, including extrapleural pneumonectomy or pleurectomy/decortication, margin status, age, and histology, were not associated with receiving adjuvant intensity-modulated radiation therapy.Many patients are unable to complete adjuvant intensity-modulated radiation therapy after cytoreduction. Failure to complete adjuvant intensity-modulated radiation therapy was associated with worse preoperative comorbidity, but not the type of surgery or margin status.

Introduction The classical micropapillary (MIP) pattern is defined in the 2015 WHO classification as tumor cells growing in papillary tufts forming florets that lack fibrovascular cores, and it is associated with poor prognosis. We observed a novel pattern that we termed a filigree MIP pattern and investigated its relationship with the classical MIP pattern. Methods Filigree pattern was defined as tumor cells growing in delicate, lace-like, narrow stacks of cells without fibrovascular cores. We required at least three piled-up nuclei from the alveolar wall basal layer, with a breadth of up to three cells across. To assess the relationship of the filigree pattern with the classical MIP pattern, we documented their frequencies in the context of the clinical and pathologic characteristics of 1468 stage I invasive adenocarcinomas, including survival analysis using cumulative incidence of recurrence by competing risks. Results We observed the filigree MIP pattern in 35% of cases. By including the filigree pattern as an MIP pattern, we identified 57 more MIP predominant cases in addition to the previously diagnosed 87 MIP predominant adenocarcinomas. These 57 cases were reclassified from papillary (n = 37), acinar (n = 16), and solid (n = 4) predominant adenocarcinoma, respectively. Of the 144 MIP predominant adenocarcinomas, the filigree predominant MIP pattern (n = 78) showed a poor prognosis like the classical predominant MIP pattern (n = 66) (p = 0.464). In addition, like the classical MIP pattern (p = 0.010), even a small amount (≥5%) of filigree MIP pattern was significantly associated with worse cumulative incidence of recurrence (p = 0.001) in multivariable analysis. Conclusion The frequent association with the classical MIP pattern and the similar poor prognosis supports inclusion of the filigree pattern in the MIP pattern subtype.

Background Lung adenocarcinoma histologic subtype is an important indicator of patient outcomes, so preoperative knowledge of subtype may be helpful to guide surgical planning. We evaluated the sensitivity and prognostic efficacy of specimens from computed tomography-guided core needle biopsies to predict histologic subtype and patient outcome after surgery. Methods We retrospectively identified 221 patients with lung adenocarcinoma who underwent computed tomography-guided lung biopsy and subsequent surgical resection. Concordance, accuracy, specificity, and sensitivity of histologic subtypes from core biopsy specimens were compared with surgically resected specimens. Tumor characteristics and biopsy procedural factors were analyzed to determine impact on diagnostic sensitivity. Histologic subtype based on biopsy specimen, clinical, tumor, and treatment variables were also examined in relation to time to progression. Results Overall concordance of biopsy samples with the predominant subtype from surgical specimens was 77%. Specificity (sensitivity) of detecting a nonaggressive and aggressive subtype were 86% (93%) and 95% (48%), respectively. Length of core specimen and percentage subtype composition in the surgically resected specimen were correlated with improved sensitivity but to a lesser extent with aggressive subtypes. Presence of an aggressive subtype in biopsy specimens was an independent predictor of progression after surgery (subdistribution hazard ratio, 2.51; 95% confidence interval, 1.28–4.94; p = 0.0075). Conclusions Specimens from computed tomography-guided core biopsies can predict lung adenocarcinoma progression after surgical resection. Future prospective studies should address the role of core biopsy in preoperative planning.

Introduction Inherited mutations are easily detected factors that influence the disease courses and optimal treatment strategies of some cancers. Germline mutations in BRCA1 associated protein 1 (BAP1) are associated with unique disease profiles in mesothelioma, atypical spitz nevi, and uveal melanoma, but the patient characteristics of an unselected population of BAP1 carriers identified by an ascertainment prevalence study are unknown. Methods We collected blood samples, cancer histories, and occupational exposures from 183 unselected patients with BAP1-related diseases. Clinical information for each patient was obtained from medical records. Germline DNA was extracted from blood samples and sequenced using a next-generation sequencing assay. We tested screening criteria developed to identify patients with a possible germline BAP1 mutation. Results Pathogenic or likely pathogenic germline BAP1 mutations were observed in 5 of 180 sequenced specimens and were exclusively found in patients identified by our screening criteria. Several patients with characteristics suspicious for a heritable deleterious mutation did not have a germline BAP1 mutation. The prevalence of pathogenic germline BAP1 mutations in patients with mesothelioma was 4.4% (95% confidence interval 1.1–11.1). Conclusions Results from the first unselected prevalence ascertainment study of germline BAP1 alterations suggest that the frequency of this mutation is low among patients with mesothelioma. The proposed screening criteria successfully identified all patients with germline BAP1-mutant mesothelioma. These screening guidelines may assist physicians in selecting patients who would benefit from genetic testing. Future efforts should validate and refine these criteria and search for other germline mutations associated with mesothelioma and related diseases.

8556 Background: While immune checkpoint inhibitors (ICI) are a standard option for patients with malignant pleural mesotheliomas (MPM), there is limited data on the rate of immune related adverse events (irAEs) and effects on clinical outcomes. Methods: 61 patients with MPM who received ICI between January 2016 and October 2020 were assessed and followed through November 2020. irAEs (CTCAE v5.0) were noted along with the time from ICI start to irAE onset. Patients were grouped into irAE ever versus never. Clinicopathologic characteristics, prior treatments, and investigator assessed clinical benefit rate (CBR; partial response [PR] + stable disease [SD]) were compared by Fisher’s Exact and Mann-Whitney Tests. Overall survival (OS) and investigator assessed progression free survival (PFS) from ICI start were compared using Kaplan Meier. In consented patients (n = 56), next generation sequencing (MSK-IMPACT) was performed with HLA genotyping analysis by POLYSOLVER software and alleles for the three major MHC class I (HLA-A, -B, -C) genes were obtained from whole exome recapture. Results: Most patients were male (72%), smokers (55%), > 70 years old (median 72, range 34-90), and had epithelioid histology (67%). No patients had baseline autoimmune disease. The median line of prior systemic therapies to ICI start was 2 (range 1-5). 17 patients (28%) developed an irAE on therapy including 7 (11%) with grade 3 to 5 events (pneumonitis, myositis, pancreatitis, nephritis, encephalitis and adrenal insufficiency). The median time from ICI start to irAE was 2.5 months (range 2 days – 5.8 months). There was no association with dual ICI (n = 6) vs single agent (n = 11) and sooner onset (2.1 vs 4.0 months; p = 0.10) nor higher grade (median grade 2 vs 3; p = 0.31) of irAEs. 1 patient developed grade 5 pneumonitis with onset 2 days after initial dose of dual-ICI. Comparing patients with irAEs to those without, there was no difference in distribution of epithelioid histology (n = 10 vs 31; p = 0.54), median age (71 vs 72 years old; p = 0.43), nor prior thoracic radiation (n = 5 vs 11; p = 0.75).There was no difference in HLA type nor the fraction of HLA alleles of individual genes amongst the groups. Patients who had an irAE were on ICI longer than those that did not (median time on ICI 5.4 vs 0.9 months, respectively; p = 0.02). OS was higher in patients with irAEs compared to those without (21.1 vs 4.7 months; p = 0.003) as was PFS (6.8 vs 1.7 months; p = 0.01). There was a significant increase in the CBR between those that had an irAE (65%; 5 PR, 6 SD) and those that did not (27%; 2 PR, 10 SD; p = 0.006). Conclusions: 28% of patients with MPM who received ICIs developed an irAE and onset tended to be early in the course of treatment. There was no clear predictive clinicopathologic feature that correlated with the occurrence of irAE. There was a significant increase in OS, PFS, and CBR in patients that had an irAE compared to those that did not.

Objective:To compare the long-term outcomes among robotic, video-assisted thoracic surgery (VATS), and open lobectomy in stage I nonsmall cell lung cancer (NSCLC).Background:Survival comparisons between robotic, VATS, and open lobectomy in NSCLC have not yet been reported. Some studies have suggeste

Purpose Stereotactic body radiation therapy (SBRT) has emerged as an effective treatment for early-stage lung cancer. The histologic subtype of surgically resected lung adenocarcinoma is recognized as a prognostic factor, with the presence of solid or micropapillary patterns predicting poor outcomes. We describe the outcomes after SBRT for early-stage lung adenocarcinoma stratified by histologic subtype. Methods and Materials We identified 119 consecutive patients (124 lesions) with stage I to IIA lung adenocarcinoma who had undergone definitive SBRT at our institution from August 2008 to August 2015 and had undergone core biopsy. Histologic subtyping was performed according to the 2015 World Health Organization classification. Of the 124 tumors, 37 (30%) were a high-risk subtype, defined as containing a component of solid and/or micropapillary pattern. The cumulative incidences of local, nodal, regional, and distant failure were compared between the high-risk and non–high-risk adenocarcinoma subtypes using Gray's test, and multivariable-adjusted hazard ratios (HRs) were estimated from propensity score–weighted Cox regression models. Results The median follow-up for the entire cohort was 17 months and for surviving patients was 21 months. The 1-year cumulative incidence of and adjusted HR for local, nodal, regional, and distant failure in high-risk versus non–high-risk lesions was 7.3% versus 2.7% (HR 16.8; 95% confidence interval [CI] 3.5-81.4), 14.8% versus 2.6% (HR 3.8; 95% CI 0.95-15.0), 4.0% versus 1.2% (HR 20.9; 95% CI 2.3-192.3), and 22.7% versus 3.6% (HR 6.9; 95% CI 2.2-21.1), respectively. No significant difference was seen with regard to overall survival. Conclusions The outcomes after SBRT for early-stage adenocarcinoma of the lung correlate highly with histologic subtype, with micropapillary and solid tumors portending significantly higher rates of locoregional and metastatic progression. In this context, the histologic subtype determined from core biopsies is a prognostic factor and could have important implications for patient selection, adjuvant treatment, biopsy methods, and clinical trial design.

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 to 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 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), whereas exon 19 deletion correlated with acinar predominant histology (P

Following immune attack, solid tumors upregulate coinhibitory ligands that bind to inhibitory receptors on T cells. This adaptive resistance compromises the efficacy of chimeric antigen receptor (CAR) T cell therapies, which redirect T cells to solid tumors. Here, we investigated whether programmed death-1-mediated (PD-1-mediated) T cell exhaustion affects mesothelin-targeted CAR T cells and explored cell-intrinsic strategies to overcome inhibition of CAR T cells. Using an orthotopic mouse model of pleural mesothelioma, we determined that relatively high doses of both CD28- and 4-1BB-based second-generation CAR T cells achieved tumor eradication. CAR-mediated CD28 and 4-1BB costimulation resulted in similar levels of T cell persistence in animals treated with low T cell doses; however, PD-1 upregulation within the tumor microenvironment inhibited T cell function. At lower doses, 4-1BB CAR T cells retained their cytotoxic and cytokine secretion functions longer than CD28 CAR T cells. The prolonged function of 4-1BB CAR T cells correlated with improved survival. PD-1/PD-1 ligand [PD-L1] pathway interference, through PD-1 antibody checkpoint blockade, cell-intrinsic PD-1 shRNA blockade, or a PD-1 dominant negative receptor, restored the effector function of CD28 CAR T cells. These findings provide mechanistic insights into human CAR T cell exhaustion in solid tumors and suggest that PD-1/PD-L1 blockade may be an effective strategy for improving the potency of CAR T cell therapies.

Non-small cell lung cancer (NSCLC) is currently the most common cause of cancer-related death throughout the world and is a challenging management problem for clinicians. Despite recent advances in screening modalities and treatment methods, there is still an expected increase in mortality in both developed and developing countries (1,2). The overall survival rate for all patients diagnosed with NSCLC is approximately 15% (2,3), which has not changed despite improvements in imaging techniques and introduction of new chemotherapeutic agents. Among NSCLC, the most common histology is adenocarcinoma (ADC), which accounts for approximately 50% of cases (3,4). In developed countries it is detected at an early-stage only in 25% of cases. The outcome of early-stage lung ADC depends on tumor size, which is currently the primary prognostic factor for disease management.

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 TNF-induced casein kinase 2 catalytic subunit (CK2α') phosphorylation of nuclear BRMS1 on serine 30 (S30), 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 S30 in BRMS1 or the use of the CK2-specific small-molecule inhibitor CX4945 abrogates CK2α'-induced cell migration and invasion 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 posttranslational mechanism by which CK2α-mediated degradation of BRMS1 promotes metastases in lung cancer. Cancer Res; 76(9); 2675–86. ©2016 AACR.

TPS262 Background: Definitive CRT is a standard-of-care for patients with medically inoperable esophageal cancer (EC, NEJM 326:1593). The NRG/RTOG 0436 study of cisplatin/paclitaxel and RT (+/- cetuximab) as definitive therapy showed that about ½ of patients have locally persistent disease (JAMA Oncol 3:1520). OBP-301 is a conditionally-restricted, replication-competent adenovirus derived from human adenovirus type 5 (Ad-5) that adds a human Telomerase Reverse Transcriptase (hTERT) gene promoter; it replicates only in tumor cells to cause lysis. It may enhance RT and may cause immunogenic cell death. A phase I study with RT in Japanese patients with inoperable EC showed tolerability and activity. Methods: In NRG-GI007, OBP-301 is added to weekly carboplatin/paclitaxel and RT to 50.4 Gy (1.8 Gy/fx ×28 fx) for patients with medically inoperable esophageal or gastroesophageal junction (GEJ) adenocarcinoma. Patients receive intratumoral OBP-301 1×1012 virus particles (vp)/ml via endoscopy (EGD) 3 days prior to CRT, then at days 12 and 26 of CRT, for a total of 3 doses. Restaging with PET and EGD occur 6-8 weeks later. Blood and tumor tissue are collected for immune- and viral-based correlative assays. Patients must be assessed to be medically inoperable and have ECOG performance status 2 of 6 patients have DLT, the dose of OBP-301 is reduced to 1×1011 vp/ml and another 6 patients will be treated. If 2 of 6 patients have DLT, then neither dose level will have met the safety rule and the trial will be ended. This trial opened to accrual on June 29, 2020. Clinicaltrials.gov NCT04391049. Funding: This project was supported by grants U10CA180868 (NRG Oncology Operations), U10CA180822 (NRG Oncology SDMC), U24CA180803 (IROC), from the National Cancer Institute (NCI) and Oncolys BioPharma. Clinical trial information: NCT04391049.

Background: We previously established the safety and antitumor efficacy of regionally delivered mesothelin-targeted M28z chimeric antigen receptor (CAR) T cells combined with programmed death-1 (PD-1) antibody (NCT02414269). As a next step, we developed next-generation CAR T cells equipped with a modified CD3z signaling domain with loss-of-function mutations within 2 of 3 ITAM motifs (1XX), and a PD-1 dominant negative receptor (PD1DNR) that provides T-cell intrinsic checkpoint blockade (M28z1XXPD1DNR CAR T cells). Herein, we provide evidence of the preclinical safety and enhanced antitumor efficacy of clinical-grade M28z1XXPD1DNR CAR T cells. Methods: Comparative cytotoxicity, proliferation, and cytokine secretion of human T cells engineered to express M28z or M28z1XXPD1DNR CAR were assessed by chromium-release, accumulation, and Luminex assays, respectively. The antitumor efficacy of a single dose (1x105 CAR T cells; E:T 1:1000) of intrapleurally administered M28z or M28z1XXPD1DNR CAR T cells was investigated in NSG mice with orthotopic pleural mesothelioma by serial bioluminescence imaging and by comparing survival. Following tumor eradication, functional persistence of CAR T cells was tested by repeated tumor challenge (increasing doses of 2x106 to 10x106 tumor cells). Results: In vitro, both M28z and M28z1XXPD1DNR CAR T cells exhibited antigen-specific cytotoxicity, accumulation, and effector cytokine secretion (table). In vivo, a single dose of M28z1XXPD1DNR CAR T cells led to tumor eradication, mice exhibited enhanced survival with weight gain, and resistance to tumor reestablishment upon 10 tumor rechallenges (table) versus a single dose of M28z CAR T cells. Table.In vitro and in vivo characteristics of M28z and M28z1XXPD1DNR CAR T-cell constructsM28zM28z1XXPD1DNRTargetMesothelinMesothelinCostimulatory domainCD28CD28CD3zNo mutations2 ITAM mutations (1XX)T-cell intrinsic checkpoint blockade (PD1DNR)NoYesIn vitro resultsHuman T-cell transduction, range25%-82%30%-89%PD-1 extracellular domain mRNA expression compared to untransduced, fold4158Cytotoxicity, rangeE:T 10:135%-45%25%-51%E:T 5:128%-44%20%-38%E:T 2:117%-32%14%-24%Accumulation, range, fold110-39053-622Effector cytokines (E:T 1:1, 24 h), rangeIL-214-23 ng/mL9-19 ng/mLTNF-α545-977 pg/mL380-852 pg/mLIFN-γ8-11 ng/mL6-15 ng/mLIn vivo resultsTumor eradication26 days19 daysMedian survival56 daysNot reachedTumor progression as measured by bioluminescence imaging following rechallengeRechallenged 3 times over 15 days+1 log+0.2 logsRechallenged 10 times over 52 days+3-4 logs+0.5 logsCurrent statusIn clinical trialIND submission pending Conclusion: Supported by the safety, tumor eradication, and functional persistence, M28z1XXPD1DNR CAR T cells will advance to IND submission and initiation of a phase I clinical trial in patients with pleural mesothelioma, and further extend our investigation to other mesothelin-expressing solid tumors. Citation Format: Stefan Kiesgen, Camille Linot, Hue T. Quach, Jasmeen Saini, Rebecca Bellis, Srijita Banerjee, Zhaohua Hou, Navin K. Chintala, Michel Sadelain, Prasad S. Adusumilli. Regional delivery of clinical-grade mesothelin-targeted CAR T cells with cell-intrinsic PD-1 checkpoint blockade: Translation to a phase I trial [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-378.

Mesothelioma affects mostly older individuals who have been occupationally exposed to asbestos. The global mesothelioma incidence and mortality rates are unknown, because data are not available from developing countries that continue to use large amounts of asbestos. The incidence rate of mesothelioma has decreased in Australia, the United States, and Western Europe, where the use of asbestos was banned or strictly regulated in the 1970s and 1980s, demonstrating the value of these preventive measures. However, in these same countries, the overall number of deaths from mesothelioma has not decreased as the size of the population and the percentage of old people have increased. Moreover, hotspots of mesothelioma may occur when carcinogenic fibers that are present in the environment are disturbed as rural areas are being developed. Novel immunohistochemical and molecular markers have improved the accuracy of diagnosis; however, about 14% (high-resource countries) to 50% (developing countries) of mesothelioma diagnoses are incorrect, resulting in inadequate treatment and complicating epidemiological studies. The discovery that germline BRCA1-asssociated protein 1 (BAP1) mutations cause mesothelioma and other cancers (BAP1 cancer syndrome) elucidated some of the key pathogenic mechanisms, and treatments targeting these molecular mechanisms and/or modulating the immune response are being tested. The role of surgery in pleural mesothelioma is controversial as it is difficult to predict who will benefit from aggressive management, even when local therapies are added to existing or novel systemic treatments. Treatment outcomes are improving, however, for peritoneal mesothelioma. Multidisciplinary international collaboration will be necessary to improve prevention, early detection, and treatment.

Objective Comparative survival between neoadjuvant chemotherapy and adjuvant chemotherapy for patients with cT2-4N0-1M0 non–small cell lung cancer has not been extensively studied. Methods Patients with cT2-4N0-1M0 non–small cell lung cancer who received platinum-based chemotherapy were retrospectively identified. Exclusion criteria included stage IV disease, induction radiotherapy, and targeted therapy. The primary end point was disease-free survival. Secondary end points were overall survival, chemotherapy tolerance, and ability of Response Evaluation Criteria In Solid Tumors response to predict survival. Survival was estimated using the Kaplan–Meier method, compared using the log-rank test and Cox proportional hazards models, and stratified using matched pairs after propensity score matching. Results In total, 330 patients met the inclusion criteria (n = 92/group after propensity-score matching; median follow-up, 42 months). Five-year disease-free survival was 49% (95% confidence interval, 39-61) for neoadjuvant chemotherapy versus 48% (95% confidence interval, 38-61) for adjuvant chemotherapy (P = .70). On multivariable analysis, disease-free survival was not associated with neoadjuvant chemotherapy or adjuvant chemotherapy (hazard ratio, 1.1; 95% confidence interval, 0.64-1.90; P = .737), nor was overall survival (hazard ratio, 1.21; 95% confidence interval, 0.63-2.30; P = .572). The neoadjuvant chemotherapy group was more likely to receive full doses and cycles of chemotherapy (P = .014/0.005) and had fewer grade 3 or greater toxicities (P = .001). Response Evaluation Criteria In Solid Tumors response to neoadjuvant chemotherapy was associated with disease-free survival (P = .035); 15% of patients receiving neoadjuvant chemotherapy (14/92) had a major pathologic response. Conclusions Timing of chemotherapy, before or after surgery, is not associated with an improvement in overall or disease-free survival among patients with cT2-4N0-1M0 non–small cell lung cancer who undergo complete surgical resection.

Introduction Major pathologic response after neoadjuvant chemotherapy (NAC) for NSCLC has been defined as 10% or less residual viable tumor without distinguishing between histologic types. We sought to investigate whether the optimal cutoff percentage of residual viable tumor for predicting survival differs between lung adenocarcinoma (ADC) and squamous cell carcinoma (SCC). Methods Tumor slides from 272 patients treated with NAC and surgery for clinical stage II-III NSCLC (ADC, n = 192; SCC, n = 80) were reviewed. The optimal cutoff percentage of viable tumor for predicting lung cancer–specific cumulative incidence of death (LC-CID) was determined using maximally selected rank statistics. LC-CID was analyzed using a competing-risks approach. Overall survival was evaluated using Kaplan-Meier methods and Cox proportional hazard analysis. Results Patients with SCC had a better response to NAC (median percentage of viable tumor: SCC versus ADC, 40% versus 60%; p = 0.027). Major pathologic response (≤10% viable tumor) was observed in 26% of SCC cases versus 12% of ADC cases (p = 0.004). The optimal cutoff percentage of viable tumor for LC-CID was 10% for SCC and 65% for ADC. On multivariable analysis, viable tumor 10% or less was an independent factor for better LC-CID (p = 0.035) in patients with SCC; in patients with ADC, viable tumor 65% or less was a factor for better LC-CID (p = 0.033) and overall survival (p = 0.050). Conclusions In response to NAC, the optimal cutoff percentage of viable tumor for predicting survival differs between ADC and SCC. Our findings have implications for the pathologic assessment of resected specimens, especially in upcoming clinical trials design.

// Yusuke Takahashi 1, 2 , Takashi Eguchi 1, 3 , Koji Kameda 1, 4 , Shaohua Lu 5, 6 , Raj G. Vaghjiani 1 , Kay See Tan 7 , William D. Travis 5 , David R. Jones 1 and Prasad S. Adusumilli 1, 8 1 Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA 2 Department of General Thoracic Surgery, Keio University School of Medicine, Tokyo, Japan 3 Division of Thoracic Surgery, Department of Surgery, Shinshu University, Matsumoto, Japan 4 Department of Thoracic Surgery, National Defense Medical College, Tokorozawa, Japan 5 Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA 6 Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, China 7 Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA 8 Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY, USA Correspondence to: Prasad S. Adusumilli, email: adusumip@mskcc.org Keywords: recurrence hazard; dynamics; solid; micropapillary; prognosis Received: August 07, 2018 Accepted: October 21, 2018 Published: November 06, 2018 ABSTRACT Background: We hypothesize that recurrence hazard following resection for stage I-IIA lung adenocarcinoma (ADC) varies according to histologic subtype, which may provide risk stratification for surveillance better than the current uniform follow-up protocol. Results: Presence (≥5%) of high-grade histologic subtypes (MIP and/or SOL) was associated with a significantly higher recurrence hazard: (1) presence of either MIP or SOL was associated with a significant increase in recurrence hazard during the first two years after surgery; (2) presence of SOL was associated with an increase in recurrence hazard—in particular, distant recurrence hazard—during the first year after surgery; (3) absence of high-grade subtypes (515/1,572 patients) was associated with a very low recurrence hazard (

Introduction The eighth edition of the TNM staging system included the proposal that the T descriptor be determined according to the invasive component, excluding lepidic component, for nonmucinous lung adenocarcinomas. We sought to conduct a clinicopathologic comparative analysis of the newly proposed classification using invasive size versus total tumor size. Methods Patients who underwent lung resection for primary lung adenocarcinoma with pathologic stage (p-Stage) I-IIA (based on total size [t]) were reviewed (n = 1704). Pathologic invasive size was measured, and tumors were reclassified using invasive size (i). Cumulative incidence of recurrence and lung cancer–specific cumulative incidence of death were analyzed using a competing-risks approach. Prognostic discrimination by p-Stage(t) and p-Stage(i) was evaluated using a concordance index (C-index). Results The use of invasive size resulted in downstaging in 377 of 1704 patients (22%), with twice as many patients with p-Stage IA1 (IA1[i] versus IA1[t]: 389 [23%] versus 195 [11%]). However, outcomes were similar between the two groups (IA1[i] versus IA1[t]: 5-year cumulative incidence of recurrence, 11% versus 13%; 5-year lung cancer–specific cumulative incidence of death, 5% versus 7%). Prognostic discrimination by p-Stage(i) was better than by p-Stage(t) (C-index for p-Stage[i] versus p-Stage[t]: recurrence, 0.614 versus 0.593; lung cancer–specific death, 0.634 versus 0.621). Conclusions When invasive size, rather than total size, was used for the T descriptor, a larger number of patients were classified with a favorable prognosis (p-Stage IA1) and better prognostic discrimination of p-Stage I-IIA nonmucinous lung adenocarcinomas was achieved.

On March 28- 29, 2017, the National Cancer Institute (NCI) Thoracic Malignacy Steering Committee, International Association for the Study of Lung Cancer, and Mesothelioma Applied Research Foundation convened the NCI-International Association for the Study of Lung Cancer- Mesothelioma Applied Research Foundation Mesothelioma Clinical Trials Planning Meeting in Bethesda, Maryland. The goal of the meeting was to bring together lead academicians, clinicians, scientists, and the U.S. Food and Drug Administration to focus on the development of clinical trials for patients in whom malignant pleural mesothelioma has been diagnosed. In light of the discovery of new cancer targets affecting the clinical development of novel agents and immunotherapies in malignant mesothelioma, the objective of this meeting was to assemble a consensus on at least two or three practice-changing multimodality clinical trials to be conducted through NCI's National Clinical Trials Network.

Objective We conducted a phase I trial of neoadjuvant nivolumab, a monoclonal antibody to the programmed cell death protein 1 checkpoint receptor, in patients with resectable non–small cell lung cancer. We analyzed perioperative outcomes to assess the safety of this strategy. Methods Patients with untreated stage I-IIIA non–small cell lung cancer underwent neoadjuvant therapy with 2 cycles of nivolumab (3 mg/kg), 4 and 2 weeks before resection. Patients underwent invasive mediastinal staging as indicated and post-treatment computed tomography. Primary study end points were safety and feasibility of neoadjuvant nivolumab followed by pulmonary resection. Data on additional surgical details were collected through chart review. Results Of 22 patients enrolled, 20 underwent resection. One was unresectable; another had small cell histologic subtype. There were no delays to surgical resection. Median time from first treatment to surgery was 33 (range, 17-43) days. There were 15 lobectomies, 2 pneumonectomies, 1 bilobectomy, 1 sleeve lobectomy, and 1 wedge resection. Of 13 procedures attempted via a video-assisted thoracoscopic surgery or robotic approach, 7 (54%) required thoracotomy. Median operative time was 228 (range, 132-312) minutes; estimated blood loss was 100 (range, 25-1000) mL; length of hospital stay was 4 (range, 2-17) days. There was no operative mortality. Morbidity occurred in 10 of 20 patients (50%). The most common postoperative complication was atrial arrhythmia (6/20; 30%). Major pathologic response was identified in 9 of 20 patients (45%). Conclusions Neoadjuvant therapy with nivolumab was not associated with unexpected perioperative morbidity or mortality. More than half of the video-assisted thoracoscopic surgery/robotic cases were converted to thoracotomy, often because of hilar inflammation and fibrosis.

OBJECTIVE: To investigate cancer- and noncancer-specific mortality following lobectomy by minimally invasive surgery (MIS) versus open thoracotomy in elderly patients with non-small cell lung cancer (NSCLC). BACKGROUND: Two-thirds of patients with NSCLC are ≥65 years of age. As age increases, the risk of competing events, such as noncancer death, also increases. METHODS: Elderly patients (≥65 years of age) who have undergone curative-intent lobectomy for stage I-III NSCLC without induction therapy (2002–2013) were included (n=1 303). Of those, 607 patients had undergone MIS and 696 had undergone thoracotomy. Propensity-score matching was performed to identify pairs of thoracotomy and MIS patients with comparable clinical characteristics (e.g., year of surgery, comorbidities, and pulmonary function). Association between surgical approach (MIS vs. thoracotomy) and lung cancer-specific and noncancer-specific cumulative incidence of death (CID) was analyzed using competing risks approach. RESULTS: Following propensity score matching of patients who had undergone thoracotomy (n=338) versus MIS (n=338), MIS was associated with shorter length of stay (p

BACKGROUND. Minimally invasive esophagectomy (MIE) may improve some perioperative outcomes over open approaches; effects on quality of life (QOL) are less clear. METHODS. A prospective trial of robotic-assisted MIE (RAMIE) and open esophagectomy (OE) was initiated, measuring QOL via the Functional Assessment of Cancer Therapy–Esophageal (FACT-E) and Brief Pain Inventory (BPI). Mixed generalized linear models assessed associations between QOL scores over time and by surgery type. RESULTS. In total, 106 patients underwent OE; 64 underwent MIE (98% RAMIE). The groups did not differ in age, sex, comorbidities, histologic subtype, stage, or induction treatment (P=0.42 to >0.95). Total FACT-E scores were lower at 1 month (P0.95), anastomotic leak (3% vs 9%; P=0.41), and 90-day mortality (2% vs 4%; P=0.85) did not differ between groups. Pulmonary (14% vs 34%; P=0.014) and infectious (17% vs 36%; P=0.029) complications were lower for RAMIE. CONCLUSIONS. RAMIE is associated with lower immediate postoperative pain severity and interference and decreased pulmonary and infectious complications. Ongoing data accrual will assess mid- and long-term outcomes in this cohort.

Lung cancer continues to be a major global health problem; the disease is diagnosed in more than 1.6 million new patients each year. However, significant progress is underway in both the prevention and treatment of lung cancer. Lung cancer therapy has now emerged as a "role model" for precision cancer medicine, with several important therapeutic breakthroughs occurring during 2015. These advances have occurred primarily in the immunotherapy field and in treatments directed against tumors harboring specific oncogenic drivers. Our knowledge about molecular mechanisms for oncogene-driven tumors and about resistance to targeted therapies has increased quickly over the past year. As a result, several regulatory approvals of new agents that significantly improve survival and quality of life for patients with lung cancer who have advanced disease have occurred. The International Association for the Study of Lung Cancer has gathered experts in different areas of lung cancer research and management to summarize the most significant scientific advancements related to prevention and therapy of lung cancer during the past year. (C) 2016 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.

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.

Objectives We investigated the role of the 2011 International Association for the Study of Lung Cancer, American Thoracic Society, and European Respiratory Society (IASLC/ATS/ERS) classification in predicting occult lymph node metastasis in clinically mediastinal node-negative lung adenocarcinoma. Methods We reviewed lung adenocarcinoma patients who had clinically N2-negative status, were evaluated by preoperative positron emission tomography combined with computed tomography (PET/CT) and had undergone lobectomy or pneumonectomy at Memorial Sloan Kettering Cancer Center (n = 297). Tumours were classified according to the 2011 IASLC/ATS/ERS classification. The associations between occult lymph node metastasis and clinicopathological variables were analysed using Fisher's exact test and logistic regression analysis. Results Thirty-two (11%) cN0-1 patients had occult mediastinal lymph node metastasis (pN2) whereas 25% of cN1 patients had pN2 disease. Increased micropapillary pattern was associated with increased risk of pN2 disease (P = 0.001). On univariate analysis, high maximum standard uptake value of the primary tumour on PET/CT (P = 0.019) and the presence of micropapillary (P = 0.014) and solid pattern (P = 0.014) were associated with occult pN2 disease. On multivariable analysis, micropapillary pattern was positively associated with risk of pN2 disease (odds ratio = 3.41; 95% confidence intervals = 1.42-8.19; P = 0.006). Conclusions The presence of micropapillary pattern is an independent predictor of occult mediastinal lymph node metastasis. Our observations have potential therapeutic implications for management of early-stage lung adenocarcinoma.

Purpose To examine the significance of the proposed International Association for the Study of Lung Cancer, American Thoracic Society, and European Respiratory Society (IASLC/ATS/ERS) histologic subtypes of lung adenocarcinoma for patterns of recurrence and, among patients who recur following resection of stage I lung adenocarcinoma, for postrecurrence survival (PRS). Patients and Methods We reviewed patients with stage I lung adenocarcinoma who had undergone complete surgical resection from 1999 to 2009 (N = 1,120). Tumors were subtyped by using the IASLC/ATS/ERS classification. The effects of the dominant subtype on recurrence and, among patients who recurred, on PRS were investigated. Results Of 1,120 patients identified, 188 had recurrent disease, 103 of whom died as a result of lung cancer. Among patients who recurred, 2-year PRS was 45%, and median PRS was 26.1 months. Compared with patients with nonsolid tumors, patients with solid predominant tumors had earlier (P = .007), more extrathoracic (P < .001), and more multisite (P = .011) recurrences. Multivariable analysis of primary tumor factors revealed that, among patients who recurred, solid predominant histologic pattern in the primary tumor (hazard ratio [HR], 1.76; P = .016), age older than 65 years (HR, 1.63; P = .01), and sublobar resection (HR, 1.6; P = .01) were significantly associated with worse PRS. Presence of extrathoracic metastasis (HR, 1.76; P = .013) and age older than 65 years at the time of recurrence (HR, 1.7; P = .014) were also significantly associated with worse PRS. Conclusion In patients with stage I primary lung adenocarcinoma, solid predominant subtype is an independent predictor of early recurrence and, among those patients who recur, of worse PRS. Our findings provide a rationale for investigating adjuvant therapy and identify novel therapeutic targets for patients with solid predominant lung adenocarcinoma.

Objective CD10 (neutral endopeptidase) is expressed in various normal and tumor cells, and its biological function can be controlled through enzymatic activity and signaling pathways. We investigated whether CD10 expression predicted disease recurrence and whether it correlated with histologic subtypes of stage I lung adenocarcinoma. Materials and methods We reviewed tumor slides of resected pathologic stage I lung adenocarcinomas (1995–2009). Tumors were classified according to the IASLC/ATS/ERS classification. CD10 immunohistochemistry was performed using tissue microarrays ( n =915). We combined the intensity (0–3) and distribution scores (0–2) for CD10 to create a total score (0–5). Risk of recurrence was estimated using competing risks methods. Results In the training cohort ( n =313), risk of recurrence of patients with high tumoral CD10 (score>1, n =57) was significantly higher (5-year cumulative incidence of recurrence [CIR], 37%) than in those with low CD10 (score≤1; n =256; 5-year CIR, 16%; P n =602, P =0.036). High tumoral CD10 was associated with higher risk of recurrence in acinar ( P =0.007) and papillary predominant tumors ( P =0.022). High tumoral CD10 was most frequently identified in micropapillary predominant (41%) and solid predominant tumors (34%). On multivariate analysis of intermediate-grade tumors, high tumoral CD10 remained a significant independent risk factor of recurrence (hazard ratio, 1.88; P =0.025). Conclusion In stage I lung adenocarcinoma, tumoral CD10 correlated with high-grade histology and was an independent predictor of recurrence in intermediate-grade tumors.

Introduction We previously reported the prognostic significance of the lung adenocarcinoma immune microenvironment. In this study, we preformed comprehensive analysis of immune markers and their associations with prognosis in patients with lung squamous cell carcinoma. Methods We reviewed surgically resected, solitary lung squamous cell carcinoma patients (n = 485; 1999–2009) who were randomly split into a training cohort (n = 331) and validation cohort (n = 154). We constructed tissue microarrays and performed immunostaining for CD3, CD45RO, CD8, CD4, FoxP3, CD20, CD68, CXCL12, CXCR4, CCR7, interleukin-7 receptor, and interleukin-12 receptor β2. Overall survival (OS) was analyzed using the log-rank test and the Cox proportional hazards model. Results Analysis of single immune cell infiltration revealed that high tumor-infiltrating CD10 + neutrophils were associated with worse prognoses in the training cohort (p = 0.021). Analysis of biologically relevant immune cell combinations identified that patients with high CD10 + neutrophil and low CD20 + lymphocyte had a significantly worse OS (5-year OS, 42%) than those with other combinations of CD10 and CD20 (5-year OS, 62%; p p = 0.032). For the multivariate analysis, high CD10/low CD20 immune cell infiltration was an independent predictor of OS in both the training cohort (hazard ratio=1.61, p = 0.006) and the validation cohort (hazard ratio=1.75; p = 0.043). Conclusion High CD10+/low CD20+ immune cell infiltration ratio is a significant prognostic factor of lung squamous cell carcinoma. Immunomodulatory therapy of tumor-specific neutrophil and B-lymphocyte responses may have applicability in the treatment of lung squamous cell carcinoma.

// Kyuichi Kadota 1, 2, 5 , Takashi Eguchi 1 , Jonathan Villena-Vargas 1 , Kaitlin M. Woo 3 , Camelia S. Sima 3 , David R. Jones 1 , William D. Travis 2 , Prasad S. Adusumilli 1, 4 1 Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA 2 Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA 3 Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA 4 Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY, USA 5 Department of Diagnostic Pathology, Faculty of Medicine, Kagawa University, Kagawa, Japan Correspondence to: Prasad S. Adusumilli, e-mail: adusumip@mskcc.org Keywords: adenocarcinoma, lung, estrogen receptor, regulatory T-cell, recurrence Received: May 07, 2015 Accepted: July 17, 2015 Published: July 29, 2015 ABSTRACT Background: Tumor biology of estrogen receptor-α (ERα) and progesterone receptor (PR) has been studied in breast cancers. However, clinical impact in lung cancer remains controversial. In our study, we investigate whether ERα and PR expression predicts disease recurrence and correlates with immunologic factors in stage I lung adenocarcinoma. Methods: We reviewed patients with pathologic stage I resected lung adenocarcinoma. Tumors were classified according to the IASLC/ATS/ERS classification. Immunostaining of ERα and PR was performed using tissue microarrays ( n = 913). Immunostaining of CD3+ and forkhead box P3 (FoxP3)+ lymphocyte infiltration, interleukin-7 receptor (IL-7R), and IL-12Rβ2 were performed. Cumulative incidence of recurrence (CIR) analysis was used to estimate probability of recurrence. Results: Nuclear ERα expression was observed in 157 (17%) patients and presented more frequently in females ( P = 0.038) and smaller tumors ( P = 0.019). Nuclear ERα expression was not identified in mucinous tumors. In pT1a patients, 5-year CIR of patients with ERα-positive tumors was significantly higher (5-year CIR, 20%) than those with ERα-negative tumors (8%; P = 0.018). This difference was statistically significant in males ( P = 0.003) but not females ( P = 0.55). On multivariate analysis, nuclear ERα expression was an independent predictor of recurrence (hazard ratio = 2.27; P = 0.030). In pT1a patients, nuclear ERα expression positively correlated with tumoral FoxP3+ lymphocytes ( P < 0.001), FoxP3/CD3 index ( P < 0.001), and IL-7R ( P = 0.022). Conclusions: Nuclear ERα expression is an independent predictor of recurrence in pT1a lung adenocarcinomas and correlates with poor prognostic immune microenvironments.

The National Lung Screening Trial was a large, multicenter, randomized controlled trial published in 2011. It found that annual screening with low-dose CT (LDCT) in a high-risk population was associated with a 20% reduction in lung cancer-specific mortality compared with conventional chest radiography. Several leading professional organizations have since put forth lung cancer screening guidelines that include the use of LDCT, largely on the basis of this study. Broad adoption of these screening recommendations, however, remains a challenge.

IntroductionTumor invasion in lung adenocarcinoma is defined as infiltration of stroma, blood vessels, or pleura. Based on observation of tumor spread through air spaces (STAS), we considered whether this could represent new patterns of invasion and investigated whether it correlated with locoregional versus distant recurrence according to limited resection versus lobectomy.MethodsWe reviewed resected small (less than or equal to 2 cm) stage I lung adenocarcinomas (n = 411; 1995–2006). Tumor STAS was defined as tumor cells—micropapillary structures, solid nests, or single cells—spreading within air spaces in the lung parenchyma beyond the edge of the main tumor. Competing risks methods were used to estimate risk of disease recurrence and its associations with clinicopathological risk factors.ResultsSTAS was observed in 155 cases (38%). In the limited resection group (n = 120), the risk of any recurrence was significantly higher in patients with STAS-positive tumors than that of patients with STAS-negative tumors (5-year cumulative incidence of recurrence, 42.6% versus 10.9%; P < 0.001); the presence of STAS correlated with higher risk of distant (P = 0.035) and locoregional recurrence (P = 0.001). However, in the lobectomy group (n = 291), the presence of STAS was not associated with either any (P = 0.50) or distant recurrence (P = 0.76). In a multivariate analysis, the presence of tumor STAS remained independently associated with the risk of developing recurrence (hazard ratio, 3.08; P = 0.014).ConclusionThe presence of STAS is a significant risk factor of recurrence in small lung adenocarcinomas treated with limited resection. These findings support our proposal that STAS should formally be recognized as a pattern of invasion in lung adenocarcinoma.

Spurred by the survival benefits seen with the use of checkpoint blockade in non-small-cell lung cancer (NSCLC), there has been a growing interest in the potential applications of immunotherapy. Despite this, the objective response rate for single-agent immunotherapy remains ≤20% in patients with advanced NSCLC. A combinatorial approach that utilizes both chemotherapy and immunotherapy is a potential strategy to increase antitumor efficacy. Accumulating evidence has shown that the immunomodulatory effects of chemotherapeutic agents can be exploited in a combinational approach. Herein, we review the influence of specific chemotherapeutic agents on the tumor immune microenvironment in preclinical and clinical studies, and establish the rationale for combination chemoimmunotherapy for the treatment of NSCLC.

Mediastinal masses have traditionally been resected using open approaches such as sternotomy and thoracotomy. These approaches require comparatively large incisions and may result in significant morbidity and protracted hospitalization. Minimally invasive approaches, such as video-assisted thoracic surgery (VATS) and robotic procedures, result in improved patient recovery and decreased length of hospital stay and have therefore become increasingly commonly used. Compared with standard VATS instrumentation, the telerobotic platform allows an increased range of motion and ease of manipulation, which can be beneficial for cases where the operative field and surgical maneuverability are constrained by the confines of the chest wall and the surrounding organs. Robotic approaches may also improve cosmesis, reduce postoperative pain, and shorten recovery times. In this chapter, we discuss considerations for robotic mediastinal surgery and describe in detail a robotic thymectomy technique.

Aims The IASLC/ATS/ERS classification of lung adenocarcinoma provides a prognostically significant histological subclassification. The aim of this study was to investigate the accuracy, limitations and interobserver agreement of frozen sections for predicting histological subtype. Methods and results Frozen section and permanent section slides from 361 resected stage I lung adenocarcinomas ≤3 cm in size were reviewed for predominant histological subtype and the presence or absence of lepidic, acinar, papillary, micropapillary and solid patterns. Fifty cases were additionally reviewed by three pathologists to determine interobserver agreement. To test the accuracy of frozen section in judging degree of invasion, five pathologists reviewed frozen section slides from 35 cases with a predominantly lepidic pattern. There was moderate agreement on predominant histological subtype between frozen sections and final diagnosis (κ = 0.565). Frozen sections had high specificity for micropapillary and solid patterns (94% and 96%, respectively), but sensitivity was low (37% and 69%, respectively). The interobserver agreement was satisfactory (κ > 0.6, except for the acinar pattern). Conclusions Frozen section can provide information on the presence of aggressive histological patterns—micropapillary and solid—with high specificity but low sensitivity. It was difficult to predict the predominant pattern on the basis of frozen sections, mostly because of sampling issues.

Currently, tumor-node-metastasis stage and histologic type are the established prognostic factors for malignant pleural mesothelioma, whereas no prognostic markers have been established for clinical practice. We investigated the prognostic value of CD10, a metalloproteinase that can promote cancer aggressiveness through enzymatic degradation and intracellular signaling crosstalk, in malignant pleural mesothelioma.CD10 immunostaining was performed for 176 cases of malignant pleural mesothelioma (epithelioid, 148; biphasic, 14; sarcomatoid, 14), and its expression was dichotomized as negative (no staining) or positive (any staining). Epithelioid tumors were classified as pleomorphic subtype when cytologic pleomorphism was ≥10 % of the tumor. Overall survival (OS) was analyzed by log-rank tests and Cox proportional hazard models.Tumoral CD10 expression was identified in 42 % of epithelioid non-pleomorphic tumors, 57 % of epithelioid pleomorphic tumors, 79 % of biphasic tumors, and 93 % of sarcomatoid tumors (p0.001). Positive CD10 expression was correlated with higher mitotic count (p = 0.002). Overall survival for patients with positive CD10 expression was significantly shorter than that for patients with negative CD10 expression in all patients (p = 0.001) and in patients with epithelioid tumor (p = 0.04). On multivariate analysis, CD10 expression was an independent prognostic factor for all patients (hazard ratio 1.48; p = 0.019).Tumoral CD10 expression correlated with aggressive histologic types and higher mitotic activity and is an independent prognostic factor for patients with malignant pleural mesothelioma.

Lung adenocarcinoma (ADC) is the most common type of lung cancer, and it has been subtyped by the International Association for the Study of Lung Cancer, American Thoracic Society, and European Respiratory Society (IASLC/ATS/ERS) histologic classification.

Background The role of postoperative radiotherapy (PORT) in patients with clinical stage III-N2 (cIII-N2) non-small cell lung cancer (NSCLC) treated with induction chemotherapy and surgical resection with persistent ypN2 disease is not well established. Methods We retrospectively reviewed a prospectively maintained database for patients with cIII-N2 NSCLC who underwent induction chemotherapy followed by resection (2004–2016). Exclusion criteria included induction radiotherapy, non–biopsy-confirmed cN2 disease, incomplete resection, ypN0/1, and nonanatomic resection. The primary outcome was locoregional recurrence (LR); secondary outcomes were disease-free survival (DFS), lung cancer–specific death (LCSD), and overall survival (OS). Associations between variables and outcomes were assessed using Fine and Gray competing risk regression for LR/LCSD and Cox proportional hazard models for survival. Results Of the 501 patients identified with cIII-N2 disease, 99 met the inclusion criteria. Median follow-up was 25 months (range, 3-137 months). Sixty-nine patients (70%) received PORT. Sixty (61%) developed a recurrence: 3 (5%) with an initial isolated LR and 57 (95%) with an initial distant recurrence. On multivariable analysis, PORT was not associated with LR (HR, 0.51 [95% CI, 0.22-1.21], p = 0.13). PORT was also not associated with DFS (p = 0.6) or LCSD (p = 0.1). PORT was associated with improved 3-year OS (55% [95% CI, 42%-71%]) versus the no-PORT group (50% [95% CI, 34%-74%]) (p = 0.04). Conclusions PORT is not independently associated with decreased LR or improved DFS/LCSD in this patient population. Given that the predominant failure pattern was distant recurrence, future clinical trials should focus on adjuvant systemic therapies, which may decrease distant recurrences in ypN2 patients.

Introduction Expression of breast cancer metastasis suppressor 1 gene ( BRMS1 ) is decreased in NSCLC cells and tumors. We hypothesized that intratumoral breast cancer metastasis suppressor 1 (BRMS1) expression is associated with lung adenocarcinoma (LUAD) histologic subtypes and overall survival (OS) and disease-free survival (DFS) in patients undergoing resection for early-stage LUAD. Methods Patients (N = 1030) who underwent complete resection for LUAD with tissue available for histologic evaluation were identified. Tissue microarrays were constructed, and immunostaining was performed and scored for intensity of BRMS1 expression. OS and DFS were estimated (by the Kaplan-Meier method) and compared between groups (by the log-rank test), stratified by stage. Hazard ratios (HRs) for hazard of death and recurrence were estimated using univariable and multivariable Cox proportional hazards models. OS and DFS nomograms were created, and model performance was examined. Results Intratumoral BRMS1 expression was high in 632 patients (61%) and low in 398 (39%). Low BRMS1 expression was associated with higher pathologic T stage ( p = 0.001), larger tumor size ( p ≤ 0.0001), greater lymphatic ( p = 0.032) and vascular ( p = 0.001) invasion, LUAD histologic subtype ( p = 0.001), and intermediate and high architectural tumor grade ( p = 0.003). Low BRMS1 expression was an independent predictor of worse OS (HR = 1.35, 95% confidence interval: 1.10–1.65, p = 0.004) and DFS (HR = 1.27, 95% confidence interval: 1.05–1.54, p = 0.012). OS and DFS nomograms showed excellent predictive performance based on discrimination and calibration. Conclusions Among patients with surgically resected LUAD, OS and DFS were significantly worse in cases with low intratumoral BRMS1 expression. Our findings suggest that BRMS1 is an independent biomarker with prognostic significance in surgically resected LUAD.

Perioperative blood transfusions have been implicated in decreased overall survival (OS) and disease-free survival (DFS) after resection for non-small cell lung cancer (NSCLC). We investigated the effects of single- and multiple-unit blood transfusions on OS, DFS, and recurrence after anatomic pulmonary resection.From January 1, 2000, to June 30, 2016, 5709 consecutive patients underwent pulmonary resection for NSCLC at our institution. Exclusion criteria were stage IIIB-IV disease, incomplete resections, ill-defined histologic subtypes, and nonanatomic wedge resections. For the 0 versus single-unit analysis, propensity scores were calculated from a logistic regression model that predicted the probability of patients receiving a single-unit transfusion. The resulting matching weights were incorporated into Cox models for OS, DFS, and cumulative incidence of recurrence, to compare no versus single-unit blood transfusion. We determined whether increasing numbers of blood transfusions influenced survival or recurrence using multivariable Cox models.Approximately 10% of patients received perioperative blood transfusion (median follow-up, 7.46 years [25th-75th percentile, 3.98-11.8]). There was no difference in OS, DFS, or cumulative incidence of recurrence between patients receiving no transfusion and those receiving single-unit transfusion (P .05). However, a dose-response relationship was observed, demonstrating worse OS (overall P .001), DFS (overall P .001), and recurrence (overall P = .010) with increasing units of blood transfused.Although a single-unit blood transfusion did not affect survival in patients undergoing resection for NSCLC, greater unit perioperative blood transfusions were associated with significantly decreased long-term outcomes in a dose-dependent manner, suggesting avoidance or minimization of transfusions could improve long-term survival after lung resection.

Objectives The International Association for the Study of Lung Cancer, American Thoracic Society and European Respiratory Society lung adenocarcinoma classification in 2011 defined three lepidic predominant patterns including adenocarcinoma in situ, minimally invasive adenocarcinoma and lepidic predominant adenocarcinoma. We sought to correlate the radiology and pathology findings and identify any computed tomography (CT) features which can be associated with invasive growth. Materials and methods An institutional review board approved, retrospective study was conducted evaluating 63 patients with resected, pathologically confirmed, adenocarcinomas with predominant lepidic patterns. Preoperative CT images of the nodules were assessed using quantitative and qualitative radiographic descriptors while blinded to pathologic sub-classification and size. Maximum diameter was measured after evaluation of the axial, sagittal and coronal planes. Radiologic − pathologic associations were examined using Fisher’s exact test, the Kruskal-Wallis test and the Spearman correlation coefficient (ρ). Results and conclusion Increasing maximum diameter of the whole lesion (ground glass and solid component) on CT was significantly associated with invasiveness (p = .003), as was the maximum pathologic specimen diameter (p = .008). Larger diameter of the solid component on CT was also found in lepidic predominant adenocarcinoma compared to minimally invasive adenocarcinoma (median 10.5 vs 2 mm, p = .005). More invasive tumors had higher visual estimated percentage solid component compared to whole lesion measurement on CT (p = .014). CT and pathologic measurements were positively correlated, although only moderately (ρ = .66) for the maximum whole lesion size and fair (ρ = .49) for solid/invasive component maximum measurements. Larger whole lesion size and solid component size of lepidic predominant pattern adenocarcinomas are associated with lesion invasiveness, although radiologic and pathologic lesion measurements are only fair-moderately positively correlated.