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1.
Int J Mol Sci ; 22(6)2021 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-33809722

RESUMO

Medullary thyroid carcinoma (MTC) is a tumor deriving from the thyroid C cells. Vandetanib (VAN) and cabozantinib (CAB) are two tyrosine kinase inhibitors targeting REarranged during Transfection (RET) and other kinase receptors and are approved for the treatment of advanced MTC. We aim to compare the in vitro and in vivo anti-tumor activity of VAN and CAB in MTC. The effects of VAN and CAB on viability, cell cycle, and apoptosis of TT and MZ-CRC-1 cells are evaluated in vitro using an MTT assay, DNA flow cytometry with propidium iodide, and Annexin V-FITC/propidium iodide staining, respectively. In vivo, the anti-angiogenic potential of VAN and CAB is evaluated in Tg(fli1a:EGFP)y1 transgenic fluorescent zebrafish embryos by analyzing the effects on the physiological development of the sub-intestinal vein plexus and the tumor-induced angiogenesis after TT and MZ-CRC-1 xenotransplantation. VAN and CAB exert comparable effects on TT and MZ-CRC-1 viability inhibition and cell cycle perturbation, and stimulated apoptosis with a prominent effect by VAN in MZ-CRC-1 and CAB in TT cells. Regarding zebrafish, both drugs inhibit angiogenesis in a dose-dependent manner, in particular CAB shows a more potent anti-angiogenic activity than VAN. To conclude, although VAN and CAB show comparable antiproliferative effects in MTC, the anti-angiogenic activity of CAB appears to be more relevant.


Assuntos
Inibidores da Angiogênese/uso terapêutico , Anilidas/uso terapêutico , Carcinoma Neuroendócrino/tratamento farmacológico , Piperidinas/uso terapêutico , Piridinas/uso terapêutico , Quinazolinas/uso terapêutico , Neoplasias da Glândula Tireoide/tratamento farmacológico , Peixe-Zebra/fisiologia , Anilidas/farmacologia , Animais , Apoptose/efeitos dos fármacos , Carcinoma Neuroendócrino/irrigação sanguínea , Carcinoma Neuroendócrino/patologia , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Embrião não Mamífero/irrigação sanguínea , Embrião não Mamífero/efeitos dos fármacos , Humanos , Neovascularização Patológica/tratamento farmacológico , Neovascularização Fisiológica/efeitos dos fármacos , Piridinas/farmacologia , Neoplasias da Glândula Tireoide/irrigação sanguínea , Neoplasias da Glândula Tireoide/patologia , Peixe-Zebra/embriologia
2.
Gan To Kagaku Ryoho ; 48(3): 397-399, 2021 Mar.
Artigo em Japonês | MEDLINE | ID: mdl-33790167

RESUMO

A 75-year-old man presented to a local clinic with anal pain, and a palpable anal tumor on was found on digital examination of the rectum. A biopsy led to the diagnosis of neuroendocrine carcinoma. Besides the anal tumor, an right-inguinal lymph node was revealed on computed tomography(CT). Positron emission tomography-CT showed abnormal uptake in the 2 regions. He was diagnosed with lymph node metastases from anal canal carcinoma, and an abdominoperineal resection was performed. The resected specimen included the anal canal tumor with a size of 27×18 mm in diameter. On immunohistochemistry, the anal canal tumor was strongly positive for synaptophysin and positive for chromogranin A, with a Ki- 67 positivity index of 70%. After the surgery, he was administered chemotherapy with 4 courses of cisplatin and CPT-11. One year after the surgery, CT revealed lymph node recurrence. Therefore, cisplatin and CPT-11 therapy was repeated. After 11 courses of the cisplatin and CPT-11 treatment, tumor regrowth was still detected. The treatment protocol was changed to an amrubicin monotherapy regimen. However, the patient's general condition worsened after the therapies, and he died 38 months after the surgery.


Assuntos
Neoplasias do Ânus , Carcinoma Neuroendócrino , Idoso , Canal Anal , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Ânus/tratamento farmacológico , Neoplasias do Ânus/cirurgia , Carcinoma Neuroendócrino/tratamento farmacológico , Carcinoma Neuroendócrino/cirurgia , Humanos , Masculino , Recidiva Local de Neoplasia
3.
Molecules ; 26(3)2021 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-33525725

RESUMO

RET (rearranged during transfection) kinase, one of the receptor tyrosine kinases, plays a crucial role in the development of the human nervous system. It is also involved in various cell signaling networks responsible for the normal cell division, growth, migration, and survival. Previously reported clinical studies revealed that deregulation or aberrant activation of RET signaling can cause several types of human cancer. For example, medullary thyroid carcinoma (MTC) and multiple endocrine neoplasia (MEN2A, MEN2B) occur due to sporadic mutation or germline RET mutation. A number of RET kinase inhibitors have been approved by the FDA for the treatment of cancer, such as cabozantinib, vandetanib, lenvatinib, and sorafenib. However, each of these drugs is a multikinase inhibitor. Hence, RET is an important therapeutic target for cancer drug design. In this work, we have performed various molecular modelling studies, such as molecular docking and dynamics simulation for the most active compound of the pyrazole series as RET kinase inhibitors. Furthermore, molecular mechanics Poisson-Boltzmann surface area (MM/PBSA) free energy calculation and 3-dimensional quantitative structure-activity relationship (3D-QSAR) were performed using g_mmpbsa and SYBYL-X 2.1 package. The results of this study revealed the crucial binding site residues at the active site of RET kinase and contour map analysis showed important structural characteristics for the design of new highly active inhibitors. Therefore, we have designed ten RET kinase inhibitors, which showed higher inhibitory activity than the most active compound of the series. The results of our study provide insights to design more potent and selective RET kinase inhibitors.


Assuntos
Inibidores de Proteínas Quinases/farmacologia , Pirazóis/farmacologia , Antineoplásicos/farmacologia , Carcinoma Neuroendócrino/tratamento farmacológico , Carcinoma Neuroendócrino/metabolismo , Linhagem Celular Tumoral , Humanos , Simulação de Acoplamento Molecular/métodos , Relação Quantitativa Estrutura-Atividade , Receptores Proteína Tirosina Quinases/metabolismo , Transdução de Sinais/efeitos dos fármacos , Neoplasias da Glândula Tireoide/tratamento farmacológico , Neoplasias da Glândula Tireoide/metabolismo , Transfecção/métodos
4.
Medicine (Baltimore) ; 100(1): e23835, 2021 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-33429744

RESUMO

ABSTRACT: Immune check-point inhibitors (ICIs) have changed our view on how to treat cancer. Despite their approval in treatment of many different cancers, efficacy of immune check-point inhibitors (ICI) in neuroendocrine neoplasia is limited and poorly understood. Established treatment options of neuroendocrine tumors (NET) and neuroendocrine carcinomas (NECs) are based on surgery, tumor-targeted medical treatments, Peptide Receptor Radionuclide Therapy (PRRT), and locoregional therapies. However, in many patients these treatments lose efficacy over time, and novel therapies are urgently needed. We report on 8 patients diagnosed with neuroendocrine neoplasms (NEN) that were treated with ICI (pembrolizumab, avelumab, nivolumab plus ipilimumab) as salvage therapy. In this cohort, we observed tumor response with partial remission in 3 patients and stable disease in 1 patient. Four patients showed progressive disease. Of note, responses were observed both in PD-L1 positive and PD-L1 negative patients. Here, we discuss clinical courses of these patients in the context of available literature to highlight limitations and drawbacks currently preventing the use of ICI in routine management of patients with NEN.


Assuntos
Carcinoma Neuroendócrino/tratamento farmacológico , /farmacologia , Adulto , Anticorpos Monoclonais Humanizados/farmacologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Carcinoma Neuroendócrino/patologia , Feminino , Humanos , Ipilimumab/farmacologia , Ipilimumab/uso terapêutico , Masculino , Pessoa de Meia-Idade , Nivolumabe/farmacologia , Nivolumabe/uso terapêutico , Centros de Atenção Terciária/organização & administração , Centros de Atenção Terciária/tendências
5.
Am J Surg Pathol ; 45(1): 25-34, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33177340

RESUMO

Assessment of the Ki67 index is critical for grading well-differentiated neuroendocrine tumors (WD-NETs), which can show a broad range of labeling that defines the WHO grade (G1-G3). Poorly differentiated neuroendocrine carcinomas (PD-NECs) have a relatively high Ki67 index, >20% in all cases and commonly exceeding 50%. After anecdotally observing PD-NECs with an unexpectedly low and heterogeneous Ki67 index following chemotherapy in 5 cases, we identified 15 additional cases of treated high-grade neuroendocrine neoplasms (HG-NENs). The study cohort comprised 20 cases; 11 PD-NECs, 8 mixed adenoneuroendocrine carcinomas, and 1 WD-NET, G3 from various anatomic sites (gastrointestinal tract, pancreas, larynx, lung, and breast). The Ki67 index was evaluated on pretreatment (when available) and posttreatment samples. Topographic heterogeneity in the Ki67 index was expressed using a semi-quantitative score of 0 (no heterogeneity) to 5 (>80% difference between maximal Ki67 and minimal Ki67 indices). Relative to the pretreatment group (n=9, mean Ki67 of 86.3%, range 80% to 100%), the neoplasms in the posttreatment group (n=20, mean Ki67 of 47.7%, range 1% to 90%) showed a significantly lower Ki67 index (18/20 cases). Of the 18 cases with a relatively low Ki67 index, 15 showed heterogeneous labeling (mean heterogeneity score of 2.3, range 1 to 5) and in 3 cases it was a homogeneously low. This phenomenon was observed in all subtypes of HG-NENs. In 6 cases, the alterations in Ki67 index following treatment were sufficient to place these HG-NENs in the WHO G1 or G2 grade, erroneously suggesting a diagnosis of WD-NET, and in 9 cases there was sufficient heterogeneity in the Ki67 index to suggest that a limited biopsy may sample an area of low Ki67, even though hotspot regions with a Ki67 index of >20% persisted. In 7 cases, the alterations in the Ki67 index were accompanied by morphologic features resembling a WD-NET. These observations suggest that there is a potential for misinterpretation of previously treated PD-NECs as WD-NETs, or for assigning a lower grade in G3 WD-NETs. While the prognostic significance of treatment-associated alterations in Ki67 index is unknown, awareness of this phenomenon is important to avoid this diagnostic pitfall when evaluating treated NENs.


Assuntos
Carcinoma Neuroendócrino/patologia , Antígeno Ki-67/análise , Gradação de Tumores/métodos , Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/análise , Carcinoma Neuroendócrino/tratamento farmacológico , Humanos , Índice Mitótico
6.
Int J Mol Sci ; 21(24)2020 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-33352665

RESUMO

Evolution of tumor-immune microenviroments (TIMEs) occurs during tumor growth and dissemination. Understanding inter-site tumor-immune heterogeneity is essential to harness the immune system for cancer therapy. While the development of immunotherapy against lung cancer with driver mutations and neuroendocrine tumors is ongoing, little is known about the TIME of large cell neuroendocrine carcinoma (LCNEC) or anaplastic lymphoma kinase (ALK) rearrangement-positive lung cancer. We present a case study of a 32-year-old female patient with ALK-rearrangement-positive LCNEC, who had multiple distant metastases including mediastinal lymph-node, bilateral breasts, multiple bones, liver and brain. Multiple biopsy samples obtained from primary lung and three metastatic tumors were analyzed by fluorescent multiplex immunohistochemistry. Tissue localizations of tumor-infiltrating lymphocytes in the tumor nest and surrounding stroma were evaluated. T cell and B cell infiltrations were decreased with distance from primary lung lesion. Although each tumor displayed a unique TIME, all tumors exhibited concomitant regression after treatment with an ALK-inhibitor. This study provides the first evidence of the coexistence of distinct TIME within a single individual with ALK-rearrangement-positive LCNEC. The present study contributes to our understanding of heterogeneous TIMEs between primary and metastatic lesions and provides new insights into the complex interplay between host-immunity and cancer cells in primary and metastatic lesions.


Assuntos
Quinase do Linfoma Anaplásico/genética , Carcinoma Neuroendócrino/patologia , Rearranjo Gênico , Neoplasias Pulmonares/patologia , Linfócitos do Interstício Tumoral , Microambiente Tumoral , Adulto , Carcinoma Neuroendócrino/tratamento farmacológico , Carcinoma Neuroendócrino/genética , Feminino , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Prognóstico , Inibidores de Proteínas Quinases/uso terapêutico
7.
Medicine (Baltimore) ; 99(43): e22652, 2020 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-33120755

RESUMO

RATIONALE: Poorly differentiated neuroendocrine carcinoma of the breast is a rare cancer with poor prognosis. There is no standard treatment for the disease. Neoadjuvant therapies and surgery are considered to be the main treatment when the tumor diameter is greater than 5.0 cm. Neoadjuvant therapies include chemotherapy and endocrine therapy. However, the effect of neoadjuvant endocrine therapy is not clear in the disease. PATIENT CONCERNS: In August 2014, a 28-year-old premenopausal woman noted a mass that was approximately 3.0 cm*2.0 cm in size on her right breast with pain. Subsequently, the mass has been always increasing significantly. In August 2015, the mass was approximately 7.0 cm*5.0 cm in size, accompanied by pain, no nipple retraction and discharge, no orange peel-like skin changes, and no dimples. In addition, she had no salient past history. DIAGNOSES: Histopathological examinations by a biopsy with a thick needle (hollow needle) and surgical resection confirmed poorly differentiated neuroendocrine carcinoma of the right breast. INTERVENTIONS: First and remarkably, she underwent 3 months of neoadjuvant endocrine therapy (goserelin once every 28 days, and letrozole 10 mg every day). Then, she underwent surgery - stage I breast reconstruction by using prosthesis. Adjuvant endocrine therapy has been used since the operation. OUTCOMES: According to response evaluation criteria in solid tumors 1.1, the tumor was shrunk by 78.87% after neoadjuvant endocrine therapy. No salient complications were observed. We have followed her for 48 months, and there are no signs of recurrence and metastasis. LESSONS: Poorly differentiated neuroendocrine carcinoma of the breast is rare and has a poor prognosis. Currently, there is no standard treatment for this disease. Studies show estrogen receptor and progesterone receptor of neuroendocrine carcinoma of the breast are often highly expressed. In the case, it can be observed that estrogen receptor and progesterone receptor are highly expressed. Therefore, neoadjuvant endocrine therapy may be considered in neuroendocrine carcinoma of the breast when the mass is large and the patient refuses neoadjuvant chemotherapy. We hope to provide an attractive evidence for neoadjuvant endocrine therapy of neuroendocrine carcinoma of the breast. However, more cases are still being needed for research.


Assuntos
Antineoplásicos Hormonais/administração & dosagem , Inibidores da Aromatase/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Carcinoma Neuroendócrino/tratamento farmacológico , Gosserrelina/administração & dosagem , Letrozol/administração & dosagem , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/patologia , Carcinoma Neuroendócrino/diagnóstico , Carcinoma Neuroendócrino/patologia , Feminino , Humanos , Terapia Neoadjuvante/métodos
8.
Anticancer Res ; 40(10): 5933-5938, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32988925

RESUMO

BACKGROUND/AIM: Primary small cell neuroendocrine carcinoma (SCNEC) of the adrenal gland is extremely rare with limited reports in the literature. There remain no definitive treatment guidelines, largely due to the rarity of the malignancy. CASE REPORT: We present the case of a 62-year-old Caucasian male who presented with low back pain and was found to have a large retroperitoneal mass arising from the left adrenal gland, measuring 18.3 × 12.2 centimeters (cm). Biopsy was consistent with small cell carcinoma/high grade neuroendocrine carcinoma. Staging workup including CT chest and bone scan was negative. The patient was treated with chemotherapy, radiation therapy, and surgery; complete pathological response of the left adrenal tumor was achieved. Surveillance imaging every three months continued to show no evidence of recurrent disease. CONCLUSION: Primary SCNEC of the adrenal gland is rare and lacks standard treatment guidelines. Our case represents a possible treatment approach that may provide better clinical outcomes, however, further investigations are necessary to help define ideal treatment guidelines.


Assuntos
Neoplasias das Glândulas Suprarrenais/diagnóstico , Glândulas Suprarrenais/cirurgia , Carcinoma Neuroendócrino/diagnóstico , Carcinoma de Células Pequenas/diagnóstico , Neoplasias das Glândulas Suprarrenais/tratamento farmacológico , Neoplasias das Glândulas Suprarrenais/radioterapia , Neoplasias das Glândulas Suprarrenais/cirurgia , Glândulas Suprarrenais/diagnóstico por imagem , Glândulas Suprarrenais/patologia , Carcinoma Neuroendócrino/tratamento farmacológico , Carcinoma Neuroendócrino/radioterapia , Carcinoma Neuroendócrino/cirurgia , Carcinoma de Células Pequenas/tratamento farmacológico , Carcinoma de Células Pequenas/radioterapia , Carcinoma de Células Pequenas/cirurgia , Humanos , Masculino , Pessoa de Meia-Idade , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons
9.
Gan To Kagaku Ryoho ; 47(8): 1205-1208, 2020 Aug.
Artigo em Japonês | MEDLINE | ID: mdl-32829355

RESUMO

Standard regimens for extrapulmonary neuroendocrine carcinomas(EPNEC)are not established. Treatment used for small cell lung cancer is also used for EPNECs. Amrubicin(AMR) monotherapy is used as salvage therapy for small cell lung cancer, but its efficacy in EPNEC is not clear. The aim of this study was to estimate the efficacy of AMR monotherapy in EPNEC. We retrospectively investigated patients with EPNEC who received first-line platinum-based chemotherapy between April 2007 and March 2019. The time to treatment failure(TTF)and the efficacy and toxicity was analyzed in the patients who received AMR monotherapy. Among 43 patients with EPNEC, 14(13 males, one female; median age, 58 years)received AMR monotherapy. Primary site included the pancreas(n=3), stomach(n=3), rectum(n=1), anal canal(n=1), salivary glands(n= 1), urothelial(n=1), bladder(n=1), prostate(n=1), and 2 patients had primary unknown cancer. Pathological type included small cell(n=4), large cell(n=2), and other types(n=8). Prior chemotherapy comprised CDDP plus CPT-11(n =5), CDDP plus ETP(n=2), and CBDCA plus ETP(n=6). The median TTF was 49(20-61)days. One patient had a partial response and the disease control rate was 33%. The common adverse events of >Grade 3 were leukopenia(69%), neutropenia(62%), and febrile neutropenia(23%). AMR monotherapy was clinically effective and safe for EPNEC.


Assuntos
Antraciclinas/uso terapêutico , Carcinoma Neuroendócrino , Antineoplásicos , Protocolos de Quimioterapia Combinada Antineoplásica , Carcinoma Neuroendócrino/tratamento farmacológico , Feminino , Humanos , Neoplasias Pulmonares , Masculino , Pessoa de Meia-Idade , Platina , Estudos Retrospectivos , Resultado do Tratamento
10.
Gan To Kagaku Ryoho ; 47(4): 722-724, 2020 Apr.
Artigo em Japonês | MEDLINE | ID: mdl-32389996

RESUMO

A 68-year-old man presented to our hospital. An upper gastrointestinal tract endoscopy performed elsewhere revealed an elevated lesion with a circumferential esophageal cancer(identified as small cell carcinoma). Perthe treatment forsmall cell cancer and the standard treatment for esophageal neuroendocrine carcinoma, 7 courses of CBDCA(5mg/m2)plus ETP (100mg/m2)were administered. The lesion shrank and the lymph node swelling disappeared and the patient was deemed to be in partial remission. Nine months later, however, the primary tumor increased in size. A transthoracic subtotal esophagectomy( laparoscope-assisted), 2 area dissection, and gastric tube reconstruction(post-sternal)were performed at 2 years and 10 months afterdiagnosis.


Assuntos
Carcinoma Neuroendócrino , Neoplasias Esofágicas , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica , Carcinoma Neuroendócrino/tratamento farmacológico , Carcinoma Neuroendócrino/cirurgia , Dissecação , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/cirurgia , Esofagectomia , Humanos , Masculino
11.
Am J Clin Oncol ; 43(5): 305-310, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32343515

RESUMO

OBJECTIVES: Gastrointestinal neuroendocrine carcinoma (NEC) is a lethal, uncommon, and understudied neoplasm. We present the efficacy and safety of first-line capecitabine (CP), oxaliplatin, irinotecan, and bevacizumab (CAPOXIRI-BEV) combination followed by pazopanib plus CP maintenance therapy in patients with advanced high-grade poorly differentiated gastrointestinal NEC. METHODS: This was a two-stage phase II study conducted at multiple institutions. Patients were consecutively enrolled and had advanced NEC of the colon or small bowel. Patients received irinotecan 125 mg/m, oxaliplatin 80 mg/m on day 1, CP 1000 mg/m twice daily on days 1 to 14, plus bevacizumab 8 mg/kg on day 1 for six 21-day cycles. Maintenance therapy was given to those who responded (complete response/partial response) or had stable disease after 6 cycles with CAPOXIRI-BEV with pazopanib 800 mg daily plus CP 1600 mg/m daily on days 1 to 14 every 3 weeks until disease progression or unacceptable toxicity. Patients who progressed on CAPOXIRI-BEV received standard etoposide-carboplatin. The primary endpoint was overall response rate. RESULTS: Twenty-two patients were enrolled of whom 19 were evaluable. The median age was 60 years. The overall response rate (3 complete response/6 partial response) was 47.4% (95% confidence interval: 29.5-76.1), the overall disease control rate was 78.9% (95% confidence interval: 62.6-99.6), and, at median 30 (11 to 41 mo) months' follow-up, 5 patients (26.3%) were still alive. Median progression-free survival was 13 months, and the 1-year progression-free survival rate was 52.6%. The median overall survival was 29 months. The median overall survival of the 9 patients who responded versus those with stable disease/progressive disease was 30.5 versus 14 months, respectively. The median duration of response was 16 months. Predictable toxicity was observed. CONCLUSIONS: First-line CAPOXIRI-BEV followed by pazopanib plus CP maintenance therapy for advanced NEC demonstrates promising efficacy and predictable toxicity. Further investigation is warranted.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Neuroendócrino/tratamento farmacológico , Neoplasias Gastrointestinais/tratamento farmacológico , Adulto , Idoso , Bevacizumab/administração & dosagem , Bevacizumab/efeitos adversos , Capecitabina/administração & dosagem , Capecitabina/efeitos adversos , Carcinoma Neuroendócrino/mortalidade , Feminino , Neoplasias Gastrointestinais/mortalidade , Humanos , Irinotecano/administração & dosagem , Irinotecano/efeitos adversos , Masculino , Pessoa de Meia-Idade , Oxaliplatina/administração & dosagem , Oxaliplatina/efeitos adversos , Intervalo Livre de Progressão , Pirimidinas/administração & dosagem , Pirimidinas/efeitos adversos , Sulfonamidas/administração & dosagem , Sulfonamidas/efeitos adversos
12.
J Cancer Res Clin Oncol ; 146(8): 2135-2142, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32306127

RESUMO

PURPOSE: The impact of neoadjuvant chemotherapy (NAC) on patients with neuroendocrine carcinoma (NEC) and mixed adenoneuroendocrine carcinoma (MANEC) of the stomach is unclear. The aim of this retrospective study was to evaluate the effects of NAC on patients with these conditions. METHODS: This study included patients with locally advanced NEC or MANEC of the stomach who underwent gastrectomy. Histologic and prognostic effects of NAC were assessed. The overall survival (OS) rate was used to compare treatment efficacies between NAC patients and surgery-first patients. RESULTS: Of the 69 patients included in this study, 20 received NAC and 49 underwent surgery first after diagnosis. A total of 13 patients responded to NAC (including 3 with complete remission and 10 with partial remission) and 7 patients acquired stable disease status according to the Response Evaluation Criteria in Solid Tumors version 1.1. One patient (5%) achieved a pathological complete response after NAC. Pathological tumor regression grades 1, 2, 3, 4, and 5 were observed in 1 (5%), 5 (25%), 3 (15%), 10 (50%), and 1 (5%) patient(s) with NAC, respectively. The incidence of postoperative complications was similar in the two groups. Patients in the NAC group demonstrated better OS than did patients in the surgery-first group (P = 0.032). Multivariate analyses showed that NAC, adjuvant chemotherapy, and the clinical N stage were independent factors affecting OS. CONCLUSION: In patients with locally advanced NEC and MANEC of the stomach, NAC significantly improved OS.


Assuntos
Adenocarcinoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Neuroendócrino/tratamento farmacológico , Neoplasias Gástricas/tratamento farmacológico , Adenocarcinoma/patologia , Adenocarcinoma/cirurgia , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma Neuroendócrino/patologia , Carcinoma Neuroendócrino/cirurgia , Estudos de Casos e Controles , Quimioterapia Adjuvante , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante , Estudos Retrospectivos , Neoplasias Gástricas/patologia , Neoplasias Gástricas/cirurgia , Taxa de Sobrevida , Resultado do Tratamento
13.
An. sist. sanit. Navar ; 43(1): 103-106, ene.-abr. 2020.
Artigo em Espanhol | IBECS | ID: ibc-193684

RESUMO

Everolimus es un inhibidor de mTOR, empleado en oncología y como inmunosupresor en el trasplante de órgano sólido. Sus efectos adversos a nivel metabólico son muy frecuentes, especialmente los más severos. Puede ocasionar hiperglucemia, hipercolesterolemia e hipertrigliceridemia, por lo que la monitorización de los parámetros metabólicos en las sucesivas visitas es vital para detectar e iniciar tratamientos que puedan prevenir las complicaciones. Se presenta el caso de una mujer con diagnóstico de tumor neuroendocrino intestinal que desarrolló dos pancreatitis agudas secundarias a hipertrigliceridemia severa por everolimus. Tras inicio de tratamiento con fibratos y omega-3, se normalizó la cifra de triglicéridos sin presentar nuevas complicaciones metabólicas ni digestivas secundarias al fármaco. La recomendación en pacientes con cáncer en tratamiento activo con everolimus es mantener los triglicéridos por debajo de 500 o 300 mg/dL, dependiendo de si la esperanza de vida es inferior o superior a un año, respectivamente


Everolimus is an mTOR inhibitor, approved as a treatment for cancer and as an immunosuppressant agent in solid organ transplantation; it frequently produces toxic metabolic effects, particularly of the most severe kind. Its use can cause hyperglycemia, hypercholesterolemia and hypertriglyceridemia; thus, metabolic values should be monitored regularly to prevent these adverse events. We present the case of a woman with an intestinal neuroendocrine tumor who developed two episodes of acute pancreatitis, secondary to severe hypertriglyceridemia caused by everolimus. After treatment with fibrates and omega-3, triglyceride levels returned to baseline, without developing new metabolic or digestive complications. Targeted levels of triglyceride for cancer patients treated with everolimus, should be below 500 or 300 mg/dL, depending on whether life expectancy is less or longer than one year, respectively


Assuntos
Humanos , Feminino , Adulto , Hipolipemiantes/administração & dosagem , Pancreatite Necrosante Aguda/tratamento farmacológico , Hipertrigliceridemia/induzido quimicamente , Everolimo/administração & dosagem , Carcinoma Neuroendócrino/diagnóstico , Carcinoma Neuroendócrino/tratamento farmacológico , Imunossupressores/administração & dosagem , Everolimo/efeitos adversos , Tomografia Computadorizada de Emissão , Íleo/diagnóstico por imagem , Proteína Regulatória Associada a mTOR/antagonistas & inibidores
14.
Orv Hetil ; 161(8): 313-319, 2020 Feb.
Artigo em Húngaro | MEDLINE | ID: mdl-32073294

RESUMO

Small-cell lung carcinoma (SCLC) and the rare large-cell neuroendocrine carcinoma belong to the high grade pulmonary neuroendocrine carcinomas. Making the correct diagnosis and selection of treatment modalities require multidisciplinary meetings due to the morphological overlaps, aggressive behaviour and debated therapeutic guidelines of these entities. A 52-year-old woman was admitted to the hospital because of headache, nausea and tenebrous vision. The CT revealed metastatic tumour mass in the occipital lobe and in the cerebellum. Both tumours were removed and resulted in histological diagnosis of metastatic neuroendocrine carcinoma. Chest X-ray established contrast-enhancing lesion in the left lung. Bronchoscopy was performed and histological examination revealed large-cell neuroendocrine carcinoma. Postoperative skull irradiation and small-cell lung cancer chemotherapy protocol were utilized. Due to atelectasis and progression, chest irradiation was initiated, which was interrupted because of novel brain metastases. Further chemotherapy followed the non-small-cell lung cancer protocol. After 3 months, thoracic progression, brain and disseminated bone metastases were diagnosed. After a 14-month-long therapy, the patient deceased. Large-cell neuroendocrine carcinoma has a poor prognosis, the incidence of brain metastasis is 25-50%. In early stage large-cell neuroendocrine carcinoma, lobectomy is the standard treatment and adjuvant chemotherapy should also be considered. Although the non-small-cell lung cancer chemotherapy protocol is approved widely in the treatment of large-cell neuroendocrine carcinoma, the utility of SCLC scheme has also been suggested. Orv Hetil. 2020; 161(8): 313-319.


Assuntos
Carcinoma de Células Grandes/diagnóstico , Carcinoma de Células Grandes/tratamento farmacológico , Carcinoma Neuroendócrino/diagnóstico , Carcinoma Neuroendócrino/tratamento farmacológico , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica , Quimioterapia Adjuvante , Feminino , Humanos , Pessoa de Meia-Idade
15.
Ann Otol Rhinol Laryngol ; 129(7): 657-661, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32037846

RESUMO

BACKGROUND: Medullary thyroid carcinoma (MTC) accounts for 1% to 2% of thyroid cancers in the United States. When identified early, total thyroidectomy is most often curative. However, in advanced disease, more aggressive treatment such as laryngectomy and esophagectomy may be indicated. Postsurgical fistula formation and leak is a potential complication in such cases. These fistulas are most likely to occur at the anastomotic site in cases of laryngectomy or esophagectomy. Concomitant chemotherapy and radiation increase this risk. Tyrosine kinase inhibitors (TKI) such as Cabozantinib are used as therapy for metastatic MTC. These drugs have previously been associated with dehiscence of anastomotic sites in the gastrointestinal tract. While previously identified in the bowel, this report represents the first documented case of gastropharyngeal anastomosis leak described in the context of TKI use for head and neck cancer. CASE PRESENTATION: We present the case of a 72-year-old male previously diagnosed with MTC. His gastropharyngeal anastomosis status-post laryngopharyngectomy and gastric pull up had been stable for 23 years. Over the past year, he developed back pain and was found to have spinal metastases of MTC. He was subsequently started on Cabozantinib to slow the progression of the disease. Within months of starting this TKI, a bleeding pharyngocutaneous fistula developed at the anastomosis site of the gastric pull up and pharynx. Upon discontinuation of Cabozantinib, the fistula healed with no further complications. CONCLUSIONS: To our knowledge, this is the first documented case of gastropharyngeal anastomotic leak related to TKI use. A causal relationship is highly plausible given the previously stable anastomosis and the suspicious advent of complications within months of initiation of this new drug. While previously limited to cases of intraabdominal bowel dehiscence, this report now suggests that wound dehiscence must be considered a known side effect of TKIs throughout the gastrointestinal tract, including the gastropharynx. As such, the risk of anastomotic dehiscence should be discussed with the patient prior to starting a TKI.


Assuntos
Fístula Anastomótica/induzido quimicamente , Anilidas/efeitos adversos , Carcinoma Neuroendócrino/tratamento farmacológico , Faringe/cirurgia , Inibidores de Proteínas Quinases/efeitos adversos , Piridinas/efeitos adversos , Neoplasias da Coluna Vertebral/tratamento farmacológico , Estômago/cirurgia , Neoplasias da Glândula Tireoide/tratamento farmacológico , Idoso , Anastomose Cirúrgica , Carcinoma Neuroendócrino/secundário , Carcinoma Neuroendócrino/cirurgia , Esofagectomia , Humanos , Laringectomia , Masculino , Neoplasias da Coluna Vertebral/secundário , Neoplasias da Glândula Tireoide/secundário , Neoplasias da Glândula Tireoide/cirurgia , Tireoidectomia
16.
Int J Mol Sci ; 21(3)2020 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-32041153

RESUMO

Neuroendocrine prostate cancer (NEPC) can arise de novo, but much more commonly occurs as a consequence of a selective pressure from androgen deprivation therapy or androgen receptor antagonists used for prostate cancer (PCa) treatment. The process is known as neuroendocrine transdifferentiation. There is little molecular characterization of NEPCs and consequently there is no standard treatment for this kind of tumors, characterized by highly metastases rates and poor survival. For this purpose, we profiled 54 PCa samples with more than 10-years follow-up for gene and miRNA expression. We divided samples into two groups (NE-like vs. AdenoPCa), according to their clinical and molecular features. NE-like tumors were characterized by a neuroendocrine fingerprint made of known neuroendocrine markers and novel molecules, including long non-coding RNAs and components of the estrogen receptor signaling. A gene expression signature able to predict NEPC was built and tested on independently published datasets. This study identified molecular features (protein-coding, long non-coding, and microRNAs), at the time of surgery, that may anticipate the NE transformation process of prostate adenocarcinoma. Our results may contribute to improving the diagnosis and treatment of this subgroup of tumors for which traditional therapy regimens do not show beneficial effects.


Assuntos
Adenocarcinoma/genética , Carcinoma Neuroendócrino/genética , MicroRNAs/genética , Neoplasias da Próstata/genética , RNA Longo não Codificante/genética , Adenocarcinoma/tratamento farmacológico , Idoso , Antagonistas de Receptores de Andrógenos/efeitos adversos , Antagonistas de Receptores de Andrógenos/uso terapêutico , Androgênios/metabolismo , Carcinoma Neuroendócrino/tratamento farmacológico , Transdiferenciação Celular/fisiologia , Receptor alfa de Estrogênio/metabolismo , Estrogênios/metabolismo , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Masculino , Pessoa de Meia-Idade , Próstata/patologia , Neoplasias da Próstata/tratamento farmacológico , Receptores Androgênicos/metabolismo , Transdução de Sinais
18.
Rev. esp. med. nucl. imagen mol. (Ed. impr.) ; 39(1): 31-34, ene.-feb. 2020. ilus
Artigo em Espanhol | IBECS | ID: ibc-195944

RESUMO

Se realizó una PET/TC con 68Ga DOTANOC a un varón de 64 años con tumor neuroendocrino de grado III, para estadificación. La lesión pancreática, múltiples ganglios peripancreáticos y diversas metástasis de gran tamaño en ambos lóbulos hepáticos, se mostraron con captación intensa. Tras 3 ciclos de quimioterapia con cisplatino y etopósido, el tumor primario y las metástasis disminuyeron de tamaño, aunque se reveló una mayor captación en la PET/TC con 68Ga DOTANOC de seguimiento. Otra biopsia hepática reflejó un descenso significativo del índice de proliferación de Ki-67, del 35 al 1%. El paciente recibió 2 ciclos de terapia con radionúclidos de receptores peptídicos con 177Lu DOTANOC


A 64-year-old man with pancreatic grade III neuroendocrine carcinoma underwent 68Ga DOTANOC PET/CT scan for staging. The pancreatic lesion, multiple peripancreatic lymph nodes and multiple gross metastases in both hepatic lobes were revealed with intense uptake. After 3 cycles of chemotherapy containing cisplatin and etoposide the primary and metastatic lesions were decreased in size, however showing higher uptake on follow-up 68Ga DOTANOC PET/CT scan. Another biopsy from liver demonstrated a significant decrease in Ki-67 proliferation index from 35 to 1%. The patient received 2 cycles of peptide receptor-targeted radionuclide therapy with 177Lu DOTANOC


Assuntos
Humanos , Masculino , Pessoa de Meia-Idade , Carcinoma Neuroendócrino , Neoplasias Hepáticas , Compostos Organometálicos , Neoplasias Pancreáticas , Tomografia Computadorizada por Raios X/métodos , Compostos Radiofarmacêuticos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Neuroendócrino/diagnóstico por imagem , Carcinoma Neuroendócrino/tratamento farmacológico , Carcinoma Neuroendócrino/patologia , Carcinoma Neuroendócrino/secundário , Desdiferenciação Celular , Proliferação de Células , Cisplatino/administração & dosagem , Etoposídeo/administração & dosagem , Antígeno Ki-67/análise , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/secundário , Metástase Linfática/diagnóstico por imagem , Octreotida/análogos & derivados , Octreotida/uso terapêutico , Compostos Organometálicos/uso terapêutico , Neoplasias Pancreáticas/diagnóstico por imagem , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/patologia
19.
Anticancer Res ; 40(1): 121-132, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31892560

RESUMO

BACKGROUND/AIM: Pancreatic neuroendocrine tumors (pNETs) are rare pancreatic neoplasms, and therapeutic options for pNETs are limited. Metformin is an anti-hypoglycemic drug that appears to have anticancer effects. However, little is known about the effect of metformin on pNETs. In this study, we investigated the anti-proliferative effect of metformin on a human pNET cell line. MATERIALS AND METHODS: The anti-proliferative properties of metformin were evaluated in QGP-1 and NCI-H727 cells using a cell counting kit-8 assay. Xenograft mouse models were used to assess the tumor effect in vivo. RESULTS: Metformin inhibited the proliferation and anti-tumor growth of QGP-1 cells, accompanied by their arrest during the cell cycle at the G0/G1 phase. Immunohistochemical analysis of tumor tissues revealed down-regulation of cyclin D1 and proliferating cell nuclear antigen in the metformin-treated group. Additionally, metformin induced apoptosis, and the expression of survivin and claspin were decreased in metformin-treated QGP-1 cells according to the apoptosis array. Furthermore, the angiogenic related protein TIMP-1 was down-regulated, and its miRNA expression was altered by metformin in QGP-1 cells. CONCLUSION: Taken together, our study demonstrated the therapeutic potential of metformin and provides molecular mechanistic insights into its anti-tumoral effect on pNETs. This study is the first one describing anti-tumoral effects in pNETs.


Assuntos
Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Metformina/farmacologia , Biomarcadores , Carcinoma Neuroendócrino/tratamento farmacológico , Carcinoma Neuroendócrino/metabolismo , Carcinoma Neuroendócrino/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , MicroRNAs/genética , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/metabolismo , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Transdução de Sinais/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
20.
Proc Natl Acad Sci U S A ; 117(4): 2032-2042, 2020 01 28.
Artigo em Inglês | MEDLINE | ID: mdl-31932422

RESUMO

Resistance to androgen deprivation therapy, or castration-resistant prostate cancer (CRPC), is often accompanied by metastasis and is currently the ultimate cause of prostate cancer-associated deaths in men. Recently, secondary hormonal therapies have led to an increase of neuroendocrine prostate cancer (NEPC), a highly aggressive variant of CRPC. Here, we identify that high levels of cell surface receptor Trop2 are predictive of recurrence of localized prostate cancer. Moreover, Trop2 is significantly elevated in CRPC and NEPC, drives prostate cancer growth, and induces neuroendocrine phenotype. Overexpression of Trop2 induces tumor growth and metastasis while loss of Trop2 suppresses these abilities in vivo. Trop2-driven NEPC displays a significant up-regulation of PARP1, and PARP inhibitors significantly delay tumor growth and metastatic colonization and reverse neuroendocrine features in Trop2-driven NEPC. Our findings establish Trop2 as a driver and therapeutic target for metastatic prostate cancer with neuroendocrine phenotype and suggest that high Trop2 levels could identify cancers that are sensitive to Trop2-targeting therapies and PARP1 inhibition.


Assuntos
Antígenos de Neoplasias/metabolismo , Biomarcadores Tumorais/metabolismo , Neoplasias Ósseas/secundário , Carcinoma Neuroendócrino/patologia , Moléculas de Adesão Celular/metabolismo , Regulação Neoplásica da Expressão Gênica , Poli(ADP-Ribose) Polimerase-1/metabolismo , Neoplasias de Próstata Resistentes à Castração/patologia , Animais , Antígenos de Neoplasias/genética , Apoptose , Biomarcadores Tumorais/genética , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/metabolismo , Carcinoma Neuroendócrino/tratamento farmacológico , Carcinoma Neuroendócrino/metabolismo , Moléculas de Adesão Celular/genética , Movimento Celular , Proliferação de Células , Seguimentos , Humanos , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Invasividade Neoplásica , Fenótipo , Poli(ADP-Ribose) Polimerase-1/antagonistas & inibidores , Poli(ADP-Ribose) Polimerase-1/genética , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Prognóstico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/metabolismo , Taxa de Sobrevida , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
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