The Incidence of Winged Scapula after Thoracic Cancer Surgery: A Prospective Cohort Study.

BACKGROUND: Lung cancer is the leading cause of cancer-related deaths, and surgery is still the first treatment of choice in early and locally advanced cases. One of the iatrogenic complications is the serratus anterior palsy, which could lead to a winged scapula (WS). Unfortunately, the incidence of this deficit in thoracic surgery is unclear. Our primary aim was to determine the incidence of WS in lung cancer patients in a single-center experience. METHODS: We conducted a retrospective analysis of prospectively collected data with patients eligible for oncological thoracic surgery from March 2013 until January 2014. A physical evaluation of the WS was performed pre- and postoperatively, at the discharge and after 1 year of follow-up. RESULTS: A total of 485 patients were evaluated; 135 (27.8%) showed WS. Longer operative time (p < 0.0001), type of surgery (p < 0.0001), lymphadenectomy (p < 0.0001), and neoadjuvant treatment prior surgery (p = 0.0005) were significantly related to the WS injury. Multivariable analysis showed that type of surgery was significantly associated with WS (p < 0.0001). After 1 year, 41.6% still had WS. CONCLUSION: The incidence of WS was similar to the literature. As WS incidence is underdiagnosed, assessment and correct education about possible deficits or impairments should be improved. Moreover, when a minimally invasive approach is not planned, it is a good clinical practice to discuss surgical strategies with surgeons to reduce this deficit.

Multi-omics integrative modelling for stereotactic body radiotherapy in early-stage non-small cell lung cancer: clinical trial protocol of the MONDRIAN study.

BACKGROUND: Currently, main treatment strategies for early-stage non-small cell lung cancer (ES-NSCLC) disease are surgery or stereotactic body radiation therapy (SBRT), with successful local control rates for both approaches. However, regional and distant failure remain critical in SBRT, and it is paramount to identify predictive factors of response to identify high-risk patients who may benefit from more aggressive approaches. The main endpoint of the MONDRIAN trial is to identify multi-omic biomarkers of SBRT response integrating information from the individual fields of radiomics, genomics and proteomics. METHODS: MONDRIAN is a prospective observational explorative cohort clinical study, with a data-driven, bottom-up approach. It is expected to enroll 100 ES-NSCLC SBRT candidates treated at an Italian tertiary cancer center with well-recognized expertise in SBRT and thoracic surgery. To identify predictors specific to SBRT, MONDRIAN will include data from 200 patients treated with surgery, in a 1:2 ratio, with comparable clinical characteristics. The project will have an overall expected duration of 60 months, and will be structured into five main tasks: (i) Clinical Study; (ii) Imaging/ Radiomic Study, (iii) Gene Expression Study, (iv) Proteomic Study, (v) Integrative Model Building. DISCUSSION: Thanks to its multi-disciplinary nature, MONDRIAN is expected to provide the opportunity to characterize ES-NSCLC from a multi-omic perspective, with a Radiation Oncology-oriented focus. Other than contributing to a mechanistic understanding of the disease, the study will assist the identification of high-risk patients in a largely unexplored clinical setting. Ultimately, this would orient further clinical research efforts on the combination of SBRT and systemic treatments, such as immunotherapy, with the perspective of improving oncological outcomes in this subset of patients. TRIAL REGISTRATION: The study was prospectively registered at clinicaltrials.gov (NCT05974475).

A prognostic score from a multicentric retrospective analysis of patients affected by sarcoma with metachronous lung metastases undergoing metastasectomy.

BACKGROUND: Despite the lack of evidence-based on prospective randomized studies, surgery has become the cornerstone of the treatment in patients with pulmonary oligometastatic sarcomas. Our study aimed to construct a composite prognostic score for metachronous oligometastatic sarcoma patients. METHODS: A retrospective analysis was performed on data patients who underwent radical surgery for metachronous metastases in six research institutes from January 2010 to December 2018. The log-hazard ratio (HR) obtained from the Cox model was used to derive weighting factors for a continuous prognostic index designed to identify differential outcome risks. RESULTS: A total of 251 patients were enrolled in the study. In the multivariate analysis, a longer disease-free interval (DFI) and a lower neutrophil-to-lymphocytes ratio (NLR) were predictive of a better overall survival (OS) and disease-free survival (DFS). A prognostic score was developed based on DFI and NLR data, identifying 2 risk class groups for DFS (3-years DFS 20.2% for the high-risk group [HRG]and 46.4% for the low-risk group [LRG] [<0.0001]) and 3 risk groups for OS (3 years OS 53.9% for the HRG vs. 76.9% for the intermediate-risk group and 100% of the LRG (p < 0.0001)). CONCLUSION: The proposed prognostic score effectively predicts outcomes for patients with lung metachronous oligo-metastases from the surgically treated sarcoma.

Multimodal therapy for synchronous bone oligometastatic NSCLC: The role of surgery.

OBJECTIVES: The study aimed to assess the feasibility of radical surgical treatment for selected bone-oligometastatic non-small cell lung cancer (NSCLC) patients and to identify prognostic factors associated with survival. MATERIALS AND METHODS: The clinical records of 27 patients with bone synchronous oligometastatic NSCLC were retrospectively analyzed. RESULTS: Thirteen (48.1%) bone metastases were treated by surgery and 14 (51.9%) by local radiotherapy. Eighteen (66.7%) patients underwent induction chemotherapy before lung surgery, and 3 (11.1%) concurrent radiotherapy. Pulmonary surgery was a major lung resection in 23 (85.2%) cases. Intraoperative and 30-days mortality was null. Only one major (ARDS) and 10 (37.04%) mild complications (like air leakage, arrhythmia, and mucus retention) were recorded. 1-year and 5-years OS from the diagnosis and 1-year, 3- years disease-free survival (DFS) were 96%, 38%, and 66%, 30%, respectively. After stepwise Cox regression analysis, local recurrence (p = 0.05) and metachronous metastases (p = 0.04) maintained their independent prognostic value as overall survival negative determinants. Nodal upstaging (p = 0.04) and nonsurgical treatment of bone lesion (p = 0.03) turned out to be independent risk factors for shorter DFS; the vertebral localization of bone metastases showed only a remarkable trend towards significance (p = 0.06) as a risk factor for a worse DFS. CONCLUSIONS: In selected patients, surgical treatment of primary NSCLC and bone synchronous metastasis seems to be safe and feasible and rewarding survivals may be expected.

The Weekday Effect on Morbidity of Lung Cancer Surgery: A Real-World Analysis.

BACKGROUND: Many authors have investigated the possible adverse effects among patients who underwent elective surgery on Friday when compared with patients operated earlier in the week. Nonetheless, the weekday effect is still a matter of debate. This study aimed at investigating the postoperative morbidity rates after lung cancer surgery and their relationship with the weekday the surgery took place. MATERIALS AND METHODS: We retrospectively reviewed the clinical records of patients who underwent elective thoracotomic lobectomies for lung cancer. Categorical data were analyzed using the chi-square test or Fisher's exact test. Association between predictors and binary outcomes while considering the weekday stratification was determined with Cochran-Mantel-Haenszel statistics. To characterize the typical Friday patient, a multiple logistic regression analysis was performed. RESULTS: A total of 817 patients (2015-2019) were identified. Complication rates divided by day of surgery were 164 (20.07%) for patients operated on Mondays, 182 (22.27%) on Tuesdays, 205 (25.09%) on Wednesdays, 172 (21.05%) on Thursdays, and 94 (11.51%) on Fridays. Crude morbidity rates by weekday were Monday 21.53%, Tuesday 20.51%, Wednesday 27.70%, Thursday 20.0%, and Friday 10.26%. No overall association between day of surgery and overall morbidity was found (ρ = 0.095). Median hospital length of stay was 5 days (range: 2-45 days), and there were no statistically significant differences between days. The Cochran-Mantel-Haenszel statistics showed no association between morbidity and the weekday. CONCLUSION: In patients undergoing elective lobectomies for lung cancer, the weekday of surgery was not statistically significantly associated with an increase in the risk of postoperative morbidity.

Safety Analysis of Salvage Surgery for Advanced Stages or Metastatic Lung Cancers.

This case series aimed to analyze the outcomes of patients referred for salvage pulmonary resections after treatment with chemotherapy and immunotherapy for previously metastatic or unresectable tumors.From October 2016, after multidisciplinary board discussion, eight patients (median: 67 years, range: 52-78 years) underwent medical treatment due to advanced-stage diseases (stage cIIIA-cIVa). Four patients underwent cisplatin-based chemotherapy and, due to progression, were moved to an immunotherapy second line (nivolumab: two patients and pembrolizumab: two patients). Instead, four patients underwent combined cisplatin-based chemotherapy and immune checkpoint inhibitors (atezolizumab: two patients and pembrolizumab: two patients). After a multidisciplinary evaluation for salvage surgery, six patients underwent lobectomies, one patient underwent left pneumonectomy, and one patient underwent upper right lobectomy enlarged to the posterior arches of four ribs. The median duration of surgery was 179 minutes (range: 122-246 minutes). At the final pathological stage, three patients showed a complete major response (ypT0 ypN0), one patient was ypT1a ypN0, one ypT3 ypN0, 2 ypT3 ypN1, and one ypT4 ypN0. The hospital length of stay was 6 days (range: 3-23 days). Two patients had a postoperative complication. At the time of follow-up (median: 15.3 months [range: 1-32 months]), six patients were alive without evidence of the recurrence. Two patients died due to recurrence progression (N3 lymph nodes involvement) of the disease after 6 and 32 months.In stage IIIB-IVA nonsmall cell lung cancer, salvage lung surgeries after chemotherapy and immunotherapy are feasible, with high rates of R0 resection. Surgery can be technically tricky without significant morbidity and encouraging outcomes (even with a short-interval follow-up).

Primary Intrathoracic Neurogenic Tumors: Clinical, Pathological, and Long-Term Outcomes.

BACKGROUND: Intrathoracic neurogenic tumors (INTs) are uncommon neoplasms arising from nerve tissues. We report our single-center experience in treating these rare INTs. METHODS: Using a prospective institutional database, clinical, surgical, and pathological records of patients receiving resection of INT between May 1998 and June 2018 were analyzed. Survival was calculated by Kaplan-Meier method. RESULTS: There were 82 patients (24 females) with an average age of 53 years (29-75 years). Mean diameter was 32 mm (range, 12-68 mm). Histology included 49 schwannomas (11 malignant), 15 neurinomas (2 malignant), 14 neurilemmomas, and 4 paragangliomas. Tumor was located in the posterior mediastinum in 52 patients, in the thoracic inlet in 12, in the anterior mediastinum in 7, in the lung parenchyma in 5, and in the chest wall in 3. In three (3.6%) patients, the tumor showed an intraspinal extension. Symptoms were reported in 51 patients (62.2%) and included cough in 23, dyspnea in 15, neurologic symptoms in 11, and wheezing in 2. Operation was performed by thoracotomy in 42 (51.2%) cases and less invasive technique in 40 (48.8%) cases. Resection was completed in 80 patients (97.6%). Postoperative radiotherapy was administered in two cases. Intraoperative and postoperative mortalities were nil. Morbidity occurred in four patients (4.8%) including two prolonged air leaks, one hemothorax, and one chylothorax. Five-year survival was 97% (mean follow-up, 4.9 years). Malignant tumors had a worse prognosis (p = 0.02). No recurrence occurred during the follow-up neither for malignant nor for benign tumors. CONCLUSION: The treatment of choice for INTs is complete resection which will be tailored to tumor size, location, and extension. Long-term prognosis is favorable for benign neurogenic tumors.

Preliminary Results of Extracorporeal Membrane Oxygenation Assisted Tracheal Sleeve Pneumonectomy for Cancer.

OBJECTIVE: Tracheal sleeve pneumonectomy is a challenge in lung cancer management and in achieving long-term oncological results. In November 2018, we started a prospective study on the role of extracorporeal membrane oxygenation (ECMO) in tracheal sleeve pneumonectomy. We aim to present our preliminary results. METHODS: From November 2018 to November 2019, six patients (three men and three women; median age: 61 years) were eligible for tracheal sleeve pneumonectomy for lung cancer employing the veno-venous ECMO during tracheobronchial anastomosis. RESULTS: Only in one patient, an intrapericardial pneumonectomy without ECMO support was performed, but cannulas were maintained during surgery. The median length of surgery was 201 minutes (range: 162-292 minutes), and the average duration of the apneic phase was 38 minutes (range: 31-45 minutes). No complications correlated to the positioning of the cannulas were recorded. There was only one major postoperative complication (hemothorax). At the time of follow-up, all patients were alive; one patient alive with bone metastasis was being treated with radiotherapy. CONCLUSION: ECMO-assisted oncological surgery was rarely described, and its advantages include hemodynamic stability with low bleeding complications and a clean operating field. As suggested by our preliminary data, ECMO-assisted could be a useful alternative strategy in select lung cancer patients.

Thymoma and pure red cell aplasia with hypoplasia of megakaryocytopoiesis: A rare and life-treating condition.

Thymic tumors are rare diseases with an incidence of 0.15 cases per 100,000 person-years. They can be associated with a variety of other syndromes, such as Myasthenia Gravis or autoimmune disorders. Among them, pure red cell aplasia is a hemato-pathological condition characterized by anemia, reticulocytopenia and erythroid cell hypoplasia of bone marrow. Here, we reported a case of a 62-year-old female with a long history of neurologic symptoms due to Myasthenia Gravis. She was diagnosed with thymoma, with mediastinal mass and pleural thickening. After chemoradiotherapy treatment, she was surgically resected successfully, but she developed anemia and severe thrombocytopenia, worsening in respiratory failure requiring intubation. A bone marrow biopsy was performed resulting in a red-cell aplasia with marked hypoplasia of megakaryocytopoiesis compatible with pure red cell aplasia with acquired thrombocytopenia. Considering that there are no standard treatments, clinical condition improvement was achieved only after some lines of medical treatment. Our data, together with the few already published, help to raise the attention towards acquired cytopenias and the need to optimize the treatment for a potentially life-threatening condition.

Atrial Resection without Cardiopulmonary Bypass for Lung Cancer.

BACKGROUND: Results of resection of lung cancer invading left atrium (T4atrium) without cardiopulmonary bypass (CPB) remain controversial. We reviewed our experience analyzing surgical results and postoperative outcomes. METHODS: Patients who underwent extended lung resection for T4atrium without CPB between 1998 and 2018 were retrospectively reviewed using a prospective database. RESULTS: The study included 44 patients (34 males and 10 females; median age: 63 years). Twenty-five patients underwent preoperative mediastinal staging and 27 received induction treatment (IT). Surgery included 40 (90.9%) pneumonectomies, 3 (6.8%) lobectomies, and 1 bilobectomy (2.3%). Pathological nodal status was N0 in 10 patients (22.7%), N1 in 18 (40.9%), and N2 in 16 (36.4%). Four patients receiving IT had a complete pathological response (9.1%). Eight (18.2%) patients had microscopic tumor evidence on atrial resected margins. Mortality was nil. The major complication rate was 11.4%, including one bronchopleural fistula, one cardiac herniation, and three hemothoraces, all requiring reintervention. The minor complication rate was 25.5%. After a median survival of 37 months (range: 1-144 months), 20 (45.4%) patients were alive. Five-year survival rate and disease-free interval were 39 and 45.8%, respectively. Patients with N0 and R0 disease had a best prognosis (log-rank test: p = 0.03 and p = 0.01, respectively). IT neither influenced survival nor postoperative complications. On multivariate analysis, pN0 (p = 0.04 [95% confidence interval [CI]: 0.65-9.66] and negative atrial margins (p = 0.02 [95% CI: 0.96-8.35]) were positive independent prognostic factors. CONCLUSIONS: T4atrium is technically feasible without mortality and acceptable morbidity. Patients with N2 cancers should not be operated. T4atrium should not be systematically considered as a definitive contraindication to surgery.

Treatment of Chylothorax after Lung Resection: Indications, Timing, and Outcomes.

BACKGROUND: Chylothorax following pulmonary resection and lymphadenectomy for cancer is a potential severe complication in thoracic surgery. In the present study, we investigated the efficacy of the nonsurgical approach as well as the need for reoperation after conservative approach failure. METHODS: Chylothorax was diagnosed when chylous leakage from the chest drainage was observed and confirmed by the presence of triglycerides in the pleural fluid. We initially treated all the patients conservatively with complete oral intake cessation and total parenteral nutrition; if drainage output remained more than 800 mL/d after the first 5 days or major pleural effusion was observed at chest X-ray after chest tube removal, surgical treatment of chylothorax was indicated. RESULTS: Between January 1998 and December 2018, 5,072 patients underwent standard anatomical resection and mediastinal lymph node dissection for cancer at our institution. Among them, 30 patients (0.6%) developed chylothorax: 20 patients were effectively treated only by nil per os and low-fat diet, while 10 patients (33.3%) required surgical treatment. Mean age was 63 years; there were 24 male patients (80%); right-sided chylothorax was more frequent than left-sided chylothorax (22 vs. 8, respectively) although not statistically significant (p = 0.38); the only factor that seems to influence the need for reoperation is chylothorax flow rate during conservative treatment (p = 0.06). CONCLUSION: Conservative treatment is effective in the case of low flow-rate chylothorax (< 800 mL/d); in the case of a higher flow rate, surgical exploration is needed and thoracic duct ligation-with or without lymphatic sites clipping-provides definitive lymphostasis.

Surgical Treatment of Bilateral Lung Cancers: Long-Term Outcomes and Prognostic Factors.

BACKGROUND: Bilateral lung neoplasms are becoming more common, but distinguishing two primary lung cancers from metastatic disease can be difficult and only long-term follow-up after treatment can disclose the real behavior of the disease.The present study aimed to identify the appropriate candidates for bilateral surgical resections from the perspective of short-term postoperative complications and long-term outcomes. METHODS: Two hundred and fifteen consecutive patients undergoing bilateral pulmonary resection for lung cancers over a 20-year period were analyzed. Preoperative patient characteristics were noted, including demographic information, operative details, pathologic information including histology and tumor stage according to the eighth edition of the tumor nodes metastases staging system, and the use of neoadjuvant or adjuvant treatments. RESULTS: Patients receiving the second pulmonary resection more than 24 months from the first procedure as well as patients receiving bilateral lobectomies had higher overall 3-, 5-, and 10-year survival rates compared with the others. CONCLUSION: Patients receiving the second resection more than 24 months from the first procedure have the best long-term results irrespective of the type of resection.

Ten Years' Experience in Robotic-Assisted Thoracic Surgery for Early Stage Lung Cancer.

BACKGROUND: This study analyzed the short- and long-term outcomes of robotic-assisted thoracic surgery (RATS) for early stage non-small cell lung cancer (NSCLC). METHODS: From November 2006 to December 2016, we performed 363 RATS procedures. This study retrospectively reviewed 339 patients who underwent RATS for clinical stages I (n = 318) or II (n = 21) NSCLC. RESULTS: Twenty-nine patients underwent segmentectomy, 307 lobectomy, and 3 pneumonectomy. Conversion occurred in 22 patients (6.5%): 15 (4.4%) due to technical issues, 4 (1.2%) for oncological reasons, and 3 (0.9%) for bleeding. The median number of N1 and N2 stations resected was 2 and 3, respectively, and the median number of N1 and N2 lymph nodes resected was 9 and 6, respectively. Median operative time was 192 minutes for lobectomy, 172 minutes for segmentectomy, and 275 minutes for pneumonectomy. Median length of hospital stay was 5 days (2-191). The most common postoperative complication was prolonged air leak (12.1%). Major complications occurred in eight patients (2.4%). The 30-day and 90-day operative mortality was 0% and 0.3%, respectively. Two and 5-year cancer-specific survival rate was 96.1% and 91.5%, respectively. Five-year survival rate was 96.2% for patients who underwent segmentectomy, and 89.1% for lobectomy. All three patients who underwent pneumonectomy were alive at 5 years with no disease. CONCLUSIONS: Besides the well-known short-term outcomes showing very low morbidity and mortality rates, mediastinal lymph node dissection during RATS adequately assesses lymph node stations detecting occult lymph node metastasis and leading to excellent oncologic results. However, these results await longer follow-up studies.

Stereotactic body radiation therapy for mediastinal lymph node metastases: how do we fly in a 'no-fly zone'?

PURPOSE: To evaluate the treatment-induced toxicity (as primary endpoint) and the efficacy (as secondary endpoint) of stereotactic body radiation therapy (SBRT) in the treatment of mediastinal lymph nodes (LNs) in the so-called no-fly zone (NFZ) in cancers with various histology. MATERIAL AND METHODS: Forty-two patients were retrospectively analyzed. Institutional dose/volume constraints for organs at risk (OARs) derived by published data were strictly respected. The correlation between treatment-related variables and toxicity was investigated by logistic regression, Chi-squared test or Fisher's exact test. Overall survival (OS), cause-specific survival (CSS), progression-free survival (PFS) and local control (LC) were collected from the follow-up reports. The impact of potential predictive factors on LC, PFS and OS were estimated by Cox proportional-hazard regression. RESULTS: Median follow-up time was 16 months (range 1-41). Four patients had esophageal G1 toxicity. Ten and six patients had G1 and G2 pulmonary toxicity, respectively. Treatment site and irradiation technique were significantly correlated with G ≥ 2 and G ≥ 1 toxicity, respectively. OS probability at 19 months was 88.3% and corresponded to CSS. LC probability at 16 months was 66.3% (median LC duration: 22 months, range 1-41). Fifteen patients (35.7%) were disease-free at 25 months (median time, range 1-41). The biologically effective dose (BED) and the target dose coverage indexes were significantly correlated with LC. CONCLUSIONS: SBRT can be considered as a safe treatment option for selected patients with oligo-metastases/recurrences in the NFZ, if strict dose/volume constraints are applied.

Video-Thoracoscopic Management of Postpneumonectomy Empyema.

BACKGROUND: Postpneumonectomy empyema (PPE) is a serious complication even when it is not associated with bronchopleural fistula (BPF). Besides irrigation, an aggressive treatment is usually applied for removing infected material. However, a minimally invasive approach might achieve satisfactory results in selected patients. METHODS: We retrospectively identified 18 patients presenting with PPE receiving video-thoracoscopic approach. Of these 18 patients, pneumonectomy was performed for nonsmall cell lung cancer in 15 cases, for mesothelioma in 2, and for trauma in 1 case. There were 14 males and 4 females, (mean age, 62 years; range, 44-73 days). Empyema was confirmed by thoracentesis and bacteriological examination. All patients had immediate chest tube drainage and underwent thoracoscopic debridement of the empyema. Fifteen patients had no proven BPF; two had suspicious BPF, and one had a minor (<3 mm) BPF. RESULTS: Median time from pneumonectomy to empyema diagnosis was 129 days (range, 7-6205 days). Median time from drain position to video-assisted thoracoscopic surgery (VATS) procedure was 10 days (range, 2-78 days). A bacterium was isolated in 13 cases (72.2%). There was no mortality and no morbidity related to the procedure. The average duration of thoracoscopic debridement was 56 minutes (range, 40-90 minutes). Median postoperative stay was 7 days (range, 6-18 days). Only in one patient an open-window thoracostomy was performed. Median follow-up of the 18 patients receiving thoracoscopy was 41.5 months (range, 1-78 months). None had recurrent empyema. The patient with a minor BPF remained asymptomatic and is doing well at 48 months follow-up. CONCLUSIONS: Thoracoscopy might be a valid approach for patients presenting with PPE with or without minimal BPF. Video-thoracoscopic debridement of postpneumonectomy space is an efficient method to treat PPE.

Stem Cells Application in Thoracic Surgery: Current Perspective and Future Directions.

Two main fields of clinical applications of stem cells in thoracic surgery have been explored: (a) regenerative medicine, that is a branch of translational research in tissue engineering and molecular biology dealing with the replacement, engineering or regeneration of cells, tissues and organs to restore normal function; (b) drug loading and delivery, that is an emerging field proposing stem cells as vectors to deliver anti-cancer agents for targeted therapies.Bronchopleural fistula is a pathological connection between the bronchus and the pleural cavity that may develop after lung resection, thus causing pleural empyema due to colonization by resident airway bacteria; stem cells and regenerative medicine approach can effectively contribute to impaired bronchial healing, thus preventive a septic and ventilator catastrophe.In the field of thoracic oncology, MSC are probably one of the best choice for anticancer drug delivery, emerging as potential experimental approach to malignant mesothelioma treatment.The goal of this review is to focus on clinical applications of stem cell technologies in thoracic surgery, emphasizing regenerative medicine aspects as well as drug loading and delivery in thoracic oncology.

The Electronic Nose's Emerging Role in Respiratory Medicine.

New interest has grown in the respiratory disorder diagnosis and monitoring, throughout electronic nose technologies. This technology has several advantages compared to classic approach. In this short letter, we aim to emphasize electronic nose role in respiratory medicine.

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.

Long-Term Results and Prognostic Factors of Pulmonary Metastasectomy in Patients with Metastatic Transitional Cell Carcinoma.

Objective We wanted to assess the prognostic factors and the efficacy of the treatment in patients who underwent lung resections for transitional cell carcinoma metastases. Materials and Methods This is a retrospective, multicenter study. Between January 1995 and May 2014, 69 patients underwent lung metastasectomy with curative intent. We evaluated primary site of the tumor, the role of adjuvant chemotherapy after urological operation, disease-free interval (DFI; lower or higher than 24 months), type of lung resection, number of lung metastases, presence of metastatic lymph nodes, and diameter of the metastasis (less or more than 3 cm). Results Among 69 patients, 55 (79%) had bladder as primary site of disease and 12 of them received a transurethral bladder resection. Fourteen (21%) patients developed primary tumor in the renal pelvis or ureter; 53 (76%) patients presented with a single metastasis, 16 (24%) with multiple metastasis. The median DFI was 37 months and the median follow-up was 50 months. Sampling lymphadenectomy was done in 42 patients and nodal metastases were found in 7 patients. The overall 5-year survival was 52%, median 62 months. At univariate analysis, the DFI had a significant impact on survival (5-year survival of 58% for patients with DFI ≥ 24 months vs. 46%; p = 0.048) and diameter of metastasis (5-year survival of 59% for diameter less than 3 cm group vs. 33%; p = 0.001). The multivariate analysis confirmed metastasis' diameter as an independent prognostic factor (p = 0.001). Conclusion Our study found that, in addition to DFI that remains a common prognostic factor in patients with metastatic lung disease, in lung metastases by transitional cell carcinoma, the diameter of the lesion is another significant prognostic factor.

Transcription factor PREP1 induces EMT and metastasis by controlling the TGF-ß-SMAD3 pathway in non-small cell lung adenocarcinoma.

Pre-B-cell leukemia homeobox (Pbx)-regulating protein-1 (Prep1) is a ubiquitous homeoprotein involved in early development, genomic stability, insulin sensitivity, and hematopoiesis. Previously we have shown that Prep1 is a haploinsufficient tumor suppressor that inhibits neoplastic transformation by competing with myeloid ecotropic integration site 1 for binding to the common heterodimeric partner Pbx1. Epithelial-mesenchymal transition (EMT) is controlled by complex networks of proinvasive transcription factors responsive to paracrine factors such as TGF-ß. Here we show that, in addition to inhibiting primary tumor growth, PREP1 is a novel EMT inducer and prometastatic transcription factor. In human non-small cell lung cancer (NSCLC) cells, PREP1 overexpression is sufficient to trigger EMT, whereas PREP1 down-regulation inhibits the induction of EMT in response to TGF-ß. PREP1 modulates the cellular sensitivity to TGF-ß by inducing the small mothers against decapentaplegic homolog 3 (SMAD3) nuclear translocation through mechanisms dependent, at least in part, on PREP1-mediated transactivation of a regulatory element in the SMAD3 first intron. Along with the stabilization and accumulation of PBX1, PREP1 induces the expression of multiple activator protein 1 components including the proinvasive Fos-related antigen 1 (FRA-1) oncoprotein. Both FRA-1 and PBX1 are required for the mesenchymal changes triggered by PREP1 in lung tumor cells. Finally, we show that the PREP1-induced mesenchymal transformation correlates with significantly increased lung colonization by cells overexpressing PREP1. Accordingly, we have detected PREP1 accumulation in a large number of human brain metastases of various solid tumors, including NSCLC. These findings point to a novel role of the PREP1 homeoprotein in the control of the TGF-ß pathway, EMT, and metastasis in NSCLC.