Maria Cattoni

Improvement in TNM staging of pulmonary neuroendocrine tumors requires histology and regrouping of tumor size

Objective Neuroendocrine tumors of the lung are currently staged with the 7th edition TNM non–small cell lung cancer staging system. This decision, based on data analysis without data on histology or disease‐specific survival, makes its applicability limited. This study proposes a specific staging system for these tumors. Methods We retrospectively analyzed 510 consecutive patients (female/male, 313/197; median age, 61 years; interquartile range, 51‐70) undergoing lung resection for a primary neuroendocrine tumor between 2000 and 2015 in 8 centers. Multivariable analysis was performed using a Cox proportional hazard model to identify factors associated with disease‐specific survival. A new staging system was proposed on the basis of the results of this analysis. Kaplan–Meier disease‐specific survival was analyzed by stage using the proposed and the 7th TNM staging system. Results Follow‐up was completed in 490 of 510 patients at a median of 51 months (interquartile range, 18‐99). Histology (G1‐typical carcinoid vs G2‐atypical carcinoid vs G3‐large‐cell neuroendocrine carcinoma) and pT were independently associated with survival, but pN was not. After regrouping histology and pT, we proposed the following staging system: IA (pT1‐2G1), IB (pT3G1, pT1G2), IIA (pT4G1, pT2‐3G2, pT1G3), IIB (pT4G2, pT2‐3G3), and III (pT4G3). The 5‐year survivals were 97.9%, 81.0%, 69.1%, 51.8%, and 0%, respectively. By using the 7th TNM, 5‐year survivals were 95.0%, 92.3%, 67.7%, 70.9%, and 65.1% for stage IA, IB, IIA, IIB, and III, respectively. Conclusions Incorporating histology and regrouping tumor stage create a unique neuroendocrine tumor staging system that seems to predict survival better than the 7th TNM classification.

Systematic review and critique of circulating miRNAs as biomarkers of stage I-II non-small cell lung cancer

Selected circulating microRNAs (miRNAs) have been suggested for non-invasive screening of non-small cell lung cancer (NSCLC), however the numerous proposed miRNA signatures are inconsistent. Aiming to identify miRNAs suitable specifically for stage I-II NSCLC screening in serum/plasma samples, we searched the databases “Pubmed”, “Medline”, “Scopus”, “Embase” and “WOS” and systematically reviewed the publications reporting quantitative data on the efficacy [sensitivity, specificity and/or area under the curve (AUC)] of circulating miRNAs as biomarkers of NSCLC stage I and/or II. The 20 studies fulfilling the search criteria included 1110 NSCLC patients and 1009 controls, and were of medium quality according to Quality Assessment of Diagnostic Accuracy Studies checklist. In these studies, the patient cohorts as well as the control groups were heterogeneous for demographics and clinicopathological characteristics; moreover, numerous pre-analytical and analytical variables likely influenced miRNA determinations, and potential bias of hemolysis was often underestimated. We identified four circulating miRNAs scarcely influenced by hemolysis, each featuring high sensitivity (> 80%) and AUC (> 0.80) as biomarkers of stage I-II NSCLC: miR-223, miR-20a, miR-448 and miR-145; four other miRNAs showed high specificity (> 90%): miR-628-3p, miR-29c, miR-210 and miR-1244. In a model of two-step screening for stage I-II NSCLC using first the above panel of serum miRNAs with high sensitivity and high AUC, and subsequently the panel with high specificity, the estimated overall sensitivity is 91.6% and overall specificity is 93.4%. These and other circulating miRNAs suggested for stage I-II NSCLC screening require validation in multiple independent studies before they can be proposed for clinical application.

LINE-1 hypomethylation is associated to specific clinico-pathological features in Stage I non-small cell lung cancer

OBJECTIVES We hypothesize that selected genetic and/or epigenetic changes associated with advanced tumours may help identifying early non-small cell lung cancers (NSCLCs) that recur after resection. Among epigenetic changes, long interspersed nuclear element-1 (LINE-1) hypomethylation is seen early during carcinogenesis and may act in concert with genetic alterations to cancer progression. LINE-1 hypomethylation and gene mutations frequently involved in lung cancer, were analysed to evaluate their prognostic role in resected stage I NSCLC. METHODS Gene mutations and LINE-1 methylation were analysed in 167 Caucasian patients with stage I NSCLC, namely 100 adenocarcinomas (ADC) and 67 squamous-cell carcinomas (SqCC), using mass-spectrometry and pyrosequencing. We evaluated the correlation between molecular results and clinico-pathological data: age, gender, smoking status, period of surgery, histology, grading, pathological stage, p53 expression, LINE-1 hypomethylation. These variables have been assessed as possible predictors of cancer related survival by regression analysis. RESULTS Frequency and spectrum of gene mutations were significantly different in ADCs compared with SqCCs. p53 positivity was more common in SqCC, while EGFR or KRAS mutations were mainly detected in ADC. LINE1 hypomethylation was associated with SqCC histology, p53 immunoreactivity and smoking habit. Stage IB, LINE-1 hypomethylation and PIK3CA mutation independently predicted a worse cancer-related survival. When combined into a scoring system, their prognostic power was strengthened. CONCLUSIONS In many stage I NSCLC a mutation pattern of advanced disease was observed. Stage IB, LINE-1 hypomethylation and PIK3CA mutation were associated to poor prognosis. Genetic and epigenetic events occurring in early carcinogenesis may help identifying stage I NSCLC patients who deserve adjuvant therapy.

Comparison of multiple techniques for endobronchial ultrasound-transbronchial needle aspiration specimen preparation in a single institution experience

BACKGROUND The optimal method for specimen preparation of endobronchial ultrasound-transbronchial needle aspiration (EBUS-TBNA) is still controversial. This study aims to compare several techniques available for EBUS-TBNA specimen acquisition and processing, in order to identify the best performing technique. METHODS We retrospectively reviewed the data of 199 consecutive patients [male, 73%; median age, 64 years (IQR: 52-74 years)] undergoing EBUS-TBNA at our institution from 2012 through 2014 for diagnosis of hilar-mediastinal lymph node enlargement suspect of neoplastic (n=139) or granulomatous (n=60) disease. All procedures were performed by two experienced bronchoscopists, under conscious sedation and local anaesthesia, using 21/22-Gauge (G) needle, without rapid on-site evaluation (ROSE). Five specimen-processing techniques were used: cytology slides in 42 cases (21%); cell-block in 25 (13%); core-tissue in 60 (30%); combination of cytology slides and core-tissue in 51 (26%); combination of cytology slides and cell-block in 21 (10%). To assess the diagnostic accuracy of each tissue-processing technique we compared the EBUS-TBNA results to those obtained with surgical lymphadenectomy, or 1-year follow-up in non-operated patients. RESULTS Diagnostic yield, accuracy and area under the curve (AUC) were as follows. Cytology slides: 81%, 80%, 0.90; cell-block: 48%, 33%, 0.67; core-tissue: 87%, 99%, 0.96; cytology slides + core-tissue: 80%, 100%, 1.00; cytology slides + cell-block: 86%, 100%, 1.00. Cytology slides and core-tissue method showed non-significantly different diagnostic yield (P=0.435) and AUC (P=0.152). CONCLUSIONS In our single-institution experience, cytology slides and core-tissue preparations demonstrated high and similar diagnostic performance. Cytology slides combination with core-tissue or cell-block showed the highest performance, however these combination methods were more resource-consuming.

Resection rate of lung cancer in Teesside (UK) and Varese (Italy): a comparison after implementation of the National Cancer Plan

Background In a lung cancer survey in 2000 we showed significantly less favourable stage distribution and lower resection rate in Teesside (UK) than in the comparable industrialised area of Varese (Italy). Lung cancer services in Teesside were subsequently reorganised according to National Cancer Plan recommendations. Methods For all new lung cancer cases diagnosed in Teesside (n=324) and Varese (n=260) during the 12 months October 2010 to September 2011 (hereafter ‘the 2010 cohort’), demographic, clinico-pathological and disease management data were prospectively recorded using the same database and protocol as the 2000 survey. Findings were analysed focusing on resection rate. Results In the 2010 cohort compared with 2000, both in Teesside and Varese emergency referral decreased (p<0.001), performance status improved (p<0.001), but cancer stage shift was not seen; resection rate improved in Teesside, from 7% to 11% (p=0.054), and was unchanged in Varese (24%). Moreover, in Teesside compared with Varese the stage distribution remained less favourable, stage I–II non-small cell lung cancer (NSCLC) proportion being respectively 12% and 19% (p=0.040), and resection rate in all lung cancers remained lower (11% and 24%; p<0.001). On multivariate analysis, resection predictors in Teesside were as follows: stage I–II NSCLC (OR 86.14; 95% CI 31.80 to 233.37), performance status 0–1 (OR 5.02; 95% CI 1.48 to 17.07), belonging to 2010 cohort (OR 2.85; 95% CI 1.06 to 7.64). Conclusions In Teesside the main independent predictor of resection was disease stage; in 2010–2011 compared with 2000, lung cancer service improved but stage shift did not occur, and resection rate increased but remained significantly lower than in Varese.

Assessment of the aggregate risk score to predict mortality after surgical biopsy for interstitial lung disease

OBJECTIVES An aggregate risk score (range 0-6 points) for predicting mortality after surgical biopsy for interstitial lung disease (ILD) was recently developed from four independent variables: intensive care unit treatment (2 points), age >67 years (1.5 points), immunosuppression (1.5 points), open biopsy (1 point). In the development cohort, patients were grouped in four classes of aggregate score (A, B, C, D) showing incremental risk of death within 90 days from biopsy. We tested this mortality risk model in an independent cohort. METHODS The aggregate risk score and the corresponding class of 90-day mortality risk was retrospectively determined in 151 consecutive patients undergoing biopsy for uncertain ILD at the Center for Thoracic Surgery, University of Insubria (Varese, Italy) in 1997-2012. We evaluated, by Spearmans ρ test, the correlation between aggregate risk score and mortality rate in the development cohort and in our cohort. Fishers exact test was used for comparison of overall mortality rate between the two cohorts. RESULTS The mortality rate correlation with risk score differed in our cohort (ρ = 0.127; P = 0.06) compared with the development cohort (ρ = 0.352; P < 0.0001). In our dataset mortality polarized: it was minimal in Classes A and B (2% and 0%, respectively), 33% in Classes C and D. This skewed mortality distribution was possibly contributed by significantly lower overall mortality rate in our cohort than in the development cohort (2.6% vs 10.6%; P = 0.0017). Despite the difference in mortality distribution, in our dataset, we confirmed that ILD patients with aggregate score >2 (Classes C and D) were at exceedingly high risk of postoperative mortality. CONCLUSIONS The aggregate score is a simple and useful risk score for ILD. Our dataset confirms that lung biopsy is reasonably safe in Class A and B patients while, in Class C and D patients, it is indicated only if histology would substantially change management and prognosis.

A 90-day mortality risk model as a support in managing patients undergoing video-assisted thoracic surgery for lung cancer

The introduction of the video-assisted thoracoscopic (VATS) approach for lung lobectomy in the treatment of lung cancer has led to a reduction of postoperative morbidity, length of stay and, in some studies, of mortality when compared to thoracotomy (1-3). The improvement of postoperative outcomes as a consequence of this mini-invasive approach, which minimize tissue injury and immune-stress response, has allowed a rapid diffusion of this technique that is currently preferred to thoracotomy approach in several experienced centers.

Natural Killer Cells from Malignant Pleural Effusion Are Endowed with a Decidual-Like Proangiogenic Polarization

Natural killer (NK) cells are crucial in tumor recognition and eradication, but their activity is impaired in cancer patients, becoming poorly cytotoxic. A particular type of NK cells, from the decidua, has low cytotoxicity and shows proangiogenic functions. We investigated whether NK cells from peripheral blood (PB) and pleural effusions of patients develop decidual-like NK phenotype and whether exposure to IL-2 can restore their killing ability in the presence of pleural fluids. NK cells from pleural effusion of patients with inflammatory conditions (iPE, n = 18), primary tumor (ptPE, n = 18), and metastatic tumor (tmPE, n = 27) acquired the CD56brightCD16− phenotype. NK cells from both ptPE and tmPE showed increased expression for the CD49a and CD69 decidual-like (dNK) markers and decreased levels of the CD57 maturation marker. NK from all the PE analyzed showed impaired degranulation capability and reduced perforin release. PE-NK cells efficiently responded to IL-2 stimulation in vitro. Addition of TGFβ or cell-free pleural fluid to IL-2 in the culture medium abrogated NK cell CD107a and IFNγ expression even in healthy donors (n = 14) NK. We found that tmPE-NK cells produce VEGF and support the formation of capillary-like structures in endothelial cells. Our results suggest that the PE tumor microenvironment can shape NK cell polarization towards a low cytotoxic, decidual-like, highly proangiogenic phenotype and that IL-2 treatment is not sufficient to limit this process.

Is there a role for traditional nuclear medicine imaging in the management of pulmonary carcinoid tumours

OBJECTIVES The clinical utility of fluorodeoxyglucose-positron emission tomography (FDG-PET) and somatostatin receptor scintigraphy (SRS) in pulmonary carcinoids staging is unclear. This study aims to determine the role of FDG-PET and SRS in detecting hilar-mediastinal lymph node metastasis from these tumours. METHODS We retrospectively collected the data of 380 patients who underwent lung resection for primary pulmonary carcinoid in seven centres between 2000 and 2015. Patients without nodal sampling ( n  = 78) were excluded. In 302 patients [35% men, median age 58 (interquartile range 47-68) years] the results of preoperative computed tomography (CT) scan, FDG-PET and SRS were analysed and compared to the pathological findings after resection to determine the respective utility of these two nuclear tests. RESULTS The sensitivity, specificity and negative predictive value in detecting N1 and N2 disease were respectively 33% and 46%, 93% and 90%, 88% and 95% for computed-tomography-scan, 38% and 60%, 93% and 95%, 88% and 95% for FDG-PET, 22% and 33%, 95% and 98%, 84% and 87% for SRS. The diagnostic accuracy for N1 and N2 disease of CT scan was not significantly different from that of FDG-PET ( P  =   1.0 and P  =   0.37 for N1 and N2 disease respectively) and of SRS ( P  =   0.47 and P  =   0.35 for N1 and N2 disease respectively). The sensitivity and specificity of these imaging tests were also similar when analysed by typical vs atypical histology. CONCLUSIONS CT scan, FDG-PET and SRS showed similar performance in terms of nodal staging for pulmonary carcinoid. These findings suggest that additional nuclear imaging beyond CT scan is not required as long as a lymphadenectomy or nodal sampling is completed at resection.

PS01.25: Large Cell Neuroendocrine Carcinoma of the Lung: Prognostic Factors of Survival and Recurrence After R0 Surgical Resection: Topic: Surgery

Maria Cattoni, Eric Vallieres, Lisa M. Brown, Amir A. Sarkeshik, Stefano Margaritora, Alessandra Siciliani, Pier Luigi Filosso, Francesco Guerrera, Andrea Imperatori, Nicola Rotolo, Farhood Farjah, Grace Wandell, Kimberly Costas, Catherine Mann, Michal Hubka, Stephen Kaplan, Alexander S. Farivar, Ralph W. Aye, Brian Louie Swedish Cancer Institute, Seattle, WA/United States of America, UC Davis Medical Center, Sacramento, CA/United States of America, Catholic University ‘Sacred Heart’, Rome/Italy, San Giovanni Battista Hospital, Torino/Italy, University of Insubria, Ospedale di Circolo, Varese/Italy, University of Washington Medical Center, Seattle, WA/United States of America, Providence Regional Medical Center, Everett, WA/United States of America, Virginia Mason Hospital & Seattle Medical Center, Seattle, WA/United States of America