Deep Sequencing Analysis Identified a Specific Subset of Mutations Distinctive of Biphasic Malignant Pleural Mesothelioma.

Malignant Pleural Mesothelioma (MPM) is a heterogeneous disease. Morphologically, three different phenotypes are distinguishable: epithelioid (e-), sarcomatoid (s-) and biphasic (biph-) MPM, the latest, being a mixture of e- and s-MPM cells. Being an intermediate entity, management of biph-MPM, remains debatable and controversial, with different guidelines recommending distinct approaches. Identification of biph-MPM associated genetic alterations, through deep sequencing analysis, may provide useful tools to understand these lesions. A retrospective cohort of 69 surgically resected MPMs, 39 biph-MPMs (56.5%) and 30 e-MPMs (43.5%) was selected. A separate set of 16 biph-MPM was used as validation set. Deep sequencing analysis on an MPM-specific custom panel (MPM_geneset) comprising 1041 amplicons spanning 34 genes was performed. A total of 588 variants and 5309 mutational events were detected. In total, 91.3% of MPMs showed at least one mutation and 76.8% showed co-occurrence of more than one alteration. Mutations in MXRA5 (p = 0.05) and NOD2 (p = 0.018) were significantly associated with biph-MPM both in the training and validation cohort and correlated with the extent of the sarcomatoid component. Mutations in NOD2 and XRCC6 correlated with patients' survival. We demonstrated that biph-MPM are associated with a specific mutation set, and that genetic analysis at diagnosis may improve patients' risk stratification.

Prognostic factors of lung cancer in lymphoma survivors (the LuCiLyS study).

BACKGROUND: Second cancer is the leading cause of death in lymphoma survivors, with lung cancer representing the most common solid tumor. Limited information exists about the treatment and prognosis of second lung cancer following lymphoma. Herein, we evaluated the outcome and prognostic factors of Lung Cancer in Lymphoma Survivors (the LuCiLyS study) to improve the patient selection for lung cancer treatment. METHODS: This is a retrospective multicentre study including consecutive patients treated for lymphoma disease that subsequently developed non-small cell lung cancer (NSCLC). Data regarding lymphoma including age, symptoms, histology, disease stage, treatment received and lymphoma status at the time of lung cancer diagnosis, and data on lung carcinoma as age, smoking history, latency from lymphoma, symptoms, histology, disease stage, treatment received, and survival were evaluated to identify the significant prognostic factors for overall survival. RESULTS: Our study population included 164 patients, 145 of which underwent lung cancer resection. The median overall survival was 63 (range, 58-85) months, and the 5-year survival rate 54%. At univariable analysis no-active lymphoma (HR: 2.19; P=0.0152); early lymphoma stage (HR: 1.95; P=0.01); adenocarcinoma histology (HR: 0.59; P=0.0421); early lung cancer stage (HR: 3.18; P<0.0001); incidental diagnosis of lung cancer (HR: 1.71; P<0.0001); and lung cancer resection (HR: 2.79; P<0.0001) were favorable prognostic factors. At multivariable analysis, no-active lymphoma (HR: 2.68; P=0.004); early lung cancer stage (HR: 2.37; P<0.0001); incidental diagnosis of lung cancer (HR: 2.00; P<0.0001); and lung cancer resection (HR: 2.07; P<0.0001) remained favorable prognostic factors. Patients with non-active lymphoma (n=146) versus those with active lymphoma (n=18) at lung cancer diagnosis presented better median survival (64 vs. 37 months; HR: 2.4; P=0.02), but median lung cancer specific survival showed no significant difference (27 vs. 19 months; HR: 0.3; P=0.17). CONCLUSIONS: The presence and/or a history of lymphoma should not be a contraindication to resection of lung cancer. Inclusion of lymphoma survivors in a lung cancer-screening program may lead to early detection of lung cancer, and improve the survival.

Survival results in biphasic malignant pleural mesothelioma patients: A multicentric analysis.

OBJECTIVE: The best strategy of care for biphasic malignant pleural mesothelioma (Biph-MPM) is controversial. In this study, a large dataset of Biph-MPM cases was reviewed to identify prognostic factors and to evaluate the role of a multimodal approach, including cancer-directed surgery. METHODS: A total of 213 patients with Biph-MPM treated at 4 tertiary centers who experienced MPM from January 2009 to December 2016 were selected, and clinical, pathologic, and surgical information was retrieved. A Cox regression model was used to identify predictors of survival, and the Kaplan-Meier method was used to summarize overall survival. RESULTS: The mean age and the male/female ratio were 68.4 ± 9.5 years and 5:1, respectively. Tumors were assigned to stages I (127, 59.6%), II (3, 1.4%), III (76, 35.4%), and IV (7, 3.3%) according to the Eighth Tumor, Node, Metastasis (TNM) edition. A multimodal treatment including pleurectomy/decortication was performed in 58 patients (27.2%), chemotherapy alone in 99 patients (46.5%), and best supportive care in 56 (26.3%). The median overall survival was 11 months. A univariate analysis revealed that survival was significantly associated with the percentage forced expiratory volume in 1 second (P < .0001), performance status (P = .0002), multimodal treatment including surgery (P < .0001), and TNM stage (P = .011). A multivariable analysis confirmed performance status, percentage forced expiratory volume in 1 second, TNM, and a multimodal approach as independent variables affecting long-term survival. CONCLUSIONS: Despite the overall poor prognosis of biphasic histology, a multimodal approach, including cancer-directed surgery, is associated with improved long-term results in very selected patients with Biph-MPM.

Is Adjuvant Chemotherapy Worthwhile After Radical Resection for Single Lung Metastasis From Colorectal Cancer? A Multicentric Analysis Evaluating the Risk of Recurrence.

Background: Adjuvant chemotherapy after resection of colorectal cancer (CRC) lung metastases may reduce recurrences and improve survival. The choice of best candidates for adjuvant chemotherapy in this setting is controversial, especially when a single lung metastases (SLM) is resected. The aim of this study is to evaluate the risk of recurrence after radical resection for single lung metastasis from CRC. Patients and methods: Demographic, clinical, and pathological data were retrospectively collected for patients radically operated on for single pulmonary metastasis from CRC in 4 centers. Survival was computed by Kaplan-Meyer methods. Chi-square, log-rank test, and for multivariate analysis, Cox-regression and binary logistic regression were used when indicated. Results: The sample consisted of 344 patients, mean age 65 yrs. Overall 5 yrs survival was 61.9%. Recurrence occurred in 113 pts (32.8%). At univariate analysis, age > 70 (p = 0.046) and tumor size > 2 cm (p = 0.038) were predictive of the worst survival chance, while synchronous lung metastasis (p = 0.039), previous resection of extrathoracic metastasis (p = 0.017), uptake at FDG-PET scan (p = 0.006) and short (<12 months) disease-free interval (DFI) prior to lung metastasectomy (p = 0.048) were risk factors for recurrence. At multivariate analysis, only high CEA (>4 ng/mL) was associated with worst survival (HR: 4.3, p = 0.014), while prior abdominal surgery (HR: 3, p = 0.033), PET positivity (HR: 2.7, p = 0.041), and DFI > 12 months (HR: 0.14, p < 0.001) confirmed to predict recurrence of disease. Conclusions: Surgical resection of solitary lung metastases from CRC is associated with prolonged survival. High value of CEA, PET positivity, previous extrathoracic resected metastasis, and short (<12 months) DFI were found to be predictive of death or disease recurrence and might identify in this scenario patients at higher risk which could potential benefit of chemotherapy.

Thoracic Hyper-IgG4-Related Disease Mimicking Malignant Pleural Mesothelioma.

We report a rare case of a IgG4-related disease presenting with recurrent pleural effusion, pleural thickness and multiple mediastinal lymphadenopathies and no involvement of other extrathoracic organs. A 65-year-old man with a previous asbestos exposure presented with cough and pain discomfort. A large right pleural effusion was detected and evacuated (siero-haematic liquid). With the suspicious of a pleural mesothelioma, a CT-scan before and a 18F-FDG PET/CT-scan later were performed revealing multiple pleural thickenings and multiple mediastinal lymphadenopathies with radiotracer uptake. EBUS-TBNA EBUS-TBNA did not result in a formal pathological diagnosis; thus, multiple pleural biopsy were performed via right thoracoscopy. At pathology the pleura was markedly thickened by a chronic fibroinflammatory process with scattered lymphoid follicles and a large number of mature plasma cells. Immunohistochemistry shows a mixed B (CD20+) and T (CD3+) population of lymphocytes, without light chain restriction and an increased number of IgG4-positive plasma cells. A presumptive diagnosis of IgG4-related disease was formulated. Total body CT-scan excluded other organ involvement. Blood test showed elevated serum IgG4 concentrations (253 mg/dL) and mild elevation of acute-phase reactants (C-reactive protein 10.7 mg/L). Autoimmune profile was negative. A diagnosis of definite IgG4-related disease was made, and treatment with prednisone 50 mg/day was started.

Diagnostic performances of 68Ga-DOTATOC versus 18Fluorodeoxyglucose positron emission tomography in pulmonary carcinoid tumours and interrelationship with histological features.

Few data are available about radio-receptorial positron emission tomography (PET) results by the use of 68Ga-DOTA-peptides in pulmonary carcinoid tumours. In this study, we retrospectively analysed 68Ga-DOTATOC/PET and 18Fluorodeoxyglucose (FDG) PET diagnostic performances in 62 pulmonary carcinoids (occurring in 57 patients) and interrelationship with histological features. All patients underwent at least 1 PET/computed tomography: 26 patients received 68Ga-DOTATOC, 52 patients had 18F-FDG and 20 patients received both techniques. There were 55 typical carcinoids and 7 atypical carcinoids. 68Ga-DOTATOC/PET recorded an 88.4% overall detection rate (DR) (meanSUVmax: 15.5); 18F-FDG/PET a DR of 53.8% (meanSUVmax: 3.2). When adopted a maximum standardized uptake value-threshold of 1.5, DRs of 68Ga-DOTATOC and 18F-FDG/PET increased to 100% and 80.8%, respectively. Moreover, DRs in both techniques vary considerably according to histology with 68Ga-DOTATOC/PET having better performances in typical carcinoids than in atypical carcinoids (DR: 91.7% vs 50.0%, P = 0.076). We also observed a significant correlation between a low number of mitoses (<2/10 high-power field) and 68Ga-DOTATOC/PET-positivity (P = 0.004), and an association trend (P = 0.076) between necrosis and 68Ga-DOTATOC/PET-negativity. In conclusion, 68Ga-DOTATOC had better diagnostic performances than 18F-FDG/PET in detecting pulmonary carcinoids. DRs of both techniques remarkably varied according to histology with 68Ga-DOTATOC/PET performing at its best in typical carcinoids, whereas 18F-FDG/PET did the same in atypical carcinoids.68Ga-DOTATOC/PET results were presumably associated with the number of mitoses and the presence of necrosis.

Effect of Contract Research Organization Bureaucracy in Clinical Trial Management: A Model From Lung Cancer.

INTRODUCTION: Contract research organization (CRO) support is largely included in clinical trial management, although its effect in terms of time savings and benefit has not yet been quantified. We performed a retrospective multicenter analysis of lung cancer trials to explore differences in term of trial activation timelines and accrual for studies with and without CRO involvement. MATERIALS AND METHODS: Results regarding study timelines from feasibility data to first patient enrollment were collected from 7 Italian thoracic oncology departments. The final accruals (screened/enrolled patients) are reported. We considered CRO/sponsor-administered and CRO-free trials according to who was responsible for the management of the crucial setup phases. RESULTS: Of 113 trials, 62 (54.9%) were CRO-administered, 34 (30.1%) were sponsor-administered, and 17 (15.0%) were CRO-free. The median time from feasibility invitation to documentation obtainment was 151 days in the CRO-administered trials versus 128 in the sponsor-administered and 120 in the CRO-free trials. The time from document submission to contract signature was 142 days in the CRO-administered versus 128 in the sponsor-administered and 132 in the CRO-free trials. The time from global accrual opening to first patient enrollment was 247 days for the CRO-administered versus 194 in the sponsor-administered and 151 in the CRO-free trials. No significant differences were observed in terms of the median overall timeline: 21 months in the CRO-administered, 15 in the sponsor-administered, and 18 months in the CRO-free studies (P = .29). CONCLUSION: Although no statistically significant differences were identified, the results of our analysis support the idea that bureaucratic procedures might require more time in CRO-administered trials than in sponsor-administered and CRO-free studies. This bureaucratic delay could negatively affect Italian patients' screening and enrollment compared with other countries.