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.

PUREAIR protocol: randomized controlled trial of intensive pulmonary rehabilitation versus standard care in patients undergoing surgical resection for lung cancer.

BACKGROUND: Non-small cell lung cancer is the most common type of lung cancer. Surgery is proven to be the most effective treatment in early stages, despite its potential impact on quality of life. Pulmonary rehabilitation, either before or after surgery, is associated with reduced morbidity related symptoms and improved exercise capacity, lung function and quality of life. METHODS: We describe the study protocol for the open-label randomized controlled trial we are conducting on patients affected by primary lung cancer (stages I-II) eligible for surgical treatment. The control group receives standard care consisting in one educational session before surgery and early inpatient postoperative physiotherapy. The treatment group receives, in addition to standard care, intensive rehabilitation involving 14 preoperative sessions (6 outpatient and 8 home-based) and 39 postoperative sessions (15 outpatient and 24 home-based) with aerobic, resistance and respiratory training, as well as scar massage and group bodyweight exercise training. Assessments are performed at baseline, the day before surgery and one month and six months after surgery. The main outcome is the long-term exercise capacity measured with the Six-Minute Walk Test; short-term exercise capacity, lung function, postoperative morbidity, length of hospital stay, quality of life (Short Form 12), mood disturbances (Hospital Anxiety and Depression Scale) and pain (Numeric Rating Scale) are also recorded and analysed. Patient compliance and treatment-related side effects are also collected. Statistical analyses will be performed according to the intention-to-treat approach. T-test for independent samples will be used for continuous variables after assessment of normality of distribution. Chi-square test will be used for categorical variables. Expecting a 10% dropout rate, assuming α of 5% and power of 80%, we planned to enrol 140 patients to demonstrate a statistically significant difference of 25 m at Six-Minute Walk Test. DISCUSSION: Pulmonary Resection and Intensive Rehabilitation study (PuReAIR) will contribute significantly in investigating the effects of perioperative rehabilitation on exercise capacity, symptoms, lung function and long-term outcomes in surgically treated lung cancer patients. This study protocol will facilitate interpretation of future results and wide application of evidence-based practice. TRIAL REGISTRATION: ClinicalTrials.gov Registry n. NCT02405273 [31.03.2015].

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.

Primary Sarcomatoid Carcinoma of the Lung: Radiometabolic ((18)F-FDG PET/CT) Findings and Correlation with Clinico-Pathological and Survival Results.

INTRODUCTION: Pulmonary sarcomatoid carcinoma (PSC) is a very rare and uninvestigated subtype of non-small cell lung cancer (NSCLC). METHODS: The aims of this study were to define the radiometabolic features (by (18)F-FDG PET/CT) in a bi-centric cohort of 49 PSC patients and to explore their relation with clinico-pathological characteristics and long-term survival results after surgical treatment. RESULTS: There were 40 males and 9 females aged 65.2 ± 10.47 years. Overall long-term survival was 26.7 % at 5 years. Mean and median values of SUVmax were 15.21 and 15, respectively (SD ±5.5). Performing an age-, gender- and staging-matched analysis comparing PSC Stage-I only with a cohort of Stage-I NSCLC (n = 93), we observed significantly higher SUVmax values in PSC group (15.11 vs 7.66, p = 0.001). CONCLUSIONS: No differences in terms of SUVmax were found with regard to tumour dimensions, histology (pure vs mixed, pleomorphic vs others), pathological stage and pattern of recurrence. P-stage, surgical radicality, vascular/lymphatic invasion but not SUVmax affected long-term survival in PSC.

Time-Trend Analysis of Pulmonary and Diaphragmatic Functionality in Patients with Diaphragmatic Palsy or with Chronic Diaphragmatic Hernia after Surgical Treatment.

Background The aim of this study was to assess long-term pulmonary and diaphragmatic function in two cohorts of patients: the first one affected by diaphragmatic palsy (DP) who underwent plication reinforced by rib-fixed mesh and the second one affected by chronic diaphragmatic hernia (TDH) who underwent surgical reduction and direct suture. Materials and Methods From 1996 to 2011, 10 patients with unilateral DP and 6 patients with TDH underwent elective surgery. Preoperative and long-term (12 months) follow-up assessments were completed in all patients, including pulmonary function tests (PFTs) with diffusion of the lung for carbon monoxide (DLCO), measure of maximum inspiratory pressure (MIP) assessed both in standing and in supine positions, blood gas analysis, chest computed tomographic (CT) scan, and dyspnea score. The Pearson chi-square test, Fisher exact test, and Student t-test were applied when indicated. Results At long-term (12 months) postoperative follow-up, patients operated for DP showed a significant improvement in terms of forced expiratory volume in 1 second (FEV1%) (+ 18.2%, p < 0.001), forced vital capacity (FVC%) (+ 12.8%, p < 0.001), DLCO% (+ 8.3%, p = 0.04), and Po 2 (+ 9.86 mm Hg, p < 0.001) when compared with baseline values. Conversely, when considering the TDH group, only the levels of Po 2 were found to be significantly higher in the postoperative assessment (+ 8.3 mm Hg, p = 0.04). Although MIP increased in both the groups after surgery, a persistent and significant decrease of MIP was detected in TDH group when comparing the levels assessed in supine position with those measured in the standing position (p < 0.001). Medical Research Council dyspnea scale improved in the DP group by a factor of 0.80 (p < 0.001) and in the TDH group by a factor of 0.33 (p = 0.175). Conclusion In patients who underwent surgery for DP, good long-term results may be predicted in terms of pulmonary flows, volumes, and DLCO. Conversely, in patients who underwent elective surgery for chronic TDH, a persistent overall restrictive pattern, lower MIP values in supine position, and paradoxical motion could be expected.

Bronchopulmonary Carcinoids causing Cushing Syndrome: Results from a Multicentric Study Suggesting a More Aggressive Behavior.

OBJECTIVE: Cushing syndrome (CS) caused by bronchopulmonary carcinoids (BCs) is a very rare entity. The aim of this study was to revisit the features of a multicenter clinical series to identify significant prognostic factors. METHODS: From January 2002 to December 2013, the clinical and pathological data of 23 patients (treated in five different institutions) were retrospectively reviewed. Survival analysis was performed to explore the relative weight of potential prognostic factors. RESULTS: Median age and male/female ratio were 48 years and 14/9, respectively. Most (> 80%) of the patients presented with CS-related symptoms at diagnosis. Tumor location was peripheral in 13 patients (57%) and central in 10 (43%). All patients but two (treated with chemotherapy) underwent surgical resection with curative intent. Definitive cyto/histology was indicative of typical carcinoid (TC) in 16 cases (70%) and atypical carcinoid (AC) in 7 cases (30%). A complete remission of CS was obtained in 16 cases (70%). Lymph nodal involvement was detected in 11 cases (48%), with N2 disease occurring in 7 (∼ 30% of all cases). Four patients (22%) experienced a relapse of the disease after radical surgery. Overall 5-year survival (long-term survival, LTS) was 60%, better in TCs when compared with AC (LTS: 66 v s. 48%, p = 0.28). Log-rank analysis identified ECOG performance status, cTNM and cN staging, pTNM and pN staging, persistence of CS and relapses (local p = 0.006; distant p = 0.001) as significant prognostic factors in this cohort of patients. CONCLUSION: BCs causing CS are characterized by a high rate of lymph-nodal involvement, a suboptimal prognosis (5-year survival = 60%, 66% in TCs) and a remarkable risk of relapse even after radical resection. Advanced stage, lymph-nodal involvement and the persisting of the CS after treatment correlate with a poor prognosis.

Soluble Epidermal Growth Factor Receptors (sEGFRs) in Cancer: Biological Aspects and Clinical Relevance.

The identification of molecules that can reliably detect the presence of a tumor or predict its behavior is one of the biggest challenges of research in cancer biology. Biological fluids are intriguing mediums, containing many molecules that express the individual health status and, accordingly, may be useful in establishing the potential risk of cancer, defining differential diagnosis and prognosis, predicting the response to treatment, and monitoring the disease progression. The existence of circulating soluble growth factor receptors (sGFRs) deriving from their membrane counterparts has stimulated the interest of researchers to investigate the use of such molecules as potential cancer biomarkers. But what are the origins of circulating sGFRs? Are they naturally occurring molecules or tumor-derived products? Among these, the epidermal growth factor receptor (EGFR) is a cell-surface molecule significantly involved in cancer development and progression; it can be processed into biological active soluble isoforms (sEGFR). We have carried out an extensive review of the currently available literature on the sEGFRs and their mechanisms of regulation and biological function, with the intent to clarify the role of these molecules in cancer (and other pathological conditions) and, on the basis of the retrieved evidences, speculate about their potential use in the clinical setting.

Preliminary Evidence on the Diagnostic and Molecular Role of Circulating Soluble EGFR in Non-Small Cell Lung Cancer.

Assessment of biological diagnostic factors providing clinically-relevant information to guide physician decision-making are still needed for diseases with poor outcomes, such as non-small cell lung cancer (NSCLC). Epidermal growth factor receptor (EGFR) is a promising molecule in the clinical management of NSCLC. While the EGFR transmembrane form has been extensively investigated in large clinical trials, the soluble, circulating EGFR isoform (sEGFR), which may have a potential clinical use, has rarely been considered. This study investigates the use of sEGFR as a potential diagnostic biomarker for NSCLC and also characterizes the biological function of sEGFR to clarify the molecular mechanisms involved in the course of action of this protein. Plasma sEGFR levels from a heterogeneous cohort of 37 non-advanced NSCLC patients and 54 healthy subjects were analyzed by using an enzyme-linked immunosorbent assay. The biological function of sEGFR was analyzed in vitro using NSCLC cell lines, investigating effects on cell proliferation and migration. We found that plasma sEGFR was significantly decreased in the NSCLC patient group as compared to the control group (median value: 48.6 vs. 55.6 ng/mL respectively; p = 0.0002). Moreover, we demonstrated that sEGFR inhibits growth and migration of NSCLC cells in vitro through molecular mechanisms that included perturbation of EGF/EGFR cell signaling and holoreceptor internalization. These data show that sEGFR is a potential circulating biomarker with a physiological protective role, providing a first approach to the functional role of the soluble isoform of EGFR. However, the impact of these data on daily clinical practice needs to be further investigated in larger prospective studies.

PET/CT assessment of neuroendocrine tumors of the lung with special emphasis on bronchial carcinoids.

Pulmonary neuroendocrine tumors (pNETs) arise from bronchial mucosal cells known as enterochromaffin cells which are part of the diffuse neuroendocrine system. The pathological spectrum of pNETs ranges from low-/intermediate-grade neoplasms such as bronchial carcinoids (BCs), also known as typical or atypical carcinoids, to high-grade neoplasms as large-cell neuroendocrine carcinoma and small-cell lung cancer. The tumor biology of pNETs still represents a matter of open debate. The distinct features among the different pNETs include not only their pathologic characteristics but also their clinical behavior, epidemiology, treatment, and prognosis. In this sense, a correct pathological identification in the preoperative setting is a key element for planning the best strategy of care in pNETs and especially in BCs. Controversial results have been reported on the diagnostic accuracy of fluorine-18-fluorodeoxyglucose positron emission tomography or positron emission tomography/computed tomography (F-18-FDG PET or PET/CT) in BCs. On the other hand, there is increasing evidence supporting the use of PET with somatostatin analogues (DOTA-TOC, DOTA-NOC, or DOTA-TATE) labeled with gallium-68 (Ga-68) in pNETs. Herein, we review the pertinent literature aiming to better define the current state of art of PET/CT in the detection and histological differentiation of pNETs with special emphasis on BCs.

The Influence of COVID-19 on New Lung Cancer Diagnoses, by Stage and Treatment, in Northern Italy.

The COVID-19 pandemic has had a significant impact on new cancer diagnoses. This study aims to evaluate the implications of the lockdown period on new lung cancer diagnoses in northern Italy. We compared 2020 with 2019 cancer registry data, reporting the variations by age, stage, and treatments. In 2020, 303 lung cancer cases were registered, 21 fewer than in 2019. Cases fell in men (-31 patients, 9.6%) but not in women (+10 patients, +3.1%). A significant drop in stage I from 19.8% to 12.9% (p < 0.05) and an increase in stage III (12.7% vs. 19.1%; p < 0.05) was observed. Histological confirmation dropped (70.1% vs. 60.1%; p < 0.05) while cytology increased (12% vs. 20.8%; p < 0.01). Surgery declined (28.7% vs. 21.5%; p < 0.05) but increased in stage III (19.5% vs. 25.9%; p = 0.46), while chemotherapy increased (17.6% vs. 34.3%; p < 0.01) for all stages. During the pandemic, new lung cancer diagnoses dropped only in men. The reorganization of health services has ensured a decrease in surgical interventions (due to the unavailability of operating rooms) counterbalanced by an increase in chemotherapy.

Clinical Relevance of Subcentimetric Lymph Node Biopsy in the Diagnosis of Ocular Sarcoidosis.

PURPOSE: To evaluate the clinical relevance of subcentimetric lymph node biopsy via mediastinoscopy in patients with presumed ocular sarcoidosis (OS). METHODS: Retrospective study of consecutive patients who underwent biopsy via mediastinoscopy for suspected OS. The biopsy outcomes and clinical features of patients with subcentimetric nodes and of those with lymph nodes >1 cm were compared. RESULTS: A total of 67 patients with presumed OS were included. Forty-two patients (63%) had lymph nodes ≥1 cm in diameter, while 25(37%) showed subcentimetric lymph nodes. Biopsy was consistent with sarcoidosis in 83% of patients with lymph nodes ≥1 cm and in 76% of patients with subcentimetric lymph nodes (p = .60). Patients with OS who had subcentimetric lymph nodes had less lymphopenia (p = .01), lower lysozyme values (p = .03) and a longer diagnostic delay compared to those with larger lymph nodes. CONCLUSIONS: The biopsy of subcentimetric lymph nodes via mediastinoscopy may provide a histological diagnosis and reduce diagnostic delay.

Rehabilitation for lung cancer patients undergoing surgery: results of the PUREAIR randomized trial.

BACKGROUND: Surgery for non-small cell lung cancer is proven to be the most effective treatment in early stages, although concerns exist on its negative impact on patients' overall fitness. AIM: To establish whether intensive pulmonary rehabilitation, preoperative and postoperative, improves exercise capacity in patients undergoing lung resection. DESIGN: Single center, unblinded, designed for superiority, 1:1 randomized controlled trial with two parallel arms. SETTING: S. Maria Nuova Hospital of Reggio Emilia (Reggio Emilia, Italy). POPULATION: Patients referred from local lung cancer multidisciplinary team for lung resection. METHODS: Patients were randomized to either standard of care (SC) or SC + intensive perioperative pulmonary rehabilitation (SC+PR). The primary aim was to investigate the effectiveness of pulmonary rehabilitation in improving exercise capacity six months after surgery. Additionally, we wanted to investigate the same effect shortly after surgery (at one month), as well as the overall impact of rehabilitation on lung function, postoperative complications and length of stay, quality of life, mood disturbances and pain. Sample was sized based on the primary outcome assuming a minimal clinically significant difference of 25 meters in exercise tolerance, measured with 6 minutes walking test. RESULTS: The exercise tolerance at 6 months after surgery was significantly higher in patients undertaking PR compared to SC (+48.9 meters vs. -7.5 meters respectively, difference: +56.4 meters, 95% CI: 29.6-83.0, P<0.001) and it showed significantly lower impairment at 1 month after surgery in the intervention group (-3.0 meters vs. -30.1 meters difference: +27.1 meters, 95% CI: 3.4-50.8, P=0.025). No other significant differences between groups were found. CONCLUSIONS: Comparison between groups showed that pulmonary rehabilitation, administered pre and postoperatively, significantly improved exercise capacity at 6 months in patients undergoing lung resection; it also significantly reduced the decrease in exercise tolerance observed 1 month after surgery. CLINICAL REHABILITATION IMPACT: The PUREAIR trial highlights the importance of combined preoperative and postoperative rehabilitation in reducing physical deconditioning in lung cancer patients undergoing surgery. Comprehensive pulmonary rehabilitation improves exercise capacity at 1 and 6 months after surgery. The PUREAIR trial results increase knowledge on comprehensive rehabilitation's outcomes in the first six months after surgery.

18F-fluorodeoxyglucose positron emission tomography in malignant pleural mesothelioma: diagnostic and prognostic performance and its correlation to pathological results.

Although 18F-fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) scan has been generally validated in the staging of malignant pleural mesothelioma (MPM), its diagnostic and prognostic performances are not clearly established. Aiming to identify possible factors causing 18F-fluorodeoxyglucose PET/CT false-negative results and influencing prognosis in MPM patients, we analysed clinical, radiometabolic and pathological features in 141 MPM patients who underwent diagnostic 18F-fluorodeoxyglucose PET/CT scan (January 2009-July 2018) at 2 high-volume institutions. The Fisher's exact test and the Cox model were used in statistical analysis. Overall detection rate was 88.3% with 16 patients (11.6%) presenting with a standardized uptake value (SUV) max <2.5 (PET-negative). PET-negative cases were more frequently detected in older patients (P = 0.027) and early-stage tumours (33.3% false-negative in stage I and 40.0% false-negative in T1-tumours, with P = 0.014 both). Mean SUVmax value was higher in sarcomatoid (11.8 ± 4.6) and biphasic MPM (9.3 ± 7.0), rather than in epithelioid MPM (6.9 ± 3.8, P < 0.001). Concerning overall survival, SUVmax (both as continuous and as categorical variable) was found to be a prognostic factor, in addition to stage (P = 0.032) and histology (P = 0.014) as confirmed by multivariable analysis (hazard ratio 2.65, confidence interval 1.23-5.70; P < 0.001). In the light of such results, we highlight that a low fluorodeoxyglucose uptake might be observed in more than 10% MPMs, especially in early-stage tumours affecting elderly patients. Furthermore, high SUVmax values significantly correlated with a worse prognosis.