Prognostic Impact of Node-Spreading Pattern in Surgically Treated Small-Cell Lung Cancer: A Multicentric Analysis.

OBJECTIVE: Although surgery in selected small-cell lung cancer (SCLC) patients has been proposed as a part of multimodality therapy, so far, the prognostic impact of node-spreading pattern has not been fully elucidated. To investigate this issue, a retrospective analysis was performed. METHODS: From 01/1996 to 12/2012, clinico-pathological, surgical, and oncological features were retrospectively reviewed in a multicentric cohort of 154 surgically treated SCLC patients. A multivariate Cox proportional hazard model was developed using stepwise regression, in order to identify independent outcome predictors. Overall (OS), cancer-specific (CSS), and Relapse-free survival (RFS) were calculated by Kaplan-Meier method. RESULTS: Overall, median OS, CSS, and RFS were 29 (95 % CI 18-39), 48 (95 % CI 19-78), and 22 (95 % CI 17-27) months, respectively. Lymphadenectomy was performed in 140 (90.9 %) patients (median number of harvested nodes: 11.5). Sixty-seven (47.9 %) pN0-cases experienced the best long-term survival (CSS: 71, RFS: 62 months; p < 0.0001). Among node-positive patients, no prognostic differences were found between pN1 and pN2 involvement (CSS: 22 vs. 15, and RFS: 14 vs. 10 months, respectively; p = 0.99). By splitting node-positive SCLC according to concurrent N1-invasion, N0N2-patients showed a worse CSS compared to those cases with combined N1N2-involvement (N0N2: 8 months vs. N1N2: 22 months; p = 0.04). On the other hand, the number of metastatic stations (p = 0.80) and the specific node-level (p = 0.85) did not affect CSS. At multivariate analysis, pN+ (HR: 3.05, 95 % CI 1.21-7.67, p = 0.02) and ratio between metastatic and resected lymph-nodes (RL, HR: 1.02, 95 % CI 1.00-1.04, p = 0.03) were independent predictors of CSS. Moreover, node-positive patients (HR: 3.60, 95 % CI 1.95-6.63, p < 0.0001) with tumor size ≥5 cm (HR: 1.85, 95 % CI 0.88-3.88, p = 0.10) experienced a worse RFS. CONCLUSIONS: In selected surgically treated SCLC, the long-term survival may be stratified according to the node-spreading pattern.

Incidence and Management of Post-Lobectomy and Pneumonectomy Bronchopleural Fistula.

INTRODUCTION: Bronchopleural fistula is a rare but potentially fatal complication of pulmonary resections and proper management is essential for its resolution. In this study, we analyzed the incidence of fistula after pulmonary resection and reported data about endoscopic and conservative treatments of this complication. METHODS: From January 2003 to December 2013, 835 patients underwent anatomic lung resections: 786 (94.1 %) had a lobectomy and 49 (5.9 %) a pneumonectomy. Bronchopleural fistula was suspected by clinical signs and confirmed by endoscopic visualization. RESULTS: Eighteen patients (2.2 %) developed a bronchopleural fistula, 11 in lobectomy group (1.4 %) and 7 in pneumonectomy group (14.3 %). The fistula size ranged between <1 mm and 6 mm and mean time of fistula onset was 33.9 ± 54.9 days after surgery. Of 18 patients who developed fistula, one died due to acute respiratory failure and another one was reoperated and then died to causes unrelated to the treatment. All the remaining 16 patients were treated with a conservative therapy that consisted in keeping or replacing a drainage chest tube. Nine of them underwent also endoscopic closure of the fistula using biological or synthetic glues. The mean period of time elapsed for the resolution of this complication was shorter with combined (conservative + endoscopic) than with conservative treatment alone (15.4 ± 13.2 vs. 25.8 ± 13.2 days, respectively), but without significant difference between the two methods (p: 0.299). CONCLUSION: Endoscopic therapy, associated with a conservative treatment, is a safe and useful option in the management of the postoperative bronchopleural fistula.

CT-guided fine-needle ago-biopsy of pulmonary nodules: predictive factors for diagnosis and pneumothorax occurrence.

OBJECTIVE: To evaluate variables that could predict diagnosis during CT-guided fine-needle aspiration. METHODS: Data from 249 patients who underwent FNAB from January 2010 to December 2012 were analyzed in a retrospective observational study. RESULTS: Mean age was 66.7 ± 11.5 years, male/female ratio 158/91 (63 vs. 37 %). The nodules were in right lung in 123 patients (49 %), in left lung in 126 patients (51 %), the upper, lower and middle lobe localizations were, respectively in 122 (49 %), 100 (40 %) and 17 (6 %) patients. Mean nodule-chest wall distance was 63.89 ± 21.38 mm. The tumor location, the needle diameter, the presence of necrosis or cavitation, the node-chest wall distance and the number of passages were not related to the diagnostic outcome (p = NS). The nodule diameter was predictive of diagnosis. Odds ratio for a 10-30 mm tumor was 2.51 (95 % OR: 1.24-5.08, p value = 0.011), the odds ratio for a 30-50 mm tumor was 2.39 (95 % OR: 1.22-4.69, p value = 0.011), and the odds ratio for a tumor larger than 50 mm was 4.44 (95 % OR: 1.89-10.44, p value = 0.001). Post-procedure pneumothorax occurred in 62 cases (25 %). The determinant factors for pneumothorax occurrence were emphysema, odds ratio 6.87 (95 % CI 1.07-44.10, p value = 0.04), and the number of pleural passages, odds ratio of 5.47 (95 % OR: 1.92-15.58), 7.44 (95 % OR: 2.58-21.5), 6.13 (95 % OR: 2.07-18.11) p value = 0.001 for one, two, three or more of three passages, respectively. CONCLUSIONS: In our experience, nodule size is the most important diagnostic factor during fine-needle aspiration, while the number of passages and the presence of emphysema constitute risk factors for pneumothorax occurrence.

EGFR-targeted therapy for non-small cell lung cancer: focus on EGFR oncogenic mutation.

The two essential requirements for pathologic specimens in the era of personalized therapies for non-small cell lung carcinoma (NSCLC) are accurate subtyping as adenocarcinoma (ADC) versus squamous cell carcinoma (SqCC) and suitability for EGFR molecular testing, as well as for testing of other oncogenes such as EML4-ALK and KRAS. Actually, the value of EGFR expressed in patients with NSCLC in predicting a benefit in terms of survival from treatment with an epidermal growth factor receptor targeted therapy is still in debate, while there is a convincing evidence on the predictive role of the EGFR mutational status with regard to the response to tyrosine kinase inhibitors (TKIs).This is a literature overview on the state-of-the-art of EGFR oncogenic mutation in NSCLC. It is designed to highlight the preclinical rationale driving the molecular footprint assessment, the progressive development of a specific pharmacological treatment and the best method to identify those NSCLC who would most likely benefit from treatment with EGFR-targeted therapy. This is supported by the belief that a rationale for the prioritization of specific regimens based on patient-tailored therapy could be closer than commonly expected.

Chemoradiotherapy followed by surgery versus surgery alone in esophageal cancer patients: is it time for additional evidence?

Recent efforts to improve survival in patients with locally advanced esophageal carcinoma have combined both systemic and local therapy. However, the role of neoadjuvant chemoradiotherapy in technically operable IIa-III esophageal carcinoma is still unresolved.

Inhibition of non-neuronal alpha7-nicotinic receptor reduces tumorigenicity in A549 NSCLC xenografts.

Nicotinic acetylcholine receptors (nAChR) are expressed on bronchial epithelial and non-small cell lung cancer cells and are involved in cell growth regulation. Nicotine (classical nAChR agonist) induced cell proliferation, whereas nAChR antagonists, d- tubocurarine or alpha-cobratoxin (alpha-CbT), induced cell death. In the current study, we further explored the antitumor potential mechanisms and activities of alpha-CbT. NOD/SCID mice were grafted intraperitoneally or orthotopically and treated with alpha-CbT. alpha-CbT treatment [0.04 ng/kg or 0.12 ng/kg] induced a strong reduction in tumor size ( approximately 90%) in comparison with mice treated with the vehicle alone. Tumor inhibition was related to severe induction of apoptosis. Moreover, neoangiogenesis was strongly inhibited (reduction of cells positive to vascular endothelial growth factor and CD31). Biochemical analyses of the cells, isolated by the primary lung tumor in alpha-CbT-treated mice, showed apoptosis features characterized by: (i) inhibition of BAD phosphorylation at Ser(112) and Ser(136); (ii) BAD dissociation from 14-3-3; (iii) BAD association with BCL-XL; and (iv) cleavage of caspase-9. Moreover, these cells were unable to grow in soft agar and develop tumor, when reinjected into mice. The small interfering RNA-mediated silencing of the alpha7-nAChR gene confirmed that alpha-CbT specifically inhibited the alpha7-nAChR-mediated survival pathway in A549 cells. Furthermore, the specificity of alpha-CbT is reinforced by the lack of effect of short chain toxin (Erabutoxin-a). Once more, the no effect of the low-affinity R33E-modified alpha-CbT strengthened the specificity of this inhibition. Although alpha7-nAChR antagonists, such as alpha-CbT, are unlikely to be a primary therapy, it may provide lead compounds for the design of clinically useful drugs.

ACTH-producing tumorlets and carcinoids of the lung: clinico-pathologic study of 63 cases and review of the literature.

Adrenocorticotropic hormone (ACTH)-secreting lung carcinoids represent the principal cause of ectopic Cushing syndrome, but the prevalence of ACTH expression and the association between ACTH production and Cushing syndrome in lung carcinoids have scarcely been investigated. In addition, available information on the prognostic meaning of ACTH production is controversial. The aims of this multicentric retrospective study, also including a review of the literature, were to describe the clinico-pathologic features of ACTH-producing lung carcinoids, to assess recurrence and specific survival rates, and to evaluate potential prognostic factors. To identify ACTH production in 254 unselected and radically resected lung carcinoids, we used a double approach including RT-PCR (mRNA encoding for pro-opiomelanocortin) and immunohistochemistry (antibodies against ACTH and ß-endorphin). Sixty-three (24.8%) tumors produced ACTH and 11 of them (17.4%), representing 4.3% of the whole series, were associated with Cushing syndrome. The median follow-up time was 71 months. The 10-year overall and specific survival rates were 88.5% and 98.2%, respectively, with difference neither between functioning and nonfunctioning tumors nor between ACTH-positive and ACTH-negative carcinoids. At univariate analysis, histological type (typical or atypical) and Ki67 index significantly correlated with tumor recurrence. The literature review identified 172 previously reported patients with functioning ACTH-secreting lung carcinoids, and the meta-analysis of survival showed that 92% of them were alive after a mean follow-up time of 50 months. Our results demonstrate that ACTH-producing lung carcinoids are not rare, are not always associated with Cushing syndrome, and do not represent an aggressive variant of lung carcinoid.

Management of locally advanced non-small cell lung cancer in the modern era: A national Italian survey on diagnosis, treatment and multidisciplinary approach.

Concurrent chemotherapy and radiotherapy (cCRT) is considered the standard treatment of locally advanced non-small cell lung cancer (LA-NSCLC). Unfortunately, management is still heterogeneous across different specialists. A multidisciplinary approach is needed in this setting due to recent, promising results obtained by consolidative immunotherapy. The aim of this survey is to assess current LA-NSCLC management in Italy. From January to April 2018, a 15-question survey focusing on diagnostic/therapeutic LA-NSCLC management was sent to 1,478 e-mail addresses that belonged to pneumologists, thoracic surgeons, and radiation and medical oncologists. 421 answers were analyzed: 176 radiation oncologists, 86 medical oncologists, 92 pneumologists, 64 thoracic surgeons and 3 other specialists. More than a half of the respondents had been practicing for >10 years after completing residency training. Some discrepancies were observed in clinical LA-NSCLC management: the lack of a regularly planned multidisciplinary tumor board, the use of upfront surgery in multistation stage IIIA, and territorial diffusion of cCRT in unresectable LA-NSCLC. Our analysis demonstrated good compliance with international guidelines in the diagnostic workup of LA-NSCLC. We observed a relationship between high clinical experience and good clinical practice. A multidisciplinary approach is mandatory for managing LA-NSCLC.

Natural agents targeting the alpha7-nicotinic-receptor in NSCLC: a promising prospective in anti-cancer drug development.

Nicotinic acetylcholine receptors (nAChR) are expressed on normal bronchial epithelial and nonsmall cell lung cancer (NSCLC) cells and are involved in cell growth regulation. Nicotine induced cell proliferation. The purpose of this study was to determine if interruption of autocrine nicotinic cholinergic signaling might inhibit A549 NSCLC cell growth. For this purpose alpha-Cobratoxin (alpha-CbT), a high affinity alpha7-nAChR antagonist was studied. Cell growth decrease was evaluated by Clonogenic and MTT assays. Evidence of apoptosis was identified staining cell with Annexin-V/PI. Characterization of the basal NF-kappaB activity was done using the Trans-AM NF-kappaB assay colorimetric kit. "In vivo" antitumour activity was evaluated in orthotopically transplanted nude mice monitored by In vivo Imaging System technology. alpha-CbT caused concentration-dependent cell growth decrease, mitochondrial apoptosis caspases-9 and 3-dependent, but caspase-2 and p53-independent and down-regulation of basal high levels of activated NF-kappaB. alpha-CbT treatment determines a significant reduction of tumor growth in nude mice orthotopically engrafted with A549-luciferase cells (4.6% of living cells vs. 31% in untreated mice). No sign of toxicity was reported related to treatment. These findings suggest that alpha7-nAChR antagonists namely alpha-CbT may be useful adjuvant for treatment of NSCLC and potentially other cancers.

Novel prognostic groups in thymic epithelial tumors: assessment of risk and therapeutic strategy selection.

PURPOSE: To assess the role of multimodality treatment on patients with thymic epithelial tumors (TETs) (i.e., thymomas and thymic squamous cell carcinoma) and to define the prognostic classes according to the Masaoka and World Health Organization histologic classification systems. METHODS AND MATERIALS: Primary surgery was the mainstay of therapy. Extended thymectomy was performed in all cases. The cases were primarily staged according to the Masaoka system. Adjuvant radiotherapy was given to patients diagnosed with Masaoka Stage II, III, and IVA TET. Adjuvant chemotherapy was administered in selected cases. RESULTS: We reviewed the records of 120 patients with TETs, with a mean follow-up of 13.8 years. Of the 120 patients, 98 (81.6%) received adjuvant radiotherapy. Of these 98 patients, Grade 1-2 pulmonary or esophageal toxicity was acute in 12 (12.2%) and late in 8 (8.2%). The median overall survival was 21.6 years. Of the 120 patients, 106 were rediagnosed and reclassified according to the World Health Organization system, and the survival rate was correlated with it. Three different prognostic classes were defined: favorable, Masaoka Stage I and histologic grade A, AB, B1, B2 or Masaoka Stage II and histologic grade A, AB, B1; unfavorable, Stage IV disease or histologic grade C or Stage III and histologic grade B3; intermediate, all other combinations. The 10- and 20-year survival rate was 95% and 81% for the favorable group, 90% and 65% for the intermediate group, and 50% and 0% for the unfavorable group, respectively. Local recurrence, distant recurrence, and tumor-related deaths were also evaluated. CONCLUSION: The analysis of our experience singled out three novel prognostic classes and the assessment of risk identified treatment selection criteria.

Analysis of risk factors in the development of bronchopleural fistula after major anatomic lung resection: experience of a single centre.

BACKGROUND: The bronchopleural fistula (BPF) is a rare but potentially fatal complication of major thoracic surgery. The purpose of this work is to investigate the risk factors associated with the development of fistulas after lobectomy and pneumonectomy. METHODS: We retrospectively reviewed the records of 835 patients who underwent major anatomic lung resection at our centre from January 2003 to December 2013. Of these, 49 underwent pneumonectomy (P group) and 786 lobectomy (L group). RESULTS: A total of 18 patients (2.6%) developed a BPF in the postoperative period, of which there were 11 in the L group (1.3%) and seven in the P group (14.28%). The 30-day mortality was 0.05% (one patient after right pneumonectomy). In the L group, three patients developed a fistula after a left lobectomy and eight after a right one, of which four developed after bilobectomy. Univariate analysis showed that induction therapy, lower lobectomy, manual suture of the bronchus, 'not covered' bronchial stump, empyema, postoperative anaemia and pulmonary infections and mechanical ventilation >24 h are associated with the development of fistulas after lobectomy. Multivariate analysis confirmed that induction therapy, manual closure of the bronchus, postoperative pulmonary infections and anaemia are the main risk factors involved in our series. In the P group, four patients developed a fistula after a right pneumonectomy and three after a left one. Postoperative empyema and pulmonary infections, mechanical ventilation >24 h and female gender emerged as the main risk factors on univariate analysis, while on multivariate analysis, only the female gender presented a trend towards significance. CONCLUSIONS: Postoperative pulmonary infections, empyema and mechanical ventilation >24 h are strongly associated with the development of BPFs after both pneumonectomy and lobectomy in our series.

Current Practices in the Management of Pulmonary Ground-Glass Opacities: A Survey of SICT Members.

BACKGROUND: Several gray areas and controversies exist concerning the management of pulmonary ground-glass opacities (GGOs), and there is a lack of consensus among clinicians on this topic. One of the main aims of the Italian Society of Thoracic Surgery is to promote education and research, so we decided to perform a survey on this topic to estimate current trends in practice in a large sample of thoracic surgeons. METHODS: A total of 160 thoracic surgeons responded, namely, completed our questionnaire (response rate, 53%; 160 of 302). The survey was composed of 36 questions divided into six subsections: (1) demographic characteristics of the respondents; (2) terminology and taxonomy; (3) radiologic and radiometabolic evaluation; (4) diagnostic approach and indications for surgery; (5) surgical management; and (6) radiologic surveillance. RESULTS: We observed some divergence of opinion regarding the definition of mixed GGOs, the role of 18F fluorodeoxyglucose positron emission tomography and computed tomography scans, indications for nonsurgical biopsy, intraoperative techniques for localizing GGOs, indications for surgery, extension of lung resection and lymph node dissection according to the radiologic scenario, use of intraoperative frozen section analysis, and radiologic surveillance of pure GGOs. CONCLUSIONS: This topic warrants more investigation in the future. An upcoming consensus conference of Italian Society of Thoracic Surgery experts (also open to experts in other specialties) could provide updated indications for GGO management based on the literature, expert opinions, and the results of the present survey.

Post-operative respiratory rehabilitation after lung resection for non-small cell lung cancer.

BACKGROUND: To investigate the efficacy of an inpatient Pulmonary Rehabilitation program (i-PR) after lung resection (LR) for Non-Small Cell Lung Cancer (NSCLC). PATIENTS AND METHODS: From January 2001 to December 2004, 211 out of 618 patients who underwent LR were considered eligible for i-PR. Twenty-five patients accepted the i-PR and were included in the case group. The remaining 186 who refused i-PR were taken as controls. RESULTS: The two study groups were comparable for demographic and surgical characteristics, as well as for the peri-operative morbidity (4% in the controls and 3% among patients undergoing i-PR). Most functional parameters among treated patients were improved when baseline versus 1-month figures were compared, despite the strong correction for multiple comparison limited statistical significance to Borg scale dyspnoea on exertion - median - (2 versus 0; p<0.01); pH (7.45 versus 7.42; p<0.05); timed walk-6MWD (297.8m versus 393.4m; p<0.01) and Hb saturation during 6MWD (95.4% versus 93.9%; p<0.05). On the contrary, global function in the group of controls was homogeneously decreased (FEV(1) and PEF p<0.01) after operation. The comparison of treated and untreated patients 1 month after the operation did not show any significant difference in terms of FEV(1), FVC, PEF, distance, Hb saturation, and KCO that instead were homogeneously and significantly worse at baseline (before the surgical operation) in the case group. CONCLUSIONS: Respiratory Function and exercise capacity significantly improve following a post-operative 4-week i-PR in lung resected patients. i-PR could be regarded as a component of the management of patients who have undergone LR for cancer.

[Thymectomy in myasthenia gravis: video-assisted procedures]. / La chirurgia della miastenia: procedure videoassistite.

OBJECTIVE: We describe the technique, the benefits and the drawbacks of an original video-assisted thymectomy (VAT), performed through an inframammary cosmetic incision and median sternotomy in myasthenia gravis (MG) patients. This procedure is clinically valuable and cosmetically satisfactory so as to be very well accepted by patients, especially by young women. Minimal-access thymectomy has become increasingly popular as surgical treatment for patients with nonthymomatous myasthenia gravis because of its comparable efficacy, safety, and lesser degree of tissue trauma with conventional open surgery. METHODS: We report a review/interview of 180 MG patients treated between 1993 and 2005. According to Myasthenia Gravis Foundation of America (MGFA), complete stable remission (CSR) and pharmacologic remission (PR) were calculated at the end of a minimal period of 12 months. RESULTS: A clinical remission was obtained in 41.1% (CR 27.8%, PR 13.3%), who had been followed for at least 12 months from surgery. 95% of these patients judged their cosmetic results to be excellent or good. CONCLUSIONS: Thymectomy in MG video-assisted infra-mammary cosmetic incision has shown to be a useful surgical approach as demonstrated by the good functional and very good aesthetic results, associated with a very low morbidity and no mortality.

Recurrence of thymoma: re-operation and outcome.

INTRODUCTION: The treatment of recurrent thymomas remains still controversial. PATIENTS AND METHODS: From 1972 to 2006, 265 (114 males and 118 females ) patients with thymoma underwent surgery at Catholic University of Sacred Heart. Twenty of these 265 patients developed a recurrence of the initial thymoma, and they represent the population of the present study. RESULTS: One patient died of sudden death related to respiratory failure. The overall morbidity rate was 33% and the morbidity rate among myasthenic patients was 60%. 10 patients died during the follow-up; 2 of unrelated diseases, 2 of myasthenia gravis, and 6 of tumor growth. The overall actuarial survival rates were 43% and 37% at 5 and 10 years, respectively. Recurrences never appeared in patients with I stage of Masaoka and in type A and AB. CONCLUSIONS: Considering the particular spread of thymoma and the encouraging results of the aggressive surgical approach, re-resection should be recommended in respectable recurrent thymomas.

[Malignant pleural effusion]. / Versamenti pleurici maligni.

Malignant pleural effusion is a frequent condition with important prognostic repercussions on duration and quality of life. The neoplasms that more frequently determine pleural effusion are lung and breast cancer and pleural mesothelioma. Lymphomas, tumours of the genitourinary tract and gastrointestinal tract as a group account for a further 25%. Surgical treatment has palliative purposes and finalized to reduction symptoms and to improve quality of life. More frequent clinical presentation is a massive pleural efusion associated to dyspnoea and cough. Pleural aspiration is the first choice treatment but the recurrence rate equals to 100% within 1 month. Repeated pleural aspirations are indicated in those patients that have lower expectation of life. The recurrence risk can be reduced with chemical pleurodesis that allows the adhesion between pleural surfaces. Pleurodesis can be realized by the instillation of several substances by the tube of drainage (slurry) or during thoracoscopy (poudrage). Video Assisted Thoracoscopy (VATS) is a safe and well tolerated technique, a complication rate is lower than 0.5%, VATS can be used to obtain diagnosis and to treat patients with malignant pleural effusion and better expectation of life.

Gene expression signature for angiogenic and nonangiogenic non-small-cell lung cancer.

Angiogenesis is regarded as essential for tumour growth. However, we have demonstrated that some other aggressive non-small-cell lung carcinomas (n-SCLC) do not have angiogenesis. In this study, using cDNA microarray analysis, we demonstrate that angiogenic and nonangiogenic tumour types can be distinguished by their gene expression profiles. Tissue samples from 42 n-SCLC patients were obtained with consent. In all, 12 tumours were nonangiogenic and 30 angiogenic. The two groups were matched by age, sex, smoking and tumour stage. Total RNAs were extracted followed by microarray hybridization and image scan procedure. Data were analysed using GeneSpring 5.1 software. A total of 62 genes were found to be able to separate angiogenic from nonangiogenic tumours. Nonangiogenic tumours have higher levels of genes concerned with mitochondrial metabolism, mRNA transcription, protein synthesis and the cell cycle. Angiogenic tumours have higher levels of genes coding for membrane vesicles, integrins, remodelling, angiogenesis and apoptosis. These results further support our first finding that nonangiogenic lung tumours are fast-growing tumours filling the alveoli in the absence of vascular remodelling. We raise the hypothesis that in nonangiogenic tumours, hypoxia leads to a higher activation of the mitochondrial respiratory chain, which allows tumour growth without triggering angiogenesis.