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1.
Tuberk Toraks ; 67(3): 197-204, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31709951

RESUMO

Introduction: The results of standard chemotherapy in lung cancer are not very satisfactory, so it is important to identify genetic mutations that provide targeted therapies. Recent reports have suggested influences of racial difference on the frequency of mutation in lung cancer. We aimed to determine the frequency and regional distribution of genetic mutations of non-small cell lung cancer (NSCLC) in Turkey. Materials and Methods: Regional distribution of genetic mutations in lung cancer in Turkey (REDIGMA) study was carried out as a prospective, cross-sectional, observational study in a large number of centers in which lung cancer patients were followed and could perform genetic mutation analysis on patients' biopsy materials. Result: The 703 patients (77.7% male, mean age 63.3 ± 12.5 years) who were diagnosed as NSCLC from 25 different centers were included in the study. Tumor samples from patients were reported as 87.1% adenocarcinoma, 6.4% squamous cell carcinoma and 6.5% other. Mutation tests were found to be positive in 18.9% of these patients. The mutations were 69.9% EGFR, 26.3% ALK, 1.6% ROS and 2.2% PDL. Mutations were higher in women and non-smokers (p<0.000, p<0.001). Again, the frequency of mutations in adenocarcinoma was higher in metastatic disease. There was no difference between the patient's age, area of residence, comorbidity and clinical stage and mutation frequency. Conclusions: Our study revealed that the EGFR mutation rate in Turkey with NSCLC was similar to East European, African-American and Caucasian patients, and was lower than in East Asia.


Assuntos
Adenocarcinoma/genética , Carcinoma de Células Grandes/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma de Células Escamosas/genética , Neoplasias Pulmonares/genética , Adenocarcinoma/patologia , Idoso , Carcinoma de Células Grandes/patologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma de Células Escamosas/patologia , Estudos Transversais , Receptores ErbB/genética , Feminino , Humanos , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Mutação , Estadiamento de Neoplasias , Estudos Prospectivos , Turquia
2.
Acta Gastroenterol Belg ; 82(3): 433-436, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31566333

RESUMO

Large cell neuroendocrine carcinoma of the gallbladder is extremely rare. We present a case report and review of literature. We report the rare outcome of survival at 19 month follow-up and hope to raise awareness about this lesion, its treatment modalities and lend credence to the proposed mechanism of its pathogenesis.


Assuntos
Carcinoma de Células Grandes/patologia , Carcinoma Neuroendócrino/patologia , Neoplasias da Vesícula Biliar/patologia , Carcinoma de Células Grandes/cirurgia , Carcinoma Neuroendócrino/cirurgia , Neoplasias da Vesícula Biliar/cirurgia , Humanos , Resultado do Tratamento
3.
J Ovarian Res ; 12(1): 95, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31615543

RESUMO

BACKGROUND: Large cell neuroendocrine carcinoma is a very rare ovarian neoplasm that has a poor clinical outcome even in the early stage, and there is as yet no established treatment. Diagnostic laparoscopy has been used to determine the possibility of primary optimal cytoreductive surgery or neoadjuvant chemotherapy in patients with advanced epithelial ovarian cancer. However, the role of diagnostic laparoscopy is still unclear in large cell neuroendocrine carcinoma due to its rarity. CASE PRESENTATION: A 31-year-old woman with abdominal distention was referred to our hospital. She was strongly suspected of having advanced ovarian cancer because of a huge pelvic mass, massive ascites, and their appearance on medical imaging. However, cytological examinations from ascitic fluid by abdominal paracentesis did not show any malignant cells. She underwent diagnostic laparoscopy to evaluate the possibility of primary optimal cytoreductive surgery, and only tissue sampling was performed for pathological diagnosis because of the countless disseminated lesions of various sizes in the intraperitoneal organs. The patient had no postoperative complications, leading to the early start of postoperative chemotherapy. CONCLUSIONS: To date, there have been no systematic reviews that focused on determining the treatment strategy using laparoscopy. Diagnostic laparoscopy can be helpful to determine the optimal treatment, including primary debulking surgery, neoadjuvant chemotherapy, or best supportive care, assisting in decision-making particularly for patients with advanced large cell neuroendocrine carcinoma with carcinomatous peritonitis.


Assuntos
Abdome/patologia , Carcinoma de Células Grandes/diagnóstico , Carcinoma Neuroendócrino/diagnóstico , Ovário/patologia , Adulto , Líquido Ascítico/patologia , Carcinoma de Células Grandes/patologia , Carcinoma de Células Grandes/cirurgia , Carcinoma Neuroendócrino/patologia , Carcinoma Neuroendócrino/cirurgia , Procedimentos Cirúrgicos de Citorredução , Feminino , Humanos , Ovário/diagnóstico por imagem , Paracentese/métodos , Peritonite/diagnóstico , Peritonite/patologia
4.
J Neurooncol ; 145(1): 159-165, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31485922

RESUMO

INTRODUCTION: Single-fraction stereotactic radiosurgery (SRS) is delivered predominantly via two modalities: Gamma Knife, and linear accelerator (LINAC). Implementation of the American Tax Payer Relief Act (ATRA) in 2013 represented the first time limitations specifically targeting SRS reimbursement were introduced into federal law. The subsequent impact of the ATRA on SRS utilization in the United States (US) has yet to be examined. METHODS: The National Cancer Database from 2010-2016 identified brain metastases patients from non-small cell lung cancer throughout the US having undergone SRS. Utilization between GKRS and LINAC was assessed before (2010-2012), during (2013-2014) and after (2015-2016) ATRA implementation. RESULTS: In 2013, there was a substantial decrease of LINAC SRS in favor of GKRS in non-academic centers. Over the 3-year span immediately preceding ATRA implementation, 39% of all eligible SRS cases received LINAC. There was a modest decrease in LINAC utilization over the 2 years immediately following ATRA implementation (35%), followed by an increase over the next two years (40%). SRS modality showed differences over the three time periods (unadjusted, p = 0.043), primarily in non-academic centers (unadjusted, p = 0.003). CONCLUSIONS: ATRA implementation in 2013 caused an initial spike in Gamma Knife SRS utilization, followed by a decline to rates similar to the years before implementation. These findings indicate that the ATRA provision mandating Medicare reduction of outpatient payment rates for Gamma Knife to be equivalent with those of LINAC SRS had a significant short-term impact on the radiosurgical treatment of metastatic brain disease throughout the US, serving as a reminder of the importance/impact of public policy on treatment modality utilization by physicians and hospitals.


Assuntos
Neoplasias Encefálicas/cirurgia , Carcinoma Pulmonar de Células não Pequenas/cirurgia , Política de Saúde/legislação & jurisprudência , Neoplasias Pulmonares/cirurgia , Padrões de Prática Médica/estatística & dados numéricos , Radiocirurgia/economia , Radiocirurgia/legislação & jurisprudência , Adenocarcinoma de Pulmão/economia , Adenocarcinoma de Pulmão/patologia , Adenocarcinoma de Pulmão/cirurgia , Idoso , American Recovery and Reinvestment Act , Neoplasias Encefálicas/economia , Neoplasias Encefálicas/secundário , Carcinoma de Células Grandes/economia , Carcinoma de Células Grandes/patologia , Carcinoma de Células Grandes/cirurgia , Carcinoma Pulmonar de Células não Pequenas/economia , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma de Células Escamosas/economia , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/cirurgia , Feminino , Financiamento Governamental , Seguimentos , Humanos , Neoplasias Pulmonares/economia , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Estados Unidos
5.
Pathologica ; 111(2): 70-75, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31388199

RESUMO

Neuroendocrine tumors (NET) are a heterogeneous group of malignancies with a broad spectrum of histomorphologies, tissue origins, and clinical outcomes, which arise from neural crest cells with neuroendocrine differentiation. Salivary gland tumors account for 3-6% of all head and neck neoplasms, while large cell neuroendocrine carcinomas (LCNEC) of the salivary gland are extremely rare, with few cases reported in literature, and only 5 cases involving submandibular gland. The rarity of these tumors in salivary glands is probably related to the scarcity of neuroendocrine cells in this tissue, whose presence is still a matter of debate. Regardless of their low frequency, it is imperative to differentiate these tumors from the much more common squamous cell carcinomas and metastatic NETs, due to different therapeutic approach and prognosis. In this paper, we report the case of a 21-year-old man, with a LCNEC involving a submandibular gland followed by several recurrences over the years. In addition, we include a comprehensive review of the available literature on this topic.


Assuntos
Carcinoma de Células Grandes/diagnóstico por imagem , Carcinoma Neuroendócrino/diagnóstico por imagem , Recidiva Local de Neoplasia/diagnóstico por imagem , Neoplasias da Glândula Submandibular/diagnóstico por imagem , Carcinoma de Células Grandes/patologia , Carcinoma de Células Grandes/terapia , Carcinoma Neuroendócrino/patologia , Carcinoma Neuroendócrino/terapia , Humanos , Masculino , Recidiva Local de Neoplasia/diagnóstico , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/terapia , Glândula Submandibular/diagnóstico por imagem , Glândula Submandibular/patologia , Neoplasias da Glândula Submandibular/patologia , Neoplasias da Glândula Submandibular/terapia , Adulto Jovem
6.
Nat Commun ; 10(1): 3407, 2019 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-31431620

RESUMO

The worldwide incidence of pulmonary carcinoids is increasing, but little is known about their molecular characteristics. Through machine learning and multi-omics factor analysis, we compare and contrast the genomic profiles of 116 pulmonary carcinoids (including 35 atypical), 75 large-cell neuroendocrine carcinomas (LCNEC), and 66 small-cell lung cancers. Here we report that the integrative analyses on 257 lung neuroendocrine neoplasms stratify atypical carcinoids into two prognostic groups with a 10-year overall survival of 88% and 27%, respectively. We identify therapeutically relevant molecular groups of pulmonary carcinoids, suggesting DLL3 and the immune system as candidate therapeutic targets; we confirm the value of OTP expression levels for the prognosis and diagnosis of these diseases, and we unveil the group of supra-carcinoids. This group comprises samples with carcinoid-like morphology yet the molecular and clinical features of the deadly LCNEC, further supporting the previously proposed molecular link between the low- and high-grade lung neuroendocrine neoplasms.


Assuntos
Biomarcadores Tumorais/genética , Tumor Carcinoide/genética , Carcinoma de Células Grandes/genética , Neoplasias Pulmonares/genética , Carcinoma de Pequenas Células do Pulmão/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Tumor Carcinoide/mortalidade , Tumor Carcinoide/patologia , Carcinoma de Células Grandes/mortalidade , Carcinoma de Células Grandes/patologia , Hibridização Genômica Comparativa , Conjuntos de Dados como Assunto , Feminino , Genômica , Proteínas de Homeodomínio/genética , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Pulmão/patologia , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Aprendizado de Máquina , Masculino , Proteínas de Membrana/genética , Pessoa de Meia-Idade , Proteínas do Tecido Nervoso/genética , Prognóstico , Carcinoma de Pequenas Células do Pulmão/mortalidade , Carcinoma de Pequenas Células do Pulmão/patologia , Taxa de Sobrevida , Adulto Jovem
7.
Cancer Sci ; 110(10): 3215-3224, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31432603

RESUMO

Patient-derived xenograft (PDX) models are a useful tool in cancer biology research. However, the number of lung cancer PDX is limited. In the present study, we successfully established 10 PDX, including three adenocarcinoma (AD), six squamous cell carcinoma (SQ) and one large cell carcinoma (LA), from 30 patients with non-small cell lung cancer (NSCLC) (18 AD, 10 SQ, and 2 LA), mainly in SCID hairless outbred (SHO) mice (Crlj:SHO-Prkdcscid Hrhr ). Histology of SQ, advanced clinical stage (III-IV), status of lymph node metastasis (N2-3), and maximum standardized uptake value ≥10 when evaluated using a delayed 18 F-fluoro-2-deoxy-d-glucose positron emission tomography (FDG-PET) scan was associated with successful PDX establishment. Histological analyses showed that PDX had histology similar to that of patients' surgically resected tumors (SRT), whereas components of the microenvironment were replaced with murine cells after several passages. Next-generation sequencing analyses showed that after two to six passages, PDX preserved the majority of the somatic mutations and mRNA expressions of the corresponding SRT. Two out of three PDX with AD histology had epidermal growth factor receptor (EGFR) mutations (L858R or exon 19 deletion) and were sensitive to EGFR tyrosine kinase inhibitors (EGFR-TKI), such as gefitinib and osimertinib. Furthermore, in one of the two PDX with an EGFR mutation, osimertinib resistance was induced that was associated with epithelial-to-mesenchymal transition. This study presented 10 serially transplantable PDX of NSCLC in SHO mice and showed the use of PDX with an EGFR mutation for analyses of EGFR-TKI resistance.


Assuntos
Adenocarcinoma de Pulmão/patologia , Carcinoma de Células Grandes/patologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma de Células Escamosas/patologia , Neoplasias Pulmonares/patologia , Adenocarcinoma de Pulmão/tratamento farmacológico , Adenocarcinoma de Pulmão/genética , Idoso , Idoso de 80 Anos ou mais , Animais , Carcinoma de Células Grandes/tratamento farmacológico , Carcinoma de Células Grandes/genética , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Feminino , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Masculino , Camundongos , Camundongos Pelados , Camundongos SCID , Pessoa de Meia-Idade , Mutação , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Microambiente Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
8.
Cancer Treat Rev ; 78: 42-51, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31437725

RESUMO

The poorly differentiated neuroendocrine carcinomas (NECs) of the larynx are rare tumors that comprise of a small cell-type (SCNEC) and a large cell-type (LCNEC). In order to consolidate the current knowledge about their characteristics and management a systematic review of the available literature was performed. The PubMed/Medline and Scopus databases search resulted in 141 articles published between 1972 and 2019, describing 273 patients: 230 cases were of SCNEC histology (84.2%) and 43 cases were LCNECs (15.8%). Comparing both histological entities, patients with LCNECs were older (63.2 vs. 58.7 years, p = 0.036) than SCNEC patients and had more often primary tumor in a supraglottic larynx (79.5 vs. 56.1%, p = 0.039), advanced-stage neck disease (N2-3, 56.8 vs. 40%, p = 0.061), surgery-based treatment (83.7 vs. 51.9%, p < 0.001) and had no radiotherapy (44.2 vs. 29%, p = 0.071). At presentation, systemic metastases were diagnosed in 12.1% of the patients, whereas disease relapse was experienced by two-thirds (65.3%) of those initially staged M0; systemic relapse, alone or in combination with local/regional recurrence, was the most frequent type of failure (in 71.9%). On multivariate analysis, more advanced disease stage and SCNEC histology adversely influenced disease-specific survival. Wide variations in the pattern of care, including radiotherapy doses and chemotherapy regimens, were found among long-term survivors without known disease at ≥ 24 months of follow-up (N = 36). We conclude that the most effective treatment for poorly differentiated NECs has yet to be determined.


Assuntos
Carcinoma de Células Grandes/patologia , Carcinoma Neuroendócrino/patologia , Carcinoma de Células Pequenas/patologia , Neoplasias Laríngeas/patologia , Carcinoma de Células Grandes/terapia , Carcinoma Neuroendócrino/terapia , Carcinoma de Células Pequenas/terapia , Terapia Combinada , Humanos , Neoplasias Laríngeas/terapia , Prognóstico , Taxa de Sobrevida
9.
Intern Med ; 58(22): 3305-3311, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31366794

RESUMO

A rare case of lung cancer with the simultaneous production of granulocyte colony-stimulating factor (G-CSF) and interleukin-6 (IL-6) is reported. A 79-year-old man was admitted to our hospital due to cachectic symptoms and an increased inflammatory response. Laboratory tests and imaging studies suggested metastatic lung cancer with high serum levels of G-CSF and IL-6. He died of progressive disease, and an autopsy showed that the lung tumor had positive protein expression of both cytokines and a solid growth of large-cell carcinoma with sarcomatoid changes, possibly resulting from the epithelial-mesenchymal transition mediated by IL-6 and leading to widespread metastases.


Assuntos
Carcinoma de Células Grandes/patologia , Transição Epitelial-Mesenquimal/fisiologia , Neoplasias Pulmonares/patologia , Idoso , Autopsia , Fator Estimulador de Colônias de Granulócitos/metabolismo , Humanos , Interleucina-6/metabolismo , Masculino , Sarcoma/patologia
10.
Intern Med ; 58(22): 3289-3294, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31327819

RESUMO

We herein report the case of a 74-year-old woman with a lung tumor. She presented with complaints of blurred and rapid, progressively impaired vision. A visual field examination revealed bilateral concentric contraction of the visual field and a ring scotoma in the right eye. She was diagnosed with cancer-associated retinopathy (CAR) combined with large-cell neuroendocrine carcinoma (LCNEC) of the lung via a visual field examination and underwent thoracoscopic surgery. CAR has been mostly associated with small-cell lung cancer (SCLC). Combined LCNEC is relatively rare and accounts for 10.6% of all LCNECs. This is the first case report of CAR-combined LCNEC.


Assuntos
Carcinoma de Células Grandes/patologia , Neoplasias Pulmonares/patologia , Síndromes Paraneoplásicas Oculares/patologia , Idoso , Carcinoma de Células Grandes/diagnóstico , Feminino , Humanos , Pulmão/patologia , Neoplasias Pulmonares/diagnóstico , Síndromes Paraneoplásicas Oculares/cirurgia
11.
Ann Surg Oncol ; 26(11): 3756-3764, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31313037

RESUMO

BACKGROUND: We evaluated the association between genetic variants in the Notch pathway and survival outcomes of patients with surgically resected NSCLC. METHODS: Sixty-four single nucleotide polymorphisms (SNPs) in the Notch pathway genes were evaluated in the discovery study (n = 354) and two sequential validation studies (n = 772 and n = 746, respectively). The association of genotype with overall survival (OS) and disease-free survival (DFS) was evaluated. RESULTS: Of the 64 SNPs analyzed in the discovery study, 9 were significantly associated with OS or DFS. Among them, the association remained significant only for Deltex-1 (DTX1) rs1732786A>G in the first validation study. The second validation study confirmed again the association between DTX1 rs1732786A>G and survival outcomes. In the combined analysis, rs1732786A>G was significantly associated with better OS and DFS (adjusted HR ·aHR· for OS, 0.75; 95% CI 0.64-0.87; P = 0.0002; aHR for DFS, 0.79; 95% CI 0.71-0.89; P = 0.0001). In vitro luciferase assay showed that the rs1732786G allele was associated with higher promoter activity compared to rs1732786A allele. Consistently, relative mRNA expression level of DTX1 showed significant positive correlation with rs1732786 A-to-G change (Ptrend = 0.02) in tumor tissues. CONCLUSIONS: These results suggest that DTX1 rs1732786 is a potential prognostic factor that may have clinical utility in the management of early stage NSCLC.


Assuntos
Adenocarcinoma/mortalidade , Carcinoma de Células Grandes/mortalidade , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma de Células Escamosas/mortalidade , Neoplasias Pulmonares/mortalidade , Polimorfismo de Nucleotídeo Único , Ubiquitina-Proteína Ligases/genética , Adenocarcinoma/genética , Adenocarcinoma/patologia , Adenocarcinoma/cirurgia , Idoso , Biomarcadores Tumorais/genética , Carcinoma de Células Grandes/genética , Carcinoma de Células Grandes/patologia , Carcinoma de Células Grandes/cirurgia , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/cirurgia , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/cirurgia , Feminino , Seguimentos , Genótipo , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/cirurgia , Masculino , Prognóstico , Taxa de Sobrevida
12.
World J Surg Oncol ; 17(1): 126, 2019 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-31325969

RESUMO

BACKGROUND: The pure large cell type is a rare variant of primary neuroendocrine carcinoma of the gallbladder. Few reports have mentioned extended survival. Although a multimodal treatment has been described in the treatment of such rare disease, redo liver resection has not yet been mentioned. CASE REPORT: A 67-year-old lady was found to have poorly differentiated, high grade, pure large cell neuroendocrine tumor of the gallbladder after cholecystectomy for gallstones. After the diagnosis, staging workup showed a lesion in segment IVB/V of the liver, and chromogranin was elevated (982 mcg/L). The patient underwent central inferior hepatectomy and wedge excision of a lesion in segment III (discovered intra-operatively), with hilar lymphadenectomy. Three months after the first liver resection, she developed a new liver lesion II/III and underwent left lateral liver resection. The patient remained disease-free for 4 months following the second liver resection but then developed recurrent liver disease and was started on chemotherapy. Further progression led to multi-organ failure and death at 26 months from initial diagnosis. CONCLUSION: This is the first reported repeat liver resection in such a rare disease that has led to extended overall survival. We suggest that a group of selected patients with this rare malignancy, and liver-limited disease, may benefit from repeated liver resection.


Assuntos
Carcinoma de Células Grandes/cirurgia , Carcinoma Neuroendócrino/cirurgia , Neoplasias da Vesícula Biliar/cirurgia , Hepatectomia/métodos , Excisão de Linfonodo/métodos , Reoperação , Idoso , Carcinoma de Células Grandes/patologia , Carcinoma Neuroendócrino/patologia , Feminino , Neoplasias da Vesícula Biliar/patologia , Humanos , Prognóstico
13.
Bull Cancer ; 106(9): 725-733, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31202557

RESUMO

BACKGROUND: Despite recent progress, non-small cell lung cancer (NSCLC) first-line treatment remains a platinum-based doublet in most cases. No guidelines exist beyond third line. Chemotherapy rechallenge is an option, but little data is available in NSCLC. Our study aims to describe patients who underwent chemotherapy rechallenge while assessing its efficacy and safety. METHODS: Consecutive patients with advanced-stage NSCLC receiving first-line treatment in Tenon hospital in 2011 were included, with a 5-year follow-up. Patients were analyzed according to chemotherapy rechallenge or not. Chemotherapy rechallenge was defined as re-initiation of a previously administered chemotherapy agent at any point in the treatment sequence, with at least one treatment regimen between first use and rechallenge. RESULTS: Of 149 patients, 18 underwent chemotherapy rechallenge (12%). They were younger (56 vs. 61 years, P=0.04), mostly women (61% vs. 30%, P=0.02), with lepidic adenocarcinoma (23% vs. 3.5%, P=0.03), a better general state of health (100% performance status 0-1 vs. 74%, P=0.04), and fewer cardiovascular comorbidities (16% vs. 42%, P=0.04). They were more likely to have received a receptor tyrosine kinase inhibitor treatment (89% vs. 43%, P=0.0003). Progression-free survival was longer at first use than at rechallenge (median 9.2 vs. 2.7 months, P=0.002). No increased toxicity was observed at rechallenge compared to first use. Finally, a subsequent line of treatment was given after rechallenge in 61% of the patients. CONCLUSION: Patients eligible for chemotherapy rechallenge were those with good prognostic factors. Chemotherapy rechallenge may provide a well-tolerated additional line of treatment, with decreased efficacy compared to its first application.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Grandes/tratamento farmacológico , Carcinoma de Células Grandes/mortalidade , Carcinoma de Células Grandes/patologia , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/mortalidade , Carcinoma de Células Escamosas/patologia , Ex-Fumantes , Feminino , Seguimentos , Humanos , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Intervalo Livre de Progressão , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Retratamento/métodos , Retratamento/estatística & dados numéricos , Fumantes
14.
PLoS One ; 14(6): e0217105, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31166966

RESUMO

Small-cell lung carcinoma (SCLC) and large-cell neuroendocrine lung carcinoma (LCNEC) are high-grade lung neuroendocrine tumors (NET). However, comparative protein expression within SCLC and LCNEC remains unclear. Here, protein expression profiles were obtained via mass spectrometry-based proteomic analysis. Weighted gene co-expression network analysis (WGCNA) identified co-expressed modules and hub genes. Of 34 identified modules, six were significant and selected for protein-protein interaction (PPI) network analysis and pathway enrichment. Within the six modules, the activation of cellular processes and complexes, such as alternative mRNA splicing, translation initiation, nucleosome remodeling and deacetylase (NuRD) complex, SWItch/Sucrose Non-Fermentable (SWI/SNF) superfamily-type complex, chromatin remodeling pathway, and mRNA metabolic processes, were significant to SCLC. Modules enriched in processes, including signal recognition particle (SRP)-dependent co-translational protein targeting to membrane, nuclear-transcribed mRNA catabolic process of nonsense-mediated decay (NMD), and cellular macromolecule catabolic process, were characteristically activated in LCNEC. Novel high-degree hub genes were identified for each module. Master and upstream regulators were predicted via causal network analysis. This study provides an understanding of the molecular differences in tumorigenesis and malignancy between SCLC and LCNEC and may help identify potential therapeutic targets.


Assuntos
Carcinoma de Células Grandes/genética , Carcinoma Neuroendócrino/genética , Perfilação da Expressão Gênica , Redes Reguladoras de Genes , Neoplasias Pulmonares/genética , Proteômica , Carcinoma de Pequenas Células do Pulmão/genética , Idoso , Carcinoma de Células Grandes/metabolismo , Carcinoma de Células Grandes/patologia , Carcinoma Neuroendócrino/metabolismo , Carcinoma Neuroendócrino/patologia , Feminino , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Mapeamento de Interação de Proteínas , Carcinoma de Pequenas Células do Pulmão/metabolismo , Carcinoma de Pequenas Células do Pulmão/patologia
15.
Medicine (Baltimore) ; 98(21): e15613, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31124939

RESUMO

RATIONALE: The incidence of primary large-cell neuroendocrine carcinoma (LCNEC) is extremely rare in the urinary tract. In the present study, we investigated a case of primary LCNEC associated with the upper ureter. PATIENT CONCERN: A 58-year-old Korean female patient with right ureter mass, which was accidentally detected. An enhancing mass measuring 3.3 cm in size was found in the computed tomography (CT) scan. No definitive evidence of lymph node and distant metastasis was observed. DIAGNOSIS: Histopathological analysis revealed large atypical epithelial cells in upper ureter mass, based on neuroendocrine morphology. Immunohistochemistry was positive for synaptophysin, CD 56, and cytokeratin. Accordingly, the upper ureter mass was finally diagnosed as LCNEC stage III, pT3 cN0 cM0. INTERVENTION: Right nephroureterectomy was conducted. OUTCOMES: Multiple metastatic lesions were detected in the right adrenal, paracaval, and right pararenal space of the patient in a CT scan 3 months post-surgery. The patient chemotherapy and radiation therapy were proceeded for metastatic and recurred mass. But patient died by multiorgan failure LESSONS:: In summary, this case study demonstrated that LCNEC can develop even in the upper ureter for the first time, despite the absence of neuroendocrine cells in the normal urothelium. The occurrence of LCNEC in the ureter is still very rare but is possible. Therefore, further studies are needed to establish appropriate treatment strategies.


Assuntos
Carcinoma de Células Grandes/patologia , Carcinoma Neuroendócrino/patologia , Neoplasias Ureterais/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Ureter/patologia
16.
Diagn Pathol ; 14(1): 47, 2019 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-31109352

RESUMO

BACKGROUND: Small cell lung cancer (SCLC) is usually diagnosed in the advanced stage. It has a very poor prognosis, with no advancements in therapy in the last few decades. A recent phase 1 clinical study, using an antibody-drug conjugate directed against DLL3, showed promising results. A prerequisite for this therapy is an immunohistochemical test for DLL3 expression. The antibody used in the clinical trial was bound to a specific platform, which is not available in all pathology laboratories. In this study, the expression of DLL3 was analyzed using different DLL3 antibodies in high-grade neuroendocrine tumors of the lung and cell cultures. Additionally, correlation of DLL3 expression with Rb1 loss and TP53 mutation was evaluated. METHODS: The study cohort consisted of surgically resected cases, 24 SCLC and 29 large cell neuroendocrine carcinoma (LCNEC), from which tissue microarrays (TMAs) were constructed. The validation cohort included 46 SCLC samples, mostly small biopsies. Additionally, well-characterized SCLC cell lines were used. Immunohistochemical analysis was performed using four different DLL3 antibodies, as well as TP53 and Rb1 antibodies. Expression was evaluated microscopically and manually scored. RESULTS: The comparison of all DLL3 antibodies showed poor results for the overall agreement, as well as positive and negative agreement. Differences were observed regardless of the applied cut-off values and the tumor type. The antibody used in the clinical trial was the only which always positively stained the tumor cells obtained from cell cultures with known DLL3 expression and was negative on cells that did not express DLL3. There was no correlation between p53 and DLL3 expression in SCLC and LCNEC. RB1 loss in SCLC showed statistical significant correlation with the DLL3 positivity (p = 0.037), while no correlation was found in LCNEC. CONCLUSION: The DLL3 antibody used in the clinical trial demonstrated superiority in the detection of DLL3 expression. Cell cultures, which can be used for DLL3 antibodies as positive and negative probes, were established. Evidence of DLL3 expression in high proportions of patients with LCNEC might provide basis for studies of new therapy options in this group of patients.


Assuntos
Anticorpos/imunologia , Carcinoma de Células Grandes/diagnóstico , Carcinoma Neuroendócrino/diagnóstico , Peptídeos e Proteínas de Sinalização Intracelular/imunologia , Neoplasias Pulmonares/diagnóstico , Proteínas de Membrana/imunologia , Tumores Neuroendócrinos/diagnóstico , Carcinoma de Pequenas Células do Pulmão/diagnóstico , Carcinoma de Células Grandes/patologia , Carcinoma Neuroendócrino/patologia , Linhagem Celular Tumoral , Estudos de Coortes , Humanos , Imuno-Histoquímica , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Pulmão/patologia , Neoplasias Pulmonares/patologia , Proteínas de Membrana/metabolismo , Mutação , Tumores Neuroendócrinos/patologia , Prognóstico , Proteínas de Ligação a Retinoblastoma/imunologia , Proteínas de Ligação a Retinoblastoma/metabolismo , Carcinoma de Pequenas Células do Pulmão/patologia , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/imunologia , Proteína Supressora de Tumor p53/metabolismo , Ubiquitina-Proteína Ligases/imunologia , Ubiquitina-Proteína Ligases/metabolismo
17.
Med Sci Monit ; 25: 3636-3646, 2019 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-31095532

RESUMO

BACKGROUND The aim of this study was to assess the incidence, clinicopathologic characteristics, prognostic factors, and treatment outcomes in lung large cell neuroendocrine carcinoma (LCNEC). MATERIAL AND METHODS Patients diagnosed with lung LCNEC between 2000 and 2013 were identified using the Surveillance, Epidemiology, and End-Results database. Kaplan-Meier methods and univariate and multivariate analyses were used for statistical analysis. RESULTS A total of 2097 patients were identified. The total age-adjusted incidence rate of lung LCNEC was 0.3/100 000, with a rise in incidence over the study period. The 5-year lung cancer-specific survival (LCSS) and overall survival (OS) were 20.7% and 16.7%, respectively. Multivariate analysis indicated that age ³65 years, male sex, advanced tumor stage, advanced nodal stage, not undergoing surgery. and not undergoing chemotherapy were independent adverse indicators for survival outcomes. After stratification by tumor stage, undergoing surgery was associated with more favorable LCSS and OS compared with those without surgery, regardless of tumor stage. CONCLUSIONS LCNEC is a rare lung cancer subtype with a dismal prognosis. Primary surgical treatment has significant survival benefits, even for stage IV patients. The optimal treatment strategies for lung LCNEC require further investigation.


Assuntos
Carcinoma de Células Grandes/epidemiologia , Carcinoma de Células Grandes/patologia , Carcinoma Neuroendócrino/epidemiologia , Neoplasias Pulmonares/epidemiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Neuroendócrino/patologia , Feminino , Humanos , Incidência , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Programa de SEER , Resultado do Tratamento , Estados Unidos/epidemiologia
18.
Histopathology ; 75(2): 247-253, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30990915

RESUMO

AIMS: Pure large-cell neuroendocrine carcinoma (LCNEC) is an uncommon but well-recognised primary tumour of the colorectum. It is characterised by large cells organised in a discernible neuroendocrine pattern with >20 mitoses per 10 high-power fields (HPFs), and/or a Ki67 index of >20%, and coagulative tumour necrosis is invariably present. These features are supplemented by positivity for neuroendocrine immunohistochemical markers. The aim of this study was to highlight three primary LCNECs of the colorectum. METHODS AND RESULTS: All three patients were elderly females, aged 79, 85 and 89 years, who presented with ascending colon (two) tumours and a rectal tumour. All three tumours were large, ulcerated, polypoid masses (85, 76 and 55 mm; average size 72 mm) and were pT3N2. Histologically, the tumours were composed of packets and nests of cells with rosettes; other areas were in sheets composed of large cells. The mitotic counts were 23/10 HPFs, 27/10 HPFs and 24/10 HPFs, respectively. There was no mucosal dysplasia, precursor adenoma or associated adenocarcinoma component. All cases contained mainly peritumoral lymphoid aggregates, with smaller numbers of intratumoral lymphocytes. Synaptophysin, chromogranin (less intensely) and epithelial markers were expressed in all cases in the majority of the tumour cells. The Ki67 proliferative indices were 95%, 100%, and 80%, respectively. Two patients survived for 48 and 72 months, whereas the third is alive after 12 months without evidence of recurrence. CONCLUSIONS: These unusual primary colorectal LCNECs with an accompanying lymphoid component are characterised by loss of MLH1/PMS2, BRAF mutation, microsatellite instability, and Epstein-Barr virus negativity. The patients also have better overall survival than those with LCNECs lacking an accompanying lymphoid component.


Assuntos
Carcinoma de Células Grandes/patologia , Carcinoma Neuroendócrino/patologia , Neoplasias Colorretais/patologia , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/genética , Carcinoma de Células Grandes/genética , Carcinoma Neuroendócrino/genética , Neoplasias Colorretais/genética , Feminino , Herpesvirus Humano 4 , Humanos , Endonuclease PMS2 de Reparo de Erro de Pareamento/genética , Proteína 1 Homóloga a MutL/genética , Prognóstico , Proteínas Proto-Oncogênicas B-raf/genética
19.
J Neurooncol ; 143(2): 337-347, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30982197

RESUMO

BACKGROUND: Stereotactic radiosurgery (SRS) can enhance immune activation and improve disease control through stimulation of anti-tumor immunity. However, patients with cancer receiving chemotherapy are often immunosuppressed, which may impact the efficacy of SRS. Here we investigate the relationship between systemic lymphopenia and response to SRS in patients with brain-metastatic lung cancer. METHODS: We reviewed 125 patients with lung cancer brain metastases treated with SRS between January 2014 and May 2017. Complete blood counts from the time of SRS were reviewed, and lymphopenia was defined as absolute lymphocyte count < 1×109 cells/L. Kaplan-Meier survival analysis and cox proportional-hazards models were used to evaluate risks of progression and death. RESULTS: The median age was 65 years (range 43-86), with 54% female patients. Lymphopenia was present in 60 patients. In univariate analysis, lymphopenic patients had significantly shorter PFS (HR = 2.995, p < 0.0001) and OS (HR = 3.928, p < 0.0001). When accounting for age, gender, smoking history, ECOG score, surgery, and tumor histology in a multivariate model, lymphopenia remained significantly predictive of worse PFS (HR = 1.912, p = 0.002) and OS (HR = 2.257, p < 0.001). Patients who received immunotherapy within 3 months of SRS demonstrated significantly shorter PFS (HR = 3.578, p = 0.006) and OS (HR = 6.409, p = 0.001) if lymphopenic. CONCLUSIONS: Brain-metastatic lung cancer patients with lymphopenia treated with SRS had significantly worse PFS and OS. The effect of lymphopenia was even more pronounced in patients receiving immunotherapy. These data demonstrate the significant impact of deficient immunity on disease control and survival. Lymphopenic patients may benefit from interventions to improve immune function prior to SRS for brain metastases.


Assuntos
Neoplasias Encefálicas/terapia , Imunoterapia/mortalidade , Neoplasias Pulmonares/terapia , Linfopenia/etiologia , Radiocirurgia/mortalidade , Carcinoma de Pequenas Células do Pulmão/terapia , Adenocarcinoma/patologia , Adenocarcinoma/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Encefálicas/secundário , Carcinoma de Células Grandes/patologia , Carcinoma de Células Grandes/terapia , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/terapia , Terapia Combinada , Progressão da Doença , Feminino , Seguimentos , Humanos , Neoplasias Pulmonares/patologia , Linfopenia/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Carcinoma de Pequenas Células do Pulmão/patologia , Taxa de Sobrevida
20.
BMC Cancer ; 19(1): 238, 2019 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-30876473

RESUMO

BACKGROUND: The purpose of the present study was to characterize the prevalence, associated factors, and to construct a nomogram for predicting bone metastasis (BM) with different histological types of lung cancer. PATIENTS AND METHODS: This study was a descriptive study that basing on the invasive lung cancer patients diagnosed between 2010 and 2014 in Surveillance, Epidemiology, and End Results program. A total of 125,652 adult patients were retrieved. Logistic regression analysis was conducted to investigate homogeneous and heterogeneous factors for BM occurrence. Nomogram was constructed to predict the risk for developing BM and the performance was evaluated by the receiver operating characteristics curve (ROC) and the calibration curve. The overall survival of the patients with BM was analyzed using the Kaplan-Meier method and the survival differences were tested by the log-rank test. RESULTS: A total of 25,645 (20.9%) were reported to have BM, and the prevalence in adenocarcinoma, squamous cell carcinoma, small cell lung cancer (SCLC), large cell lung cancer (LCLC), and non-small cell lung cancer/not otherwise specified lung cancer (NSCLC/NOS) were 24.4, 12.5, 24.7, 19.5 and 19.4%, respectively, with significant difference (P < 0.001). Male gender, more metastatic sites and lymphatic metastasis were positively associated with BM in all lung cancer subtypes. Larger tumor size was positively associated with BM in all the lung cancer subtypes except for NSCLC/NOS. Poorly differentiated histology was positively associated with adenocarcinoma, squamous cell carcinoma and NSCLC/NOS. The calibration curve and ROC curve exhibited good performance for predicting BM. The median survival of the bone metastatic lung cancer patients was 4.00 (95%CI: 3.89-4.11) months. With the increased number of the other metastatic sites (brain, lung and liver metastasis), the survival significantly decreased (p < 0.001). CONCLUSION: Different lung cancer histological subtypes exhibited distinct prevalence and homogeneity and heterogeneity associated factors for BM. The nomogram has good calibration and discrimination for predicting BM of lung cancer.


Assuntos
Neoplasias Ósseas/epidemiologia , Neoplasias Ósseas/secundário , Neoplasias Pulmonares/epidemiologia , Neoplasias Pulmonares/patologia , Nomogramas , Adulto , Idoso , Carcinoma de Células Grandes/epidemiologia , Carcinoma de Células Grandes/patologia , Carcinoma Pulmonar de Células não Pequenas/epidemiologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma de Células Escamosas/epidemiologia , Carcinoma de Células Escamosas/patologia , Feminino , Humanos , Modelos Logísticos , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Prevalência , Prognóstico , Programa de SEER , Fatores Sexuais , Carcinoma de Pequenas Células do Pulmão/epidemiologia , Carcinoma de Pequenas Células do Pulmão/patologia , Análise de Sobrevida , Carga Tumoral , Estados Unidos/epidemiologia
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