Risk of recurrence in stage I adenocarcinoma of the lung: a multi-institutional study on synergism between type of surgery and type of nodal staging.

BACKGROUND: In last years, an increasing interest emerges on the role of sub-lobar resection and lobe-specific lymph nodal dissection in the treatment of early-stage lung cancer. The aim of our study was to define the impact on cumulative incidence of recurrence (CIR) of type of surgical resection and type of nodal staging in this subset of patients. Furthermore, we evaluated the possible synergism between the different kinds of procedure. METHODS: An analysis of 969 consecutive stage I pulmonary adenocarcinoma patients, operated in six Thoracic Surgery Institutions between 2001 and 2013, was conducted. Type of surgical resection included lobectomy and sub-lobar resection; while pneumonectomy and bilobectomy were excluded from the analysis. Nodal staging procedures were classified in nodal sampling (NS), lobe-specific lymph node dissection (LS-ND) and systematic lymph node dissection (SND). Multivariable-adjusted comparisons for CIR was performed using Fine and Grey model, taking into account of death by any cause as competing event. In order to evaluate synergism between the different procedures, the test of interaction between type of surgical resection and type of nodal staging was carried out and results presented in a stratified way. RESULTS: Eight-hundred forty-six (87%) patients were submitted to lobectomy, while 123 (13%) to sub-lobar resection. Four-hundred fifty-five (47%) patients received SND, 98 (10%) LS-ND and 416 (43%) NS. Two-hundred forty-seven (26%) patients developed a local/distant recurrence with a 5-year CIR of 24.2%. Multivariable-adjusted comparisons showed an independent negative effect of sub-lobar resection (HR =1.52; 95% CI: 1.07-2.17), LS-ND (HR =1.74; 95% CI: 1.16-2.6) and NS (HR =1.49; 95% CI: 1.12-1.98) on CIR. Test of interaction showed a homogeneity of results among subgroups. CONCLUSIONS: Patients affected by stage I pulmonary adenocarcinoma and submitted to lobectomy presented a significant lower recurrence rate than those submitted to sub-lobar resection. Moreover, SND presented an independent positive effect on recurrence development than other lymph node assessment strategy. Finally, lobectomy in combination with systematic lymph nodal resection showed the best results in term of CIR.

Optimal surgical approach to thymic malignancies: New trends challenging old dogmas.

Until recently, the surgical approach to thymic tumors has remained basically unchanged. The collaborative effort led by ITMIG with the collaboration of regional and society-based interest groups (ESTS, JART) produced an enthusiastic surge of interest in testing the new technological advances in thoracic surgery and many historical dogmas in thymic surgery have been questioned and challenged. The present review addresses the new trends in the optimal surgical management of thymic tumors based on the review of the current literature. 1. Minimally-invasive techniques (MIT) including video-assisted thoracic surgery (VATS) and robotic-assisted thoracic Surgery (RATS) are now to be considered the standard of care in early-stage thymic tumors. MIT are no inferior to open approaches in terms of postoperative complications, loco-regional recurrence rates and survival. MIT are associated with a shorter length of stay, reduced intraoperative blood loss and better cosmetic results. 2. The adoption of the ITMIG/IASLC TNM staging system for thymic tumors requires a paradigm shift among thoracic surgeons to include regional lymphadenectomy according to the IASLC/ITMIG nodal map in the surgical management of thymic tumors. 3. A limited thymectomy instead of total thymectomy along with the removal of the thymic tumor in nonmyasthenic Stage I-II tumors has been proposed by some authors, although the results are not uniform. Until more mature data is available, adherence to the current guidelines recommending total thymectomy in addition to thymomectomy is always indicated. 4. In locally-advanced Stage IVa patients with pleural involvement, major pleural resections, including pleurectomy/decortication or extrapleural pneumonectomy are indicated, provided a complete resection of the pleural deposits is anticipated, usually in a multidisciplinary setting, with excellent long-term results. The incorporation of these new concepts and techniques in the surgical armamentarium of the thoracic surgeons dealing with thymic malignancies will certainly be of help in the optimal management of these patients.

Cell of origin markers identify different prognostic subgroups of lung adenocarcinoma.

Strong prognostic markers able to stratify lung adenocarcinoma (ADC) patients are lacking. We evaluated whether a six-immunohistochemical markers panel (TTF1, SP-A, Napsin A, MUC5AC, CDX2 and CK5), defining the putative neoplastic "cell of origin," allows to identify prognostic subgroups among lung ADC. We screened a large cohort of ADC specimens (2003-2013) from Torino Institutional Repository identifying: (i) marker positivity by immunohistochemistry, (ii) main morphological appearance by light microscopy, (iii) presence of "hotspot" mutations of candidate genes by Sequenom technology. To evaluate possible predictors of survival and time to recurrence, uni- and multivariable-adjusted comparisons were performed. We identified 4 different subgroups: "alveolar," "bronchiolar," "mixed" and "null type." Alveolar-differentiated ADC were more common in young (P=.065), female (P=.083) patients, frequently harboring EGFR-mutated (P=.003) tumors with acinar pattern (P<.001). Bronchiolar-differentiated ADC were more associated with mucinous and solid pattern (P<.001), higher degree of vascular invasion (P=.01) and KRAS gene mutations (P=.07). Bronchiolar, mixed, and null types were independent negative predictors for overall survival, and the latter two had a shorter time to recurrence. This "Cell of Origin" classifier is more predictable than morphology and genetics and is an independent predictor of survival on a multivariate analysis.

The utility of blood neuroendocrine gene transcript measurement in the diagnosis of bronchopulmonary neuroendocrine tumours and as a tool to evaluate surgical resection and disease progression.

OBJECTIVES: The management of bronchopulmonary neuroendocrine tumours (BPNETs) is difficult, since imaging, histology and biomarkers have a limited value in diagnosis, predicting outcome and defining therapeutic efficacy. We evaluated a NET multigene blood test (NETest) to diagnose BPNETs, assess disease status and evaluate surgical resection. METHODS: (i) Diagnostic cohort: BP carcinoids (n = 118)-typical carcinoid, n = 67 and atypical carcinoid, n = 51; other lung NEN (large-cell neuroendocrine carcinoma and small-cell lung carcinoma, n = 13); adenocarcinoma, (n = 26); squamous cell carcinoma (n = 23); controls (n = 90) and chronic obstructive pulmonary disease (n = 18). (ii) Surgical cohort, n = 28: BP carcinoids (n = 16: typical carcinoid 12; atypical carcinoid 4); large-cell neuroendocrine carcinoma, n = 3; lung adenocarcinoma, n = 8 and squamous cell carcinoma, n = 1. Blood sampling was performed presurgery and 30 days post-surgery. Transcript levels measured by quantitative polymerase chain reaction were calculated as activity scores (0-100% scale: normal < 14%) and compared with chromogranin A (enzyme-linked immunosorbent assay; normal <109 ng/ml). RESULTS: NETest was significantly elevated in carcinoids (48.7 ± 27%) versus controls (6 ± 6%, P < 0.001) with metrics: sensitivity 93%, specificity 89%, positive predictive value 92% and negative predictive value 91%. NETest differentiated progressive disease (73 ± 22%) from stable disease (36 ± 19%, P < 0.001) and R0 resections (10 ± 5%, P < 0.001, area under the curve: 0.98). Levels in chronic obstructive pulmonary disease and lung cancers were 18-24% while elevated in small-cell lung carcinoma/large-cell neuroendocrine carcinoma (59 ± 10%). In BPNETs on postoperative Day 30, NETest decreased by 60% (P < 0.001). Chromogranin A was elevated in only 40% of carcinoids and not altered by surgery. CONCLUSIONS: Blood NET gene levels accurately identified BPNETs (100%) and differentiated these from controls, benign and malignant lung disease. Progressive disease could be identified and surgical resection verified. Chromogranin A had no clinical utility. Monitoring NET transcript levels in blood will facilitate management by detecting residual tumour and identifying progressive disease.

Neuroendocrine tumors of the thymus.

Primary neuroendocrine tumors of the thymus (NETTs) are rare and biologically very aggressive neoplasms, usually located in the anterior mediastinal space. They are more frequently observed in males, in their fourth/fifth decades of life. In 50% of cases, NETTs are associated with endocrinopaties [Cushing's syndrome, acromegaly or Multiple Endocrine Neoplasia-1 (MEN-1) syndrome]. NETTs very often present with invasion of the surrounding mediastinal anatomical structures. Surgery, even in advanced stages, is the mainstay of treatment: a compete resection through a median sternotomy or a combined access (sternotomy + thoracotomy) should be always attempted. Induction chemotherapy (± radiotherapy) is usually administered in advanced neoplasms, with the aim to achieve tumor shinkage, increasing, therefore, the chance to obtain a complete resection. Postoperative radiotherapy (± chemotherapy) is administered in case of invasive lesions, or incomplete resections. NETTs long-term outcome is poor, even in case of completely resected tumors, due to high risk of recurrence or distant metastases development. Prognosis mainly depends on tumor stage, invasivity, completeness of resection, possible association with endocrinopaties and recurrence/distant metastases development.

Low Accuracy of Computed Tomography and Positron Emission Tomography to Detect Lung and Lymph Node Metastases of Colorectal Cancer.

BACKGROUND: Minimally invasive surgery, stereotactic radiotherapy, and radiofrequency ablation are commonly proposed in the case of pulmonary colorectal-metastasis as alternatives to conventional open surgery. Preoperative imaging assessment by computed tomography (CT) scan and fluorodeoxyglucose positron emission tomography (FDG-PET) are critical to guide oncologic radical treatment. Our aim was to investigate the accuracy of CT and FDG-PET for the evaluation of the number of pulmonary colorectal metastases and thoracic lymph nodal involvement (LNI). METHODS: Patients who underwent lung surgical resection for pulmonary colorectal metastases from 2004 to 2014 were analyzed. Concordance between histology, CT scan, and FDG-PET findings were assessed. RESULTS: Data of 521 patients were analyzed. Of those, FDG-PET was performed in 435 (83.5%). A moderate agreement between both CT scan (kappa index: 0.42) and FDG-PET (kappa index: 0.42) findings and the histologically proven number of metastases was observed. The number of histologically proven metastases was correctly discriminated in 61.7% of cases with CT scan and in 61.8% of cases with FDG-PET. Multiple metastases were discovered in 20.9% of clinical single metastasis cases with CT scan, and in 24.4% of those cases with FDG-PET. One hundred fifty patients (29.1%) presented with pathologic LNI. A poor agreement was observed between LNI and CT scan findings (kappa index: 0.02), and a weak agreement was observed concerning LNI and FDG-PET findings (kappa index: 0.39). CONCLUSIONS: Computed tomography and FDG-PET have limitations if the objective is to detect all malignant nodules and to discriminate the LNI in cases of pulmonary metastases of colorectal cancer.

Pleurectomy-decortication in malignant pleural mesothelioma: are different surgical techniques associated with different outcomes? Results from a multicentre study.

OBJECTIVES: The potential benefit of surgery for malignant pleural mesothelioma (MPM), especially concerning pleurectomy/decortication (P/D), is unclear from the literature. The aim of this study was to evaluate the outcome after multimodality treatment of MPM involving different types of P/D and to analyse the prognostic factors. METHODS: We reviewed 314 patients affected by MPM who were operated on in 11 Italian centres from 1 January 2007 to 11 October 2014. RESULTS: The characteristics of the population were male/female ratio: 3.7/1, and median age at operation was 67.8 years. The epithelioid histotype was observed in 79.9% of patients; neoadjuvant chemotherapy was given to 57% of patients and Stage III disease was found following a pathological analysis in 62.3% of cases. A total of 162 (51.6%) patients underwent extended P/D (EP/D); 115 (36.6%) patients had P/D and 37 (11.8%) received only a partial pleurectomy. Adjuvant radiotherapy was delivered in 39.2% of patients. Median overall survival time after surgery was 23.0 [95% confidence interval (CI): 19.6-29.1] months. On multivariable (Cox) analysis, pathological Stage III-IV [ P = 0.004, hazard ratio (HR):1.34; 95% CI: 1.09-1.64], EP/D and P/D ( P = 0.006, HR for EP/D: 0.46; 95% CI: 0.29-0.74; HR for P/D: 0.52; 95% CI: 0.31-0.87), left-sided disease ( P = 0.01, HR: 1.52; 95% CI: 1.09-2.12) and pathological status T4 ( P = 0.0003, HR: 1.38; 95% CI: 1.14-1.66) were found to be independent significant predictors of overall survival. CONCLUSIONS: Whether the P/D is extended or not, it shows similarly good outcomes in terms of early results and survival rate. In contrast, a partial pleurectomy, which leaves gross tumour behind, has no impact on survival.

Epidermal growth factor receptor mutations are linked to skip N2 lymph node metastasis in resected non-small-cell lung cancer adenocarcinomas.

Objectives: The impact of skip N2 metastases (i.e. N2 lymph node metastases without N1) on survival in surgically resected non-small lung cancer remains an intriguing and rarely investigated topic. The goal of our study was to elucidate (i) skip N2 influence on overall survival (OS) and time to recurrence (TTR) in patients with resected lung adenocarcinoma and (ii) its link with epidermal growth factor receptor ( EGFR ) and v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog ( KRAS ) mutations. Methods: A retrospective analysis of 279 consecutive patients with lung pN2 adenocarcinoma, operated in two institutions between 2003 and 2013, was conducted. OS and TTR were calculated using the Kaplan-Meier method. Crude and multivariable-adjusted comparisons by skip N2 for OS and TTR were performed using the Cox method with shared frailty (accounting for the within-centre correlation). Associations between skip N2 metastasis, clinicopathological characteristics and EGFR and KRAS mutations were investigated using the Fisher exact test and Cramér's V -test. Results: The mean age at the time of surgery was 63 years (±12), and the median follow-up time was 36 months (min 3; max 101). Skip N2 was observed in 54 patients (19%). EGFR mutations were observed in 38 patients (14%); KRAS mutations were seen in 86 patients (31%). Patients with skip N2 metastasis were predominantly non-smokers ( P = 0.001), underwent segmentectomy or limited resections ( P = 0.004) and were not submitted to adjuvant therapy ( P = 0.022). Moreover, there was a correlation between EGFR mutations and skip N2 (Cramér's V : 0.25, P < 0.001). Indeed, EGFR mutations were significantly more frequent in skip N2 tumours (33%) compared with non-skip tumours (10%), P < 0.001. No correlation between skip N2 and KRAS mutations was observed (Cramér's V : 0.05, P = 0.46). The multivariable-adjusted model showed a significant skip N2 protective effect on OS (hazard ratio, HR 0.503; P = 0.014; 95% confidence interval, CI: 0.291-0.8704) but not on TTR (HR 0.788; P = 0.446; 95% CI: 0.427-1.454). Conclusions: In our series, lung adenocarcinoma skip N2 metastasis demonstrated a favourable prognosis. The presence of EGFR mutations could have significance in the better survival and in the specific anatomic pathway of lymphatic metastases exhibited by skip N2 tumours.

KRAS exon 2 codon 13 mutation is associated with a better prognosis than codon 12 mutation following lung metastasectomy in colorectal cancer.

INTRODUCTION: The utilization of molecular markers as routinely used biomarkers is steadily increasing. We aimed to evaluate the potential different prognostic values of KRAS exon 2 codons 12 and 13 after lung metastasectomy in colorectal cancer (CRC). RESULTS: KRAS codon 12 mutations were observed in 116 patients (77%), whereas codon 13 mutations were observed in 34 patients (23%). KRAS codon 13 mutations were associated with both longer time to pulmonary recurrence (TTPR) (median TTPR: 78 months (95% CI: 50.61-82.56) vs 56 months (95% CI: 68.71-127.51), P = 0.008) and improved overall survival (OS) (median OS: 82 months vs 54 months (95% CI: 48.93-59.07), P = 0.009). Multivariate analysis confirmed that codon 13 mutations were associated with better outcomes (TTPR: HR: 0.40 (95% CI: 0.17-0.93), P = 0.033); OS: HR: 0.39 (95% CI: 0.14-1.07), P = 0.07). Otherwise, no significant difference in OS (P = 0.78) or TTPR (P = 0.72) based on the type of amino-acid substitutions was observed among KRAS codon 12 mutations. MATERIALS AND METHODS: We retrospectively reviewed data from 525 patients who underwent a lung metastasectomy for CRC in two departments of thoracic surgery from 1998 to 2015 and focused on 150 patients that had KRAS exon 2 codon 12/13 mutations. CONCLUSIONS: KRAS exon 2 codon 13 mutations, compared to codon 12 mutations, seem to be associated with better outcomes following lung metastasectomy in CRC. Prospective multicenter studies are necessary to fully understand the prognostic value of KRAS mutations in the lung metastases of CRC.