Shamus R. Carr

Impact of tumor size on outcomes after anatomic lung resection for stage 1A non–small cell lung cancer based on the current staging system

OBJECTIVE Anatomic segmentectomy may achieve results comparable to lobectomy for early-stage non-small cell lung cancer. The 7th edition of the AJCC Cancer Staging Handbook stratified the previous T1 tumor designation into T1a and T1b subsets, which still define stage 1A node-negative non-small cell lung cancer. We are left to hypothesize whether this classification may aid in directing the extent of surgical resection. We retrospectively reviewed our anatomic segmentectomy and lobectomy management of stage 1A non-small cell lung cancer to determine differences in survival and local recurrence rates based on the new stratification. METHODS We performed a retrospective review of 429 patients undergoing resection of pathologically confirmed stage 1A non-small cell lung cancer via lobectomy or anatomic segmentectomy. Primary outcome variables included mortality, recurrence, and survival. Recurrence-free and cancer-specific survivals were estimated using the Kaplan-Meier method. RESULTS Patients undergoing segmentectomy were older than patients undergoing lobectomy (mean age 69.2 vs 66.8 years, P < .006). The mean preoperative forced expiratory volume in 1 second was significantly lower in the segmentectomy group than in the lobectomy group (71.8% vs 81.1%, P = .02). Mortality was similar after segmentectomy (1.1%) and lobectomy (1.2%). There was no difference in mortality, recurrence rates (14.0% vs 14.7%, P = 1.00), or 5-year cancer-specific survival (T1a: 90% vs 91%, P = .984; T1b: 82% vs 78%, P = .892) when comparing segmentectomy and lobectomy for pathologic stage 1A non-small cell lung cancer, when stratified by T stage. CONCLUSIONS Anatomic segmentectomy may achieve equivalent recurrence and survival compared with lobectomy for patients with stage 1A non-small cell lung cancer. Prospective studies will be necessary to delineate the potential merits of anatomic segmentectomy in this setting.

Sox2 Cooperates with Lkb1 Loss in a Mouse Model of Squamous Cell Lung Cancer

SUMMARY Squamous cell carcinoma (SCC) of the lung is the second most common subtype of lung cancer. With limited treatment options, the 5-year survival rate of SCC is only 15%. Although genomic alterations in SCC have been characterized, identifying the alterations that drive SCC is critical for improving treatment strategies. Mouse models of SCC are currently limited. Using lentiviral delivery of Sox2 specifically to the mouse lung, we tested the ability of Sox2 to promote tumorigenesis in multiple tumor suppressor backgrounds. Expression of Sox2, frequently amplified in human SCC, specifically cooperates with loss of Lkb1 to promote squamous lung tumors. Mouse tumors exhibit characteristic histopathology and biomarker expression similar to human SCC. They also mimic human SCCs by activation of therapeutically relevant pathways including STAT and mTOR. This model may be utilized to test the contribution of additional driver alterations in SCC, as well as for preclinical drug discovery.

Evidence for a genetical contribution to non-smoking-related lung cancer

Background The majority of lung cancers are smoking-related, with environmental and genetical factors contributing. The interplay between environmental and genetical contributions in non-smoking-related lung cancers is less clear. Methods We analysed a population-based computerised genealogy resource linked to a state-wide cancer registry of lung cancer cases (n=5544) for evidence of a genetical contribution to lung cancer predisposition in smoking (n=1747) and non-smoking cases (n=784). Statistical methods were used to test for significant excess relatedness of cases and estimate relative risk (RR) in close and distant relatives of lung cancer cases. Results Significant excess relatedness was observed for all lung cancer cases (p<0.001) and for the subsets of smoking-related (p<0.001) and non-smoking-related (p<0.001) cases when all pairwise relationships were considered. Only the non-smoking-related subset of cases showed significant excess relatedness when close relationships were ignored (p=0.020). First-degree, second-degree, and fourth-degree relatives of non-smoking-related lung cancer cases had significantly elevated RR. An even higher elevated RR was observed for first-degree, second-degree, third-degree and fourth-degree relatives of smoking-related lung cancer cases. Conclusions Non-smoking-related lung cancer cases show significant excess relatedness for close and distant relationships, providing strong evidence for a genetical contribution as well as an environmental contribution. Significant excess relatedness for only close family relationships in all lung cancer cases and in only smoking-related lung cancer cases implies environmental contribution. Additionally, the highest RR for lung cancer was observed in the relatives of smoking-related lung cancer, suggesting predisposition gene carriers who smoke are at highest risk for lung cancer. Screening and gene identification should focus on high-risk pedigrees.

Peritoneal perfusion with oxygenated perfluorocarbon augments systemic oxygenation.

Background Despite maximal ventilatory support, many patients die from hypoxia in the setting of potentially reversible pulmonary failure. There remains a pressing need for additional pulmonary supportive care measures, especially techniques that do not require systemic anticoagulation. The objective of our experiments was to determine whether systemic oxygenation could be increased in a large animal, with induced hypoxia, by perfusing the abdominal cavity with oxygenated perfluorocarbons. Methods Fifteen pigs with a mean (± SD) weight of 45 ± 5 kg were intubated and rendered hypoxic by ventilating them with a blend of nitrogen and oxygen to achieve subatmospheric concentrations of inspired oxygen ranging from 18 to 10%, resulting in baseline mean Pao2 range of 65.9 ± 9.7 to 26.6 ± 2.8 mm Hg, respectively. Peritoneal perfusion was performed in eight animals with oxygenated perfluorocarbon and in seven control animals with oxygenated saline solution. Results The average increase in Pao2 with oxygenated perfluorocarbon perfusion, compared to oxygenated saline solution perfusion, ranged from 8.1 to 18.2 mm Hg. A common treatment effect was estimated across all fraction of inspired oxygen (Fio2) values, representing the average mean difference in oxygen uptake between oxygenated perfluorocarbon and saline solution, irrespective of the level of Fio2. This average was 12.8 mm Hg (95% confidence interval, 7.4 to 18.2; p < 0.001). The most clinically relevant results occurred at an Fio2 of 14%, resulting in a baseline mean Pao2 of 39.4 ± 5.0 mm Hg with oxygenated saline solution perfusion, and a mean Pao2 of 55.3 ± 7.6 mm Hg with oxygenated perfluorocarbon perfusion. This corresponded to an increase in arterial oxygen saturation from 73 to 89%. Conclusion These results of our principle experiments demonstrate that the peritoneal cavity can be used for gas exchange and, in our model, yielded clinically relevant increases in systemic arterial oxygen levels. This technique may have the potential for the supportive care of patients dying from hypoxia in the setting of reversible lung injury.

Oncological outcomes from trimodality therapy receiving definitive doses of neoadjuvant chemoradiation (≥60 Gy) and factors influencing consideration for surgery in stage III non-small cell lung cancer

Purpose Guidelines for locally advanced non-small cell lung cancer (LA-NSCLC) recommend definitive chemoradiation therapy (CRT) for cN2-N3 disease, reserving surgery for patients with minimal nodal involvement at presentation. The current literature suggests that surgery after CRT for stage III NSCLC can improve freedom-from-recurrence (FFR) but has not consistently demonstrated an improvement in overall survival, perhaps partly due to the low (45-50.4 Gy) preoperative doses delivered that result in low rates of mediastinal nodal clearance. We therefore analyzed factors associated with trimodality therapy receipt and determined outcomes in patients with LA-NSCLC who were treated with definitive doses (≥60 Gy) of neoadjuvant CRT prior to surgery. Methods and materials We retrospectively analyzed 355 consecutive patients with LA-NSCLC who were treated with curative intent between January 2000 and December 2013. The Kaplan-Meier method was used to estimate the overall survival and FFR of patients who were initially planned to receive trimodality treatment but never underwent surgery (unplanned bimodality) compared with those who were never considered to be surgical candidates (planned bimodality) and those who underwent surgical resection after CRT (trimodality). Cox proportional hazards regression with forward selection was used for multivariate analyses, and the Fisher exact test was used to test contingency tables. Results Patients who received trimodality therapy had a longer median survival than those with unplanned or planned bimodality therapy at 59.9, 20.1, and 17.3 months, respectively (P < .001). The survival benefit with surgery persisted in patients with stage IIIB (P < .001) and N3 (P = .010) nodal disease when mediastinal nodal clearance was achieved. FFR was also improved with surgical resection (P = .001). Race (P < .001), stage (P < .001), performance status (P < .001), age (P < .001), and diagnosis of chronic obstructive pulmonary disease (P = .009) were significant indicators that influenced both the decision to initially choose trimodality therapy at consultation and to actually perform surgical resection. Conclusions Trimodality treatment significantly improves survival and FFR in patients with LA-NSCLC when definitive doses of radiation with neoadjuvant chemotherapy are employed. We identified important demographic features that predict the use of surgical intervention in patients with stage III NSCLC.

Esophageal Preservation in the Setting of High-Grade Dysplasia and Superficial Cancer

The principle treatment for high-grade dysplasia and superficial esophageal cancer is considered esophagectomy. However, novel technologies and innovations in technique have enabled esophageal preservation by endoscopic management in select patients. The concepts and evidence pertaining to esophageal preservation in early stage malignancy are reviewed in detail. A treatment algorithm based upon the current evidence surrounding esophageal preservation is presented.

A novel technique for light delivery through branched or bent anatomic structures

OBJECTIVE Photodynamic therapy is an effective cancer treatment, but light delivery constraints currently limit its application to superficial, easily visualized tumors. The goal of this study was to determine whether it would be possible to manipulate the optical properties of irregularly shaped anatomic structures for the purpose of light delivery. Such a technique could potentially expand the role of photodynamic therapy to treat tumors currently viewed as inaccessible to visible light. METHODS Ex vivo sheep tracheas and lungs were filled with substances of varying refractive indices. The effects on transmission of visible light of a known wavelength introduced into the proximal lumen of the organs were studied. Data were collected with naked-eye observation, standard photography, charge-coupled device imaging, and direct light measurement. RESULTS Filling a lung or trachea with a liquid possessing a refractive index higher than that of tissue dramatically increases the ability to deliver light around bends and through a branched network. CONCLUSION It is possible to manipulate the optical properties of an ex vivo organ for the purpose of enhanced light delivery.

MA03.10 Population-Based Relative Risks for Lung Cancer Based on Complete Family History of Lung Cancer

MA03.09 Transcriptome-Wide Association Study Reveals Candidate Causal Genes for Lung Cancer A. Clemenceau, M. Lamontagne, R. Carreras Torres, M. Obeidat, W. Timens, P. Joubert, C. Amos, J. Mckay, Y. Bossé Institut Universitaire de Cardiologie Et de Pneumologie de Québec, Québec, QC/ CA, International Agency for Research on Cancer, World Health Organization, Lyon/FR, The University of British Columbia Centre for Heart Lung Innovation, St Paul’S Hospital, Vancouver, BC/CA, Department of Pathology and Medical Biology, Griac Research Institute, University of Groningen, University Medical Center Groningen, Groningen/NL, The Geisel School of Medicine at Dartmouth, Houston, TX/US, Department of Molecular Medicine, Laval University, Québec, QC/CA

Genetic Contribution to Nonsquamous, Non–Small Cell Lung Cancer in Nonsmokers

Introduction: Lung carcinogenesis is strongly influenced by environmental and heritable factors. The genetic contribution to the different histologic subtypes is unknown. Methods: A population‐based computerized genealogy resource linked to a statewide cancer registry of lung cancer cases (N = 5408) was analyzed to evaluate the heritable contribution to lung cancer histologic subtype in smokers (n = 1751) and nonsmokers (n = 818). Statistical methods were used to test for significant excess relatedness of lung cancer cases. Results: Significant excess distant relatedness was observed for all lung cancer histologic subgroups analyzed except for the SCLC subset (p = 0.213). When histologic subsets of smokers and nonsmokers with lung cancer were considered, excess relatedness was observed only in nonsmokers with NSCLC (n = 653 [p = 0.026]) and, in particular, in those nonsmokers with the nonsquamous histologic subtype (n = 561 [p = 0.036]). A total of 61 pedigrees demonstrating a significant excess risk of nonsquamous lung cancer in nonsmokers were identified, and an excess of cases in females was observed among the individuals with these high‐risk pedigrees. Conclusions: This analysis supports a genetic predisposition to lung cancer carcinogenesis in nonsmokers with nonsquamous NSCLC.

Lymph Node Size Predicts for Asymptomatic Brain Metastases in Patients With Non–small-cell Lung Cancer at Diagnosis

Background: We questioned whether the National Comprehensive Cancer Network recommendations for brain magnetic resonance imaging (MRI) for patients with stage ≥ IB non–small‐cell lung cancer (NSCLC) was high‐yield compared with American College of Clinical Pharmacy and National Institute for Health and Care Excellence guidelines recommending stage III and above NSCLC. We present the prevalence and factors predictive of asymptomatic brain metastases at diagnosis in patients with NSCLC without extracranial metastases. Materials and Methods: A retrospective analysis of 193 consecutive, treatment‐naïve patients with NSCLC diagnosed between January 2010 and August 2015 was performed. Exclusion criteria included no brain MRI staging, symptomatic brain metastases, or stage IV based on extracranial disease. Univariate and multivariate logistic regression was performed. Results: The patient characteristics include median age of 65 years (range, 36‐90 years), 51% adenocarcinoma/36% squamous carcinoma, and pre‐MRI stage grouping of 31% I, 22% II, 34% IIIA, and 13% IIIB. The overall prevalence of brain metastases was 5.7% (n = 11). One (2.4%) stage IA and 1 (5.6%) stage IB patient had asymptomatic brain metastases at diagnosis, both were adenocarcinomas. On univariate analysis, increasing lymph nodal stage (P = .02), lymph nodal size > 2 cm (P = .009), multi‐lymph nodal N1/N2 station involvement (P = .027), and overall stage (P = .005) were associated with asymptomatic brain metastases. On multivariate analysis, increasing lymph nodal size remained significant (odds ratio, 1.545; P = .009). Conclusion: Our series shows a 5.7% rate of asymptomatic brain metastasis for patients with stage I to III NSCLC. Increasing lymph nodal size was the only predictor of asymptomatic brain metastases, suggesting over‐utilization of MRI in early‐stage disease, especially in lymph node‐negative patients with NSCLC. Future efforts will explore the utility of baseline MRI in lymph node‐positive stage II and all stage IIIA patients.