The Prognostic Role of the Number of Involved Structures in Thymic Epithelial Tumors: Results from the ESTS Database.

BACKGROUND: The role of the number of involved structures (NIS) in thymic epithelial tumors (TETs) has been investigated for inclusion in future staging systems, but large cohort results still are missing. This study aimed to analyze the prognostic role of NIS for patients included in the European Society of Thoracic Surgeons (ESTS) thymic database who underwent surgical resection. METHODS: Clinical and pathologic data of patients from the ESTS thymic database who underwent surgery for TET from January 2000 to July 2019 with infiltration of surrounding structures were reviewed and analyzed. Patients' clinical data, tumor characteristics, and NIS were collected and correlated with CSS using Kaplan-Meier curves. The log-rank test was used to assess differences between subgroups. A multivariable model was built using logistic regression analysis. RESULTS: The final analysis was performed on 303 patients. Histology showed thymoma for 216 patients (71.3%) and NET/thymic carcinoma [TC]) for 87 patients (28.7%). The most frequently infiltrated structures were the pleura (198 cases, 65.3%) and the pericardium in (185 cases, 61.1%), whereas lung was involved in 96 cases (31.7%), great vessels in 74 cases (24.4%), and the phrenic nerve in 31 cases (10.2%). Multiple structures (range, 2-7) were involved in 183 cases (60.4%). Recurrence resulted in the death of 46 patients. The CSS mortality rate was 89% at 5 years and 82% at 10 years. In the univariable analysis, the favorable prognostic factors were neoadjuvant therapy, Masaoka stage 3, absence of metastases, absence of myasthenia gravis, complete resection, thymoma histology, and no more than two NIS. Patients with more than two NIS presented with a significantly worse CSS than patients with no more than two NIS (CSS 5- and 10-year rates: 9.5% and 83.5% vs 93.2% and 91.2%, respectively; p = 0.04). The negative independent prognostic factors confirmed by the multivariable analysis were incomplete resection (hazard ratio [HR] 2.543; 95% confidence interval [CI] 1.010-6.407; p = 0.048) and more than two NIS (HR 1.395; 95% CI 1.021-1.905; p = 0.036). CONCLUSIONS: The study showed that more than two involved structures are a negative independent prognostic factor in infiltrative thymic epithelial tumors that could be used for prognostic stratification.

BRCA1-associated protein 1: Tumor predisposition syndrome and Kury-Isidor syndrome, from genotype-phenotype correlation to clinical management.

The BAP1 tumor suppressor gene encodes a deubiquitinase enzyme involved in several cellular activities, including DNA repair and apoptosis. Germline pathogenic variants in BAP1 have been associated with heritable conditions including BAP1 tumor predisposition syndrome 1 (BAP1-TPDS1) and a neurodevelopmental disorder known as Kury-Isidor syndrome (KURIS). Both these conditions are caused by monoallelic, dominant alterations of BAP1 but have never been reported in the same subject or family, suggesting a mutually exclusive genotype-phenotype correlation. This distinction is extremely important considering the early onset and aggressive nature of the types of cancer reported in individuals with TPDS1. Genetic counseling in subjects with germline BAP1 variants is fundamental to predicting the effect of the variant and the expected phenotype, assessing the potential risk of developing cancer for the tested subject and the family members who may carry the same variant and providing the multidisciplinary clinical team with the proper information to establish precise surveillance and management protocols.

Lung cancer multi-omics digital human avatars for integrating precision medicine into clinical practice: the LANTERN study.

BACKGROUND: The current management of lung cancer patients has reached a high level of complexity. Indeed, besides the traditional clinical variables (e.g., age, sex, TNM stage), new omics data have recently been introduced in clinical practice, thereby making more complex the decision-making process. With the advent of Artificial intelligence (AI) techniques, various omics datasets may be used to create more accurate predictive models paving the way for a better care in lung cancer patients. METHODS: The LANTERN study is a multi-center observational clinical trial involving a multidisciplinary consortium of five institutions from different European countries. The aim of this trial is to develop accurate several predictive models for lung cancer patients, through the creation of Digital Human Avatars (DHA), defined as digital representations of patients using various omics-based variables and integrating well-established clinical factors with genomic data, quantitative imaging data etc. A total of 600 lung cancer patients will be prospectively enrolled by the recruiting centers and multi-omics data will be collected. Data will then be modelled and parameterized in an experimental context of cutting-edge big data analysis. All data variables will be recorded according to a shared common ontology based on variable-specific domains in order to enhance their direct actionability. An exploratory analysis will then initiate the biomarker identification process. The second phase of the project will focus on creating multiple multivariate models trained though advanced machine learning (ML) and AI techniques for the specific areas of interest. Finally, the developed models will be validated in order to test their robustness, transferability and generalizability, leading to the development of the DHA. All the potential clinical and scientific stakeholders will be involved in the DHA development process. The main goals aim of LANTERN project are: i) To develop predictive models for lung cancer diagnosis and histological characterization; (ii) to set up personalized predictive models for individual-specific treatments; iii) to enable feedback data loops for preventive healthcare strategies and quality of life management. DISCUSSION: The LANTERN project will develop a predictive platform based on integration of multi-omics data. This will enhance the generation of important and valuable information assets, in order to identify new biomarkers that can be used for early detection, improved tumor diagnosis and personalization of treatment protocols. ETHICS COMMITTEE APPROVAL NUMBER: 5420 - 0002485/23 from Fondazione Policlinico Universitario Agostino Gemelli IRCCS - Università Cattolica del Sacro Cuore Ethics Committee. TRIAL REGISTRATION: clinicaltrial.gov - NCT05802771.

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

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

Association of the Extent of Resection with Survival in Multiple Primary Lung Cancer: A Systematic Review.

BACKGROUND: The incidence of synchronous multiple primary lung cancer (SMPLC) has progressively increased, due to recent advances in imaging. To date, no guidelines defining recommendations for patients' selection and no standard treatment of cases with SMPLC have been defined.The primary aim of this systematic review was to assess survival among patients treated with lobectomy or sublobar resection MPLC. METHODS: Comprehensive literature search of Medline, the Cochrane Library, reference lists, and ongoing studies was performed according to a prospectively registered design (PROSPERO: CRD42019115487). All studies published between 1998 and December 2020 that examined treatments with lobectomy compared to sublobar resection were included. Two double-blind investigators independently selected articles.Primary outcomes were to assess the 5-year overall survival (OS) rate among patients treated with lobectomy or sublobar resection and the impact of lymph node status on 5-year OS and 5-year disease-free survival in patients with MPLC. RESULTS: The search yielded 424 articles; 4 observational studies met the inclusion criteria and collectively evaluated 298 patients with a mean age ranging from 61.5 to 67 years. A total of 112 patients were treated for bilateral synchronous tumors and 186 patients for unilateral multiple synchronous tumors. All included studies showed that the type of resection, lobectomy or limited resection, had no significant impact on survival. CONCLUSION: Limited resection is a valuable treatment option for MPLC. However, the clinical level of evidence of the studies found is low and randomized studies are needed to clarify the extent of resection in MPLC.

Lymphadenectomy for lung carcinoids: Which factors may predict nodal upstaging? A multi centric, retrospective study.

OBJECTIVE: To investigate risk factors for nodal upstaging in patients with lung carcinoids and to understand which type of lymphadenectomy is most appropriate. METHODS: Data regarding patients with lung carcinoids, who underwent surgical resection and lymphadenectomy in five institutions from January 1, 2005 to December 31, 2019, were collected and retrospectively analyzed. Clinical and pathological tumor characteristics were correlated to analyze lymph node upstaging. RESULTS: The analysis was conducted on 283 patients. Pathology showed 230 typical and 53 atypical carcinoids. Nodal and mediastinal upstaging occurred in 33 (11.6%) and 16 (5.6%) patients, respectively. At the univariable analysis, nodal upstaging was significantly correlated with central location (p = 0.003), atypical histology (p < 0.001), pT dimension (p = 0.004), and advanced age (p = 0.043). The multivariable analysis confirmed atypical histology (odds ratio [OR]: 11.030; 95% confidence interval [CI]: 4.837-25.153, p < 0.001) and central location (OR: 3.295; 95% CI: 1.440-7.540, p = 0.005) as independent prognostic factors for nodal upstaging. Atypical histology (p < 0.001), pT dimension (p = 0.036), number of harvested lymph node stations (p = 0.047), and type of lymphadenectomy (p < 0.001) correlated significantly with mediastinal upstaging. The multivariable analysis confirmed atypical histology (OR: 5.408; 95% CI: 1.391-21.020, p = 0.015) and pT (OR: 1.052; 95% CI: 1.021-1.084, p = 0.001) as independent prognostic factors. CONCLUSION: Atypical histology, dimension, and central location are associated with a high-risk for occult hilo-mediastinal metastases, and mediastinal radical dissection may predict nodal upstaging. Thus, we suggest radical mediastinal lymph node dissection in high-risk tumors, reserving sampling, or lobe-specific dissection in peripheral, small typical carcinoids.

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

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

Role of Peripheral Blood Markers for Detecting Response and Predicting Prognosis in Patients with Non-small-cell Lung Cancer Undergoing Neoadjuvant Therapy and Surgery.

INTRODUCTION: To date, no validated predictors of response before neoadjuvant therapy (NAD) are currently available in locally advanced non-small-cell lung cancer (NSCLC). In this study, different peripheral blood markers were investigated before NAD (pre-NAD) and after NAD/before surgery (post-NAD) to evaluate their influence on the treatment outcomes. METHODS: Patients affected by locally advanced NSCLC (cT1-T4/N0-2/M0) who underwent NAD followed by surgery from January 1996 to December 2019 were considered for this retrospective analysis. The impact of peripheral blood markers on downstaging post-NAD and on overall survival (OS) was evaluated using multivariate logistic and Cox regression models. Time to event analysis was performed by means of Kaplan-Meier survival curves and Log Rank tests at 5 years from surgery. RESULTS: Two hundred and seventy-two consecutive patients were included. Most of the patients had Stage III NSCLC (83.5%). N2 disease was reported in 188 (69.1%) patients. Surgical resection was performed in patients with stable disease or downstaging post-NAD. Nodal downstaging was observed in 80% of clinical N2 (cN2) patients. The median follow-up of the total series was 74 months (range 6-302). Five-year OS in the overall population and in N2 population was 74.6% and 73.5%, respectively. The pre-surgery platelets level (PLT) (p = 0.019) and the variation (pre-NAD/post-NAD) of the neutrophil/lymphocyte ratio (p = 0.024) were identified as independent prognostic factors of OS. The preoperative PLT value (p value = 0.031) was confirmed as the only predictor of NAD response. CONCLUSIONS: The clinical role of peripheral blood markers in locally advanced NSCLC needs to be further investigated. Based on these preliminary results, these factors may be used as auxiliary markers for the prediction of response to neoadjuvant treatment and as prognostic factors for stratification in multimodal approaches.

Application of the International System for Reporting Serous Fluid Cytopathology (TIS): A retrospective institutional study.

BACKGROUND: Cytology of serous effusions is an important diagnostic tool for the diagnosis of cancer, staging, and prognosis of the patient. Herein, we retrospectively applied the International System for Reporting Serous Fluid Cytopathology (TIS) and provided the corresponding risks of malignancy (ROMs). METHODS: Pleural, pericardial, and peritoneal effusion samples were retrieved from the archives of our department and reclassified according to the TIS. The ROM for each category was calculated based on available surgical follow-up. RESULTS: A total of 3790 effusions were studied. Pleural samples (1292) were reclassified as follows: 27 (2.1%) as non-diagnostic (ND), 1014 (78.5%) as negative for malignancy (NFM), 86 (6.6%) as atypia of undetermined significance (AUS), 29 (2.3%) as suspicious of malignancy (SFM), and 136 (10.5%) as malignant (M). Pericardial samples (241) were reclassified as follows: 4 (1.6%) as ND, 173 (71.8%) as NFM, 10 (4.1%) as AUS, 7 (3%) as SFM, and 47 (19.5%), as M. Peritoneal cases (2257) were re-categorised as follows: 31 (1.4%) as ND, 1897 (84%) as NFM, 39 (1.7%) as AUS, 53 (2.4%) as SFM, and 237 (10.5%) as M. The respective ROM values for each category were 18.5%, 15%, 45.3%, 93%, and 100% in pleural effusions; 25%, 13.2%, 35%, 100%, and 100% in pericardial effusions; and 19.3%, 10.4%, 43.5%, 100%, and 100% in peritoneal effusions. CONCLUSIONS: Pleural, pericardial, and peritoneal cytology show high specificity and moderate sensitivity in the evaluation of serous effusions. The ROMs reported in our study were mostly concordant with those published according to the TIS.

The value of cytology in distinguishing malignant mesothelioma: An institutional experience of 210 cases reclassified according to the International System for Reporting Serous Fluid Cytopathology (ISRSFC).

OBJECTIVE: Malignant mesothelioma (MM) is usually diagnosed by histological examination of tissue samples; however, effusion cytology offers an opportunity to identify a strong possibility for mesothelioma diagnosis at an early stage. We conducted a retrospective analysis of cytological specimens from a large series of histologically proven MM diagnosed over 19 years. The cases were reviewed and reclassified according to the International System for Reporting Serous Fluid Cytopathology (ISRSFC). METHODS: A total of 450 cases were identified. Cytological analysis was present in 210 patients (164 pleural and 46 peritoneal effusions). All cases were reviewed and reclassified according to the proposed ISRSFC scheme. A comparison among the cytomorphological features was made throughout the different diagnostic categories. RESULTS: The 210 cases were histologically diagnosed as follows: 192 (91.4%) cases had an epithelioid type and 18 (8.6%) had a sarcomatoid subtype of MM. The cytological cases were reclassified as follows: 2 (0.9%) as non-diagnostic (ND), 81 (38.6%) as negative for malignancy (NFM), 4 (1.9%) as atypia of undetermined significance (AUS), 11 (5.2%) as suspicious for malignancy (SFM), 112 (53.4%) as malignant (MAL). Sarcomatoid cells in the MAL category were characterised cytomorphologically by more pronounced discohesion. In comparison with the epithelioid subtype, the tumour cells appeared solitary with moderate or marked nuclear pleomorphism, and irregular chromatin. CONCLUSIONS: It is important to recognise the cytological characteristics of this aggressive entity to suggest an early and precise possible diagnosis. Morphological features, coupled with clinico-radiological data may help the clinicians in adequately managing the patients.

Prognostic factors for survival in advanced thymomas: The role of the number of involved structures.

BACKGROUND AND OBJECTIVES: The Masoka-Koga and tumor node metastases staging systems for thymoma are based on structures involved, but the prognostic role of the number of infiltrated/involved structures is still debated. We analyzed the prognostic role of involved structures and their combinations in locally advanced thymomas patients. METHODS: Data on 174 surgically treated locally advanced thymoma patients from 1/01/1990 to 31/12/2015 were reviewed. Clinical and pathological characteristic, involved structures, number of involved structures and different combinations were correlated to cancer specific survival (CSS) using Kaplan-Meier product-limit method. RESULTS: Five and 10-year CSS was 92% and 87%. Masaoka Stage 3 (p < 0.001), absence of pericardial involvement (p = 0.001), number of involved structures (p = 0.018), R0 (p < 0.001) and adjuvant radiotherapy (p = 0.008) were favorable prognostic CSS factors. A significant better prognosis was present in ≤2 involved structures vs >2 involved structures (5- and 10-year CSS: 95% and 93% vs. 80% and 51%). Multivariable analysis confirmed as independent prognostic factor R0 (p = 0.033, hazard ratio [HR]: 0.093, 95% confidence interval [CI] 0.010-0.827) and number of involved structures (p = 0.046, HR: 0.187, 95% CI: 0.036-0.968). In Masaoka Stage 3, patients with ≤2 involved structures had a significant better CSS than patients with >2 (10-year CSS: 98% vs. 73%, p = 0.008). CONCLUSIONS: The number of involved structures and the concomitant involvement of the pericardium seems to be associated with a poor prognosis in surgically treated advanced thymoma patients.

Non-Small Cell Lung Cancer with Chest Wall Involvement: Integrated Treatment or Surgery Alone?

BACKGROUND: The aim of this study was to identify prognostic factors in patients affected by non-small cell lung cancer (NSCLC) with chest wall (CW) involvement, analyzing different strategies of treatment and surgical approaches. METHODS: Records of 59 patients affected by NSCLC with CW involvement underwent surgery were retrospectively reviewed, from January 2000 to March 2013. RESULTS: Induction therapy was administered to 18 (30.5%) patients while adjuvant treatment to 36 (61.0%). In 36 (61%) patients, lung resection was associated only with a parietal pleural resection while in 23 (39%) with CW en-bloc resection. Overall 5-year survival was 34%. Prognostic factors were evaluated in the 51 (86.4%) completely resected (R0) patients.Five-year survival was 60% in patients undergoing induction therapy followed by surgery and 24% in those who underwent surgery as first treatment (p = 0.11). Five-year survival was better in the neoadjuvant group than that in the surgery group in IIB (T3N0) p-stage (100 vs 28%, p = 0.03), while in the IIIA (T3N1-2,T4N0) p-stage it was of 25 vs 0%, respectively (p = 0.53).No 5-year survival difference was found in case of parietal pleural resection versus CW en-bloc resection (p = 0.27) and in case of only parietal pleural involvement versus soft tissue (p = 0.78).In case of incomplete resection (R1), patients undergoing adjuvant radiotherapy had better 2-year survival than patients untreated: 60% vs 0% (p = 0.025). CONCLUSIONS: Type of surgical resection and the deep of infiltration of disease do not influence survival in this subset of patients. Integrated treatments seem to be suitable: neoadjuvant therapies ensure a better survival rate than surgery alone in IIB and IIIA patients, instead adjuvant radiotherapy proves a fundamental option in incomplete resections.

Digital Devices Improve Chest Tube Management: Results from a Prospective Randomized Trial.

BACKGROUND: Digital devices could help clinical practice measuring the air leak, but their role is still debated. Aim of this study is to test advantages using these devices. METHODS: From June 2012 to May 2015, we enrolled 95 patients undergoing lobectomy or wedge resection in a prospective randomized trial. Patients were divided into two groups: group D (digital, 50 patients) evaluated with digital device and group E (empirical, 45 patients) evaluated with water seal. Logistic regression analysis and receiver operating characteristic (ROC) curve analysis were used to select and assess predictors of persistent air leak. In group D, chest drain was removed if the air leak was absent or < 0.5 L/h for 12 consecutive hours and in group E if clinical signs of air leak were absent. RESULTS: Mean hospitalization and mean chest tube stay was 6.0 ± 3.3 and 4.4 ± 3.2 days, respectively, prolonged air leak occurred in nine (8%). Hospitalization was 5.8 ± 2.5 versus 6.2 ± 4.2 days (p = 0.5), while mean chest tube stay was 4.1 ± 2.0 versus 4.6 ± 3.5 days (p = 0.4) in group D and group E, respectively. Clamping test was needed in one patient in group D and in seven in group E (p = 0.019). At multivariate analysis, heart disease (p < 0.0001), lobectomy (p < 0.0001), fused fissure (p < 0.0001), and air leakage in first postoperative (p.o.) day were predictors of persistent air leak (AUC on the ROC curve of 69.7%, sensibility: 77.8%). In group D, an air leak value > 0.2 L/h with spikes over 0.5 L/h in third p.o. was predictive of persistent air leak, with chest tube duration of 7.73 ± 5.20 versus 4.32 ± 1.33 days (AUC: 83%, sensitivity: 80%, p < 0.0001). CONCLUSION: In our experience, digital devices reduced observer variability and mistakes in chest tube management, thus identifying patients at risk for prolonged air leak.