RESUMO
INTRODUCTION: Small cell lung cancer (SCLC) accounts for 15% of lung cancers worldwide. It is an aggressive tumor that is typically diagnosed at an advanced stage. Treatment involves chemo-immunotherapy and/or radiotherapy. Identifying druggable targets activated by specific genetic alterations represents a significant challenge in improving patient outcomes. METHODS: We conducted a retrospective examination of molecular findings in lung cancer patients' records from 2021 to 2022. We discovered a unique case of SCLC harboring the SYN2-PPARG fusion. Histopathological analysis confirmed the diagnosis of SCLC. CASE REPORT: A 60-year-old woman, a heavy smoker, came to our attention due to a persistent cough with slight hemoptysis. Imaging, including axial contrast-enhanced computed tomography, revealed an advanced disease with extra-thoracic spread. Tumor histology showed a sheet-like proliferation of small-sized cells with a neuroendocrine phenotype and a high proliferation tumor cell fraction. Molecular genetic analysis using NGS approach revealed a fusion involving the SYN2 and PPARG genes. CONCLUSION: The SYN2-PPARG fusion has recently been documented in sinonasal adenocarcinoma and has been reported in only a single SCLC case previously. Highlighting the molecular heterogeneity within this aggressive form of lung cancer could potentially aid in the selection of specific therapies.
Assuntos
Adenocarcinoma , Neoplasias Pulmonares , Carcinoma de Pequenas Células do Pulmão , Feminino , Humanos , Pessoa de Meia-Idade , Carcinoma de Pequenas Células do Pulmão/genética , Carcinoma de Pequenas Células do Pulmão/patologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , PPAR gama , Estudos Retrospectivos , Adenocarcinoma/patologiaRESUMO
BACKGROUND: The development of targeted agents, such as osimertinib for EGFR-mutated non-small-cell lung cancer (NSCLC), has drastically improved patient outcome, but tumor resistance eventually always occurs. In osimertinib-resistant NSCLC, the emergence of a second molecular driver alteration (such as ALK, RET, FGFR3 fusions or BRAF, KRAS mutations) has been described. Whether those alterations and the activating EGFR mutations occur within a single cancer cell or in distinct cell populations is largely debated. PATIENTS AND METHODS: Tumor sequencing was used to identify the acquired resistance mechanisms to osimertinib in the MATCH-R trial (NCT0251782). We implemented single-cell next-generation sequencing to investigate tumor heterogeneity on patient's frozen tissues in which multiple alterations have been identified. Patient-derived models, cell lines, and patient-derived xenografts were exposed to specific inhibitors to investigate combination treatment strategies. RESULTS: Among the 45 patients included in MATCH-R who progressed on osimertinib, 9 developed a second targetable alteration (n = 2 FGFR3-TACC3, n = 1 KIF5B-RET, n = 1 STRN-ALK fusions; n = 2 BRAFV600E, n = 1 KRASG12V, n = 1 KRASG12R, n = 1 KRASG12D mutations). Single-cell analysis revealed that the two driver alterations coexist within one single cancer cell in the four patients whose frozen samples were fully contributive. A high degree of heterogeneity within samples and sequential acquisitions of molecular events were highlighted. A combination treatment concomitantly targeting the two driver alterations was required on the corresponding patient-derived models to restore cell sensitivity, which was consistent with clinical data showing efficacy of brigatinib in the patient with ALK fusion after progression to osimertinib and crizotinib administered sequentially. CONCLUSIONS: Distinct molecular driver alterations at osimertinib resistance coexist with initial EGFR mutations in single cancer cells. The clonal evolution of cancer cell populations emphasized their heterogeneity leading to osimertinib relapse. Combining two targeted treatments is effective to achieve clinical benefit.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Acrilamidas , Compostos de Anilina/farmacologia , Compostos de Anilina/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Evolução Clonal/genética , DNA , Resistencia a Medicamentos Antineoplásicos/genética , Receptores ErbB/genética , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Proteínas Associadas aos Microtúbulos/genética , Mutação , Recidiva Local de Neoplasia/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas p21(ras)/genéticaRESUMO
Artificial intelligence approaches in medicine are more and more used and are extremely promising due to the growing number of data produced and the variety of data they allow to exploit. Thus, the computational analysis of medical images in particular, radiological (radiomics), or anatomopathological (pathomics), has shown many very interesting results for the prediction of the prognosis and the response of cancer patients. Radiotherapy is a discipline that particularly benefits from these new approaches based on computer science and imaging. This review will present the main principles of an artificial intelligence approach and in particular machine learning, the principles of a radiomic and pathomic approach and the potential of their use for the prediction of the prognosis of patients treated with radiotherapy.
Assuntos
Aprendizado de Máquina , Neoplasias/diagnóstico por imagem , Neoplasias/patologia , Inteligência Artificial , Biomarcadores Tumorais , Diagnóstico por Computador/métodos , Humanos , Neoplasias/mortalidade , Neoplasias/radioterapia , Prognóstico , Radioterapia (Especialidade) , Resultado do TratamentoRESUMO
Aberrant activation of RET is a critical driver of growth and proliferation in diverse solid tumours. Multikinase inhibitors (MKIs) showing anti-RET activities have been tested in RET-altered tumours with variable results. The low target specificity with consequent increase in side-effects and off-target toxicities resulting in dose reduction and drug discontinuation are some of the major issues with MKIs. To overcome these issues, new selective RET inhibitors such as pralsetinib (BLU-667) and selpercatinib (LOXO-292) have been developed in clinical trials, with selpercatinib recently approved by the Food and Drug Administration (FDA). The results of these trials showed marked and durable antitumour activity and manageable toxicity profiles in patients with RET-altered tumours. The European Society for Medical Oncology (ESMO) Translational Research and Precision Medicine Working Group (TR and PM WG) launched a collaborative project to review the available methods for the detection of RET gene alterations, their potential applications and strategies for the implementation of a rational approach for the detection of RET fusion genes and mutations in human malignancies. We present here recommendations for the routine clinical detection of targetable RET rearrangements and mutations.
Assuntos
Oncologia , Proteínas Proto-Oncogênicas c-ret , Humanos , Mutação , Proteínas Proto-Oncogênicas c-ret/genética , Pirazóis , Piridinas , Pirimidinas , Padrões de Referência , Guias de Prática Clínica como AssuntoAssuntos
Tumor Carcinoide , Neoplasias Pulmonares , Neoplasias do Timo , Tumor Carcinoide/diagnóstico , Tumor Carcinoide/epidemiologia , Tumor Carcinoide/terapia , Seguimentos , Humanos , Pulmão , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/epidemiologia , Neoplasias Pulmonares/terapia , Prognóstico , Neoplasias do Timo/diagnóstico , Neoplasias do Timo/epidemiologia , Neoplasias do Timo/terapiaRESUMO
The establishment of clinically relevant models for tumor metastasis and drug testing is a major challenge in cancer research. Here we report a physiologically relevant assay enabling quantitative analysis of metastatic capacity of tumor cells following implantation into the chorioallantoic membrane (CAM). Engraftment of as few as 103 non-small cell lung cancer (NSCLC) and prostate cancer (PCa) cell lines was sufficient for both primary tumor and metastasis formation. Standard 2D-imaging as well as 3D optical tomography imaging were used for the detection of fluorescent metastatic foci in the chick embryo. H2228- and H1975-initiated metastases were confirmed by genomic analysis. We quantified the inhibitory effect of docetaxel on LNCaP, and that of cisplatin on A549- and H1299-initiated metastatic growths. The CAM assay also mimicked the sensitivity of ALK-rearranged H2228 and EGFR-mutated H1975 NSCLC cells to tyrosine kinase inhibitors crizotinib and gefitinib respectively, as well as sensitivity of LNCaP cells to androgen-dependent enzalutamide therapy. The assay was suggested to reconstitute the bone metastatic tropism of PCa cells. We show that the CAM chick embryo model may be a powerful preclinical platform for testing and targeting of the metastatic capacity of cancer cells.
Assuntos
Antineoplásicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Membrana Corioalantoide , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Metástase Neoplásica/tratamento farmacológico , Metástase Neoplásica/genética , Neoplasias da Próstata/patologia , Animais , Benzamidas , Embrião de Galinha , Cisplatino/farmacologia , Crizotinibe/farmacologia , Docetaxel/farmacologia , Gefitinibe/farmacologia , Masculino , Células Neoplásicas Circulantes , Nitrilas , Feniltioidantoína/análogos & derivados , Feniltioidantoína/farmacologiaRESUMO
Highly proliferative lung carcinoids (HPLC) have been recently reported but information about this subset remains scarce. OBJECTIVES: Clinical and pathological data of 630 patients with lung carcinoids (LC) referred to Gustave Roussy Institute (GR) and European Institute of Oncology (IEO) were retrospectively reviewed to select HPLC and analyze their frequency, behavior and compare their outcome to conventional LC with Ki-67 ≤ 20 % and mitotic count (MC)≤10/2 mm2. MATERIALS AND METHODS: Selection criteria were: diagnosis of LC confirmed by local pathologist, and available clinical and follow-up data. Patients with Ki-67 > 20 % and/or MC > 10/ 2 mm2 in primary or metastatic specimens were identified as HPLC. RESULTS: 30/514 patients (6%) met the selection criteria of HPLC. Based on primary tumor evaluation, 22/25 (88 %) were classified as atypical carcinoids (AC). Median MC was 4.5/2 mm2 (1-11) 6/2 mm2 (3-15) in primary tumors and metastasis, respectively. Median Ki-67 was respectively 23 % (15-65) and 25 % (8-60). Recurrence rate was 66 % (12/18) in HPLC and 9 % (33/352) in conventional LC. Median RFS was 24 (10-NR) months in HPLC, 288 (141-NR) months in LC with Ki-67 index≤5 % and NR (148-NR) months in LC with Ki-67 6-20% (p < 001). Median OS was 203 (83-NR) months in LC with Ki-67 index≤5%, 101 (79-NR) months in LC with Ki-67 index 6-20 % and 53 (39-NR) months in HPLC (p = 002). Among 20 metastatic patients with HPLC, median PFS under platinum-based chemotherapy, everolimus, alkylating-based chemotherapy, FOLFOX and PRRT was 5.1 (95 % CI 0.7-9.4), 12.1(95 %CI 0.3-24), 6.8 (95 % CI 0-14.9), 10.2 (95 % CI 0.4-19.9) and 14.2 months (95 % CI 0-30) respectively. Best response was stable disease (SD) under platinum-based chemotherapy and partial response (PR) under alkylating-based chemotherapy and FOLFOX. CONCLUSION: This study confirms the existence and rarity of HPLC. Their characteristics and clinical behavior are more similar to LC rather than neuroendocrine carcinomas (NECs), suggesting that this entity could be managed accordingly.
Assuntos
Tumor Carcinoide , Carcinoma Neuroendócrino , Neoplasias Pulmonares , Tumores Neuroendócrinos , Tumor Carcinoide/diagnóstico , Humanos , Antígeno Ki-67 , Pulmão , Neoplasias Pulmonares/diagnóstico , Recidiva Local de Neoplasia , Estudos RetrospectivosAssuntos
Anticorpos Monoclonais Humanizados/efeitos adversos , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Pulmonares/induzido quimicamente , Melanoma/tratamento farmacológico , Nódulos Pulmonares Múltiplos/induzido quimicamente , Pneumonia/induzido quimicamente , Neoplasias Cutâneas/tratamento farmacológico , Adulto , Antineoplásicos Imunológicos/efeitos adversos , Neoplasias Ósseas/secundário , Humanos , Neoplasias Pulmonares/cirurgia , Metástase Linfática , Melanoma/patologia , Nódulos Pulmonares Múltiplos/cirurgia , Pneumonia/cirurgia , Prognóstico , Neoplasias Cutâneas/secundárioRESUMO
OBJECTIVE: To evaluate the natural history of MEN1-related bronchial endocrine tumors (br-NETs) and to determine their histological characteristics, survival and causes of death. br-NETs frequency ranges from 3 to 13% and may reach 32% depending on the number of patients evaluated and on the criteria required for diagnosis. METHODS: The 1023-patient series of symptomatic MEN1 patients followed up in a median of 48.7 [35.5-59.6] years by the Groupe d'étude des Tumeurs Endocrines was analyzed using time-to-event techniques. RESULTS: br-NETs were found in 51 patients (4.8%, [95% CI 3.6-6.2%]) and were discovered by imaging in 86% of cases (CT scan, Octreoscan, Chest X-ray, MRI). Median age at diagnosis was 45 years [28-66]. Histological examination showed 27 (53%) typical carcinoids (TC), 16 (31%) atypical carcinoids (AC), 2 (4%) large cell neuroendocrine carcinomas (LCNEC), 3(6%) small cell neuroendocrine carcinomas (SCLC), 3(6%) TC associated with AC. Overall survival was not different from the rest of the cohort (HR 0.29, [95% CI 0.02-5.14]). AC tended to have a worse prognosis than TC (p = 0.08). Seven deaths were directly related to br-NETs (three AC, three SCLC and one LCNEC). Patients who underwent surgery survived longer (p = 10-4) and were metastasis free, while 8 of 14 non-operated patients were metastatic. There were no operative deaths. CONCLUSIONS: Around 5% of MEN1 patients develop br-NETs. br-NETs do not decrease overall survival in MEN1 patients, but poorly differentiated and aggressive br-NETs can cause death. br-NETs must be screened carefully. A biopsy is essential to operate on patients in time.
Assuntos
Neoplasias Brônquicas/patologia , Neoplasia Endócrina Múltipla Tipo 1/patologia , Tumores Neuroendócrinos/patologia , Adulto , Idoso , Neoplasias Brônquicas/diagnóstico , Neoplasias Brônquicas/mortalidade , Causas de Morte , Estudos de Coortes , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasia Endócrina Múltipla Tipo 1/diagnóstico , Neoplasia Endócrina Múltipla Tipo 1/mortalidade , Tumores Neuroendócrinos/diagnóstico , Tumores Neuroendócrinos/mortalidade , Análise de SobrevidaRESUMO
BACKGROUND: Diagnosis and management of poorly differentiated gastro-entero-pancreatic (GEP) neuroendocrine carcinomas (NECs) remain challenging. Recent studies suggest prognostic heterogeneity. We designed within the French Group of Endocrine Tumours a prospective cohort to gain insight in the prognostic stratification and treatment of GEP-NEC. PATIENTS AND METHODS: All patients with a diagnosis of GEP-NEC between 1st January 2010 and 31st December 2013 could be included in this national cohort. Adenoneuroendocrine tumours were excluded. RESULTS: 253 patients from 49 centres were included. Median age was 66 years. Main primary locations were pancreas (21%), colorectal (27%), oesophagus-stomach (18%); primary location was unknown in 20%. Tumours were metastatic at diagnosis in 78% of cases. Performance status (PS) at diagnosis was 0-1 in 79% of patients. Among the 147 (58%) cases reviewed by an expert pathological network, 39% were classified as small cell NEC and 61% as large cell NEC. Median Ki67 index was 75% (range, 20-100). Median overall survival was 15.6 (13.6-17.0) months. Significant adverse prognostic factors in univariate analysis were PS > 1 (hazard ratio [HR] = 2.5), metastatic disease (HR = 1.6), NSE>2 upper limit of normal [ULN]; HR = 3.2), CgA>2 ULN (HR = 1.7) and lactate dehydrogenase >2 ULN (HR = 2.1). After first-line palliative chemotherapy (CT1) with platinum-etoposide (n = 152), objective response, progression-free survival and overall survival were 50%, 6.2 and 11.6 months; they were 24%, 2.9 and 5.9, respectively, after post-CT1 FOLFIRI regimen (n = 72). CONCLUSIONS: We report a large prospective series of GEP-NEC which show the predominance of large cell type and advanced stage at diagnosis. Prognosis was found more homogeneous than previously reported, mainly impacted by PS and tumour burden.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Neuroendócrino/patologia , Neoplasias Gastrointestinais/patologia , Neoplasias Pancreáticas/patologia , Idoso , Carboplatina/administração & dosagem , Carcinoma Neuroendócrino/mortalidade , Transformação Celular Neoplásica/patologia , Cisplatino/administração & dosagem , Estudos de Coortes , Etoposídeo/administração & dosagem , Feminino , Neoplasias Gastrointestinais/mortalidade , Humanos , Masculino , Metástase Neoplásica , Neoplasias Pancreáticas/mortalidade , PrognósticoRESUMO
Pancreatic neuroendocrine tumors (PNETs) are rare and represent a heterogeneous disease. PNET can be functioning or non-functioning with different clinical presentations and different prognosis based on WHO and pTNM classifications. The role of imaging includes the localization of small functioning tumor, differentiation of these tumors from adenocarcinoma, identification of signs of malignancy and evaluation of extent. PNETs have a broad spectrum of appearance. On CT and MRI, most of functioning PNETs are well defined small tumors with intense and homogeneous enhancement on arterial and portal phases. However, some PNETs with a more fibrous content may have a more delayed enhancement that is best depicted on the delayed phase. Other PNETs can present as purely cystic, complex cystic and solid tumors and calcified tumors. Non-functioning PNETs are larger with less intense and more heterogeneous enhancement. Functional imaging is useful for disease staging, to detect disease recurrence or the primary but also to select patient candidate for peptide receptor radiometabolic treatment. Somatostatin receptor scintigraphy (SRS) (Octreoscan®) is still the most available technique. Gallium 68-SST analogue PET have been demonstrated to be more sensitive than SRS-SPEC and it will be the future of functional imaging for NET. Finally, 18FDG PET/CT is indicated for more aggressive PNET as defined either by negative SRS and huge tumor burden or ki67 above 10% or poorly differentiated PNEC tumors.
Assuntos
Imageamento por Ressonância Magnética , Tumores Neuroendócrinos/diagnóstico por imagem , Neoplasias Pancreáticas/diagnóstico por imagem , Tomografia Computadorizada por Raios X , Endossonografia , Gastrinoma/diagnóstico por imagem , Gastrinoma/patologia , Humanos , Insulinoma/diagnóstico por imagem , Insulinoma/patologia , Metástase Linfática/diagnóstico por imagem , Metástase Linfática/patologia , Gradação de Tumores , Estadiamento de Neoplasias , Tumores Neuroendócrinos/patologia , Neoplasias Pancreáticas/patologia , PrognósticoRESUMO
OBJECTIVES: The aim of this retrospective study was to analyse the efficacy of gemcitabine-oxaliplatin (gemox) or 5-fluorouracil-oxaliplatin (folfox) in the treatment of metastatic pulmonary carcinoid tumors. PATIENTS AND METHODS: 45 patients were included in two tertiary referral centers between January 1999 and January 2013. Typical, atypical carcinoids or not otherwise specified carcinoids were diagnosed according to WHO criteria in 19%, 57%, and 24% of cases by two expert pathologists. Patients had synchronous (38%) or metachronous (62%) metastastic disease (median of 2 (1-5) metastatic sites). Seventy-nine percent had progressive disease before start of chemotherapy. Treatment consisted of: gemcitabine 1000mg/m(2) and oxaliplatin 100mg/m(2) every 2 weeks (gemox regimen, n=24) or 5-fluorouracil (5-FU) (400mg/m(2) in bolus injection and 5-FU 2400mg/m(2) in 46h-infusion) and oxaliplatin 85mg/m(2) (folfox regimen, n=21) every 2 weeks. Tumor response was assessed according to RECIST criteria every 8-12 weeks. Progression free survival and overall survival were assessed using Kaplan Meier curves. RESULTS: Patients received oxaliplatin-based chemotherapy in first-line (20%), second-line (33%), or post-second-line (47%) systemic treatment. The median number of cycles was 8 (1-12). Nine (20%) stopped oxaliplatin before 8 cycles because of toxicity. Nine patients (20%) had a partial response and 29 (64%) had stable disease. Median progression free survival (PFS) was 15 (6-25) months. Median overall survival (OS) was 34 (21-49) months. No significant difference was observed in response and PFS between either regimens. CONCLUSIONS: Our results suggest that either gemcitabine-oxaliplatin or 5-fluorouracil-oxaliplatin combinations are attractive chemotherapy regimen in metastatic pulmonary carcinoid tumors.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Tumor Carcinoide/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Tumor Carcinoide/patologia , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Intervalo Livre de Doença , Feminino , Fluoruracila/administração & dosagem , Humanos , Leucovorina/administração & dosagem , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Compostos Organoplatínicos/administração & dosagem , Estudos Retrospectivos , Resultado do TratamentoRESUMO
OBJECTIVES: The goals of this study were to assess the diagnostic accuracy of shear wave elastography (SWE) using the results of histopathological analysis as a standard of reference and compare the results of SWE and those of transient elastography (TE) to the degree of fibrosis as evaluated by histomorphometry. PATIENTS AND METHODS: Adult patients who were scheduled to undergo liver biopsy were prospectively enrolled in the study. The diagnostic performances of SWE were assessed using AUROC curve analysis according to fibrosis thresholds defined by ≥F2 (significant fibrosis), ≥F3 (advanced fibrosis) and F4 (cirrhosis). Additional analyses using the Obuchowski measures for pairwise comparisons of fibrosis stages were performed. In a subgroup of 55 patients, the relationships between stiffness as measured using SWE and TE and the percentage of fibrosis were compared using Spearman's rank coefficient. RESULTS: Among the initially enrolled 170 patients, 148/170 (87%) had successful SWE acquisition and formed the study population. SWE sensitivity and specificity were respectively 85.1% and 82.7% (≥F2), 88.9% and 90.3% (≥F3), 93.3% and 98.3% (F4). The AUROC curves of SWE along with their 95% confidence intervals (CI) were respectively 0.904 (95%CI: 0.845-0.946) for fibrosis ≥F2; 0.958 (95%CI: 0.912-0.984) for fibrosis ≥F3 and 0.988 (95%CI: 0.955-0.999) for fibrosis=F4. The global Obuchowski measure was 0.953±0.007. In the subgroup study, a significant correlation was found between the percentage of fibrosis and stiffness as assessed by SWE (r=0.77; 95%CI: 0.63-0.86; P<0.0001) and by TE (r=0.65; 95%CI: 0.47-0.78; P<0.01). CONCLUSION: SWE is accurate to assess liver fibrosis in patients with chronic liver disease.
Assuntos
Técnicas de Imagem por Elasticidade , Cirrose Hepática/diagnóstico por imagem , Cirrose Hepática/patologia , Doença Crônica , Feminino , Humanos , Cirrose Hepática/etiologia , Hepatopatias/complicações , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Reprodutibilidade dos Testes , Índice de Gravidade de DoençaRESUMO
There is no standard for second-line chemotherapy in poorly differentiated grade 3 neuroendocrine carcinoma (G3-NEC) patients. We analyzed the antitumor efficacy of 5-fluorouracil and oxaliplatin (FOLFOX) chemotherapy in this population. A single-center retrospective analysis of consecutive G3-NEC patients treated with FOLFOX chemotherapy after failure of a cisplatinum-based regimen between December 2003 and June 2012 was performed. Progression-free survival (PFS), overall survival (OS), response rate, and safety were assessed according to RECIST 1.1 and NCI.CTC v4 criteria. Twenty consecutive patients were included (seven males and 13 females; median age 55; range 23-87 years) with a performance status of 0-1 in 75% of them. Primary location was gastroenteropancreatic in 12, thoracic in four, other in two, and unknown in two patients. There were 12 (65%) large-cell and 7 (30%) small-cell G3-NEC tumors, and 1 (5%) unknown. All patients had distant metastases. Twelve (60%) patients received FOLFOX as second-line treatment and 8 (40%) as third-line treatment or later and the median number of administered cycles was 6 (range 3-14). The median follow-up was 19 months. Median PFS was 4.5 months. Among the 17 evaluable patients, five partial responses (29%), six stable diseases (35%), and six progressive diseases (35%) were observed. Median OS was 9.9 months. Main Grade 3-4 toxicities were neutropenia (35%), thrombopenia (20%), nausea/vomiting (10%), anemia (10%), and elevated liver transaminases (10%). Our results indicate that the FOLFOX regimen could be considered as a second-line option in poorly differentiated G3-NEC patients after cisplatinum-based first-line treatment but warrant further confirmation in future larger prospective studies.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Neuroendócrino/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Carcinoma Neuroendócrino/patologia , Intervalo Livre de Doença , Feminino , Fluoruracila/administração & dosagem , Humanos , Leucovorina/administração & dosagem , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Compostos Organoplatínicos/administração & dosagem , Estudos Retrospectivos , Adulto JovemRESUMO
BACKGROUND: O(6)-Methylguanine-DNA methyltransferase (MGMT) loss of expression has been suggested to be predictive of response to temozolomide in neuroendocrine tumours (NETs), but so far, only limited data are available. We evaluated the prognostic and predictive value of MGMT status, assessed by two molecular methods and immunohistochemistry, in a large series of NETs of different origins. METHODS: A total of 107 patients, including 53 treated by alkylants (temozolomide, dacarbazine or streptozotocin), were retrospectively studied. In each case, we used methyl-specific PCR (MS-PCR) and pyrosequencing for evaluation of promoter methylation and immunohistochemistry for evaluation of protein status. RESULTS: MGMT promoter methylation was detected in 12 out of 99 (12%) interpretable cases by MS-PCR and in 24 out of 99 (24%) by pyrosequencing. O(6)-Methylguanine-DNA methyltransferase loss of expression was observed in 29 out of 89 (33%) interpretable cases. Status of MGMT was not correlated with overall survival (OS) from diagnosis. Progression-free survival and OS from first alkylant use (temozolomide, dacarbazine and streptozotocin) were higher in patients with MGMT protein loss (respectively, 20.2 vs 7.6 months, P<0.001 and 105 vs 34 months, P=0.006) or MGMT promoter methylation assessed by pyrosequencing (respectively, 26.4 vs 10.8 months, P=0.002 and 77 vs 43 months, P=0.026). CONCLUSIONS: Our results suggest that MGMT status is associated with response to alkylant-based chemotherapy in NETs.
Assuntos
Antineoplásicos Alquilantes/uso terapêutico , Tumores Neuroendócrinos/tratamento farmacológico , O(6)-Metilguanina-DNA Metiltransferase/genética , Neoplasias Pancreáticas/tratamento farmacológico , Metilação de DNA , Feminino , Regulação Enzimológica da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias do Íleo/tratamento farmacológico , Neoplasias do Íleo/genética , Neoplasias do Íleo/mortalidade , Masculino , Tumores Neuroendócrinos/genética , Tumores Neuroendócrinos/mortalidade , O(6)-Metilguanina-DNA Metiltransferase/metabolismo , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/mortalidade , Prognóstico , Regiões Promotoras Genéticas , Estudos Retrospectivos , Resultado do TratamentoRESUMO
OBJECTIVE: Concerning death-rates were reported following prostate biopsy but the lack of contexts in which event occurred makes it difficult to take any position. Therefore, we aimed to determine the 120-day post-biopsy mortality rate. MATERIAL AND METHODS: Between 2000 and 2011, 8804 men underwent prostate biopsy in the hospice civils de Lyon. We studied retrospectively, the mortality rate after each of the 11,816 procedures. Biopsies imputability was assessed by examining all medical records. Dates of death were extracted from our local patient management database, which is updated trimestrially with death notifications from the French National Institute for Statistics and Economic Studies. RESULTS: In our study 42 deaths occurred within 120days after 11,816 prostate biopsies (0.36%). Of the 42 records: 9 were lost to follow-up, 3 had no identifiable cause of death, 28 had an intercurrent event ruling out prostate biopsy as a cause of death. Only 2 deaths could be linked to biopsy. CONCLUSIONS: We reported at most 2 deaths possibly related to prostate biopsy over 11,816 procedures (0.02%). We confirmed the fact that prostate biopsies can be lethal but this rare outcome should not be considered as an argument against prostate screening given the circumstances in which it occurs. LEVEL OF EVIDENCE: 5.
Assuntos
Biópsia por Agulha/mortalidade , Próstata/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biópsia por Agulha/estatística & dados numéricos , França , Humanos , Masculino , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
The protein MENIN is the product of the multiple endocrine neoplasia type I (MEN1) gene. Altered MENIN expression is one of the few events that are clearly associated with foregut neuroendocrine tumours (NETs), classical oncogenes or tumour suppressors being not involved. One of the current challenges is to understand how alteration of MENIN expression contributes to the development of these tumours. We hypothesised that MENIN might regulate factors maintaining endocrine-differentiated functions. We chose the insulinoma model, a paradigmatic example of well-differentiated pancreatic NETs, to study whether MENIN interferes with the expression of v-MAF musculoaponeurotic fibrosarcoma oncogene homologue A (MAFA), a master glucose-dependent transcription factor in differentiated ß-cells. Immunohistochemical analysis of a series of human insulinomas revealed a correlated decrease in both MENIN and MAFA. Decreased MAFA expression resulting from targeted Men1 ablation was also consistently observed in mouse insulinomas. In vitro analyses using insulinoma cell lines showed that MENIN regulated MAFA protein and mRNA levels, and bound to Mafa promoter sequences. MENIN knockdown concomitantly decreased mRNA expression of both Mafa and ß-cell differentiation markers (Ins1/2, Gck, Slc2a2 and Pdx1) and, in parallel, increased the proliferation rate of tumours as measured by bromodeoxyuridine incorporation. Interestingly, MAFA knockdown alone also increased proliferation rate but did not affect the expression of candidate proliferation genes regulated by MENIN. Finally, MENIN variants with missense mutations detected in patients with MEN1 lost the WT MENIN properties to regulate MAFA. Together, our findings unveil a previously unsuspected MENIN/MAFA connection regarding control of the ß-cell differentiation/proliferation balance, which could contribute to tumorigenesis.
Assuntos
Carcinoma Neuroendócrino/patologia , Diferenciação Celular , Insulinoma/patologia , Fatores de Transcrição Maf Maior/metabolismo , Neoplasias Pancreáticas/patologia , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas/fisiologia , Adulto , Idoso , Animais , Apoptose , Western Blotting , Carcinoma Neuroendócrino/genética , Carcinoma Neuroendócrino/metabolismo , Proliferação de Células , Imunoprecipitação da Cromatina , Feminino , Glucose/farmacologia , Humanos , Técnicas Imunoenzimáticas , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/patologia , Insulinoma/genética , Insulinoma/metabolismo , Fatores de Transcrição Maf Maior/antagonistas & inibidores , Fatores de Transcrição Maf Maior/genética , Masculino , Camundongos , Camundongos Knockout , Pessoa de Meia-Idade , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Proteínas Proto-Oncogênicas/genética , RNA Mensageiro/genética , RNA Interferente Pequeno/genética , Ratos , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Células Tumorais CultivadasRESUMO
Incidentally discovered cystic tumors of the pancreas (CTP) are an increasingly frequent entity. It is essential to differentiate lesions whose malignant potential is either nil or negligible (pseudocyst, serous cystadenoma, simple cysts) from lesions with intermediate malignant potential (intraductal papillary mucinous tumor of the pancreas [IPMN] involving the secondary ducts, cystic endocrine tumor) or those with high malignant potential (mucinous cystadenoma, solid pseudopapillary tumors and IPMN involving the main pancreatic duct). The approach to defining malignant potential is based on diagnostic CT scan, magnetic resonance imaging (MRI), and endoscopic ultrasound (EUS), often complemented by EUS-guided cyst puncture for biochemical and cytological analysis of cyst fluid. Surgery for diagnostic purposes should be avoided because of its significant morbidity. For pseudocysts, simple cysts and serous cystadenomas, abstention is the general rule. Resection, preserving as much pancreatic parenchyma as possible, is the rule for IPMN involving the main pancreatic duct, mucinous cystadenomas, solid and pseudopapillary tumors, and cystic endocrine tumors. Resection is rarely indicated at the outset for IPMN involving secondary pancreatic ducts; morphologic observation is the general rule and preventive excision may be indicated secondarily. Good collaboration between surgeons, radiologists and endosonographists is necessary for optimal management of CTP.
Assuntos
Carcinoma Ductal Pancreático , Cistadenocarcinoma , Cistadenoma , Cisto Pancreático , Neoplasias Pancreáticas , Carcinoma Ductal Pancreático/diagnóstico , Carcinoma Ductal Pancreático/terapia , Cistadenocarcinoma/diagnóstico , Cistadenocarcinoma/terapia , Cistadenoma/diagnóstico , Cistadenoma/terapia , Diagnóstico Diferencial , Endossonografia , Humanos , Imageamento por Ressonância Magnética , Pancreatectomia , Cisto Pancreático/diagnóstico , Cisto Pancreático/terapia , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/terapia , Pseudocisto Pancreático/diagnóstico , Pseudocisto Pancreático/terapia , Tomografia Computadorizada por Raios X , Resultado do Tratamento , Conduta ExpectanteRESUMO
Renal cell carcinomas associated with Xp11.2 translocations form a new and little known entity of the WHO 2004 classification. An immunohistochemical (IHC) test aiming at demonstrating the nuclear expression of the protein TFE3, product of a gene frequently involved in translocation, has been proposed as a diagnostic tool. The aims of this work were to define our evaluation criteria of the immunohistochemical test with the antibody anti-TFE3 and to describe new cases of renal cell carcinomas with TFE3 translocations. Using immunohistochemistry with antibody anti-TFE3, we retrospectively studied 83 renal cell carcinomas diagnosed at Edouard Herriot Hospital and Biomnis Laboratory, Lyon, between 2003 and 2009. The patients were 50 years old or younger. We detail our experience of the IHC test using the anti-body anti-TFE3 and the interpretation criteria. This work has enabled two new cases of renal cell carcinomas associated with TFE3 translocations to be detailed, confirmed by molecular biology. The TFE3 immunohistochemical test is a useful tool that demands strict interpretation criteria. In our experience, more than 80% of nuclei stained with an intensity of ++ to +++ is necessary to suspect the diagnosis of Xp11 translocation renal cell carcinoma.