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Purpose: Lonidamine (LND) can enhance the activity of anthracyclines in patients with metastatic breast cancer. A multicenter, prospective, randomized trial was designed to determine whether the association of LND with high-dose epirubicin plus cyclophosphamide (EC) could improve disease-free survival (DFS) in patients with early breast cancer (BC) compared with EC alone. Granulocyte colony-stimulating factor (G-CSF) was added to maintain the EC dose-intensity. Patients and Methods: From October 1991 to April 1994, 506 patients with stage I/II BC were randomly assigned to four groups: (A) epirubicin 120 mg/m2 and cyclophosphamide 600 mg/m2 administered intravenously on day 1 every 21 days for four cycles (124 patients); (B) EC plus LND 450 mg/d administered orally (125 patients); (C) EC plus G-CSF administered subcutaneously (129 patients); (D) EC plus LND plus G-CSF (128 patients). Results: Median follow-up was 55 months. Five-year DFS rate was similar for LND (B+D groups; 69.6%) versus non-LND arms (A+C groups; 70.3%) and G-CSF (C+D groups; 67.2%) versus non–G-CSF arms (A+B groups; 72.9%). Five-year overall survival (OS) was comparable in LND (79.1%) versus non-LND arms (81.3%) and in G-CSF (80.6%) versus non–G-CSF arms (79.6%). DFS and OS distributions in LND and G-CSF arms did not change according to tumor size, node, receptor, and menopausal status. G-CSF dramatically reduced hematologic toxicity without having a significant impact on dose-intensity (98.1% v 95.5% for C+D and A+B groups, respectively). Conclusion: EC is active and well tolerated in patients with early breast cancer. The addition of LND or G-CSF does not improve DFS or OS.

Lung cancer is the most common cause of cancer deaths in both men and women worldwide and has a poor prognosis. Non-small-cell lung cancer (NSCLC) represents approximately 80% of all lung cancers. Surgery is the only curative treatment of NSCLC but only 15–20% of tumours can be radically resected with a survival of about 40% at 5 years. Considering these disappointing results NSCLC is one of the most frequent subjects of clinical research worldwide. Italy is playing an important role in the clinical research of NSCLC performing phase I, II and III trials, prevalently by cooperative groups, and achieving important results that contributed to define the standard treatment for NSCLC patients. In particular, Italy is leader in the clinical research of the treatment of advanced NSCLC elderly patients. Today, large controlled clinical trials are ongoing. In this paper we analyse and discuss the main trials performed by Italian groups in the fields of NSCLC.

Purpose To study the prognostic value for overall survival of baseline assessment of functional status, comorbidity, and quality of life (QoL) in elderly patients with advanced non—small-cell lung cancer treated with chemotherapy. Patients and Methods Data from 566 patients enrolled onto the phase III randomized Multicenter Italian Lung Cancer in the Elderly Study (MILES) study were analyzed. Functional status was measured as activities of daily living (ADL) and instrumental ADL (IADL). The presence of comorbidity was assessed with a checklist of 33 items; items 29 and 30 of the European Organisation for Research and Treatment of Cancer (EORTC) core questionnaire QLQ-C30 (EORTC QLQ-C30) were used to estimate QoL. ADL was dichotomized as none versus one or more dependency. For IADL and QoL, three categories were defined using first and third quartiles as cut points. Comorbidity was summarized using the Charlson scale. Analysis was performed by Cox model, and stratified by treatment arm. Results Better values of baseline QoL (P = .0003) and IADL (P = .04) were significantly associated with better prognosis, whereas ADL (P = .44) and Charlson score (P = .66) had no prognostic value. Performance status 2 (P = .006) and a higher number of metastatic sites (P = .02) also predicted shorter overall survival. Conclusions Pretreatment global QoL and IADL scores, but not ADL and comorbidity, have significant prognostic value for survival of elderly patients with advanced non—small-cell lung cancer who were treated with chemotherapy. Using these scores in clinical practice might improve prognostic prediction for treatment planning.

The present study describes supportive care (SC) in patients with advanced non-small-cell lung cancer (NSCLC), evaluating whether it is affected by concomitant chemotherapy, patient's performance status (PS) and age. Data of patients enrolled in three randomised trials of first-line chemotherapy, conducted between 1996 and 2001, were pooled. The analysis was limited to the first three cycles of treatment. Supportive care data were available for 1185 out of 1312 (90%) enrolled patients. Gastrointestinal drugs (45.7%), corticosteroids (33.4%) and analgesics (23.8%) were the most frequently observed categories. The mean number of drugs per patient was 2.43; 538 patients (45.4%) assumed three or more supportive drugs. Vinorelbine does not produce substantial variations in the SC pattern, while cisplatin-based treatment requires an overall higher number of supportive drugs, with higher use of antiemetics (41 vs 27%) and antianaemics (10 vs 4%). Patients with worse PS are more exposed to corticosteroids (42 vs 30%). Elderly patients require drugs against concomitant diseases significantly more than adults (20 vs 7%) and are less frequently exposed to antiemetics (12 vs 27%). In conclusion, polypharmacotherapy is a relevant issue in patients with advanced NSCLC. Chemotherapy does not remarkably affect the pattern of SC, except for some drugs against side effects. Elderly patients assume more drugs for concomitant diseases and receive less antiemetics than adults.

Background Nivolumab has shown a survival benefit compared with docetaxel as second-line treatment for patients with previously treated advanced squamous non-small cell lung cancer (NSCLC) in a randomized phase III trial. The experiences of patients and physicians in routine clinical practice are often different from those in a controlled clinical trial setting. We present data from the entire Italian cohort of patients with squamous NSCLC enrolled in a worldwide nivolumab NSCLC expanded access program. Patients and Methods Patients with pretreated advanced squamous NSCLC received nivolumab 3 mg/kg every 2 weeks for up to 24 months. Safety was monitored throughout; efficacy data collected included objective tumor response, date of progression, and survival information. Results The Italian cohort comprised 371 patients who received at least one dose of nivolumab. In the overall population, the objective response rate (ORR) was 18%, the disease control rate (DCR) was 47%, and median overall survival (OS) was 7.9 months (95% confidence interval 6.2–9.6). In subgroup analyses, ORR, DCR, and median OS were, respectively, 17%, 48%, and 9.1 months in patients previously treated with two or more lines of therapy (n = 209) and 8%, 40%, and 10.0 months in patients treated beyond disease progression (n = 65). In the overall population, the rate of any-grade and grade 3–4 adverse events was 29% and 6%, respectively. Treatment-related adverse events led to treatment discontinuation in 14 patients (5%). There were no treatment-related deaths. Conclusion To date, this report represents the most extensive clinical experience with nivolumab in advanced squamous NSCLC in current practice outside the controlled clinical trial setting. These data suggest that the efficacy and safety profiles of nivolumab in a broad, real-world setting are consistent with those obtained in clinical trials. Implications for Practice Nivolumab is approved in the U.S. and Europe for the treatment of advanced non-small cell lung cancer (NSCLC) after failure of prior platinum-based chemotherapy. In this cohort of Italian patients with previously treated, advanced squamous NSCLC treated in a real-world setting as part of the nivolumab expanded access program, the efficacy and safety of nivolumab was consistent with that previously reported in nivolumab clinical trials.

Background. The aim of our study was to evaluateretrospectively in a large single institution setting allcases of lung resections for colorectal metastases from1998 to 2008 and to assess clinicopathologic factorsinfluencing outcome.Methods. In all, 199 patients, 125 men and 74 women,with lung metastases of colorectal cancer, 120 colon and 79rectum, underwent resection with curative intent; meaninterval between primary surgery and lung metastasis was35 months. Carcinoembryonic antigen preoperative valuewas abnormal in 52 patients; K-RAS wild-type wasdetected in 60 of 97 examined cases; 75 patients receivedpreoperative or postoperative chemotherapy or both. Asolitary lesion was described in 95 patients (47.7%), two orthree metastases in 72 (36.2%), and more than three metastasesin 26 (13.1%). Nodal status was reported in 130patients (73%). One hundred twenty patients (60.3%) underwentwedge resection, 27 (13.6%) underwent segmentectomy,and 52 (26.1%) had lobectomy. An R0 resectionwas achieved in 178 cases (89.4%).Results. Median overall survival was 4.2 years (95%confidence interval: 3.1 to 5.1) with a 5-year overallsurvival of 43% (95% confidence interval: 36% to 50%).An R1 resection (log rank p [ 0.0001), thoracic nodalinvolvement (log rank p [ 0.0002), and preoperativeabnormal carcinoembryonic antigen value (log rankp < 0.001) were significantly associated with pooroutcome in univariate analysis. In multivariate analysis,the same variables plus the number of lesions(single versus multiple, p [ 0.04) were shown to affectoutcome.Conclusions. An R0 resection, preoperative carcinoembryonicantigen, nodal involvement, and number oflesions represent strong prognostic factors in patient withlung metastases of colorectal cancer. The role of systemictreatments and biomolecular tests deserve future prospectiveinvestigations.

Palliative airway treatments are essential to improve quality and length of life in lung cancer patients with central airway obstruction. Rigid bronchoscopy has proved to be an excellent tool to provide airway access and control in this cohort of patients. The main indication for rigid bronchoscopy in adult bronchology remains central airway obstruction due to neoplastic or non-neoplastic disease. We routinely use negative pressure ventilation (NPV) under general anaesthesia to prevent intraoperative apnoea and respiratory acidosis. This procedure allows opioid sparing, a shorter recovery time and avoids manually assisted ventilation, thereby reducing the amount of oxygen needed, while maintaining optimal surgical conditions. The major indication for NPV rigid bronchoscopy at our institution has been airway obstruction by neoplastic tracheobronchial tissue, mainly treated by laser-assisted mechanical dissection. When strictly necessary, we use silicone stents for neoplastic or cicatricial strictures, reserving metal stents to cover tracheo-oesophageal fistulae. NPV rigid bronchoscopy is an excellent tool for the endoscopic treatment of locally advanced tumours of the lung, especially when patients have exhausted the conventional therapeutic resources. Laser-assisted mechanical resection and stent placement are the most effective procedures for preserving quality of life in patients with advanced stage cancer.

Introduction: Breast cancer is the leading cause of cancer death among women in the industrialized countries. The incidence of local recurrences after mastectomy and breast-conserving therapy varies between 5% and 40% depending on risk factors and primary therapy. Methods: From April 1999 to April 2011, 40 patients underwent chest wall resection and reconstruction for locally recurrent breast carcinoma with chest wall invasion. The main goal of surgery was local disease control to palliate clinical symptoms. Results: Local radical resection was achieved in 26 patients (65%). One, 2 and 5 year overall survival rates were 94.4%, 82.0% and 68.5%; 1, 2 and 5 year disease-free survival rates were 94.4%, 73.6% and 45.5% respectively.Univariate analysis indicated age (p = 0.002) and synchronous distant metastases (p = 0.020) as factors having a negative impact on overall survival; multivariate analysis disclosed age (p = 0.052) and synchronous metastases (p = 0.059) as factors with a slight negative impact on overall survival. Older age was associated with improved overall survival.Univariate analysis indicated synchronous distant metastases (p = 0.029) and the need of post resectional additional treatments (p = 0.022) as factors adversely conditioning disease-free survival or time to progression; multivariate analysis disclosed the need of post resectional additional treatments (p = 0.036) as the only factor adversely conditioning disease-free survival or time to progression. Conclusions: Chest wall resection and reconstruction for locally recurrent breast cancer is a feasible and safe procedure providing adequate local disease control and an excellent palliation of very disabling symptoms in a selected group of patients.

Introduction: Available information on perioperative blood transfusion practices in oncologic thoracic surgery is scant and outdated. The purpose of this study was to investigate transfusion requirements in patients undergoing curative resection for lung cancer and to identify possible factors predictive of perioperative blood transfusion in our cohort of patients. Methods: From 1st January 2009 to 31st December 2009, 317 patients underwent anatomic pulmonary resection. Patients who received at least 1 unit of red blood cells comprised the "transfused" group. Each case in this group was matched for surgical procedure with a control subject who did not require blood transfusion and was operated on during the same year; these patients comprised the "not transfused" group. Results: A total of 75 patients (23.6%) received at least 1 unit of red blood cells during the perioperative period. Factors conditioning perioperative blood transfusion were: preoperative hemoglobin level (p < 0.0001); procedure duration (p = 0.017); body mass index (p < 0.001); induction therapies (p = 0.017); redo procedure (p = 0.021). Age, sex, histology, stage, ASA score, side, intraoperative blood loss, and fluid infusion did not affect perioperative blood transfusion practices. Conclusions: Preoperative hemoglobin level is the major risk factor for perioperative blood transfusion practices in oncologic thoracic surgery; procedure duration, body mass index, induction therapies, and redo procedure may condition transfusional needs, although they were actually not predictive on multivariate analysis. © 2011 Society of Surgical Oncology.

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.

OBJECTIVES A few studies have already demonstrated survival benefits for local treatment in solitary metastatic non-small-cell lung cancer (NSCLC). The aim of this study is to retrospectively investigate the role of surgery in patients with oligometastatic (OM) NSCLC. METHODS Between January 1998 and December 2018, 57 patients with OM stage IV NSCLC (1 or 2) underwent a multidisciplinary approach including lung cancer surgery, local treatment of the distant metastasis (DM) and systemic medical treatments. RESULTS All patients had DM synchronous to lung cancer. Fifty-one (90%) patients had a single DM whereas 6 (11%) patients had 2 DMs. Forty-eight (84%) patients underwent induction chemotherapy. We performed 47 (82%) lobectomies, 4 (7%) segmentectomies and 6 (11%) pneumonectomies. Pathological lymph node involvement was evident in 28 (49%) patients. Adjuvant chemotherapy was administered in 20 (35%) patients. Forty-six (81%) patients had local treatment of the DM before lung resection, and 11 (19%) patients had after lung resection; 6 (11%) patients had both treatments. The median overall survival (OS) was 30 months, with the 2-, 3- and 5-year OS of 57%, 50% and 30%, respectively. OS was significantly related to lymph node involvement (P = 0.04), size of the primary tumour (P CONCLUSIONS Multidisciplinary approach is the gold standard in OM patients. Patients with no lymph node involvement are the best candidates, with an acceptable OS. Thus, patients with OM-NSCLC should not be excluded from surgery as a matter of principle.

INTRODUCTION: Robotic-assisted surgery has become the first choice for several conditions since its introduction in clinical practice in 2000. However, the U.S. Food and Drug Administration has recently raised a warning against the use of robotic surgical approaches for the cure and prevention of cancer following the publication of two studies focused on endometrial cancer. We conducted an internal audit to retrospectively analyze our experience to assess the safety and feasibility of robotic-assisted surgery compared to open surgery. METHODS: We selected a 5-year period to guarantee at least 2 years of follow-up (2011-2016) and identified 1139 patients who underwent lobectomy for non-small-cell lung cancer (NSCLC) in our division. The primary data set analyzed included 544 early-stage clinical N0 patients (348 open and 196 robotic surgeries). We compared 131 patients of each group individually matched, with demographic and clinical characteristics almost identical. RESULTS: No difference was observed between the cohorts, either in terms of recurrence-free survival (hazard ratio: 1.09; p = 0.55) or overall survival (hazard ratio: 0.86; p = 0.36). The 5-year recurrence of disease risk and overall survival were 24.9% and 83.2%, respectively, in the open group and 24.6% and 86.1%, respectively, in the robotic group. CONCLUSIONS: These data underline that robotic-assisted lobectomy for early NSCLC is a safe and feasible technique with adequate long-term and progression-free survival compared to open surgery.

Rat sarcoma (RAS) oncogenes have intensively been investigated during the last decades. Taking into account all human tumours, Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS) gene is the most frequently mutated (about 22%) among the three isoforms, followed by Neuroblastoma RAS Viral Oncogene Homolog (NRAS) (8%) and Harvey Rat Sarcoma Viral Oncogene Homolog (HRAS) (3%). In the last years, careful attention has been paid on KRAS and NRAS gene mutations in non-small-cell lung cancer (NSCLC) and colorectal cancer (CRC) patients because of their prognostic and predictive roles. In particular, a large body of literature data has been generated investigating clinical outcomes of targeted treatments in NSCLC and CRC KRAS- and NRAS-mutated patients. The latest evidences are here reviewed, providing also an overview of the real-world RAS mutation testing practice across different Italian laboratories. On this basis, we propose a knowledge-based system, www.rasatlas.com, to support the healthcare personnel in the management of patients featuring RAS gene mutations in the landscape of precision oncology.

Epidermal growth factor receptor (EGFR) exon 20 insertions occur rarely among different cancer types, with the highest frequency reported among non-small-cell lung cancer (NSCLC) patients, particularly adenocarcinomas (ADCs). Exon 20 insertions fall back in the tyrosine kinase domain, and can be clustered into two principal groups represented by in frame insertions and three to 21 bp (corresponding to 1–7 amino acids) duplications within amino acids 762 and 774. The identification of these alterations is key for an adequate management of NSCLC patients due to the possibility to treat these patients with specific targeted therapies. Next generation sequencing (NGS) technology, able to detect several hotspot gene mutations for different patients simultaneously, is the best detection approach due to its higher sensitivity and specificity compared to other techniques. Here we reviewed the principal biological characteristics, the main detection technologies and treatment options for NSCLC patients harbouring EGFR exon 20 insertions.

Objectives While the best approach to malignant pleural mesothelioma has yet to be demonstrated, surgery remains the mainstay of treatment. We analysed a group of candidates for trimodality treatment, aiming to identify prognostic factors guiding patient selection. Methods Between 2003 and 2015, 83 (31.6%) of the 283 patients with malignant pleural mesothelioma were considered for trimodality treatment to perform induction chemotherapy, extrapleural pneumonectomy and adjuvant radiotherapy. All patients underwent cisplatin-based chemotherapy. Radiotherapy was administered at a mean dose of 50.4 Gy. Results Thirty-six patients (43.4%) had 3 cycles of chemotherapy, whereas 21 (25.3%) had more than 3. Progression to chemotherapy was observed in 10.9% (9 of 83) of patients, partial response in 30.1% (25 of 83) and stable disease in 59% (49 of 83). Sixty-three patients underwent extrapleural pneumonectomy. Fifty-five patients (87.3%) had epithelial tumour. Forty-two patients (66.7%) were in pathological Stage 3. Major complications after extrapleural pneumonectomy were observed in 28 patients (44.4%), whereas 30-day postoperative mortality was 11.1% (7/63). Radiotherapy was not administered in 24 patients (38.1%) due to major complications after surgery or patient intolerance. Two patients (3.2%) died within 90 days after the end of radiotherapy. The trimodality treatment was completed in 37 (44.6%) patients. Median overall survival was 35.6 months, with 1- and 3-year overall survival of 82% and 48% for patients who completed the trimodality treatment compared with 32% and 14% for patients who did not undergo radiotherapy. Conclusions Only 45% of patients completed the planned trimodality treatment, and morbidity/mortality remained high. Nonetheless, the patients who completed treatment showed good loco-regional disease control and better overall survival.

OBJECTIVES The aim of this study was to assess the postoperative outcomes of robotic-assisted lobectomy in obese patients to determine the impact of the robotic approach on a high-risk population who were candidates for major pulmonary resection for non-small-cell lung cancer (NSCLC). METHODS Between January 2007 and August 2018, we retrospectively reviewed the medical records of 224 obese patients (body mass index ≥ 30) who underwent pulmonary lobectomy at our institution via robotic-assisted thoracic surgery (RATS, n = 51) or lateral muscle-sparing thoracotomy (n = 173). RESULTS Forty-two patients were individually matched with those who had the same pathological tumour stage and similar comorbidities and presurgical treatment. The median operative time was significantly longer in the RATS group compared to that in the thoracotomy group (200 vs 158 min; P = 0.003), whereas the length of stay was significantly better for the RATS group (5 vs 6 days; P = 0.047). Postoperative complications were significantly more frequent after open lobectomy than in the RATS group (42.9% vs 16.7%; P = 0.027). After a median follow-up of 4.4 years, the 5-year overall survival rate was 67.6% [95% confidence interval (CI) 45.7–82.2] for the RATS group, and 66.1% (95% CI 46.8–79.9) for the open surgery group (log-rank P = 0.54). The 5-year cumulative incidence of cancer-related deaths was 24.8% (95% CI 9.7–43.5) for the RATS group and 23.6% (95% CI 10.8–39.2) for the open surgery group (Gray’s test, P = 0.69). CONCLUSIONS RATS is feasible and safe for obese patients with NSCLC with advantages compared to open surgery in terms of early postoperative outcomes. In addition, the long-term survival rate was comparable to that of the open approach.

The management of multiple primary cancers, an event not so infrequent in oncology practice, is a critical issue due to the lack of literature. In this study, we reported the case of a patient with non-small cell metastatic lung cancer (NSCLC) and pancreatic ductal adenocarcinoma (PDAC) who received gefitinib in combination with gemcitabine plus nab-paclitaxel and with mFOLFOX6 in first and second line, respectively. It achieved a progression-free survival and a28-months overall survival (OS) for NSCLC and PFS-1 and OS of 20 and 13 months, respectively for PDAC. Moreover, the combination of gefitinib and chemotherapy treatmentsshowed a good safety profile. Given the insignificant frequency of this case, we performed a molecular characterization of both neoplasms with the aim to investigate the existence of particular activated pathways and/or similar immunological mutations. It is interesting to note that two neoplasms shared a common mutation ofthe B7-H3 gene, with the consecutive impairment of its expressed protein. In both PDAC and NSCLC, the expression of this protein was associated with a worse survival rate. Since B7-H3 is an anti-apoptotic protein, the reduction of its expression or function should justify a pro-apoptotic activity with a leading justification of the long survival of the patient considered in this report.

Background: The present study investigated the efficacy and safety of nivolumab in pre-treated patients with advanced NSCLC harbouring KRAS mutations. Methods: Clinical data and KRAS mutational status were analysed in patients treated with nivolumab within the Italian Expanded Access Program. Objective response rate, progression-free survival and overall survival were evaluated. Patients were monitored for adverse events using the National Cancer Institute Common Terminology Criteria for Adverse Events. Results: Among 530 patients evaluated for KRAS mutations, 206 (39%) were positive while 324 (61%) were KRAS wild-type mutations. KRAS status did not influence nivolumab efficacy in terms of ORR (20% vs 17%, P = 0.39) and DCR (47% vs 41%, P = 0.23). The median PFS and OS were 4 vs 3 months (P = 0.5) and 11.2 vs 10 months (P = 0.8) in the KRAS-positive vs the KRAS-negative group. The 3-months PFS rate was significantly higher in the KRAS-positive group as compared to the KRAS-negative group (53% vs 42%, P = 0.01). The percentage of any grade and grade 3–4 AEs were 45% vs 33% (P = 0.003) and 11% vs 6% (P = 0.03) in KRAS-positive and KRAS-negative groups, respectively. Conclusions: Nivolumab is an effective and safe treatment option for patients with previously treated, advanced non-squamous NSCLC regardless of KRAS mutations.

Background Bone metastases (BoM) are a negative prognostic factor in non-small-cell lung cancer (NSCLC). Beyond its supportive role, bone is a hematopoietic organ actively regulating immune system. We hypothesized that BoM may influence sensitivity to immunotherapy. Methods Pretreated non-squamous (cohort A) and squamous (cohort B) NSCLCs included in the Italian Expanded Access Program were evaluated for nivolumab efficacy according to BoM. Results Cohort A accounted for 1588 patients with non-squamous NSCLC, including 626 (39%) with (BoM+) and 962 (61%) without BoM (BoM-). Cohort B accounted for 371 patients with squamous histology including 120 BoM+ (32%) and 251 (68%) BoM- cases. BoM+ had lower overall response rate (ORR; Cohort A: 12% versus 23%, p

BRAF Mutant NSCLC and Immune Checkpoint Inhibitors: Results From a Real-World Experience

Introduction Nivolumab is the first checkpoint inhibitor approved for the treatment of nonsquamous NSCLC. We report results from the nivolumab Italian expanded access program focusing on never-smokers and patients with EGFR-mutant nonsqamous NSCLC. Methods Nivolumab (3 mg/kg intravenously every 2 weeks) was administered upon physicians' request to patients who had relapsed after one or more prior systemic treatments for stage IIIB/IV nonsquamous NSCLC. Efficacy and safety were evaluated in patients who received at least one dose of nivolumab. Results Of 1588 patients with nonsquamous NSCLC, 305 (19.2%) were never-smokers. EGFR status was available for 1395 patients. Of the 102 patients (6.4%) with EGFR mutation–positive tumors, 51 (50%) were never-smokers. The objective response rate was significantly higher in patients with wild-type EGFR than patients with EGFR-mutant tumors (19.6% versus 8.8% [p = 0.007]), in former and current smokers than in never-smokers (21.5% versus 9.2% [p = 0.0001]), and in never-smokers with wild-type EGFR than in never-smokers with mutant EGFR (11.0% versus 1.9% [p = 0.04]). There was no significant difference in objective response rate between smokers with wild-type EGFR and smokers with mutant EGFR (22.0% versus 20.6%). There was no statistically significant difference in median progression-free survival or in median overall survival. The median overall survival times were 11 months in patients with EGFR wild-type tumors versus 8.3 months in patients with EGFR-mutant tumors, 11.6 months in smokers versus 10.0 months in never-smokers, 11.0 months in never-smokers with EGFR wild-type tumors versus 5.6 months in never-smokers with EGFR-mutant tumors, and 14.1 months in smokers with EGFR-mutant tumors versus 11.3 months in smokers with EGFR wild-type tumors. Conclusions The data on the Italian expanded access program in populations with nonsquamous NSCLC suggest that subgroups of patients could benefit differently from nivolumab according to their EGFR mutational status and smoking habits. These results warrant further investigation.

Lung cancer is the leading cause of death for neoplasm. Lung cancer mortality is frequently associated with late diagnosis, therefore an early diagnosis is a key factor to significantly improve overall survival in high risk populations of asymptomatic patients. Conventional cancer screenings (low-dose computed tomography or chest x-ray) today offer early detection but are invasive and expensive. Previously these studies evaluated the solid and topographic cancer structure and morphology. Today the concept of tumor has been remodelled, being defined as a disease that has its own genetic, biological and metabolic identity; it is on this new awareness that we should base new screening methods. Recent research has shown great reliability of new tests such as exhaled breath analysis, serum biomarkers and urine analysis in early diagnosis of lung cancer. Analysis of new biomarkers associated with the high specificity of these new screening methods, which are non-invasive, safe, inexpensive and simple to perform, could allow a non-invasive approach to determine a big change in the early diagnosis of cancer and its survival rate. Furthermore, these new techniques put the patient at the core of a non-invasive diagnostic process and ensure a better quality of life during medical diagnosis. In this article, we want to analyze the possible benefits of these new and promising methods, suggesting a possible combination between them to ensure, as soon as possible, an early and effective diagnosis of lung cancer with a special focus on the patient, in a new era of personalized medicine.

3067Background: Nivolumab is the first checkpoint inhibitor approved for the treatment of squamous non small cell lung cancer (Sq-NSCLC) to show a survival benefit in a randomised phase III trial. ...

Background The Glasgow prognostic score (GPS) is an inflammation-based score based on albuminemia and C-reactive protein concentration proved to be associated with cancer-specific survival in several neoplasms. The present study explored the immediate postoperative value of the GPS for patients undergoing pneumonectomy for lung cancer. Methods The value of the GPS preoperatively was studied in 250 patients undergoing pneumonectomy fornon-small cell lung cancer (NSCLC). We analyzed overall postoperative complications, pulmonary and cardiac complications, 30-day postoperative death, reoperation for early complications, intensive care unit(ICU) length of stay and total length of hospital stay. Results Patients with a GPS of 0 and 1 had a mean ICU length of stay of 0.8 days, whereas patients with a GPS of 2 had a mean ICU stay of 5.0 days (p= 0.004). The postoperative mortality rate in patients with a GPS of 2 was much higher than in patients with a GPS of 1 and 2, although it was not statistically significant (p= 0.083). Conclusions A preoperative GPS of 2 effectively predicts a prolonged ICU stay in patients who undergo pneumonectomy for cancer. The score may be proposed as an easy-to-determine, economical, and fast preoperative tool to plan and optimize ICU admissions after elective pneumonectomy.

http://hdl.handle.net/20.500.11768/96503 The combined variant of small-cell lung carcinoma (SCLC) refers to the variable admixture of small cell and non-small cell carcinoma, whereas the association with sarcoma or sarcoma-like elements is exceedingly rare. A 76-year-old Caucasian man underwent right upper lobectomy with regional lymphadenectomy because of a symptomatic 7 cm-sized tumor mass. Formalin fixed-paraffin embedded material was used to highlight several differentiation cell lineages by means of immunohistochemistry, electron microscopy, and mutational assay. The tumor was discovered as being IIB stage (pT2b pN1(1/51) pM0) and featured biphasic appearance with close intermingling of SCLC (40%) and collagen-rich spindle cell sarcoma (60%). Epithelial (cytokeratins, TTF-1), neural (neurofilaments, GFAP), endocrine (chromogranin, synaptophysin, CD56), and skeletal muscle (desmin, sarcomeric actin, myogenin) markers were variably co-expressed by SCLC elements, whereas mesenchymal (vimentin), smooth muscle (actin, myosin, H-caldesmon, calponin), fibroblastic (CD10), and, more focally, skeletal muscle (desmin, sarcomeric actin and myogenin) markers were highlighted in the spindle cell sarcoma elements. TP53 codon V274F mutation in exon 8 was shared by either cell component. After undergoing adjuvant chemotherapy, the patient is currently alive and well at the 40-month follow-up. To the best of our knowledge, this is the first report of combined SCLC with quadripartite differentiation of epithelial, neuroendocrine, skeletal muscle, and myofibroblastic type, somewhere at the level of the same individual tumor cells. This tumor had probably derived for clonal evolution of a p53-mutated common ancestor lesion.

Objective Pneumonectomy is not always sufficient for the radical resection of cancer. In the present study, pneumonectomy may be associated with an extended resection of mediastinal or parietal structures. The postoperative risk and the oncologic benefits of such an extended procedure have not been sufficiently demonstrated. Methods We have defined "extended" pneumonectomy (EP) as the removal of the entire lung, associated with one or more of the following structures: superior vena cava, tracheal carina, left atrium, aorta, chest wall, or diaphragm. Our clinical database was retrospectively reviewed to identify patients who underwent EP to assess their postoperative morbidity, mortality, and long-term survival. Results Between 1998 and 2005, 47 EPs were performed. The "extended" procedure included left atrium resection in 15 patients, combined SVC and carinal resection in 9 patients, aortic resection in 8 patients (in 3 patients with prosthetic replacement), chest wall or diaphragmatic resection in 6 patients, SVC resection in 4 patients, and carinal resection in 4 patients. A partial esophageal muscular resection was performed in 1 patient. Overall 60-day mortality was 8.5%. Major postoperative complications occurred in 8 patients (17%). The 2- and 5-year survival rates for the overall population were 42% and 22.8%, respectively. Interestingly, long-term survivors were recorded only in the group of patients who received induction treatment. Conclusions Extended pneumonectomy is a feasible procedure with an acceptable risk factor. To improve the selection of patients, all candidates should undergo preoperative mediastinoscopy and induction chemotherapy. In patients with positive response to chemotherapy or stable disease, extended pneumonectomy may afford a radical resection in more than 80% of cases and may result in a permanent cure in some instances.

Summary Background The addition of cyclo-oxygenase-2 (COX-2) inhibitors and prolonged constant infusion (PCI) of gemcitabine to treatment for advanced non-small-cell lung cancer (NSCLC) might improve treatment efficacy. We aimed to assess whether the addition of rofecoxib or PCI gemcitabine could improve overall survival compared with first-line treatment with cisplatin plus gemcitabine given by standard infusion. Methods Patients with stage IV or IIIb (with supraclavicular nodes or pleural effusion) NSCLC who were under 70 years of age and who had performance status 0 or 1 were eligible for this multicentre, prospective, open-label, randomised phase III trial with 2×2 factorial design. Patients were randomly assigned to one of four treatment groups: group A, gemcitabine 1200 mg/m 2 in a 30-min intravenous infusion on days 1 and 8 and intravenous cisplatin 80 mg/m 2 on day 1, every 21 days for six cycles; group B, the same treatments as group A plus oral rofecoxib 50 mg/day until disease progression; group C, intravenous PCI gemcitabine 1200 mg/m 2 in a 120-min infusion on days 1 and 8 and intravenous cisplatin 80 mg/m 2 on day 1, every 21 days for six cycles; group D, the same drugs as group C plus oral rofecoxib 50 mg/day until disease progression. The primary endpoint was overall survival; secondary endpoints were progression-free survival, response rate, quality of life, and toxicity. Analyses were intention-to-treat. This trial is registered on the clinical trials site of the US National Institutes of Health website http://clinicaltrials.gov/ct/show/NCT00385606. Findings Between Jan 30, 2003, and May 3, 2005, 400 patients were enrolled. Median age was 60 years (range 29–71). PCI gemcitabine did not improve overall survival (median 47 weeks [95% CI 40–55] vs 44 [36–52], with standard gemcitabine infusion, hazard ratio (HR) of death 0·93 [0·74–1·17], p=0·41), progression-free survival, nor any other secondary endpoint. Vomiting and fatigue were significantly worse with PCI gemcitabine. The two rofecoxib groups were closed early (on Oct 1, 2004) due to withdrawal of the drug because of safety issues. With intention-to-treat statistical analyses limited to 240 patients (ie, those randomised before July 1, 2004) who had at least 3 months of treatment, rofecoxib did not prolong overall survival (median 44 weeks [CI 36–55] vs 44 [40–54] without rofecoxib, and HR of death 1·00 [0·75–1·34], p=0·85), or progression-free survival, but did improve response rate (41% vs 26%, p=0·02), global quality of life, physical, emotional and role functioning, fatigue, and sleeping. Rofecoxib significantly increased the incidence of diarrhoea and decreased constipation, fatigue, fever, weight loss, and pain, and analgesic consumption. Severe cardiac ischaemia was more frequent with rofecoxib than without; however, the difference was not statistically significant in the primary analysis (p=0·06) and became significant when patients who were randomised between July 1, 2004, and Sept 30, 2004, were included in the analysis (p=0·03). Interpretation Neither PCI gemcitabine nor rofecoxib prolonged survival in the patients in this study. Rofecoxib improved response rate and several quality-of-life items, including pain-related items and global quality of life. Further studies with less cardiotoxic COX-2 inhibitors are needed in NSCLC.

We conducted a large, multicenter, retrospective survey aimed to explore the impact of tumor bone involvement in Non-Small Cell Lung Cancer.Data on clinical-pathology, skeletal outcomes and bone-directed therapies for 661 deceased patients with evidence of bone metastasis were collected and statistically analyzed. Bone metastases were evident at diagnosis in 57.5% of patients. In the remaining cases median time to bone metastases appearance was 9 months. Biphosphonates were administered in 59.6% of patients. Skeletal-related events were experienced by 57.7% of patients; the most common was the need for radiotherapy. Median time to first skeletal-related event was 6 months. Median survival after bone metastases diagnosis was 9.5 months and after the first skeletal-related event was 7 months. We created a score based on four factors used to predict the overall survival from the diagnosis of bone metastases: age >65 years, non-adenocarcinoma histology, ECOG Performance Status >2, concomitant presence of visceral metastases at the bone metastases diagnosis. The presence of more than two of these factors is associated with a worse prognosis.This study demonstrates that patients affected by Non-Small Cell Lung Cancer with bone metastases represent a heterogeneous population in terms of risk of skeletal events and survival.

In the last two decades the results of medical treatment of advanced non-small cell lung cancer (NSCLC) have constantly improved even if they are still far from being considered satisfactory. Today systemic cisplatin-based chemotherapy (CT) is able to increase survival and improve cancer-related symptoms in patients with advanced ‘wet’ stage III and metastatic stage IV NSCLC, but it not clear if the benefits of CT also apply to patients with poor performance status (PS) [1, 2]. PS is the most powerful independent prognostic factor in advanced NSCLC since it is a reliable measure of functional independence, ability to perform daily activities and work, and a strong predictor of survival and adverse events as well [3]. The vast majority of prospective phase III trials had been conducted stratifying patients according to stage (III versus IV) and PS (PS 0–1 versus 2). In a retrospective analysis by the Veteran Administration Lung Group including more than 5000 patients, PS recorded according to the Karnofsky Index was the strongest prognostic factor followed by extent of disease and weigh loss [3]. The same conclusion has been reached by more recent large trials using new regimens. The survival analysis of 1960 patients treated with cisplatin-based CT in five ECOG trials showed a median survival of 3.3 months for PS2 patients as compared to 9.4 months and 6.4 months recorded for PS0 and PS1 patients, respectively [4]. A similar analysis of 2531 patients included in fourteen SWOG trials also showed that a poor PS was the strongest independent predictor of shorter median survival (PS 0–1: 6.4 months; PS >_2. 3.3 months) and lower 1-year survival rate (20% versus 9%; P _2 was 3.8 months. Data from 1052 patients treated with cisplatin-based CT in seven EORTC trials showed that, after disease extent, PS was the most important determinant of outcome [6]. In all studies a better outcome was also associated to less disease extent, presence of less than 1 metastatic lesion, absence of liver, skin or bone metastases, basal haemoglobin levels >11 gr%, normal LDH and alkaline phosphatase levels, absence of symptoms due to metastatic disease, and a preserved appetite. Recently an analysis of 1436 patients treated with third-generation doublet regimens (ECOG E5592 and E1594 trials) allowed the identification of six independent poor prognostic factors including PS2, presence of skin or liver metastases, loss of appetite, presence of less than four metastatic sites, and no prior surgical treatment. A normogram using these six pretreatment prognostic factors was elaborated and validated to predict 1-and 2-year survival in CT-naive patients. This prognostic model could be potentially useful in clinical decision making and research planning [7]. Despite the negative influence of poor PS on survival parameters, the relationship between PS score and control of cancer-related symptoms deserves some comments. A significant proportion of patients with PS2 treated with CT may experience an improvement in tumor-related symptoms even if a better PS is associated with better control. A study on nearly 300 patients showed that 48% of PS2 patients and even 30% PS3 ones may experience an improvement of cancerrelated symptoms. However a better PS was a strong prognostic factor for higher symptomatic response [8]. Only one study specifically analysed quality of life (QoL) in the different PS sub-groups [9]. Patients with PS2 reported the worst scores at baseline assessment. The drop-out rate in PS2 patients was greater than in the other PS levels (PS2 35% versus PS1 23% versus PS0 18%). Nevertheless, PS2 pts had significant benefit from CT and, with the greater potential for palliation determined by worse baseline condition, showed an improvement in QoL even higher than that of patients with PS 0–1. Overall, median survival of PS2 patients is substantially shorter than that of PS 0–1 patients, being usually

OBJECTIVES: Diaphragmatic infiltration by non-small cell lung cancer (NSCLC) is a rare occurrence and surgical results are unclear.We assessed our experience with en bloc resection of lung cancer invading the diaphragm, analysing prognostic factors and long-termoutcomes.METHODS: We analysed a prospective database of patients with NSCLC infiltrating the diaphragm who underwent en bloc resection.Univariateanalysis was performed to identify prognostic factors. Survival was calculated by the Kaplan–Meier method.RESULTS: Nineteen patients (14 men, mean age 64±11 years) were identified. Surgery included nine pneumonectomies, eight lobecto-mies and two segmentectomies. A partial diaphragmatic infiltration was observed in 10 patients (53%) and full-depth invasion in 9 (47%).Diaphragmatic reconstruction was done primarily in 13 patients (68%), and by prosthetic material in 6 (32%). Pathological nodal statusincluded nine N0, four N1 and six N2. The median hospital stay was 7 days (range, 4–36 days). The postoperative mortality rate was 5%(1/19). Two patients (10%) had major complications (acute respiratory distress syndrome and bleeding) and 10 minor complications, ar-rhythmia in 7 (37%) and pneumonia in 3 (16%). The 5-year survival was 30±11%. The median survival and disease-free survival were15±9 months (range, 1–164 months) and 9±7 months (range, 1–83 months), respectively. Factors adversely affecting survival were dia-phragmatic infiltration (50% superficial vs 0% full-depth infiltration; log-rank test, P=0.04) and nodal involvement (43% N0 vs 20% N1–2;log-rank test, P=0.03).CONCLUSIONS: Resection of NSCLC invading the diaphragm is technically feasible and could be a valid therapeutic option with accept-able morbidityand mortalityand long-term survival in highlyselected patients.Keywords: Lung cancer † Surgery † Diaphragm

Lung neuroendocrine tumors are catalogued in four categories by the World Health Organization (WHO 2004) classification. Its reproducibility and prognostic efficacy was disputed. The WHO 2010 classification of digestive neuroendocrine neoplasms is based on Ki67 proliferation assessment and proved prognostically effective. This study aims at comparing these two classifications and at defining a prognostic grading system for lung neuroendocrine tumors. The study included 399 patients who underwent surgery and with at least 1 year follow-up between 1989 and 2011. Data on 21 variables were collected, and performance of grading systems and their components was compared by Cox regression and multivariable analyses. All statistical tests were two-sided. At Cox analysis, WHO 2004 stratified patients into three major groups with statistically significant survival difference (typical carcinoid vs atypical carcinoid (AC),P=0.021; AC vs large-cell/small-cell lung neuroendocrine carcinomas,PP=0.021; and G2 vs G3,P≤0.001), mitotic count (G1 ≤2, G2 >2–47, G3 >47; G1 vs G2,P≤0.001; and G2 vs G3,P≤0.001), and presence of necrosis (G1 absent, G2 10% of sample; G1 vs G2,P≤0.001; and G2 vs G3,P≤0.001) at uni and multivariable analyses. The combination of these three variables resulted in a simple and effective grading system. A three-tiers grading system based on Ki67 index, mitotic count, and necrosis with cutoffs specifically generated for lung neuroendocrine tumors is prognostically effective and accurate.

http://hdl.handle.net/20.500.11768/96515

Background: Extended resections (ER) for lung cancer may improve survival in selected patients. However, analysis on large series is still lacking. We reviewed our experience to identify prognostic factors useful for patient selection. Methods: Between 1998 and 2010, 167 patients with involvement of one or more mediastinal organs underwent operations with the intent to perform ER. At thoracotomy, 42 patients (25%) were considered unresectable (explorative thoracotomy [ET]), and 125 (75%) underwent ER. The types of ER were superior vena cava in 43 patients (34.4%), carina in 33 (26.4%), combined with superior vena cava in 18 (14.4%), with the left atrium in 35 (28%), and with the aorta in 14 (11.2%). We excluded Pancoast tumors and vertebral resections. The minimum follow-up was 6 months. Kaplan-Meier method and log-rank test were used for statistical analysis of survival. Results: There were 136 men (81.4%), with mean age of 63 years (range, 36 to 81 years). Of the 167 patients, induction chemotherapy was administered in 119 (71.3%), including 34 ET patients (81%) and 85 ER patients (68%). Complete resection was achieved in 106 patients (84.8%). The overall 5-year survival was 23% (27% in ER and 13% in ET, p = 0.41). Overall 30-day mortality was 4.8% and morbidity was 34.1%. Factors affecting survival were complete resection (p < 0.01), pStage 0-I-II disease (p < 0.0007), and age younger than 60 years (p < 0.01). Conclusions: ER for lung cancer invading mediastinal organs could improve long-term survival (46% at 5-years in pN0). The best surgical candidates are young patients without lymph nodes involvement who undergo radical resection. Multimodality treatment is suggested in case of mediastinal lymph node involvement. © 2013 by The Society of Thoracic Surgeons.

http://hdl.handle.net/20.500.11768/96435

http://hdl.handle.net/20.500.11768/96634 Introduction: More detailed typing of non-small cell lung cancer on small biopsy specimens is increasingly required, albeit sometimes demanding with morphology alone. Little, however, is known about the likelihood of immunohistochemistry (IHC)-assessed small biopsies to effectively parallel profiling and, hence, eventual diagnoses of surgical specimens. Methods: Sixty-three preoperative biopsies and the corresponding surgical specimens from 30 consecutive squamous cell carcinomas, 22 adenocarcinomas, 2 adenosquamous carcinomas, eight sarcomatoid carcinomas, and one yolk sac tumor were jointly evaluated semiquantitatively for cytokeratins 5/6 and 7, p63, thyroid transcription factor-1, and vimentin immunoreactivity. Surgical specimens were the gold standard for morphology and IHC. Results: Hierarchic clustering analysis of both surgical specimens and biopsies showed a nonrandom and overlapping distribution of the relevant markers, which closely correlated with each other and the diverse tumor categories, as confirmed by mosaic plot analysis. There were no differences in area under the curve-receiver operating characteristic curves for each marker between any two samples, with the exception of p63 that paralleled more effectively squamous cell carcinoma on biopsies than surgical specimens. Fifty-nine of 63 (94%) lesions were correctly classified by IHC on biopsy compared with 53 of 63 (84%) by revised morphology, with the predictive positive value being 97% for squamous cell carcinoma, 88% for adenocarcinoma, and 100% for sarcomatoid and adenosquamous carcinoma. Yolk sac tumor and three of eight sarcomatoid carcinomas, however, failed any diagnostic recognition. Conclusions: Diverse cell differentiation lineages of non-small cell lung cancer may be consistently detected by IHC in small biopsies, making the eventual typing of tumors effective in most cases.

Nicotine dependence (ND) is one of the worlds leading causes of preventable death. Nicotine addiction and other forms of drug addiction continue to be significant public health problems in the world. Evidence for a genetic influence on smoking behaviour and ND has prompted a search for susceptibility genes. Evidence has recently accumulated that single nucleotide polymorphisms (SNPs) in the genetic region encoding the nicotinic acetylcholine receptor (nAChR) subunits α6, α5, α3, and β4 are associated with smoking and ND. Brain nAChR are a heterogeneous family of ion channels expressed in the various parts of the brain. A number of studies suggest that brain nAChR are critical targets for the development of pharmacotherapy for nicotine and other drug addictions. In this review, we will discuss the nAChR subtypes, their function in response to endogenous brain transmitters, and how their functions are regulated in the presence of nicotine. Additionally, we will provide an overview of the three major pharmacotherapies for smoking cessation (which have demonstrated efficacy) such as: nicotine replacement therapy (NRT), bupropion, and varenicline. An appreciation of the complexity of nAChR and their regulation will be necessary for the development of nAChR modulators as potential pharmacotherapy for drug addiction. Prevention strategies should be tailored to carriers of SNPs located on chromosome 15q and that are strongly associated with nicotine dependence and risk of lung cancer.

A 38-year-old Caucasian woman was admitted to hospital complaining of recent-onset acute night dyspnoea. A chest radiograph disclosed a bulky cystic lesion in the middle-lower field of the left lung (Figure 1), and a computed tomography scan confirmed the presence of a 91 50 98-mm multiseptated giant cystic mass arising in the lingula and compressing the adjacent pulmonary parenchyma (Figure 2). The patient’s clinical history was unremarkable apart from autoimmune hyperthyroidism under medical treatment for 4 years. The patient underwent left muscle sparing thoracotomy with resection of the entire unopened lesion and no lung tissue sacrifice. Grossly, the tumor consisted of a multiseptated giant cystic mass with gaseous content and scant liquid material (Figure 3). Histologically, it featured a typical alveolar adenoma with dual cell composition of type II pneumocytes and elongated septal mesenchymal cells, but with unusual formation of giant cystic spaces (Figures 4A, B). The immunohistochemical profile—positivity for thyroid transcription factor-1 (Figure 4C), negativity for myogenin, surfactant and cytokeratins in pneumocytes, and negativity for desmin in mesenchymal cells—was consistent with alveolar adenoma. The proliferative activity as assessed by Ki-67 immunostaining was unremarkable in both cell types (Figure 4D). The nonrandom occurrence of specific genetic alterations in alveolar adenoma in relation to its neoplastic nature, albeit benign, inasmuch as recurrence has never been recorded.1–4 Most patients are middle aged to elderly and asymptomatic, with a slight female predominance. Most tumors are found by chance, whereas the occurrence of severe tumorrelated symptoms, as described in our case, is exceptional. Conservative surgery is the best treatment and no further therapy is required.2

http://hdl.handle.net/20.500.11768/96473 Background: Prolonged air leak after pulmonary lobectomy is a common time- and cost-consuming complication. Its prevention may significantly reduce hospitalization length and costs offering patients a standard uneventful postoperative course. The aim of the present study is to identify predictors of prolonged postoperative air leak and to stratify preoperative risk factors. Methods: From July 2004 to December 2007 241 consecutive standard lobectomies were performed with curative intent for lung cancer. After excluding patients not fulfilling the inclusion criterion, 58 patients were enrolled in the "prolonged air leak" group and 63 patients were enrolled in the "standard outcome" group. Results: Total lung capacity (p = 0.0038) and percentage emphysema (p = 0.0050) calculated by computed tomography were both significantly related to prolonged postoperative air leak; the values of 4773 cc and 0.4% showed the highest predictive value in terms of sensitivity (84.5% and 75.9% respectively). Multivariate logistic regression disclosed that male sex (p = 0.0006), right side of operation (p = 0.0010) and age (p = 0.0082) were significantly related to prolonged postoperative air leak. Preoperative chemotherapy (p = 0.0940) did not affect air leak status. Conclusions: Computed tomography quantification of emphysema is the best predictor of prolonged air leak. Age, male sex and right side lobectomy are correlated to this complication. Preoperative chemotherapy is not an additional risk factor. (C) 2010 Royal College of Surgeons of Edinburgh (Scottish charity number SC005317) and Royal College of Surgeons in Ireland. Published by Elsevier Ltd. All rights reserved.

Objectives We investigated the feasibility and safety of four-arm robotic lung lobectomy in patients with lung cancer and described the robotic lobectomy technique with mediastinal lymph node dissection. Methods Over 21 months, 54 patients underwent robotic lobectomy for early-stage lung cancer at our institute. We used a da Vinci Robotic System (Intuitive Surgical, Inc, Mountain View, Calif) with three ports plus one utility incision to isolate hilum elements and perform vascular and bronchial resection using standard endoscopic staplers. Standard mediastinal lymph node dissection was performed subsequently. Surgical outcomes were compared with those in 54 patients who underwent open surgery over the same period and were matched to the robotic group using propensity scores for a series of preoperative variables. Results Conversion to open surgery was necessary in 7 (13%) cases. Postoperative complications (11/54, 20%, in each group) and median number of lymph nodes removed (17.5 robotic vs 17 open) were similar in the 2 groups. Median robotic operating time decreased by 43 minutes ( P = .02) from first tertile (18 patients) to the second-plus-third tertile (36 patients). Median postoperative hospitalization was significantly shorter after robotic (excluding first tertile) than after open operations (4.5 days vs 6 days; P = .002). Conclusions Robotic lobectomy with lymph node dissection is practicable, safe, and associated with shorter postoperative hospitalization than open surgery. From the number of lymph nodes removed it also appears oncologically acceptable for early lung cancer. Benefits in terms of postoperative pain, respiratory function, and quality of life still require evaluation. We expect that technologic developments will further simplify the robotic procedure.

Introduction Indications and results of salvage surgery in mediastinal tumors are still unclear. This study analyzes a single-center experience to assess its mortality, morbidity, and long-term results. Methods Mediastinal salvage surgery (MSS) was defined as surgical resection of persistent or recurrent primary mediastinal tumors after previous local treatments with curative intent or exclusive chemotherapy in case of bulky tumors. Clinical data of patients undergoing MSS between 1998 and 2005 were analyzed. Overall and disease-specific long-term survival was calculated. Results Twenty-one patients (15 men and 6 women, mean age 41 years) underwent MSS. Eleven patients suffered from thymic tumors (eight thymomas, three thymic carcinoma) whereas 10 patients suffered from nonthymic tumors (one lung adenocarcinoma + thymoma, two mediastinal monophasic sinovial sarcoma, one mediastinal neuroendocrine tumor, one mediastinal teratoblastoma, one mediastinal disgerminoma, one Hodgkin's lymphoma, one mediastinal atypic carcinoid, two medullary thyroid carcinoma). MSS required extended vascular resection in 10 cases and cardiopulmonary bypass in one case. Median operation time was 215 minutes (range 140–720). One postoperative death and four major complications were recorded (overall mortality 4.7%, morbidity 19.0%). With a median follow-up of 30.6 months, overall 1-, 3-, and 5-year Kaplan-Meier survival was 89.7, 71.2, and 56.6%, respectively. Thymic neoplasms had a better prognosis (1-, 3-, and 5-year survival was 100, 87.5, 87.5%, respectively) when compared with others (1-, 3-, and 5-year survival was 77.8, 53.3, 26.7%, respectively—logrank p = 0.0128). Conclusions MSS can offer a chance of curative treatment in selected patients with an acceptable morbidity and mortality. Thymic tumors obtain the best results in term of long-term survival.

Objective The impact of lymph node involvement in lung metastasectomy from extrapulmonary malignancies is uncertain. We assessed the prognostic value of lymph node status in lung metastasectomy and the prevalence of unexpected mediastinal lymph node involvement after lymph node sampling or dissection. Methods From May 1998 to October 2005, 388 patients underwent 430 pulmonary metastasectomies with curative intent. The clinical records of all patients who underwent radical lymph node dissection or sampling were reviewed retrospectively. Survival was evaluated using the Kaplan–Meier method and comparison of survival curves by log–rank test. Results A total of 124 patients (61 men, mean age 59 years) underwent 139 pulmonary metastasectomies (56 wedge resections, 30 segmentectomies, 49 lobectomies, and 4 pneumonectomies with radical lymph node dissection [88] or sampling [51]). Means of 9.4 lymph nodes and 2 lung metastases per intervention were removed. The median disease-free interval from primary treatment to lung metastasectomy was 49 months. Lymph node involvement was present in 25 patients (20%), in 10 (8%) at N1 stations (hilar or peribronchial) and in 15 (12%) at N2 stations (mediastinal), and in 7 (12.5%) after atypical resection and in 19 (23%) after typical resection. In 15 patients (12%) (60% of N+ patients), lymph node involvement was unexpected. Estimated overall 5-year survival was 46%: It was 60% for subjects with no lymph node metastasis and 17% and 0% for those with N1 and N2 disease, respectively ( P = .01). Conclusions Lymph node involvement heavily affects prognosis after pulmonary metastasectomies. In most patients, lymph node involvement was not revealed by preoperative workup.

Background. The oncologic value of superior vena cava (SVC) resection for lung and mediastinal malignancies remains controversial. In this context, we have reviewed our experience in the treatment of locally advanced lung and mediastinal tumor invading the SVC system, analyzing postoperative outcome and long-term oncologic results. Methods. The clinical data of patients who underwent SVC resection were retrospectively analyzed to assess postoperative mortality, and overall and procedure-specific morbidity. Overall survival was calculated for mediastinal and lung tumor groups. Results. From 1998 to 2004, 70 consecutive patients (52 with lung cancer and 18 with mediastinal tumors) underwent SVC system resection. There were 25 replacements (36%) of the SVC system by prosthesis, whereas the remaining underwent partial resection. Major postoperative morbidity and mortality rates in lung cancer patients were 23% and 7.7%, respectively (50% and 5.6% in mediastinal tumors). In the lung cancer group, 5-year survival probability was 31%, and it was affected by mediastinal nodal status (5-year survival in N0‐N1 patients 52%, 21% in N2 patients, 0 in N3 patients). Median survival for mediastinal tumors was 49 months. Conclusions. In conclusion, SVC resection may achieve permanent cure in patients who would have been defined as inoperable 10 years ago. In the case of mediastinal tumors, the need for SVC resection alone should not be considered a contraindication for surgery when prosthetic replacement is feasible. In the case of lung tumors, infiltration of SVC can achieve satisfactory long-term results after neoadjuvant chemotherapy, only when pathologic N2 disease is excluded by preoperative mediastinoscopy.

Anomalous pulmonary venous return is a rare congenital anomaly mainly involving the right lung and is often associated with congenital intracardiac malformations as atrial septal defect. We report a case of anomalous right upper lobe venous drainage resulting in two right upper lobe veins draining into the azygous vein and into the confluence between superior vena cava and azygous vein, respectively. Preoperative identification of such an aberrant venous drainage is useful for avoiding unexpected intraoperative bleeding.

2006;131:490-491 J Thorac Cardiovasc Surg Gasparri, Francesco Petrella, Alessandro Borri, Giuseppe Pelosi and Marco Venturino Lorenzo Spaggiari, Domenico Galetta, Giulia Veronesi, Francesco Leo, Roberto prosthesis: Preliminary results Superior vena cava replacement for lung cancer using a heterologous (bovine) http://jtcs.ctsnetjournals.org/cgi/content/full/131/2/490 located on the World Wide Web at: The online version of this article, along with updated information and services, is

Lung cancer may involve the pulmonary artery (PA) either by direct extension of the primary tumor or by invasion of the hilar lymph nodes. In these instances, a radical resection is usually a pneumonectomy despite distal functioning lung tissue. To spare the lung parenchyma, angioplastic procedures requiring removal of a portion of the arterial wall or a circumferential resection with arterial reconstruction have been used. Several techniques of pulmonary arterioplasty have been explored suggesting that the incidence of postoperative complications is acceptably low and long-term local control can be achieved. Over a period of 7 years, 84 angioplastic procedures (alone or associated with bronchoplasty) were performed at our institution. Partial PA resection was performed in 80 (95.2%) patients. Reconstruction was performed by running suture in 63 (75%) patients and using a pericardial patch in 17 (20.2%) cases (16 autologous and 1 heterologous). A complete PA resection and reconstruction was performed in four (4.8%) patients by a polytetrafluoroethylene (PTFE) prosthesis (n=2) and by a custom-made bovine pericardial conduit (n=2). The latter are the topic of this report.

Summary Occasionally, breast cancer relapses in the subclavicular region. In patients with failed multimodal treatment, or in those who develop an isolated recurrence, surgical resection may be useful to remove all macroscopically evident diseases. However, the procedure may be technically demanding and there are no published data regarding its benefits. The aim of the present study was to evaluate the feasibility and safety of subclavicular resection in breast cancer and provide indications as to whether it can contribute to disease control. We used a transpectoral approach to surgically remove isolated breast cancer recurrence in the subclavicular region in seven consecutive patients presenting over 2 years; in the eighth case a transmanubrial approach was necessary. We found that the surgical approach proposed is feasible and safe, with a 75% rate of complete resection; however, the series was characterised by a high rate of local and distant relapse. We conclude that the technique may be useful, in selected cases, for palliation only.

http://hdl.handle.net/20.500.11768/96589

http://hdl.handle.net/20.500.11768/96578

A 66-year-old nonsmoker woman had a chest computed tomography (CT) during oncological follow-up of bilateral breast cancers. The CT scan disclosed a partially-solid 17-mm nodule in the right upper lobe, a 17-mm retrosternal left mammary chain lymph node, and a 20-mm left subclavicular lymph node. Seventeen years earlier, she had been submitted to left Patey mastectomy for lobular infiltrating carcinoma (pT1c pN1b1 R0—stage IIA according to the 1987 Union Internationale Contre le Cancer classification) and, 10 months later, underwent redo breast resection for tubular ductal carcinoma (pT1c pN0G1 R0—stage I according to the1987 Union Internationale Contre le Cancer classification). The patient received bilateral breast prosthesis implantation. Seven years earlier, the patient underwent median sternotomy for mitral mechanical valve implantation, and 3 years earlier, she required breast prosthesis replacement due to prosthesis damage. Her current evaluation included a positron emission tomography (PET), which showed pathologic [18F]-fluorodeoxyglucose uptake with a maximal standardized uptake values of 4.8, 3.5, and 3.2 in the lung lesion, retrosternal lymph node, and subclavicular node, respectively (Figures 1A–C). CT-guided biopsy and bronchoalveolar lavage of the right upper lobe were nondiagnostic. She did not have an positron emission tomography because of claustrophobia. The patient underwent right axillary muscle-sparing thoracotomy and wedge resection of the right upper pulmonary nodule: frozen section disclosed adenocarcinoma, probably primary non-small cell lung cancer. Right upper lobectomy and lymphadenectomy were performed. Retrosternal dissection and mediastinal adhesiolysis (due to previous median sternotomy) allowed biopsy of the lymph node of the left internal mammary chain. Frozen section disclosed a foreign body inflammatory reaction. Subsequent biopsy of the left subclavicular lymph node revealed breast metastatic carcinoma. Definitive histology confirmed primary pT1 pN0 G1 TTF1 positive acinar adenocarcinoma of the lung (stage IA), subclavicular estrogen receptor positive breast cancer recurrence, and mediastinal silicon-induced lymphadenitis. On the one hand, clinical staging by CT and PET/CT scan in our patient suggested a diagnosis of primary lung cancer with contralateral mediastinal and subclavicular lymph node involvement (stage III B—cN3 disease) and thus not amenable to surgical exploration. An alternative explanation was nodal recurrence by breast cancer and pulmonary metastasis. Although it was known that the patient had had prosthesis rupture, the hypothesis of a foreign body reaction lymphadenitis was not entertained preoperatively mainly because of the coexisting pulmonary lesion. In addition, similar [18F]-FDG uptake values in the three different lesions (standardized uptake values of 4.8, 3.5, and 3.2) led us to consider only one disease rather than three different conditions, as was the case. Another misleading factor was the relatively recent median sternotomy that may have accounted for [18F]-FDG uptake by the internal mammary lymph node. The exceptional nature of the present case lies in the misleading concomitance of three unrelated clinical events with similar CT and PET features. Although synchronous or metachronous lung and breast cancers have been described, as well as silicon-induced lymphadenitis in patients with prosthetic augmentation mammoplasty,1 to our knowledge synchronous primary lung cancer, breast cancer recurrence, and mediastinal silicon-induced lymphadenitis have never been described in the same patient. Although rare, multiple synchronous oncologic and nononcologic diseases need to be considered during follow-up in patients treated for breast cancer to offer them the best therapeutic approach.