Nerve-Sparing Surgery in Advanced Stage Thymomas.

BACKGROUND: Phrenic nerve infiltration has been described in as many as 33% of advanced thymomas; en bloc resection causes diaphragmatic loss of function, with detrimental effects on pulmonary function. We report the outcomes of selected patients operated on for invasive thymoma with a nerve-sparing technique. METHODS: From 1990 to 2015 we used nerve-sparing surgery with the intention to treat all patients with advanced stage thymomas without preoperative evidence of hemidiaphragmatic palsy, but with macroscopic evidence of phrenic nerve involvement. All patients underwent adjuvant radiotherapy (45 to 60 Gy) with or without chemotherapy. Long-term outcomes and the pattern of recurrence were retrospectively analyzed. RESULTS: Among 140 patients with stage III and IVa operated on during the study period, 19 women and 18 men with a median age of 52 years received a nerve-sparing resection. Myasthenia gravis was associated in 25 cases. In 12 patients, phrenic palsy was observed postoperatively, and eventually 4 of them recovered. Recurrence was found in 10 patients (7 stage IVa, 3 stage III) requiring additional therapies. Three patients died of cancer-related causes, with an overall survival of 265.4 months and a disease-free survival of 233.2 months. CONCLUSIONS: Phrenic nerve preservation in cases of invasive thymomas is feasible and may warrant an acceptable local control of disease, if associated with radiotherapy. According to these results, this technique could be proposed to all patients with invasive thymoma, especially in those affected by severe comorbidities or with a poor performance status.

Is left upper lobectomy always worthwhile for early stage lung cancer? A comparison between left upper lobectomy, trisegmentectomy, and lingulectomy.

BACKGROUND AND OBJECTIVES: Lobectomy is the gold standard treatment for resectable Non-Small Cell Lung Cancer (NSCLC). We compared oncological outcomes of patients undergoing a "multi-segmentectomy" (trisegmentectomy or lingulectomy) and left upper lobectomy for early stage (T1-2, N0) NSCLC of the left upper lobe. METHODS: We retrospectively analyzed all patients with pathological early stage (T1-T2 N0) NSCLC located in left upper lobe who underwent a lobectomy, a trisegmentectomy, or a lingulectomy between 2006 and 2013, focusing on surgical and oncological outcomes. RESULTS: Among 159 patients, 105 patients underwent a lobectomy and 54 patients a multi-segmentectomy (33 lingulectomy and 21 trisegmentectomy). Actuarial mean Overall Survival was 87 months (95%CI 79-95) and 89 months (95%CI 76-101) for lobectomies and multi-segmentectomies, respectively (P-value: 0.895), while actuarial mean Disease Free Interval was 91 months (95%CI 82-100) and 96 months (95%CI 84-108) respectively (P-value: 0.565). We did not observe any difference in terms of local recurrence rate between the two groups (P = 0.337). CONCLUSIONS: Lingulectomy and trisegmentectomy lead to similar oncological outcomes compared to left upper lobectomy for T1 and T2 N0 NSCLC, and they could be used as an alternative to lobectomy even in patients with a good pulmonary function.

Symmetry structure in discrete models of biochemical systems: natural subsystems and the weak control hierarchy in a new model of computation driven by interactions.

Interaction computing is inspired by the observation that cell metabolic/regulatory systems construct order dynamically, through constrained interactions between their components and based on a wide range of possible inputs and environmental conditions. The goals of this work are to (i) identify and understand mathematically the natural subsystems and hierarchical relations in natural systems enabling this and (ii) use the resulting insights to define a new model of computation based on interactions that is useful for both biology and computation. The dynamical characteristics of the cellular pathways studied in systems biology relate, mathematically, to the computational characteristics of automata derived from them, and their internal symmetry structures to computational power. Finite discrete automata models of biological systems such as the lac operon, the Krebs cycle and p53-mdm2 genetic regulation constructed from systems biology models have canonically associated algebraic structures (their transformation semigroups). These contain permutation groups (local substructures exhibiting symmetry) that correspond to 'pools of reversibility'. These natural subsystems are related to one another in a hierarchical manner by the notion of 'weak control'. We present natural subsystems arising from several biological examples and their weak control hierarchies in detail. Finite simple non-Abelian groups are found in biological examples and can be harnessed to realize finitary universal computation. This allows ensembles of cells to achieve any desired finitary computational transformation, depending on external inputs, via suitably constrained interactions. Based on this, interaction machines that grow and change their structure recursively are introduced and applied, providing a natural model of computation driven by interactions.

Wedge resection and radiofrequency ablation for stage I nonsmall cell lung cancer.

The main aim of this study was to compare radiofrequency ablation (RFA) and wedge resection in terms of disease recurrence and survival, as intent-to-treat therapy for stage I nonsmall cell lung cancer (NSCLC) in marginal or non-surgical candidates. 121 high-risk patients, treated for stage I NSCLC with wedge resection (n=59) or RFA (n=62) in a 7-year period, were analysed. Age, sex, comorbidity score, performance status, forced expiratory volume in 1 s and forced vital capacity values, body mass index, T-stage and histology were evaluated as possible risk factors affecting disease recurrence and survival. At a median follow-up of 36 and 42 months for wedge resection and for RFA (p=0.232), local recurrence rate was 2 and 23%, respectively (p=0.002). The 1-, 2- and 5-year overall survival (disease-free interval) rates were 100% (96%), 96% (90%) and 52% (76%) for wedge resection, and 93% (87%), 72% (63%), and 35% (55%) for RFA (p=0.044 and p=0.01, respectively). None of the analysed parameters was found to be risk factor for disease recurrence and survival, except stage T2, which significantly affected disease-recurrence, overall and cancer-related survival and disease-free interval in the RFA group. Whenever possible, surgical resection, even if limited, should be preferred due to its higher disease control and survival rates. RFA can be considered a valid option for inoperable patients, especially for those with stage T1N0.

Robotic lobectomy for lung cancer: evolution in technique and technology.

OBJECTIVES: The aim of this study was to analyse the results of robotic lobectomy for lung cancer. The evolution of technique and technology was evaluated. METHODS: During the period 2004-12, all patients who underwent robotic lobectomy for clinical early-stage lung cancer were retrospectively reviewed. The patients were divided into two groups. Group 1 included 69 patients operated by the first generation of surgical robotic system. Group 2 included 160 patients treated with the latest generation of surgical robotic system. Age, gender, comorbidities, operative time, docking time, conversion rate, morbidity, mortality and length of postoperative stay were compared in both groups. RESULTS: The two groups were homogeneous in terms of age, gender and comorbidities. Histopathological analysis showed 41 and 107 adenocarcinomas, 27 and 37 squamous cell carcinomas, 1 and 7 large cell carcinomas, in Groups 1 and 2, respectively, and 5 sarcomatoid carcinomas and 4 carcinoids in Group 2. The pathological stage for Group 1 was Stage I (48 cases), Stage II (17 cases) and Stage III (4 cases). For Group 2, Stage I was found in 115 cases, Stage II in 30 cases and Stage III in 15 cases. The mean operative time was 237 (standard deviation (SD) + 66.9) and 172 (SD ± 39.6) min for Groups 1 and 2 (P = 0.002), respectively. The conversion rates were, respectively, 10.1 and 5.6% (P = 0.21), mortality rates 1.4 and 0% (P = 0.30) and morbidity rates 22 and 15% (P = 0.12). The mean length of postoperative stay was 4.4 (SD ± 3.1) and 3.8 days (SD ± 2.2) (P = 0.26), respectively. CONCLUSIONS: This study suggests a positive trend in the outcomes for patients who underwent the upgraded robotic system surgery compared with those treated by the standard system.

Exploring the concept of interaction computing through the discrete algebraic analysis of the Belousov-Zhabotinsky reaction.

Interaction computing (IC) aims to map the properties of integrable low-dimensional non-linear dynamical systems to the discrete domain of finite-state automata in an attempt to reproduce in software the self-organizing and dynamically stable properties of sub-cellular biochemical systems. As the work reported in this paper is still at the early stages of theory development it focuses on the analysis of a particularly simple chemical oscillator, the Belousov-Zhabotinsky (BZ) reaction. After retracing the rationale for IC developed over the past several years from the physical, biological, mathematical, and computer science points of view, the paper presents an elementary discussion of the Krohn-Rhodes decomposition of finite-state automata, including the holonomy decomposition of a simple automaton, and of its interpretation as an abstract positional number system. The method is then applied to the analysis of the algebraic properties of discrete finite-state automata derived from a simplified Petri net model of the BZ reaction. In the simplest possible and symmetrical case the corresponding automaton is, not surprisingly, found to contain exclusively cyclic groups. In a second, asymmetrical case, the decomposition is much more complex and includes five different simple non-abelian groups whose potential relevance arises from their ability to encode functionally complete algebras. The possible computational relevance of these findings is discussed and possible conclusions are drawn.

Long-term results of radiofrequency ablation treatment of stage I non-small cell lung cancer: a prospective intention-to-treat study.

INTRODUCTION: About one-fifth of patients with resectable non-small cell lung cancer (NSCLC) are unsuitable for surgical treatment. Radiofrequency ablation offers an alternative minimally invasive option. We report the result of an intention-to-treat study with long-term follow-up. METHODS: From 2001 to 2009, we performed 80 percutaneous radiofrequency ablations of 59 stage I NSCLC in 57 inoperable patients. Two patients were treated for two separate lesions. The study group consisted of 45 males and 12 females, with mean age of 74 years (range, 40-88 years). All patients had pathological evidence of NSCLC, which was in stage IA in 44 cases and in stage IB in the other 15 cases. The mean size of the lesions was 2.6 cm (range, 1.1-5 cm). Fourteen lesions were retreated up to five times. The procedure was always performed under local anesthesia and conscious sedation. Most of the procedures were performed under computed tomography guidance, with nine under ultrasonography guidance. RESULTS: In all cases, the procedure was technically successful. No mortality was recorded, and major morbidity consisted of four cases of pneumothorax requiring pleural drainage. At a mean follow-up of 47 months, the complete response rate was 59.3% (stage Ia 65.9%, stage Ib 40%, p = 0.01), with a mean local recurrence interval of 25.9 months. Median overall survival and cancer-specific survival were 33.4 and 41.4 months, respectively. Cancer-specific actuarial survival was 89% at 1 year, 59% at 3 years, and 40% at 5 years. CONCLUSIONS: Radiofrequency ablation treatment of early-stage NSCLC seems to be a effective minimally invasive therapy even in the long-term period, particularly for stage Ia tumors.

Surgical treatment of non-small cell lung cancer in octogenarians.

As the European population ages, surgeons are regularly faced with octogenarians with resectable early stage non-small cell lung cancer (NSCLC). We compared our experience with those reported in the literature to comprehend the feasibility, outcomes and lessons learned regarding surgical treatment. We reviewed octogenarians who underwent lung resection for NSCLC in the past nine years in our Department. The purpose of this paper is to retrospectively analyse postoperative surgical and oncological outcomes of our series, trying to find possible correlations between mortality, morbidity, survival and preoperative oncological and functional assessment, surgical approach and extent of resection. Eighty-two patients (M/F = 63/19), with a mean age 81.0 years (range 80-87 years) underwent lung resection for NSCLC: 63 lobectomies, one inferior bilobectomy, three segmentectomies, and 15 wedge resections. There were two perioperative deaths (2.4%). The overall complication rate was 30.0%, with a major complication rate of 2.5%. Actuarial cancer-related survival rates at one, three and five years were 90%, 44% and 36%, respectively, with a statistically-significant correlation with pathological stage. Octogenarians may benefit from surgical treatment of NSCLC with an acceptable morbidity and mortality rate, if an accurate preoperative selection is pursued.

Sleeve and wedge parenchyma-sparing bronchial resections in low-grade neoplasms of the bronchial airway.

OBJECTIVE: Sleeve and wedge bronchial resections without parenchymal resection may represent a surgical option in selected cases of low-grade neoplasms of the airway. We reviewed our experience analyzing the indications, the operative technique, and the results of such operations. METHODS: From 1980 to 2006, we performed 248 bronchoplastic procedures, and 26 of those were bronchoplastic procedures without parenchymal resection for low-grade neoplasms of the airway. There were 17 men and 9 women with a mean age of 49.4 years (range 19-74 years). All patients underwent a preoperative bronchoscopic study, which gave indication for such a procedure, and an intraoperative bronchoscopic examination confirming the feasibility and the good quality of the bronchial suture. The bronchial resection involved the trachea and the carina (n = 5), the main bronchi (n = 7), the intermediate bronchus (n = 2), the bronchial corner (n = 6), and the lobar bronchus (n = 6). RESULTS: The resection margins were always tumor free. There was no operative mortality. The mean hospital stay was 6.7 days (range 4-16 days). One minimal dehiscence and no stenosis of the anastomosis were observed. In 1 case we experienced a granulation that required an endoscopic treatment. The histologic type was carcinoid (n = 18), mucoepidermoid (n = 2), adenoid cystic (n = 1), chondroma (n = 2), hamartoma (n = 1), melanoma endobronchial metastasis (n = 1), and glomic tumor (n = 1). The mean follow-up was 134 months and no local relapse occurred. CONCLUSION: Bronchoplastic procedures without resection of the lung parenchyma are a suitable and fascinating technique for selected cases of low-grade endobronchial neoplasms.

Four-modality therapy in malignant pleural mesothelioma: a phase II study.

BACKGROUND: Treatment approaches in malignant pleural mesothelioma (MPM) patients range from mere palliation to aggressive anticancer therapy, and there is currently no consensus on the optimal therapeutic strategy. In 1999, we began a phase II study to investigate four-modality treatment of advanced stage MPM. METHODS: From 1999 to 2004, 49 patients with International Mesothelioma Interest Group stage II-III MPM underwent four-modality treatment with intrapleural preoperative interleukin-2 (18 x 10(6) UI/day for 3 days), pleurectomy/decortication, intrapleural postoperative epidoxorubicin (25 mg/m2 for 3 days), interleukin-2 (18 x 10(6) UI/day for 3 days), adjuvant radiotherapy (30 Gy), systemic chemotherapy (cisplatin 80 mg/m2 day 1, gemcitabine 1250 mg/m2 days 1 and 8 for up to six courses) and long-term subcutaneous interleukin-2 (3 x 10(6) UI/day on 3 days per week). RESULTS: Patients included 41 men and eight women with a median age of 61 years (range, 41-77). All patients were diagnosed with MPM by thoracoscopy before inclusion. There was no postoperative mortality. Postoperative morbidity included bleeding (n = 1) and arrhythmias (n = 3). After a median follow-up of 59 months (range, 14-81), 13 patients are still alive and the median actuarial survival is 26 months (31 and 21 months for stages II and III, respectively). The 2- and 5-year actuarial survival rates were 60.2% and 23.3%, respectively. Baseline Eastern Cooperative Oncology Group performance status significantly influenced survival time (p = 0.02). CONCLUSION: The four-modality treatment that we adopted for advanced-stage MPM was feasible, well tolerated by most of the patients, and produced a favorable median survival. This treatment approach warrants further investigation.

A phase II study of intrapleural immuno-chemotherapy, pleurectomy/decortication, radiotherapy, systemic chemotherapy and long-term sub-cutaneous IL-2 in stage II-III malignant pleural mesothelioma.

OBJECTIVE: From therapeutic nihilism to extremely aggressive management, there is a wide range of possibilities in the treatment of malignant pleural mesothelioma (MPM). Unfortunately, there is little evidence as regards the best treatment to offer to the MPM patients. In 1999, we started a phase II study based on the multimodality treatment of stage II-III MPM, the results of which have been analysed and reported. METHODS: From 1999 to 2004, 49 patients with IMIG stage II-III MPM underwent a multimodality treatment including: intrapleural pre-operative interleukin 2 (IL-2, 18x10(6) UI/day per 3 days), pleurectomy/decortication, intrapleural post-operative epidoxorubicin (25mg/m2 per 3 days), IL-2 (18x10(6) UI/day per 3 days), adjuvant radiotherapy (30Gy), systemic chemotherapy (cisplatin 80 mg/m2 day 1, gemcitabine 1250 mg/m2 day 1 and 8 up to 6 courses) and long-term sub-cutaneous IL-2 (3x10(6) UI/day 3 days per week). RESULTS: There were 41 males and 8 females with a median age of 61 years (range 41-77). All the patients had a diagnosis of MPM by thoracoscopy before inclusion. We did not experience any post-operative mortality. The histology was: 39 epitheliomorf, 6 bifasic and 4 sarcomatous. According to the IMIG the post-operative staging was III in 40 cases and II in 9 cases. With a median follow-up of 59 months (range 14-81) 13 patients are still alive and the median actuarial survival is 26 months (31 and 21 months for stage II and III, respectively). Only the Performance Status at the diagnosis affected survival significantly. CONCLUSIONS: The multimodality treatment we adopted for stage II-III MPM was feasible, well tolerated by most of the patients and produced a favourable outcome. New targeted therapies are awaited for further improvements in the treatment of this disease.

Percutaneous radiofrequency ablation of lung tumours: results in the mid-term.

INTRODUCTION: Radiofrequency ablation (RFA) of lung tumours has recently received much attention for the promising results achieved. Herein, we report the 5 years experience of a single referral centre in Europe, with particular reference to the mid-term results. METHODS: Between October 2001 and June 2005, we performed 88 RFAs of lung tumours, 9 of which were followed by surgical resection. The remaining 79 RFAs, the object of this paper, were performed to treat 64 lesions in 54 patients: 39 males and 15 females with a mean age of 71.7 years (range of 51-89). All patients had clinical or pathological evidence of the neoplastic lesion, which was non-small cell lung cancer (NSCLC) in 40 cases and a metastasis in 24 cases. The mean size of the lesions was 2.4 cm (range of 1-5). Ten lesions were re-treated from one to as many as four times. The procedure was always performed under local anaesthesia and conscious sedation. A generator of RF with max power output of 200W was utilised together with a needle with nine deployable electrodes, to achieve a target temperature of 90 degrees C that was maintained for 15-27 min according to the size of the lesions. RESULTS: In all cases, except two, the procedure was technically successful. Morbidity consisted in 10 cases (12.7%) of partial pneumothorax, 1 haematoma of the chest wall and 1 pleural effusion. At a mean follow-up of 23.7 months (range of 6-50) we recorded a 61.9% of complete responses, with a higher rate in the metastatic lesions (70.8%) and in those smaller than 3 cm (69.7%). Mean (median) overall survival and local progression-free interval were 17.3 (28.9) months and 12.9 (24.1) months, respectively. CONCLUSIONS: Efficacy of RFA in the mid-term seems to settle at a promising level, with better results for metastatic lesions and, above all, for lesions smaller than 3 cm. Notwithstanding these encouraging results, RFA remains an alternative local therapy only when surgery cannot be performed, especially in NSCLC.

Neoadjuvant chemotherapy for stage III and IVA thymomas: a single-institution experience with a long follow-up.

BACKGROUND: Since 1989 we have enrolled patients with clinical-radiological stage III-IVA thymomas, independent of the surgeon's judgment of resectability, into a prospective study of neoadjuvant chemotherapy-surgery and postoperative radiotherapy. In this article, we review our long-term experience of neoadjuvant chemotherapy of advanced stage (III-IVA) thymomas. METHODS: From 1989 to 2004, 30 patients with Masaoka stage III and IVA thymomas underwent neoadjuvant chemotherapy, surgery, and postoperative radiotherapy. The neoadjuvant and adjuvant chemotherapy consisted of three courses of cisplatin, epidoxorubicin, and etoposide every 3 weeks. Adjuvant radiotherapy consisted of 45 Gy for complete resections or 60 Gy for incomplete resections. RESULTS: The preoperative diagnosis of invasive thymomas was obtained for 16 patients: five by mediastinotomy, seven by video-assisted thoracic surgery, and four by fine needle aspiration. For 14 patients, no histological diagnosis was available, but a thymus-related syndrome was present in all.Twenty-seven patients are still alive (25 disease-free) and three have died (one disease-free). The 10-year survival rates were 85.7% and 76.1% for stage III and IVA thymomas, respectively (difference not significant). Only the World Health Organization pathological diagnosis significantly affected the survival, with type B3 having a worse prognosis than type AB, B1, and B2 thymomas (p = 0.02). CONCLUSION: The multimodality treatment of stage III and IVA thymomas by means of neoadjuvant chemotherapy provides good long-term outcomes in both stages of the disease.

Metachronous adrenal masses in resected non-small cell lung cancer patients: therapeutic implications of laparoscopic adrenalectomy.

OBJECTIVE: In literature only few reports focused on the resection of solitary adrenal gland metastasis in patients operated on for non-small cell lung cancer (NSCLC). We report our experience on laparoscopic adrenalectomy for suspected or confirmed metachronous solitary adrenal metastasis from NSCLC and discuss its therapeutic role. METHODS: From June 1993 to March 2003, 14 patients (pts), who had been undergone lung resection for NSCLC, with suspected or confirmed solitary adrenal gland metastasis at the follow-up, underwent 15 laparoscopic adrenalectomy (in 1 patient it was bilateral). All the patients had enlarged adrenal glands at the abdominal ultrasound or CT. All but 2 pts underwent at least 1 adrenal fine needle aspiration. All the patients underwent a careful staging to exclude other sites of metastasis. The adrenal gland was in 6 cases the right, in 9 cases the left. RESULTS: In 7 cases we had a preoperative cytological diagnosis of metastasis. In 1 case adrenalectomy was not performed because of infiltration of vena cava and in 1 case it was necessary to perform a small laparotomy because of bleeding. The pathologic examination confirmed in 11 cases a NSCLC metastasis while in 4 cases it was a cortical adenoma. Regarding the 10 patients with NSCLC metastases, 3 are still alive and well at 37-80 months from the lung resection. One patient (who underwent bilateral adrenalectomy) is still alive at 44 months with local relapse. Two patients died 5 and 6 months after the adrenalectomy for other causes, 1 died at 14 months for local and systemic relapse and the remaining 3 patients died at 12 to 38 months for systemic relapse. CONCLUSIONS: Laparoscopic adrenalectomy in patients resected for NSCLC is a safe mini-invasive procedure. Even though this series is still too small, laparoscopic adrenalectomy should be considered an effective therapeutic tool in case of progressive adrenal gland enlargement, also with negative cytological examinations. A bigger series and other institution experiences will clarify its oncological value.