RESUMO
Targeting cell surface molecules using radioligand and antibody-based therapies has yielded considerable success across cancers. However, it remains unclear how the expression of putative lineage markers, particularly cell surface molecules, varies in the process of lineage plasticity, wherein tumor cells alter their identity and acquire new oncogenic properties. A notable example of lineage plasticity is the transformation of prostate adenocarcinoma (PRAD) to neuroendocrine prostate cancer (NEPC)-a growing resistance mechanism that results in the loss of responsiveness to androgen blockade and portends dismal patient survival. To understand how lineage markers vary across the evolution of lineage plasticity in prostate cancer, we applied single-cell analyses to 21 human prostate tumor biopsies and two genetically engineered mouse models, together with tissue microarray analysis on 131 tumor samples. Not only did we observe a higher degree of phenotypic heterogeneity in castrate-resistant PRAD and NEPC than previously anticipated but also found that the expression of molecules targeted therapeutically, namely PSMA, STEAP1, STEAP2, TROP2, CEACAM5, and DLL3, varied within a subset of gene-regulatory networks (GRNs). We also noted that NEPC and small cell lung cancer subtypes shared a set of GRNs, indicative of conserved biologic pathways that may be exploited therapeutically across tumor types. While this extreme level of transcriptional heterogeneity, particularly in cell surface marker expression, may mitigate the durability of clinical responses to current and future antigen-directed therapies, its delineation may yield signatures for patient selection in clinical trials, potentially across distinct cancer types.
Assuntos
Análise de Célula Única , Masculino , Humanos , Análise de Célula Única/métodos , Animais , Camundongos , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Neoplasias da Próstata/tratamento farmacológico , Antígenos de Superfície/metabolismo , Antígenos de Superfície/genética , Antígenos de Neoplasias/metabolismo , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/imunologia , Biomarcadores Tumorais/metabolismo , Biomarcadores Tumorais/genética , Adenocarcinoma/genética , Adenocarcinoma/patologia , Adenocarcinoma/metabolismo , Adenocarcinoma/tratamento farmacológico , Carcinoma Neuroendócrino/genética , Carcinoma Neuroendócrino/patologia , Carcinoma Neuroendócrino/metabolismo , Carcinoma Neuroendócrino/tratamento farmacológico , Regulação Neoplásica da Expressão Gênica , Neoplasias de Próstata Resistentes à Castração/metabolismo , Neoplasias de Próstata Resistentes à Castração/patologia , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológicoRESUMO
Neuroendocrine neoplasms (NENs), which are characterized by neuroendocrine differentiation, can arise in various organs. NENs have been divided into well-differentiated neuroendocrine tumors (NETs) and poorly differentiated neuroendocrine carcinomas (NECs) based on morphological differentiation, each of which has a distinct etiology, molecular profile, and clinicopathological features. While the majority of NECs originate in the pulmonary organs, extrapulmonary NECs occur most predominantly in the gastro-entero-pancreatic (GEP) system. Although platinum-based chemotherapy is the main therapeutic option for recurrent or metastatic GEP-NEC patients, the clinical benefits are limited and associated with a poor prognosis, indicating the clinically urgent need for effective therapeutic agents. The clinical development of molecular-targeted therapies has been hampered due to the rarity of GEP-NECs and the paucity of knowledge on their biology. In this review, we summarize the biology, current treatments, and molecular profiles of GEP-NECs based on the findings of pivotal comprehensive molecular analyses; we also highlight potent therapeutic targets for future precision medicine based on the most recent results of clinical trials.
Assuntos
Carcinoma Neuroendócrino , Neoplasias Intestinais , Tumores Neuroendócrinos , Neoplasias Pancreáticas , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/terapia , Neoplasias Pancreáticas/patologia , Neoplasias Intestinais/patologia , Neoplasias Intestinais/terapia , Carcinoma Neuroendócrino/tratamento farmacológico , Carcinoma Neuroendócrino/genética , Carcinoma Neuroendócrino/patologia , Tumores Neuroendócrinos/tratamento farmacológico , Tumores Neuroendócrinos/patologiaRESUMO
Small-cell neuroendocrine carcinoma of the cervix (SCNCC) is a rare and aggressive tumor with a poor prognosis. Surgical resection followed by adjuvant therapy is the standard treatment for early-stage disease but the influence of different neo/adjuvant treatment approaches remains unclear. Retrospectively, we collected patients' characteristics and treatments in two medical centers. Disease status and survival outcomes were renewed through follow-up. Statistics analysis mainly included Kaplan-Meier methods for survival curve estimation, log-rank test for survival curve comparison, and Cox proportional hazards models for independent prognostic factors prediction. Finally, 51 patients treated by radical surgery between January 2010 and April 2020 were enrolled with a median age of 50 years (range: 32-68). 12 (23.5%) patients were at stage IIIC1 according to the International Federation of Gynecology and Obstetrics (FIGO) 2018 staging systems and the rest were at the early stage. The mean tumor size was 3.6±1.3 cm. Pathological examination found 24 cases with pure SCNCC and 27 cases with admixed SCCC. 29 (56.9%) patients had deep stromal infiltration and 19 (37.3%) patients had lymphovascular space invasion. 34 (66.7%) patients received neo/adjuvant chemotherapy and pelvic radiation was conducted in 41 (80.39%) patients with a median dose of 46 Gy (range: 40-50.4 Gy). The median follow-up time was 25.0 months. The median disease-free survival (DFS) time was 23.0 months. 27 (52.9%) patients developed distant metastasis and 14 (27.5%) experienced local failure. The median overall survival (OS) was 32.0 months. Univariate and multivariate analysis showed neoadjuvant chemotherapy as negative (HR=2.081, 95% CI 1.030-4.203, p=0.041) and adjuvant chemotherapy (HR=0.409, 95% CI 0.213-0.784, p=0.020) as positive independent prognostic factor for DFS. For OS, only lymph node metastasis was confirmed as an independent prognostic factor in both univariate analysis (HR=1.528, 95% CI 1.011-2.308, p=0.044) and multivariate analysis (HR=1.697, 95% CI 1.041-2.768, p=0.034). In conclusion, for surgically treated SCNCC, adjuvant chemotherapy showed a positive influence on DFS while neoadjuvant chemotherapy harmed DFS. OS was unaffected by either treatment choice.
Assuntos
Carcinoma Neuroendócrino , Carcinoma de Células Pequenas , Neoplasias do Colo do Útero , Feminino , Humanos , Adulto , Pessoa de Meia-Idade , Idoso , Resultado do Tratamento , Colo do Útero/patologia , Estudos Retrospectivos , Estadiamento de Neoplasias , Prognóstico , Carcinoma de Células Pequenas/cirurgia , Carcinoma de Células Pequenas/tratamento farmacológico , Neoplasias do Colo do Útero/cirurgia , Neoplasias do Colo do Útero/tratamento farmacológico , Quimioterapia Adjuvante , Carcinoma Neuroendócrino/cirurgia , Carcinoma Neuroendócrino/tratamento farmacológicoRESUMO
Neuroendocrine prostate cancer (NEPC) is a histological variant of prostate cancer and is characterized by aggressiveness and poor clinical outcomes. NEPC usually develops as a mechanism of treatment resistance in patients receiving hormone therapy for advanced prostate cancer. NEPC is sensitive to primary platinum-based chemotherapy, and has a short response duration. Second-line therapy is required in many cases, but clinical data on subsequent treatment after progression to first-line chemotherapy is limited. Here we report our experience of four cases of NEPC treated with second-line chemotherapy. Progression-free and overall survival rates were very low in three of the patients. One patient received multidisciplinary therapy using systemic and local chemotherapy and radiation therapy and survived for 24 months after initiation of second-line chemotherapy. Multidisciplinary therapy with chemotherapy and radiation is a promising option for improving the survival of patients with NEPC.
Assuntos
Carcinoma Neuroendócrino , Neoplasias da Próstata , Masculino , Humanos , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/patologia , Resultado do Tratamento , Carcinoma Neuroendócrino/tratamento farmacológico , Carcinoma Neuroendócrino/patologiaRESUMO
BACKGROUND: To date, single-agent immune checkpoint inhibitor (CPI) therapy has proven to be ineffective against biomarker-unselected extrapulmonary poorly differentiated neuroendocrine carcinomas (EP-PDNECs). The efficacy of CPI in combination with chemotherapy remains under investigation. METHODS: Patients with advanced, progressive EP-PDNECs were enrolled in a two-part study of pembrolizumab-based therapy. In Part A, patients received pembrolizumab alone. In Part B, patients received pembrolizumab plus chemotherapy. PRIMARY ENDPOINT: objective response rate (ORR). Secondary endpoints: safety, progression-free survival (PFS) and overall survival (OS). Tumours were profiled for programmed death-ligand 1 expression, microsatellite-high/mismatch repair deficient status, mutational burden (TMB), genomic correlates. Tumour growth rate was evaluated. RESULTS: Part A (N = 14): ORR (pembrolizumab alone) 7% (95% CI, 0.2-33.9%), median PFS 1.8 months (95% CI, 1.7-21.4), median OS 7.8 months (95% CI, 3.1-not reached); 14% of patients (N = 2) had grade 3/4 treatment-related adverse events (TRAEs). Part B (N = 22): ORR (pembrolizumab plus chemotherapy) 5% (95% CI, 0-22.8%), median PFS 2.0 months (95% CI, 1.9-3.4), median OS 4.8 months (95% CI, 4.1-8.2); 45% of patients (N = 10) had grade 3/4 TRAEs. The two patients with objective response had high-TMB tumours. DISCUSSION: Treatment with pembrolizumab alone and pembrolizumab plus chemotherapy was ineffective in advanced, progressive EP-PDNECs. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT03136055.
Assuntos
Carcinoma Neuroendócrino , Tumores Neuroendócrinos , Humanos , Anticorpos Monoclonais Humanizados/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma Neuroendócrino/tratamento farmacológico , Carcinoma Neuroendócrino/genética , Tumores Neuroendócrinos/tratamento farmacológico , Intervalo Livre de ProgressãoRESUMO
Large cell neuroendocrine carcinoma (LCNEC) is a rare and aggressive high-grade neuroendocrine tumor, commonly arising in the lung or in the gastrointestinal tract, with a frequent proportion of unknown primary origin (20%). In the metastatic setting, platinum-based or fluoropyrimidine-based chemotherapeutic regimens are as considered the first-line treatment, despite the limited duration of response. To date, the prognosis of advanced high-grade neuroendocrine carcinoma remains poor, suggesting the need to explore new treatment strategies in this orphan tumor. The evolving molecular landscape of LCNEC, not yet been completely defined, could explain the heterogeneous response to different chemotherapeutic regimens and suggest that treatment strategy could be driven by molecular features. v-Raf murine sarcoma viral oncogene homolog B (BRAF) mutations, well described in melanoma, thyroid cancer, colon cancer and lung adenocarcinoma, account for approximately 2% of cases in lung LCNEC. Here, we describe the case of a patient with a BRAF V600E-mutated LCNEC of unknown primary origin who partially responded to BRAF/mitogen-activated protein kinase kinase inhibitors after standard treatment. Additionally, BRAF V600E circulating tumor DNA was used to monitor disease response. Thereafter, we reviewed the available literature about the role of targeted therapy in high-grade neuroendocrine neoplasms to provide insight for future research to identify patients with driver oncogenic mutations, who can potentially benefit from target therapy.
Assuntos
Carcinoma Neuroendócrino , Neoplasias Pulmonares , Neoplasias Primárias Desconhecidas , Humanos , Carcinoma Neuroendócrino/tratamento farmacológico , Carcinoma Neuroendócrino/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Mutação , Proteínas Proto-Oncogênicas B-raf/genéticaRESUMO
OPINION STATEMENT: Genetic assessment is crucial to address the correct treatment for advanced medullary thyroid cancer (MTC). Multi tyrosine kinase inhibitors (mTKIs) cabozantinib and vandetanib are good first line options, even vandetanib prescription is currently limited to RET mutated patients. Selective RET inhibitors such as pralsetinib could be a preferred upfront treatment in case of RET mutated MTC presenting common or gatekeeper RET mutations (e.g. M918T; V804L/M). Selpercatinib, otherwise, can be prescribed as the second line after disease progression to mTKIs. The best option for subsequent lines is to consider inclusion in clinical trials or alternatively other mTKIs such as sunitinib, sorafenib, lenvatinib, or pazopanib could be evaluated. New perspectives include next-generation RET inhibitors able to overcome resistance mechanisms responsible for disease progression to standard mTKIs and RET inhibitors, and immunotherapy for MTC presenting with high tumor mutational burden.
Assuntos
Carcinoma Neuroendócrino , Neoplasias da Glândula Tireoide , Humanos , Proteínas Proto-Oncogênicas c-ret/genética , Carcinoma Neuroendócrino/diagnóstico , Carcinoma Neuroendócrino/tratamento farmacológico , Carcinoma Neuroendócrino/etiologia , Neoplasias da Glândula Tireoide/diagnóstico , Neoplasias da Glândula Tireoide/tratamento farmacológico , Neoplasias da Glândula Tireoide/etiologia , Progressão da DoençaRESUMO
INTRODUCTION: Extrapulmonary neuroendocrine carcinoma (EPNEC) is a clinicopathological entity distinct from neuroendocrine carcinoma of the lung. Here, we reviewed the clinical features, treatment modalities, and prognosis of EPNEC patients in a single-institution series. METHODS: We retrospectively reviewed the medical records of EPNEC patients and examined the clinical profiles and treatment outcomes at our hospital between 2013 and 2021. RESULTS: Thirty-one EPNEC patients (21 men and 10 women) with a median age of 65 years were included. The primary sites were as follows: stomach (n = 7); rectum and bladder (n = 3 each); prostate, esophagus, cervix, and pancreas (n = 2 each); maxillary sinus, parotid gland, gallbladder, anal canal, larynx, uterine body, ovary, appendix, anterior mediastinum, and unknown primary lesion (n = 1 each). Thirteen patients had locally advanced stage and 18 cases had distant metastases. Chemotherapy using platinum-combined CPT-11 or VP-16 was mainly performed. Various therapeutic modalities were used, especially in locally advanced cases. Ten patients underwent surgery, including initial surgery in 5 and conversion in 5 after chemotherapy. The response rate to initial chemotherapy was 56.5%, and the median overall survival in all patients was 12.8 (95% CI: 9.6-34.5) months. Survival was significantly longer in patients with locally advanced stage (80.3 months) and receiving surgery (not reached) than in those with metastatic disease (9.9 months) and without surgery (9.6 months). CONCLUSION: EPNEC occurs in various organs and has poor prognosis. Long-term survival may be possible with surgical resection in cases with early-stage disease or tumor shrinkage due to chemotherapy.
Assuntos
Carcinoma Neuroendócrino , Masculino , Humanos , Feminino , Idoso , Estudos Retrospectivos , Carcinoma Neuroendócrino/diagnóstico , Carcinoma Neuroendócrino/tratamento farmacológico , Resultado do Tratamento , Prognóstico , PlatinaRESUMO
BACKGROUND: The role of adjuvant chemotherapy in gastric neuroendocrine neoplasms (GNEC) has not been well clarified yet. The study was designed to investigate the potential effect of adjuvant chemotherapy in stage I-II GNEC patients and construct a predictive nomogram. METHOD: Stage I-II GNEC patients were included in the Surveillance, Epidemiology, and End Results (SEER) database and divided into chemotherapy and no-chemotherapy groups. We used Kaplan-Meier survival analyses, propensity score matching (PSM), and competing risk analyses. The predictive nomogram was then built and validated. RESULTS: Four hundred four patients with stage I-II GNEC were enrolled from the SEER database while 28 patients from Hangzhou TCM Hospital were identified as the external validation cohort. After PSM, similar 5-year cancer-specific survival was observed in two groups. The outcomes of competing risk analysis indicated a similar 5-year cumulative incidence of cancer-specific death (CSD) between the two cohorts (35.4% vs. 31.4%, p = 0.731). And there was no significant relation between chemotherapy and CSD in the multivariate competing risks regression analysis (HR, 0.79; 95% CI, 0.48-1.31; p = 0.36). Furthermore, based on the variables from the multivariate analysis, a competing event nomogram was created to assess the 1-, 3-, and 5-year risks of CSD. The 1-, 3-, and 5-year area under the receiver operating characteristic curve (AUC) values were 0.770, 0.759, and 0.671 in the training cohort, 0.809, 0.782, and 0.735 in the internal validation cohort, 0.786, 0.856, and 0.770 in the external validation cohort. Furthermore, calibration curves revealed that the expected and actual probabilities of CSD were relatively consistent. CONCLUSION: Stage I-II GNEC patients could not benefit from adjuvant chemotherapy after surgery. De-escalation of chemotherapy should be considered for stage I-II GNEC patients. The proposed nomogram exhibited excellent prediction ability.
Assuntos
Carcinoma Neuroendócrino , Neoplasias Gástricas , Humanos , Quimioterapia Adjuvante , Neoplasias Gástricas/tratamento farmacológico , Bases de Dados Factuais , Hospitais , Nomogramas , Carcinoma Neuroendócrino/tratamento farmacológico , Programa de SEERRESUMO
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 XenoenxertoRESUMO
AIM: There is no conclusive data on the prognosis of patients who receive paclitaxel-carboplatin (TC) plus bevacizumab therapy for advanced neuroendocrine carcinoma (NEC) of the uterine cervix, a rare histological subtype of cervical cancer. Thus, the aim of this study was to determine the efficacy of TC chemotherapy plus bevacizumab and bevacizumab single maintenance therapy for advanced NEC of the cervix. METHODS: This was a retrospective review of patients who received TC plus bevacizumab therapy for metastatic, recurrent, or persistent NEC of the cervix at seven institutions between 2015 and 2020. Relevant data were extracted from the patients' medical records and analyzed. RESULTS: Seven patients, including six with small-cell NEC and one with large-cell NEC, were included for analysis. Three patients received bevacizumab single maintenance therapy following TC plus bevacizumab therapy, whereas four patients did not receive bevacizumab single maintenance therapy. The median overall survival and progression-free survival of the patients who received bevacizumab single maintenance therapy were longer than those of the patients who did not receive the therapy (34 months vs. 10.5 months and 19 months vs. 5 months, respectively). However, the patients who received bevacizumab single maintenance therapy had received cisplatin-based chemotherapy previously. CONCLUSIONS: On the premise that cisplatin-based chemotherapy is administered as the first-line treatment for advanced NEC of the cervix, bevacizumab single maintenance therapy following TC plus bevacizumab may be considered the second- or third-line treatment. However, the risk of adverse events, such as intestinal perforation, should be discussed with patients.
Assuntos
Carcinoma Neuroendócrino , Neoplasias do Colo do Útero , Feminino , Humanos , Bevacizumab/uso terapêutico , Carboplatina , Paclitaxel/uso terapêutico , Cisplatino/uso terapêutico , Estudos Retrospectivos , Neoplasias do Colo do Útero/patologia , Colo do Útero/patologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Neuroendócrino/tratamento farmacológicoRESUMO
This manuscript investigates cabozantinib, vandetanib, pralsetinib, and selpercatinib, four tyrosine kinase inhibitors (TKIs), which are used to treat advanced and/or metastatic medullary thyroid cancer (MTC). Data on efficacy and safety are presented with the main focus on treatment-related hypertension, a well-known adverse effect (AE) of these TKIs. Taken together, TKI-induced hypertension is rarely a dose-limiting side effect. However, with increasing survival times of patients under treatment, hypertension-associated complications can be expected to be on the rise without proper medication.
Assuntos
Carcinoma Neuroendócrino , Hipertensão , Neoplasias da Glândula Tireoide , Humanos , Inibidores de Proteínas Quinases/efeitos adversos , Piperidinas/efeitos adversos , Carcinoma Neuroendócrino/tratamento farmacológico , Carcinoma Neuroendócrino/patologia , Neoplasias da Glândula Tireoide/tratamento farmacológico , Neoplasias da Glândula Tireoide/patologia , Hipertensão/tratamento farmacológico , Hipertensão/induzido quimicamenteRESUMO
A 62-year-old man with anal pain was diagnosed with rectal neuroendocrine carcinoma. There were multiple metastases in the liver, lung, paraaortic lymph node, and bone of the patient. After performing a diverting colostomy, irinotecan and cisplatin were administered. Partial response was obtained after 2 courses, and anal pain improved. However, after 8 courses, multiple skin metastases were found on his back. At the same time, the patient also complained of redness, pain, and impaired vision in the right eye. Iris metastasis was diagnosed clinically by ophthalmologic examination and with contrast- enhanced MRI. Iris metastasis was treated with 5 doses of 4 Gy irradiation, ameliorating the eye symptoms. The patient died of the original disease 13 months after the initial diagnosis; however, multidisciplinary treatment appeared effective for palliating cancer symptoms.
Assuntos
Carcinoma Neuroendócrino , Neoplasias Retais , Masculino , Humanos , Pessoa de Meia-Idade , Neoplasias Retais/cirurgia , Neoplasias Retais/tratamento farmacológico , Reto/patologia , Carcinoma Neuroendócrino/tratamento farmacológico , Carcinoma Neuroendócrino/cirurgia , Irinotecano , Iris/patologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêuticoRESUMO
BACKGROUND: Large cell neuroendocrine carcinoma(LCNEC)is a relatively rare disease classified as a subtype of neuroendocrine tumor. LCNEC has clinical and histological similarities to small cell lung cancer, both of which have a similarly poor prognosis. There are also unclear points regarding treatment. CASE: 43-years-old, male. He had repeated intermittent fever from 1 month before the consultation. Cough appeared 4 days before the consultation, and the family doctor pointed out an abnormal shadow in the right lung field, and the patient was referred. Blood test showed increased CRP 1.34 mg/dL and mild inflammatory response. Chest CT showed an increased tumor with a major axis of 16 cm in the right thoracic cavity compared to 6 months ago. FDG-PET showed accumulation of SUVmax 11.83 in the same area. A CT-guided needle biopsy was performed, and although tumor cell hyperplasia of like a plasma cells was suspected, but most of them were coagulative necrotic images and could not be diagnosed. After hospitalization, fever continued and the general condition became poor, so surgery was performed for the purpose of diagnostic treatment. Preoperatively, Interventional Radiology was used to embolize the tumor-feeding blood vessels. Intrathoracic tumor resection and partial upper and lower lobe resection were performed under thoracotomy. Postoperative histopathological examination revealed that large round to polyhedron tumor cells proliferated in sheet-like or intercellular binding sparsely, and synaptophysin was positive, which was a diagnosis of large cell neuroendocrine cell carcinoma. The general condition improved promptly after the operation, and the patient was discharged 14 days after the operation without any complications. After discharge, 4 courses of adjuvant chemotherapy (CDDP plus CPT-11)were performed. Six months after the operation, the disseminated nodule recurred in the right thoracic cavity. Chemotherapy(CBDCA plus PTX plus BEV)and radiation therapy were performed and the patient was in remission. It has been 5 years since the operation and has not recurred. SUMMARY: We report a case of rapidly increasing LCNEC with long-term remission by surgical treatment and chemoradiotherapy, with some review of the literature.
Assuntos
Carcinoma de Células Grandes , Carcinoma Neuroendócrino , Neoplasias Pulmonares , Humanos , Masculino , Adulto , Neoplasias Pulmonares/tratamento farmacológico , Pulmão/patologia , Quimiorradioterapia , Cisplatino , Irinotecano , Carcinoma Neuroendócrino/tratamento farmacológico , Carcinoma de Células Grandes/tratamento farmacológico , Carcinoma de Células Grandes/patologia , Carcinoma de Células Grandes/cirurgia , Carboplatina/uso terapêuticoRESUMO
A 78-year-old man was diagnosed with lymph node metastasis 2 months after surgery for gastric neuroendocrine carcinoma. He received chemotherapy(CDDP plus CPT-11)and showed partial response(PR)after 3 courses of the regimen. Serum CEA increased 5 months after surgery, thus nab-paclitaxel plus ramucirumab was administered. Although the lymph node kept shrinked after 2 courses of the regimen, the lymph node was detected 12 cm of the size in CT after 5 courses of the regimen. He started to receive nivolumab. The lymph nodes showed PR after 4 courses, and complete response after 6 courses of the regimen for 1 year and 4 months until now.
Assuntos
Carcinoma Neuroendócrino , Neoplasias Gástricas , Masculino , Humanos , Idoso , Nivolumabe/uso terapêutico , Metástase Linfática , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Gastrectomia , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/cirurgia , Cisplatino/uso terapêutico , Irinotecano , Carcinoma Neuroendócrino/tratamento farmacológico , Carcinoma Neuroendócrino/cirurgia , LinfonodosRESUMO
A 77-year-old man visited a clinic because of nausea and chest discomfort. On blood test, hepatobiliary enzymes were elevated, and he referred to our hospital. Contrast-enhanced CT revealed stenosis of the extrahepatic bile duct and brush cytology of the bile duct showed adenocarcinoma. We therefore performed pancreatoduodenectomy for extrahepatic bile duct cancer. Pathological diagnosis was small cell neuroendocrine carcinoma, pT3N2M0, Stage â ¢A. The patient did not receive adjuvant chemotherapy and 3 months later contrast-enhanced CT and MRI showed multiple liver metastases. The patient was treated with cisplatin plus irinotecan in the first-line, cisplatin plus etoposide in the second-line, and amrubicin in the third-line and accordingly he died 1 year and 3 months after the surgery. Chemotherapy for neuroendocrine carcinoma of the bile duct is recommended as in small cell lung cancer, but the prognosis is extremely poor. We report this case with a review of some of the literature.
Assuntos
Adenocarcinoma , Neoplasias dos Ductos Biliares , Ductos Biliares Extra-Hepáticos , Carcinoma Neuroendócrino , Masculino , Humanos , Idoso , Cisplatino/uso terapêutico , Carcinoma Neuroendócrino/tratamento farmacológico , Carcinoma Neuroendócrino/cirurgia , Ductos Biliares Extra-Hepáticos/cirurgia , Adenocarcinoma/diagnóstico , Neoplasias dos Ductos Biliares/tratamento farmacológico , Neoplasias dos Ductos Biliares/cirurgia , Neoplasias dos Ductos Biliares/diagnósticoRESUMO
A 69-year-old woman was admitted to a territory hospital because of severe right hypochondoralgia after 2 weeks of internal medicine for persistent epigastralgia. Gastroduodenal endoscopy revealed a large tumor with a fistula in the duodenal bulb that expanded to the stomach. Histopathologically, the biopsy specimen indicated a poorly differentiated adenocarcinoma and HER2 negative. Computed tomography revealed that the tumor invaded the left lobe of the liver. The patient was referred to our hospital for cancer treatment. After 1 course of chemotherapy with S-1 and CDDP, laparoscopic gastroenterostomy bypass was performed because of tumor hemorrhage and poor food intake. However, the tumor hemorrhage and poor food intake continued, and the tumor enlarged. Therefore, left hemihepatectomy and distal gastrectomy with resection of the duodenal bulb were performed 1 month after bypass surgery. Histological testing confirmed the diagnosis of duodenal large-cell neuroendocrine carcinoma invading the liver without lymph node metastasis. Adjuvant chemotherapy was not administered, and the patient has been alive without recurrence for 7 years and 3 months. Neuroendocrine carcinoma of the non-ampullary duodenum is very rare; however, a large cell type without lymph node metastasis may be a factor in the long-term prognosis.
Assuntos
Adenocarcinoma , Carcinoma Neuroendócrino , Neoplasias Gástricas , Feminino , Humanos , Idoso , Metástase Linfática/patologia , Carcinoma Neuroendócrino/tratamento farmacológico , Carcinoma Neuroendócrino/cirurgia , Duodeno/patologia , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/cirurgia , Adenocarcinoma/patologia , Hemorragia/cirurgia , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/cirurgia , Neoplasias Gástricas/patologia , GastrectomiaRESUMO
High-grade neuroendocrine tumors (NETs) of the lung consist of small-cell lung cancer (SCLC) and large-cell neuroendocrine carcinoma (LCNEC). Both exhibit aggressive malignancy with poor prognosis. The transformation of lung adenocarcinoma (ADC) to SCLC or LCNEC also contributes to acquired resistance to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs). Despite initially being responsive to chemotherapy, high-grade NET patients inevitably develop drug resistance; thus, novel therapeutic targets are urgently needed for these patients. Our study reported that VGF (nerve growth factor inducible), a factor mainly expressed in neurons during neural development, is highly expressed in SCLC and LCNEC as well as in a subset of ADCs, whereas targeting VGF attenuates cancer cell growth and tumor formation. High VGF expression was associated with advanced stage SCLC and predicted poor prognosis in lung ADC. In addition, EGFR-TKI selection enriched VGF expression in TKI-resistant ADC under epigenetic control. The VGF locus possessed the HDAC1 binding site, and treatment of ADC cells with the HDAC1 inhibitor induced VGF expression. High VGF expression was associated with chemoresistance, and silencing VGF induced BMF and BCL2L11 expression and rendered lung cancer cells sensitive to chemotherapy drugs. These findings suggested the potential of VGF as a prognostic factor and therapeutic target in lung cancers with neuroendocrine feature.
Assuntos
Adenocarcinoma de Pulmão , Carcinoma de Células Grandes , Carcinoma Neuroendócrino , Neoplasias Pulmonares , Carcinoma de Pequenas Células do Pulmão , Adenocarcinoma de Pulmão/tratamento farmacológico , Carcinoma de Células Grandes/patologia , Carcinoma Neuroendócrino/tratamento farmacológico , Carcinoma Neuroendócrino/genética , Resistencia a Medicamentos Antineoplásicos , Receptores ErbB/genética , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Fatores de Crescimento Neural , Prognóstico , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Carcinoma de Pequenas Células do Pulmão/genética , Carcinoma de Pequenas Células do Pulmão/patologiaRESUMO
OBJECTIVES: This study sought to provide contemporary data from a multi-institution with respect to DNA-repair genes (DRGs) status and its impact on effects of platinum-based chemotherapy in treatment-emergent neuroendocrine prostate cancer (t-NEPC), for which little data exist. PATIENTS AND METHODS: All patients were retrospectively collected with eligible biopsied tissues for targeted next generation sequencing (NGS). The main outcomes were radiologic progression-free survival and overall survival according to Response Evaluation Criteria in Solid Tumors, version 1.1. RESULTS: Among the 43 NEPC patients, 13/43 (30%) harbored homozygous deletions, deleterious mutations, or both in DRGs. Eleven patients (11/13, 85%) with DRGs aberrations had effective response, including 7 patients with BRCA1/2 defects and 2 with mismatch repair-deficient caused by MSH2 alterations. While significantly fewer responders (30%) were detected in patients without DRGs aberrations (odds ratio = 12.83, p = 0.003). Compared with patients without genomic DRGs aberrations, the hazard ratio (HR) for radiologic progression in those with DRGs defects was 0.42 (95% confidence interval [CI]: 0.19-0.93), and the HR for death was 0.65 (95% CI: 0.24-1.72). The most common adverse event of Grade 3 or 4 was anemia, as noted in 7 patients (16%). CONCLUSION: The DRGs status is therapeutically meaningful in t-NEPC. Given the potential responses to platinum-based chemotherapy, our findings support the clinical use of NGS in t-NEPC patients to identify DRGs aberrations.
Assuntos
Carcinoma Neuroendócrino/tratamento farmacológico , Carcinoma Neuroendócrino/genética , Reparo do DNA/genética , Compostos de Platina/uso terapêutico , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/genética , Idoso , Antineoplásicos , Proteína BRCA1/genética , Proteína BRCA2/genética , Carboplatina/uso terapêutico , Carcinoma Neuroendócrino/patologia , Cisplatino/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias da Próstata/patologia , Estudos Retrospectivos , Taxa de Sobrevida , Resultado do TratamentoRESUMO
BACKGROUND: Medullary thyroid cancer (MTC) standard of care includes multikinase inhibitors (MKIs), which can exacerbate disease-related diarrhea, primarily because of non-RET kinase inhibition. We report diarrhea and other patient-reported outcomes (PROs) with selpercatinib, a highly selective RET inhibitor, among patients with RET-mutant MTC in the ongoing, phase I/II LIBRETTO-001 trial. MATERIALS AND METHODS: Instrument completion time points were baseline (cycle 1, day 1) and approximately every other 28-day cycle until cycle 13 (every 12 weeks thereafter) for the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30, and baseline, weekly during cycle 1, and day 1 of every cycle for the modified Systemic Therapy-Induced Diarrhea Assessment Tool (mSTIDAT). A ≥10-point change from baseline in domain score was considered clinically meaningful. PROs were summarized through cycle 13 in all patients and by subgroups with or without prior exposure to MKIs vandetanib and/or cabozantinib (V/C). RESULTS: Among the overall MTC population (n = 226), 88 (39%) and 124 (55%) patients comprised the V/C-naïve and previous V/C subgroups, respectively. Compliance was >85% for both instruments at each time point. Most patients maintained/improved in all health-related quality of life (HRQoL) subscales throughout treatment. Improvements in diarrhea were clinically meaningful in 43.5% of patients overall and in 36.8% and 51.3% of V/C-naïve and previous V/C subgroups, respectively. At baseline, 80.4% of all patients reported diarrhea on mSTIDAT. The percentage of patients who reported diarrhea was reduced to less than half of all patients (range: 33.3%-48.3%) after cycle 2. CONCLUSION: These interim results demonstrate that patients with RET-mutant MTC improved/remained stable on all domains of HRQoL during treatment with selpercatinib. Future analyses will be conducted as the data mature.