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Background: Intraoperative localisation of nodal disease in non-small cell lung cancer (NSCLC) can be challenging. Lymph node localisation via radiopharmaceuticals is used in many conditions; we tested the feasibility of this approach in NSCLC. Methods: NSCLC patients were prospectively recruited. Intraoperative peri-tumoral injections of [99mTc]Tc-albumin nanocolloids were performed, followed by removing the tumour and locoregional lymph nodes. These were examined ex vivo with a gamma probe and labelled sentinel lymph nodes (SLNs) if they showed any activity or non-sentinel lymph nodes (nSLNs) if they did not. Thereafter, the surgical field was scanned with the probe; any further radioactive lymph node was removed and labelled as “extra” SLNs (eSLNs). All specimens were sent to histology, and metastatic status was recorded. Results: 48 patients were enrolled, and 290 nodal stations were identified: 179 SLNs, 87 nSLNs, and 24 eSLNs. A total of 44 nodal metastases were identified in 22 patients, with 36 of them (82%) located within SLNs. Patients with nSLNs metastases had at least a co-existing positive SLN. No metastases were found in eSLNs. Conclusions: The technique shows high sensitivity for intraoperative nodal metastases identification. This information could allow selective lymphadenectomies in low-risk patients or more aggressive approaches in high-risk patients.

The immune-specialized environment of the healthy brain is tightly regulated to prevent excessive neuroinflammation. However, after cancer development, a tissue-specific conflict between brain-preserving immune suppression and tumor-directed immune activation may ensue. To interrogate potential roles of T cells in this process, we profiled these cells from individuals with primary or metastatic brain cancers via integrated analyses on the single-cell and bulk population levels. Our analysis revealed similarities and differences in T cell biology between individuals, with the most pronounced differences observed in a subgroup of individuals with brain metastasis, characterized by accumulation of CXCL13-expressing CD39+ potentially tumor-reactive T (pTRT) cells. In this subgroup, high pTRT cell abundance was comparable to that in primary lung cancer, whereas all other brain tumors had low levels, similar to primary breast cancer. These findings indicate that T cell-mediated tumor reactivity can occur in certain brain metastases and may inform stratification for treatment with immunotherapy.

Purpose: Oncogenic gene fusions involving the 3′ region of ROS1 kinase have been identified in various human cancers. In this study, we sought to characterize ROS1 fusion genes in non–small cell lung cancer (NSCLC) and establish the fusion proteins as drug targets.Experimental Design: An NSCLC tissue microarray (TMA) panel containing 447 samples was screened for ROS1 rearrangement by FISH. This assay was also used to screen patients with NSCLC. In positive samples, the identity of the fusion partner was determined through inverse PCR and reverse transcriptase PCR. In addition, the clinical efficacy of ROS1 inhibition was assessed by treating a ROS1-positive patient with crizotinib. The HCC78 cell line, which expresses the SLC34A2–ROS1 fusion, was treated with kinase inhibitors that have activity against ROS1. The effects of ROS1 inhibition on proliferation, cell-cycle progression, and cell signaling pathways were analyzed by MTS assay, flow cytometry, and Western blotting.Results: In the TMA panel, 5 of 428 (1.2%) evaluable samples were found to be positive for ROS1 rearrangement. In addition, 1 of 48 patients tested positive for rearrangement, and this patient showed tumor shrinkage upon treatment with crizotinib. The patient and one TMA sample displayed expression of the recently identified SDC4–ROS1 fusion, whereas two TMA samples expressed the CD74–ROS1 fusion and two others expressed the SLC34A2–ROS1 fusion. In HCC78 cells, treatment with ROS1 inhibitors was antiproliferative and downregulated signaling pathways that are critical for growth and survival.Conclusions: ROS1 inhibition may be an effective treatment strategy for the subset of patients with NSCLC whose tumors express ROS1 fusion genes. Clin Cancer Res; 18(17); 4570–9. ©2012 AACR.

PDF file - 36K, Details of FISH and RT-PCR analysis of ROS1 positive patients

Purpose: The high mortality rate for lung cancer is likely to be reduced by the development of a panel of sensitive biological markers able to identify early-stage lung cancers or subjects at high risk. The aim of this study was to establish the frequency of K-ras and p53 mutations and p16INK4A, RASSF1A, and NORE1A hypermethylation in sputum of a large cohort of cancer-free heavy smokers and to assess whether these markers are suitable for a routine use in the clinical practice for the early diagnosis of pulmonary cancer.Experimental Design: Sputum samples were collected from 820 heavy smokers. Inclusion criteria consisted of radiologic and cytologic absence of pulmonary lesions, age at least 60 years, male gender, and a smoking history of at least 20 pack-years.Results: The analysis identified 56 individuals (6.9%) with one molecular alteration. p53 mutation and p16INK4A, RASSF1A, and NORE1A methylation frequencies were 1.9%, 5.1%, 0.8%, and 1.0%, respectively; no K-ras mutations were found. One patient with p53 mutations was diagnosed with an early-stage lung cancer after 3-years of follow-up. The molecular analysis of bronchoscopy samples confirmed in half of the cases alterations present in sputum without revealing additional molecular changes.Conclusions: Genetic and epigenetic abnormalities can be detected in cancer-free heavy smokers. Although the predictive value of the cancer risk is still to be established as it requires not less than 5 years of follow-up, p53 and p16INK4A are more promising candidates than K-ras, RASSF1A, and NORE1A for the pulmonary molecular screening of heavy smokers healthy individuals.

PDF file - 66K, Clinical and histopathologic features of patients included in TMA

PDF file - 35K, Primer sequences used for PCR in this study

Supplementary Tables S1-S3 from Molecular Alterations in Spontaneous Sputum of Cancer-Free Heavy Smokers: Results from a Large Screening Program

PDF file - 37K, Clinical and histopathologic features of patients screened for ROS1 at the University of Colorado

PDF file - 322K, Micrographs of H&E and IHC of two squamous cell ROS1 positive cases

PDF file - 42K

PDF file - 397K, Western blot analysis of signaling pathways in Ba/F3 cells expressing ROS1 gene fusion

(1) Background: Once lung lesions are identified on CT scans, they must be characterized by assessing the risk of malignancy. Despite the promising performance of computer-aided systems, some limitations related to the study design and technical issues undermine these tools’ efficiency; an “intelligent agent” to detect and non-invasively characterize lung lesions on CT scans is proposed. (2) Methods: Two main modules tackled the detection of lung nodules on CT scans and the diagnosis of each nodule into benign and malignant categories. Computer-aided detection (CADe) and computer aided-diagnosis (CADx) modules relied on deep learning techniques such as Retina U-Net and the convolutional neural network; (3) Results: Tests were conducted on one publicly available dataset and two local datasets featuring CT scans acquired with different devices to reveal deep learning performances in “real-world” clinical scenarios. The CADe module reached an accuracy rate of 78%, while the CADx’s accuracy, specificity, and sensitivity stand at 80%, 73%, and 85.7%, respectively; (4) Conclusions: Two different deep learning techniques have been adapted for CADe and CADx purposes in both publicly available and private CT scan datasets. Experiments have shown adequate performance in both detection and diagnosis tasks. Nevertheless, some drawbacks still characterize the supervised learning paradigm employed in networks such as CNN and Retina U-Net in real-world clinical scenarios, with CT scans from different devices with different sensors’ fingerprints and spatial resolution. Continuous reassessment of CADe and CADx’s performance is needed during their implementation in clinical practice., Cancers, 15 (2), ISSN:2072-6694

Neuroendocrine tumors (NETs) are epithelial neoplasms with predominant neuroendocrine differentiation that arise in most organs of the body. Mediastinal NETs are very rare, and account for no more than 5% of all mediastinal tumors. R0 surgery represents the milestone of treatment. Here, we describe a case of a locally advanced primary atypical carcinoid of the mediastinum. This was initially considered inoperable due to infiltration of a great vessel and was successfully resected after neoadjuvant treatment as a result of very extensive surgery. Only through an accurate preoperative diagnosis and good radiological planning is it possible to obtain satisfactory oncological results., Locally advanced primary mediastinal atypical carcinoid.

Objectives: We examined a series of malignant pleural mesothelioma (MPM) patients who consecutively underwent surgery in our institution during the last 20 years. Across this period, we changed our surgical approach to MPM, adopting extended pleurectomy and decortication (eP/D) instead of extrapleural pneumonectomy (EPP). In this study, we compare the perioperative outcomes and long-term survival of patients who underwent EPP vs. eP/D. Methods: A retrospective analysis was carried out of all the MPM patients identified from our departmental database who underwent EPP or P/D from 2000 to 2021. Clavien–Dindo criteria was adopted to score postoperative complications, while Kaplan–Meier methods and a Cox multivariable analysis were used to perform the survival analysis. Results: Of 163 patients, 78 (48%) underwent EPP and 85 (52%) eP/D. Induction chemotherapy was significantly administrated more often in the eP/D group (88% vs. 51%). Complete trimodality treatment including induction chemotherapy, radical surgery, and adjuvant radiotherapy was administered in 74% of the eP/D group versus 32% of the EPP group (p < 0.001). The postoperative morbidity rate was higher in the eP/D group (54%) compared to the EPP group (36%) (p = 0.02); no statistically significant differences were identified concerning major complications (EPP 43% vs. eP/D 24%, p = 0.08). No statistical differences were identified in 30-day mortality, 90-day mortality, median disease-free, and overall survival statistics between the two groups. The Cox multivariable analysis confirmed no induction chemotherapy (HR, 0.5; p = 0.002), RDW (HR, 1.08; p = 0.02), and the presence of pathological nodal disease (HR, 1.99; p = 0.001) as factors associated with worse survival in the entire series. Conclusions: Our data support that eP/D is a well-tolerated procedure allowing the implementation of a trimodality strategy (induction chemotherapy, surgery, and radiotherapy) in most MPM patients. When eP/D is offered in this setting, the oncological results are comparable to EPP. To obtain the best oncological results, the goal of surgical resection should be macroscopic complete resection (R0) in carefully selected patients (clinical N0).

Regulatory T (Treg) cells are a barrier for tumor immunity and a target for immunotherapy. Using single-cell transcriptomics, we found that CD4+ T cells infiltrating primary and metastatic colorectal cancer and non-small-cell lung cancer are highly enriched for two subsets of comparable size and suppressor function comprising forkhead box protein P3+ Treg and eomesodermin homolog (EOMES)+ type 1 regulatory T (Tr1)-like cells also expressing granzyme K and chitinase-3-like protein 2. EOMES+ Tr1-like cells, but not Treg cells, were clonally related to effector T cells and were clonally expanded in primary and metastatic tumors, which is consistent with their proliferation and differentiation in situ. Using chitinase-3-like protein 2 as a subset signature, we found that the EOMES+ Tr1-like subset correlates with disease progression but is also associated with response to programmed cell death protein 1–targeted immunotherapy. Collectively, these findings highlight the heterogeneity of Treg cells that accumulate in primary tumors and metastases and identify a new prospective target for cancer immunotherapy. Human primary and metastatic tumors harbor CD4+ Treg cells that can suppress antitumor immune responses. Bonnal et al. identify an intratumoral type 1 Treg-like CD4+ T cell subset that expresses the transcription factor EOMES, granzyme K and CHI3L2. This EOMES+ T cell subset correlates with disease progression but is responsive to PD-1 checkpoint blockade immunotherapy.

Background The impact of active cancer in COVID-19 patients is poorly defined; however, most studies showed a poorer outcome in cancer patients compared to the general population. Methods We analysed clinical data from 557 consecutive COVID-19 patients. Uni-multivariable analysis was performed to identify prognostic factors of COVID-19 survival; propensity score matching was used to estimate the impact of cancer. Results Of 557 consecutive COVID-19 patients, 46 had active cancer (8%). Comorbidities included diabetes (n = 137, 25%), hypertension (n = 284, 51%), coronary artery disease (n = 114, 20%) and dyslipidaemia (n = 122, 22%). Oncologic patients were older (mean age 71 vs 65, p = 0.012), more often smokers (20% vs 8%, p = 0.009), with higher neutrophil-to-lymphocyte ratio (13.3 vs 8.2, p = 0.046). Fatality rate was 50% (CI 95%: 34.9;65.1) in cancer patients and 20.2% (CI 95%: 16.8;23.9) in the non-oncologic population. Multivariable analysis showed active cancer (HRactive: 2.26, p = 0.001), age (HRage>65years: 1.08, p 248mU/mL: 2.42, p = 0.007), PaO2/FiO2 (HRcontinuous: 1.00, p 0.5ng/mL: 2.21, p

Backgrounds Oligometastatic Non-Small Cell Lung Cancer (NSCLC) patients represent a category without a standard therapeutic approach. However, in selected oligometastatic NSCLC, radical surgery seems to offer a good prognosis. This retrospective study aimed to analyse the long-term outcomes of synchronous oligometastatic patients treated with curative intent and identify the factors associated with better results and the proposal of a risk stratification system for classifying the synchronous oligometastatic NSCLC. Methods The medical records of patients from 18 centres with pathologically diagnosed synchronous oligometastatic NSCLC were retrospectively reviewed. The inclusion criteria were synchronous oligometastatic NSCLC, radical surgical treatment of the primary tumour with or without neoadjuvant/adjuvant therapy and radical treatment of all metastatic sites. The Kaplan – Meier method estimated survivals. A stratified backward stepwise Cox regression model was assessed for multivariable survival analyses. Results 281 patients were included. The most common site of metastasis was the brain, in 50.89 % patients. Median overall survival was 40 months (95 % CI: 29–53). Age ≤65 years (HR = 1.02, 95 % CI: 1.00–1.05; p = 0.019), single metastasis (HR = 0.71, 95 % CI: 0.45–1.13; p = 0.15) and presence of contralateral lung metastases (HR = 0.30, 95 % CI: 0.15 – 0.62; p = 0.001) were associated with a good prognosis. The presence of pathological N2 metastases negatively affected survival (HR = 2.00, 95 % CI: 1.21–3.32; p = 0.0065). These prognostic factors were used to build a simple risk classification scheme. Conclusions Treatment of selected synchronous oligometastatic NSCLC with curative purpose could be conducted safely and at acceptable 5-year survival levels, especially in younger patients with pN0 disease.

Primary lung signet‐ring cell carcinomas are a rare entity and only a few cases of pure signet‐ring cell carcinomas of the lung are reported in the English literature. They usually have an aggressive behavior and a poor prognosis because in most cases they are identified at an advanced stage. We present a unique case of primary signet‐ring cell carcinoma of the lung because the patient was HIV positive, a heavy smoker, and also the tumor, discovered incidentally during chest x‐ray, was a pure type of signet‐ring cell carcinoma. Surgical therapy associated with chemoradiotherapy represents the gold standard in the care of these patients., Primary lung signet‐ring cell carcinomas are a rare entity characterized by poor outcome due to the infiltrating nature of this tumor. We present a unique case of primary signet‐ring cell carcinoma of the lung in an HIV‐positive patient discovered incidentally. An early diagnosis can be of extreme importance for patient survival, as in our case.

Background: Persistent air leak is a common complication after lung resection causing prolonged length of stay and increased healthcare costs. Surgical intervention can be an option, but other more conservative approaches should be considered first. Here, we describe the use of flexible bronchoscopy to apply fibrin glue and autologous blood sequentially to the damaged lung. We named the technique “flexible thoracoscopy”. Methods: Medical records from patients with persistent air leaks after lung resection were collected retrospectively. Depending on the type of aerostasis that was performed, two groups were created: flexible thoracoscopy and surgery (thoracotomy). Flexible thoracoscopy was introduced at our institution in 2013. We entered the pleural space with a bronchoscope following the same surgical pathway that was used for tube thoracostomy. Perioperative characteristics and outcomes were analyzed using R software (ver. 3.4.4). Results: From 1997 to 2021, a total of 23 patients required an intervention for persistent air leaks. Aerostasis was performed via flexible thoracoscopy in seventeen patients (69%) and via thoracotomy in six patients (31%). The median age was 70 years (22–82). Twenty patients were males (87%). There was no difference in age, sex distribution, BMI, comorbidities and FEV1%. An ASA score of 3 was more represented in the flexible thoracoscopy group; however, no evidence of a difference was found when compared to the thoracotomy group (p = 0.124). Length of in-hospital stay and chest tube duration was also similar between groups (p = 1 and p = 0.68, respectively). Conclusions: Aerostasis achieved either by flexible thoracoscopy or by thoracotomy showed similar results. We believe that flexible thoracoscopy could be a valid alternative to facilitate minimally invasive treatments for persistent air leaks. Further studies are needed to confirm these results.

Objectives: Lung cancer detection by low-dose computed tomographic screening reduces mortality. However, it is essential to assess cost-effectiveness. We present a cost-effectiveness analysis of screening in Italians at high risk of lung cancer, from the point of view of the Italian tax-payer. Materials and methods: We used a decision model to estimate the cost-effectiveness of annual screening for 5 years in smokers (≥30 pack-years) of 55–79 years. Patients diagnosed in the COSMOS study were the screening arm; patients diagnosed and treated for lung cancer in the Lombardy Region, Italy, constituted the usual care arm. Treatment costs were extracted from our hospital database. Lung cancer survival in screened patients was adjusted for 2-year lead-time bias. Life-years and quality-adjusted life-years were estimated by stage at diagnosis, from which incremental cost-effectiveness ratios per life-year and quality-adjusted life-year gained were estimated. Results: Base-case incremental cost-effectiveness ratios were 3297 and 2944 euro per quality-adjusted life-year and life-year gained, respectively. Deterministic sensitivity analysis indicated that these values were particularly sensitive to lung cancer prevalence, screening sensitivity and specificity, screening cost, and treatment costs for stage I and IV disease. From the probabilistic sensitivity analysis incremental cost-effectiveness ratios had a 98 % probability of being

Castleman’s disease is a benign lymphoproliferative disorder affecting both lymph nodes and extranodal loci. Castleman’s disease can occur in practically any part of the body, but it occurs mainly in the thorax (~70%) followed by the abdomen and pelvis, neck and axilla. Clinically, Castleman’s disease can be classified into a unicentric or multicentric form, depending on the number of lymph nodes involved, and histologically into a hyaline vascular variant, plasma cell, mixed cellular or plasmablastic variant. In this mini-review we briefly report and focus on all clinical thoracic manifestations of Castleman’s disease resuming for each of them the possible strategy of treatment.

The aim of this study was to assess the impact of BMI on perioperative outcomes in patients undergoing VATS lobectomy or segmentectomy. Data from 5088 patients undergoing VATS lobectomy or segmentectomy, included in the VATS Group Italian Registry, were collected. BMI (kg/m

Despite the adoption of enhanced recovery programs, the reported postoperative length of stay after robotic surgery is 4 days even in highly specialized centers. We report preliminary results of a pilot study for a new protocol of early discharge (on day 2) with telehealth home monitoring after robotic lobectomy for lung cancer. All patients with a caregiver were discharged on postoperative day 2 with a telemonitoring device if they satisfied specific discharge criteria. Teleconsultations were scheduled once in the afternoon of post-operative day 2, twice on postoperative day 3, and then once a day until the chest tube removal. Post-discharge vital signs were recorded by patients at least four times daily through the device and were available for consultation by two surgeons through phone application. In case of sudden variation of vital signs or occurrence of adverse events, a direct telephone line was available for patients as well as a protected re-hospitalization path. Primary outcome was the safety evaluated by the occurrence of post-discharge complications and readmissions. Secondary outcome was the evaluation of resources optimization (hospitalization days) maintaining the standard of care. During the study period, twelve patients satisfied all preoperative clinical criteria to be enrolled in our protocol. Two of twelve enrolled patients were successively excluded because they did not satisfy discharge criteria on postoperative day 2. During telehealth home monitoring a total of 27/427 vital-sign measurements violated the threshold in seven patients. Among the threshold violations, only 1 out of 27 was a critical violation and was managed at home. No postoperative complication occurred neither readmission was needed. A mean number of three hospitalization days was avoided and an estimated economic benefit of about EUR 500 for a single patient was obtained if compared with patients submitted to VATS lobectomy in the same period. These preliminary results confirm that adoption of telemonitoring allows, in selected patients, a safe discharge on postoperative day 2 after robotic surgery for early-stage NSCLC. A potential economic benefit could derive from this protocol if this data will be confirmed in larger sample.

OBJECTIVES Thymomectomy is gaining consensus over complete thymectomy in early-stage thymoma without myasthenia gravis. This is due both to the difficulty of establishing prospective and randomized controlled studies and to the lack of well-defined selection criteria. This bicentric, retrospective propensity score-matched study aims at comparing oncological outcomes, measured in terms of overall survival and thymoma-related survival, in patients undergoing either thymomectomy or complete thymectomy. METHODS We retrospectively analysed medical records of patients with clinical early-stage (I and II) thymoma undergoing thymomectomy or complete thymectomy. Exclusion criteria were the presence of myasthenia gravis, clinical advanced tumours and thymic carcinoma. A propensity score-matching analysis was applied to reduce potential preoperative selection biases such as comorbidity (Charlson score), tumour maximal diameter and surgical approach (open versus minimal). All variables were dichotomized. RESULTS A total of 255 patients were enrolled from 2 different Hospitals, 126 underwent complete thymectomy and 129 a thymomectomy. Disease-free and thymoma-related survivals showed a 5-year rate of 87.7% and 96.0% and a 10-year rate of 82.2% and 91.9%, respectively. Propensity score-matching analysis selected a total of 176 patients equally divided between the 2 groups. No difference was found for both disease-free (P = 0.11) and thymoma-related (P = 0.37) survival in the 2 groups of resection. Multivariable Cox regression analysis showed that histology (P CONCLUSIONS Thymomectomy is an adequate surgical resection for non-myasthenic thymoma, achieving disease-free and thymoma-related survivals comparable to those after complete thymectomy.

Backgrounds: Since the application of mini-invasive surgery to pulmonary lobectomy, various studies confirmed the feasibility and the safety of the technique, with equivalent oncological standards. However, there are no studies that compare long-term postoperative pain in minimally invasive thoracic surgery. Methods: Between 1 January 2019 and 28 February 2020, we analysed pain scores at 2 weeks, 3 months, 6 months, and 1 year after the operation, where 50 patients underwent a VATS lobectomy and 50 underwent a RATS lobectomy. Pain scores are obtained through a telephone questionnaire, according to a Numerical Rating Scale (NRS). Results: The medias of the NRS scores, at 2 weeks, 3 months, 6 months, and 1 year after the operation were similar in both groups. Group I was composed of 50 patients who underwent a video-assisted lobectomy, while Group II was composed of 50 patients who underwent a robotic-assisted lobectomy. Two weeks after surgery Group I had a NRS value of 2.96 and in Group II it was 2.86; three months after in Group I the value was 2.16 and in Group II it was 2.06; six months after Group I ‘s value was 1.62 and Group II’s was 1.56; one year after in Group I the value was 1.30 and in the Group II was 1.24. For each time interval, no statistically significant differences were found (p > 0.05). Conclusions: In our analysis, RATS and VATS did not have significant differences in post-operative and long-term pain.