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WHO classification of Thoracic Tumours defines lung carcinoid tumours (LCTs) as well-differentiated neuroendocrine neoplasms (NENs) classified in low grade typical (TC) and intermediate grade atypical carcinoids (AC). Limited data exist concerning protein expression and morphologic factors able to predict disease aggressiveness. Though Ki-67 has proved to be a powerful diagnostic and prognostic factor for Gastro-entero-pancreatic NENs, its role in lung NENs is still debated. A retrospective series of 370 LCT from two oncology centers was centrally reviewed. Morphology and immunohistochemical markers (Ki-67, TTF-1, CD44, OTP, SSTR-2A, Ascl1, and p53) were studied and correlated with Overall Survival (OS), Cancer-specific survival (CSS) and Disease-free survival (DFS). Carcinoid histology was confirmed in 355 patients: 297 (83.7%) TC and 58 (16.3%) AC. Ki-67 at 3% was the best value in predicting DFS. Ki-67 ≥ 3% tumours were significantly associated with AC histology, stage III-IV, smoking, vascular invasion, tumour spread through air spaces OTP negativity, and TTF-1, Ascl1 and p53 positivity. After adjustment for center and period of diagnosis, both Ki-67 (≥3 versus <3) and histology (AC versus TC) alone significantly added prognostic information to OS and CSS multivariable model with age, stage and OTP; addition of both variables did not provide further prognostic information. Conversely, an improved significance of the DFS prediction model at multivariate analysis was seen by adding Ki-67 (≥3 versus <3, P adj = 0.01) to TC and AC histological distinction, age, lymph node involvement, residual tumour and OTP. Ki-67 ≥ 3% plays a potentially pivotal role in LCT prognosis, irrespective of histological grade.
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Tumor Carcinoide , Proteína p53 Supresora de Tumor , Humanos , Antígeno Ki-67 , Estudios Retrospectivos , PulmónRESUMEN
According to World Health Organization guidelines, atypical carcinoids (ACs) are well-differentiated lung neuroendocrine tumours with 2-10 mitoses/2 mm2 and/or foci of necrosis (usually punctate). Besides morphological criteria, no further tools in predicting AC clinical outcomes are proposed. The aim of this work was to identify novel factors able to predict AC disease aggressiveness and progression. METHODS AND RESULTS: Three hundred-seventy lung carcinoids were collected and centrally reviewed by two expert pathologists. Morphology and immunohistochemical markers (Ki-67, TTF-1, CD44, OTP, SSTR2A, Ascl1, p53, and Rb1) were studied and correlated with disease-free survival (DFS) and overall survival (OS). Fifty-eight of 370 tumours were defined as AC. Survival analysis showed that patients with Ascl1 + ACs and those with OTP-ACs had a significantly worse DFS than patients with Ascl1-ACs and OTP + ACs, respectively. Combining Ascl1 and OTP expressions, groups were formed reflecting the aggressiveness of disease (P = 0.0005). Ki-67 ≥10% patients had a significantly worse DFS than patients with Ki-67 <10%. At multivariable analysis, Ascl1 (present versus absent, hazard ratio [HR] = 3.42, 95% confidence interval [CI] 1.35-8.65, P = 0.009) and OTP (present versus absent, HR = 0.26, 95% CI 0.10-0.68, P = 0.006) were independently associated with DFS. The prognosis of patients with Ki-67 ≥10% tended to be worse compared to that with Ki-67 <10%. On the contrary, OTP (present versus absent, HR = 0.28, 95% CI 0.09-0.89, P = 0.03), tumour stage (III-IV versus I-II, HR = 4.25, 95% CI 1.42-12.73, P = 0.01) and increasing age (10-year increase, HR = 1.67, 95% CI 1.04-2.68, P = 0.03) were independently associated with OS. CONCLUSION: This retrospective analysis of lung ACs showed that Ascl1 and OTP could be the main prognostic drivers of postoperative recurrence.
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Tumor Carcinoide , Carcinoma Neuroendocrino , Neoplasias Pulmonares , Humanos , Supervivencia sin Enfermedad , Antígeno Ki-67/análisis , Estudios Retrospectivos , Tumor Carcinoide/patología , Neoplasias Pulmonares/patología , Pulmón/patología , Pronóstico , Factores de Transcripción con Motivo Hélice-Asa-Hélice BásicoRESUMEN
INTRODUCTION: Poorly differentiated neuroendocrine carcinomas (NECs) are characterized by aggressive clinical course and poor prognosis. No reliable prognostic markers have been validated to date; thus, the definition of a specific NEC prognostic algorithm represents a clinical need. This study aimed to analyze a large NEC case series to validate the specific prognostic factors identified in previous studies on gastro-entero-pancreatic and lung NECs and to assess if further prognostic parameters can be isolated. METHODS: A pooled analysis of four NEC retrospective studies was performed to evaluate the prognostic role of Ki-67 cut-off, the overall survival (OS) according to primary cancer site, and further prognostic parameters using multivariable Cox proportional hazards model and machine learning random survival forest (RSF). RESULTS: 422 NECs were analyzed. The most represented tumor site was the colorectum (n = 156, 37%), followed by the lungs (n = 111, 26%), gastroesophageal site (n = 83, 20%; 66 gastric, 79%) and pancreas (n = 42, 10%). The Ki-67 index was the most relevant predictor, followed by morphology (pure or mixed/combined NECs), stage, and site. The predicted RSF response for survival at 1, 2, or 3 years showed decreasing survival with increasing Ki-67, pure NEC morphology, stage III-IV, and colorectal NEC disease. Patients with Ki-67 <55% and mixed/combined morphology had better survival than those with pure morphology. Morphology pure or mixed/combined became irrelevant in NEC survival when Ki-67 was ≥55%. The prognosis of metastatic patients who did not receive any treatment tended to be worse compared to that of the treated group. The prognostic impact of Rb1 immunolabeling appears to be limited when multiple risk factors are simultaneously assessed. CONCLUSION: The most effective parameters to predict OS for NEC patients could be Ki-67, pure or mixed/combined morphology, stage, and site.
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Carcinoma Neuroendocrino , Tumores Neuroendocrinos , Neoplasias Pancreáticas , Neoplasias Gástricas , Humanos , Pronóstico , Estudios Retrospectivos , Antígeno Ki-67 , Neoplasias Pancreáticas/patología , Carcinoma Neuroendocrino/patología , Tumores Neuroendocrinos/patología , Neoplasias Gástricas/patologíaRESUMEN
BACKGROUND: Little information is available concerning prognostic factors for bronchopulmonary large cell neuroendocrine carcinomas (BP-LCNECs) and even less is known about combined LCNECs (Co-LCNECs). We investigated whether an integrated morphological, immunohistochemical, and molecular approach could be used for their prognostic evaluation. METHODS: Morphological (including combined features), proliferative (mitotic count/Ki-67 index), immunohistochemical (napsin A, p40, TTF-1, CD44, OTP, SSTR2A, SSTR5, mASH1, p53, RB1, and MDM2), and genomic (TP53, RB1, ATM, JAK2, KRAS, and STK11) findings were analyzed in BP-LCNECs from 5 Italian centers, and correlated with overall survival (OS). The Ki-67 index was expressed as the percentage of positive cells in hot spots as indicated in the WHO 2019 Digestive System Tumors and, for Co-LCNECs, the Ki-67 index was evaluated only in the LCNEC component. RESULTS: A total of 111 LCNECs were distinguished into 70 pure LCNECs, 35 Co-LCNECs (27 with adenocarcinoma [ADC] and 8 with squamous cell carcinoma [SqCC]), and 6 LCNECs with only napsin A immunoreactivity. The Ki-67 index cutoff at 55% evaluated in the neuroendocrine component was the most powerful predictor of OS (log-rank p = 0.0001) in all LCNECs; 34 cases had a Ki-67 index <55% (LCNEC-A) and 77 had a Ki-67 index ≥55% (LCNEC-B). Statistically significant differences in OS (log-rank p = 0.0001) were also observed between pure and Co-LCNECs. A significant difference in OS was found between pure LCNECs-A and Co-LCNECs-A (p < 0.05) but not between pure LCNECs-B and Co-LCNECs-B. Co-LCNEC-ADC and LCNEC napsin A+ cases had longer OS than pure LCNEC and Co-LCNEC-SqCC cases (log-rank p = 0.0001). On multivariable analysis, tumor location, pure versus combined features, and napsin A, but no single gene mutation, were significantly associated with OS after adjustment for Ki-67 index and study center (p < 0.05). CONCLUSIONS: The Ki-67 proliferation index and the morphological characterization of combined features in LCNECs seem to be important tools for predicting clinical outcome in BP-LCNECs.
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Carcinoma de Células Grandes/diagnóstico , Carcinoma Neuroendocrino/diagnóstico , Antígeno Ki-67/metabolismo , Neoplasias Pulmonares/diagnóstico , Carcinoma de Células Grandes/metabolismo , Carcinoma de Células Grandes/mortalidad , Carcinoma Neuroendocrino/metabolismo , Carcinoma Neuroendocrino/mortalidad , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/mortalidad , Pronóstico , Análisis de SupervivenciaRESUMEN
Background: Mutations in genes encoding one of the subunits of succinate dehydrogenase (SDH) are involved in pheochromocytoma (PHEO) and paraganglioma (PGL) development. Over the last few years, such mutations have also been associated with non-chromaffin tumors. However, immunohistochemistry (IHC) on the tumor tissue and a study on the loss of heterozygosity (LOH) aimed at demonstrating the pathogenic role of SDHx genes have only been employed in a few cases. Case report: We describe the case of a 19-year-old Caucasian man with a germline SDHB mutation, who presented with acne vulgaris resistant to medical treatment. His follow-up for chromaffin tumors was negative, while hormonal tests revealed suppressed gonadotropins with testosterone in the upper range of normality and elevated ß-human chorionic gonadotropin (ß-hCG). At the whole-body enhanced CT scan, a mediastinal lesion suggestive of a germ cell tumor (GCT) was detected. 18FDG-PET (fluorodeoxyglucose-positron emission tomography) imaging showed low glucose metabolism at the mediastinal site. Surgical removal of the mass was uneventful. Pathology confirmed the diagnosis of GCT consisting of cystic teratoma (95%) and seminoma (5%). IHC for SDHB showed normal protein expression, and genetic analysis of the tumor tissue revealed the absence of SDHB LOH. Normalization of the hormonal tests and acne attenuation were achieved after surgery. Conclusion: We report an incidental association of a germinal SDHB mutation and mediastinal GCT in a young Caucasian man. Our paper highlights the importance of IHC and genetic analysis in confirming the etiologic role of SDHx genes in nonchromaffin tumors, thus excluding incidental associations.
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Neoplasias de las Glándulas Suprarrenales , Paraganglioma , Feocromocitoma , Adulto , Humanos , Masculino , Mutación , Paraganglioma/diagnóstico por imagen , Paraganglioma/genética , Paraganglioma/cirugía , Succinato Deshidrogenasa/genética , Adulto JovenRESUMEN
BACKGROUND: Blood level of C-reactive protein (CRP) at diagnosis is a well-know prognostic bio-marker in different primary tumors, but its role has not been investigated in resectable lung metastases. The aim of our study is to assess the predictive value of baseline (CRP0) and 3rd postoperative day (CRP3) levels on long-term survival of patients undergoing lung metastasectomy. METHODS: A total of 846 consecutive patients underwent the first pulmonary resection for lung metastases between January 2003 and December 2015, including 611 (72%) single surgical procedures, 235 (28%) multiple metastasectomies, 501 (59%) epithelial primary tumors, 276 (33%) sarcomas, 66 (8%) melanomas, 286 (33.8%) with 0 risk factors (CRP0 ≤ 2 and CRP3 ≤ 84 mg/L) and 560 (66.2%) with ≥ 1 risk factor (CRP0 > 2 and/or CRP3 > 84 mg/L). RESULTS: Cumulative 5-year survival was 57% in patients with low CRP (0 risk factors) versus 43% in high CRP (≥ 1 risk factor, p < 0.0002), 62% versus 50% respectively for epithelial tumors (p < 0.0140), and 51% versus 34% for sarcomas (p < 0.0111). Multivariable Cox analysis confirmed a mortality hazard ratio of 2.5 at 1-year and 1.5 at 5-years in patients with high CRP. CONCLUSIONS: Baseline and postoperative CRP levels predict survival of patients with resectable lung metastases. These data provide a rationale for prospective clinical trials testing the efficacy of anti-inflammatory or immune-modulating agents as "adjuvant" therapy after lung metastasectomy, in patients with elevated pre- and/or postoperative CRP levels.
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Biomarcadores de Tumor/metabolismo , Proteína C-Reactiva/metabolismo , Neoplasias Pulmonares/mortalidad , Metastasectomía/mortalidad , Neumonectomía/mortalidad , Femenino , Estudios de Seguimiento , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/secundario , Neoplasias Pulmonares/cirugía , Masculino , Persona de Mediana Edad , Periodo Posoperatorio , Pronóstico , Estudios Prospectivos , Factores de Riesgo , Tasa de SupervivenciaRESUMEN
OBJECTIVES: to date, no consensus has been reached on the surgical gold-standard in pleural mesothelioma (PM). We retrospectively reviewed our experience as a tertiary referral centre, to compare short- and long-term survival of PM patients undergoing different types of surgery. METHODS: in retrospective, observational, single-centre study, we analysed all the patients histologically diagnosed with PM undergoing surgical procedures with palliative or curative intent at IRCCS Istituto Nazionale dei Tumori of Milan, Italy, from January 2003 to December 2020. The primary study endpoint was 10-year overall survival (OS) in three different types of resections: extra-pleural-pneumonectomy (EPP), pleurectomy/decortication (P/D), partial-pleurectomy/pleural-biopsy (PP/B). Secondary endpoints were postoperative hospital stay and postoperative 30-day and 90-day mortality rates. The survival function was estimated using Kaplan-Meier, and the Log-rank test was used for testing differences. Univariable and Multivariable Cox regression models were implemented to estimate Hazard Ratio (HR) for all variables of interest. RESULTS: 243 consecutive patients were enrolled, EPP was performed in 49 (20.2%), P/D in 58 (23.8%), PP/B in 136 (56.0%) patients. The median follow-up time was 19.8 months. 10-year OS was significantly better for P/D group (16%, Log-Rank test p<0.0001) compared to PP/B (1.8%) and EPP (0%). No statistically significant differences were found among the 3 surgical groups in 30- and 90-day mortality rates. At multivariable analysis, gender (male, HR=1.58), type of resection (P/D, HR=0.55) and surgery date (recent years, HR=0.61) were found to be independent prognostic factors for OS. CONCLUSIONS: in PM, lung-sparing curative approach (e.g. P/D) should be preferred in highly selected patients and in highly experienced centres, whenever appropriate. Anyway, when P/D is not indicated, adopting palliative/conservative management (e.g. PP/B) could ensure comparable results as extremely aggressive surgeries (e.g. EPP). The aim of surgery in PM should not be reaching complete resection, but rather accomplishing significant resection allowing to complete the multimodality treatment in highly selected patients in experienced centers.
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Neoplasias Pulmonares , Mesotelioma Maligno , Mesotelioma , Neoplasias Pleurales , Humanos , Masculino , Estudios Retrospectivos , Centros de Atención Terciaria , Neoplasias Pulmonares/patología , Resultado del Tratamiento , Mesotelioma Maligno/cirugía , Neoplasias Pleurales/patología , Neumonectomía/métodos , Modelos de Riesgos ProporcionalesRESUMEN
Background: The management of subsolid nodules (SSNs) in lung cancer screening (LCS) is still a topic of debate, with no current uniform strategy to deal with these lesions at risk of overdiagnosis and overtreatment. The BioMILD LCS trial has implemented a prospective conservative approach for SSNs, managing with annual low-dose computed tomography nonsolid nodules (NSNs) and part-solid nodules (PSNs) with a solid component <5â mm, regardless of the size of the nonsolid component. The present study aims to determine the lung cancer (LC) detection and survival in BioMILD volunteers with SSNs. Materials and methods: Eligible participants were 758 out of 4071 (18.6%) BioMILD volunteers without baseline LC and at least one SSN detected at the baseline or further low-dose computed tomography rounds. The outcomes of the study were LC detection and long-term survival. Results: A total of 844 NSNs and 241 PSNs were included. LC detection was 3.7% (31 out of 844) in NSNs and 7.1% (17 out of 241) in PSNs, being significantly greater in prevalent than incident nodules (8.4% versus 1.3% in NSNs; 14.1% versus 2.1% in PSNs; p-value for both nodule types p<0.01). Most LCs from SSNs were stage I (42/48, 87.5%), resectable (47/48, 97.9%), and caused no deaths. The 8-year cumulative survival of volunteers with LC derived from SSNs and not derived from SSNs was 93.8% and 74.9%, respectively. Conclusion: Conservative management of SSNs in LCS enables timely diagnosis and treatment of LCs arising from SSNs while ensuring the resection of more aggressive LCs detected away from SSNs.
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Pulmonary large cell carcinoma (LCC) is an undifferentiated neoplasm lacking morphological, histochemical, and immunohistochemical features of small cell lung cancer, adenocarcinoma (ADC), or squamous cell carcinoma (SCC). The available molecular information on this rare disease is limited. This study aimed to provide an integrated molecular overview of 16 cases evaluating the mutational asset of 409 genes and the transcriptomic profiles of 20,815 genes. Our data showed that TP53 was the most frequently inactivated gene (15/16; 93.7%) followed by RB1 (5/16; 31.3%) and KEAP1 (4/16; 25%), while CRKL and MYB genes were each amplified in 4/16 (25%) cases and MYC in 3/16 (18.8%) cases; transcriptomic analysis identified two molecular subtypes including a Pure-LCC and an adenocarcinoma like-LCC (ADLike-LCC) characterized by different activated pathways and cell of origin. In the Pure-LCC group, POU2F3 and FOXI1 were distinctive overexpressed markers. A tuft cell-like profile and the enrichment of a replication stress signature, particularly involving ATR, was related to this profile. Differently, the ADLike-LCC were characterized by an alveolar-cell transcriptomic profile and association with AIM2 inflammasome complex signature. In conclusion, our study split the histological marker-null LCC into two different transcriptomic entities, with POU2F3, FOXI1, and AIM2 genes as differential expression markers that might be probed by immunohistochemistry for the differential diagnosis between Pure-LCC and ADLike-LCC. Finally, the identification of several signatures linked to replication stress in Pure-LCC and inflammasome complex in ADLike-LCC could be useful for designing new potential therapeutic approaches for these subtypes.
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Biomarcadores de Tumor , Carcinoma de Células Grandes , Neoplasias Pulmonares , Transcriptoma , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Masculino , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/análisis , Anciano , Persona de Mediana Edad , Femenino , Carcinoma de Células Grandes/genética , Carcinoma de Células Grandes/patología , Carcinoma de Células Grandes/terapia , Perfilación de la Expresión Génica , Mutación , Anciano de 80 o más AñosRESUMEN
BACKGROUND: This multicenter analysis evaluated patient outcome and clinical pathologic features of thymic epithelial tumors after complete surgical resection and adjuvant treatment. METHODS: Histologic classification and clinical staging were performed according to WHO classification and Masaoka staging system, respectively. RESULTS: We analyzed 62 patients, 20 (32%) of whom had myasthenia at diagnosis. Clinical and pathologic staging was as follows: 31 (50%) and 30 (48%) patients had stage I disease, 19 (30%) and 22 (35%) stage II, 5 (8%) and 3 (6%) stage III, 2 (4%) and 2 (3%) stage IVa, and 5 (8%) and 5 (8%) stage IVb, respectively. Histologic examination revealed 11 (19%) type A tumors, 19 (30%) type AB tumors, 7 (12%) type B1 tumors, 11 (17%) type B2 tumors, 11 (17%) type B3 tumors, and 3 (5%) type C tumors. Adjuvant therapies comprised chemotherapy in 3 (5%) patients and radiotherapy in 16 (26%) patients. Median follow-up was 71 months (range 1-145). DFS and OS at 48, 60, and 72 months were 89 and 89%, 86 and 97%, and 95% and 92%, respectively. Myasthenia at the onset of disease (P=0.18 for DFS; P=0.97) and tumor size>5 cm (P=0.94 for DFS; P=0.56) were not prognostic factors. CONCLUSIONS: TETs are rare and indolent tumors. Complete surgical resection followed by adjuvant therapies, such as chemotherapy and/or radiotherapy, in patients at risk of recurrence show very good DFS and OS results, even in cases with radically resected pleural-pulmonary metastases.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Recurrencia Local de Neoplasia/mortalidad , Neoplasias Glandulares y Epiteliales/mortalidad , Neoplasias del Timo/mortalidad , Adulto , Anciano , Anciano de 80 o más Años , Quimioterapia Adyuvante , Terapia Combinada , Femenino , Estudios de Seguimiento , Humanos , Metástasis Linfática , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/patología , Recurrencia Local de Neoplasia/terapia , Estadificación de Neoplasias , Neoplasias Glandulares y Epiteliales/patología , Neoplasias Glandulares y Epiteliales/terapia , Periodo Posoperatorio , Pronóstico , Radioterapia Adyuvante , Estudios Retrospectivos , Tasa de Supervivencia , Neoplasias del Timo/patología , Neoplasias del Timo/terapiaRESUMEN
There is growing evidence that inflammatory, immunologic, and metabolic status is associated with cancer patients survival. Here, we built a simple algorithm to predict lung cancer outcome. Perioperative routine blood tests (RBT) of a cohort of patients with resectable primary lung cancer (LC) were analysed. Inflammatory, immunologic, and metabolic profiles were used to create a single algorithm (RBT index) predicting LC survival. A concurrent cohort of patients with resectable lung metastases (LM) was used to validate the RBT index. Charts of 2088 consecutive LC and 1129 LM patients undergoing lung resection were evaluated. Among RBT parameters, C-reactive protein (CRP), lymphocytes, neutrophils, hemoglobin, albumin and glycemia independently correlated with survival, and were used to build the RBT index. Patients with a high RBT index had a higher 5-year mortality than low RBT patients (adjusted HR 1.93, 95% CI 1.62-2.31). High RBT patients also showed a fourfold higher risk of 30-day postoperative mortality (2.3% vs. 0.5%, p 0.0019). The LM analysis validated the results of the LC cohort. We developed a simple and easily available multifunctional tool predicting short-term and long-term survival of curatively resected LC and LM. Prospective external validation of RBT index is warranted.
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Neoplasias Pulmonares , Humanos , Estudios Prospectivos , Neoplasias Pulmonares/cirugía , Pruebas Hematológicas , Proteína C-Reactiva/metabolismo , Linfocitos/metabolismo , Estudios Retrospectivos , PronósticoRESUMEN
Background: The secreted products of the metastasis suppressor gene KiSS1 may represent useful biomarkers in non-small cell lung cancer (NSCLC) but their levels in patients have remained poorly investigated. We previously found that forced expression of KiSS1 decreased the invasive capability of NSCLC drug-resistant cells and a pro-apoptotic role for KiSS1 has been proposed in head and neck cancer. Thus, we designed a translational investigation including a pilot study to analyze KiSS1 levels in liquid biopsies, and in vitro experiments to explore the biological relevance of KiSS1 modulation. Methods: KiSS1-derived peptide levels in liquid biopsies from 60 NSCLC patients were assayed by ELISA. Preclinical experiments were carried out using quantitative real time polymerase chain reaction (qRT-PCR), ELISA, annexin V-binding and caspase activation assays. Results: We compared KiSS1 release in 3 different matrices (serum, plasma and urine) and the highest levels were detectable in serum (range, 0-4.5 ng/mL). We observed increased levels of seric KiSS1 in NSCLC patients as compared to healthy donors. KiSS1 serum concentrations, after surgical procedure and/or adjuvant therapy. We observed differences among disease stages in urine samples. In preclinical models, KiSS1 mRNA levels were increased by short term exposure to azacytidine, enhanced KiSS1 release was induced by the combination of azacytidine and cisplatin and KiSS1-derived peptides enhanced cisplatin-induced apoptosis. KiSS1 increase was observed upon exposure neurons-enriched cultures to tumor cell conditioned medium. Conclusions: Our results showing a peculiar modulation of KiSS1 levels in liquid biopsies of NSCLC patients and a regulation of cisplatin-induced apoptosis by KiSS1-derived peptides support an involvement of KiSS1 in cell response to treatment and highlight its promising features as a potential biomarker in NSCLC.
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INTRODUCTION: Cytisine, a partial agonist-binding nicotine acetylcholine receptor, is a promising cessation intervention. We conducted a single-center, randomized, controlled trial (RCT) in Italy to assess the efficacy and tolerability of cytisine as a smoking cessation therapy among lung cancer screening participants. METHODS: From July 2019 to March 2020, the Screening and Multiple Intervention on Lung Epidemics RCT enrolled 869 current heavy tobacco users in a low-dose computed tomography screening program, with a randomized comparison of pharmacologic intervention with cytisine plus counseling (N = 470) versus counseling alone (N = 399). The primary outcome was continuous smoking abstinence at 12 months, biochemically verified through carbon monoxide measurement. RESULTS: At the 12-month follow-up, the quit rate was 32.1% (151 participants) in the intervention arm and 7.3% (29 participants) in the control arm. The adjusted OR of continuous abstinence was 7.2 (95% confidence interval: 4.6-11.2). Self-reported adverse events occurred more frequently in the intervention arm (399 events among 196 participants) than in the control arm (230 events among 133 participants, p < 0.01). The most common adverse events were gastrointestinal symptoms, comprising abdominal swelling, gastritis, and constipation. CONCLUSIONS: The efficacy and safety observed in the Screening and Multiple Intervention on Lung Epidemics RCT indicate that cytisine, a very low-cost medication, is a useful treatment option for smoking cessation and a feasible strategy to improve low-dose computed tomography screening outcomes with a potential benefit for all-cause mortality.
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Alcaloides , Neoplasias Pulmonares , Cese del Hábito de Fumar , Humanos , Cese del Hábito de Fumar/métodos , Nicotina/efectos adversos , Vareniclina/uso terapéutico , Detección Precoz del Cáncer , Neoplasias Pulmonares/tratamiento farmacológico , Alcaloides/efectos adversos , Azocinas/efectos adversos , Quinolizinas/efectos adversos , PulmónRESUMEN
BACKGROUND: Combined large cell neuroendocrine carcinoma (CoLCNEC) is given by the association of LCNEC with adeno or squamous or any non-neuroendocrine carcinoma. Molecular bases of CoLCNEC pathogenesis are scant and no standardized therapies are defined. METHODS: 44 CoLCNECs: 26 with adenocarcinoma (CoADC), 7 with squamous cell carcinoma (CoSQC), 3 with small cell carcinoma (CoSCLC), 4 with atypical carcinoid (CoAC) and 4 napsin-A positive LCNEC (NapA+), were assessed for alterations in 409 genes and transcriptomic profiling of 20,815 genes. RESULTS: Genes altered included TP53 (n = 30), RB1 (n = 14) and KRAS (n = 13). Targetable alterations included six KRAS G12C mutations and ALK-EML4 fusion gene. Comparison of CoLCNEC transcriptomes with 86 lung cancers of pure histology (8 AC, 19 ADC, 19 LCNEC, 11 SCLC and 29 SQC) identified CoLCNEC as a separate entity of neuroendocrine tumours with three different molecular profiles, two of which showed a non-neuroendocrine lineage. Hypomethylation, activation of MAPK signalling and association to immunotherapy signature specifically characterized each of three CoLCNEC molecular clusters. Prognostic stratification was also provided. CONCLUSIONS: CoLCNECs are an independent histologic category. Our findings support the extension of routine evaluation of KRAS mutations, fusion genes and immune-related markers to offer new perspectives in the therapeutic management of CoLCNEC.
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BACKGROUND: Three-dimensional (3D) vision systems are available for video-assisted thoracic surgery (VATS). It is unclear whether 3D-VATS is superior to bidimensional (2D) VATS systems. METHODS: We analyzed patients who received 3D-VATS (n = 171) or 2D-VATS (n = 228) lobectomy in a single institutional retrospective comparative study of 399 patients with resectable lung cancer conducted from June 2012 to December 2017. The operative and perioperative data were compared between the 2 groups. RESULTS: Operative time, length of hospital stay, number of dissected lymph nodes, and rate of postoperative complications were similar in both groups. In the 3D group, there was no conversion to thoracotomy for intraoperative major vascular injuries, while conversion to an open procedure for uncontrolled bleeding was recorded in 4 (1.7%) patients in the 2D group. Reoperation for hemostasis and/or aerostasis occurred in 6 (2.6%) patients of the 2D group (p = 0.04). CONCLUSION: Nonrandomized comparison of different surgical approaches is challenging. In our experience, 3D-VATS was safe and effective and offered excellent operative perception and sensitivity, enabling safer dissection of hilar structures. The 3D-VATS system helped skilled surgeons beyond the boundaries of more oncologically aggressive surgery.
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Neoplasias Pulmonares/diagnóstico , Cirugía Torácica Asistida por Video/métodos , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Imagenología Tridimensional/métodos , Tiempo de Internación , Escisión del Ganglio Linfático/métodos , Masculino , Persona de Mediana Edad , Tempo Operativo , Neumonectomía/métodos , Complicaciones Posoperatorias/diagnóstico , Reoperación/métodos , Estudios Retrospectivos , Toracotomía/métodos , Resultado del TratamientoRESUMEN
A 71-year-old male former smoker was referred for worsening hemoptysis from a hilar left tumor without radiologic or bronchoscopic identification of the bleeding source. He underwent an urgent upper lobectomy extended to the pericardium and left phrenic nerve to control active bleeding. Histologic analysis revealed a malignant triton tumor, a rare aggressive subtype of malignant peripheral nerve sheath tumors. This is a case report of unusual pulmonary involvement associated with hemoptysis. Despite radical surgery and multimodal treatment with adjuvant chemotherapy the patient died of systemic dissemination 10 months after surgery, with a disease-free survival of 3 months.
Asunto(s)
Neoplasias Pulmonares/patología , Neurofibrosarcoma/patología , Anciano , Diagnóstico Diferencial , Resultado Fatal , Hemoptisis/etiología , Humanos , Neoplasias Pulmonares/complicaciones , Masculino , Neurofibrosarcoma/complicaciones , Brote de los SíntomasRESUMEN
The extra-pleural pneumonectomy (EPP) is a standardised surgical procedure born for pleural tuberculosis and later used in pleural cancer treatment, especially in malignant pleural mesothelioma (MPM). This systematic review aimed to focus on the actual overall EPP role in surgical oncology. The literature search was performed from January 1985 to January 2018 In PubMed, Embase, and Cochrane according to PRISMA protocol. The search was restricted to publications in English with the research words "extrapleural pneumonectomy", "malignant pleural mesothelioma", "pleural malignancies". The results were then filtered focusing only on papers with series of patients treated with EPP, for mesothelioma and non-mesothelioma malignancies. The search was restricted to publications in English. We found a 5-year overall survival (OS) ranging from 0 to 78%. The peri-operative mortality and morbidity ranged from 0 to 11.8% and 0 to 82.6%, respectively. The most represented and described post-operative complications reported were ARDS, pericardial tamponade, cardiac herniation, pulmonary embolism, respiratory infections, respiratory failure, atrial arrhythmia, myocardial infarction. In referral centres and selected patients, EPP is a cytoreductive or radical surgical treatment in extended pleural malignancies. Prospective studies are needed to standardise the timing of the procedure in a multimodality treatment program, according to the oncological and functional indications, to keep an acceptable complications rate and post-operative quality of life status.
RESUMEN
After complex thoracic exenterations, total diaphragmatic resection and reconstruction is challenging. We describe our novel technique for total diaphragmatic replacement with permeable nonabsorbable mesh after extended pneumonectomy.