RESUMO
RATIONALE: Neuroendocrine carcinoma originating from extrahepatic bile duct is very rare, and only a few cases have been reported. Because of its scarcity of incidence, not much is known about the disease but for its aggressiveness and poor prognosis. PATIENT CONCERNS: In this report, we present 2 cases of large cell neuroendocrine carcinoma (LCNEC) originating from extrahepatic bile duct. Case 1: a 60-year-old woman presented with jaundice but no abdominal pain. Case 2: a 67-year-old man also presented with jaundice, along with abdominal discomfort and appetite loss. DIAGNOSES: Case 1: LCNEC with a focal adenocarcinoma component (pT2aN1M0, pStage IIIB). Case 2: LCNEC with a focal adenocarcinoma component (pT1N1M0, pStage IIB). INTERVENTIONS: Case 1: the patient underwent left hepatectomy and caudatectomy with hepaticojejunostomy, followed by 6 cycles of adjuvant chemotherapy (etoposide and cisplatin). Case 2: the patient underwent laparoscopic pylorus-preserving pancreatoduodenectomy, followed by 6 cycles of adjuvant chemotherapy (etoposide and cisplatin). OUTCOMES: Case 1: liver metastasis was detected 6 months postoperatively, and despite multiple chemotherapy regimens, the patient died 24 months post-surgery. Case 2: liver metastasis was detected 23 months postoperatively. The patient is still alive 36 months post-surgery after receiving multiple chemotherapy regimens and radiotherapy. LESSONS: Given the rarity of LCNEC, it is essential to continue collecting and reporting additional case studies to build a more comprehensive understanding of the disease. Although the prognosis for LCNEC is generally poor, the use of a multidisciplinary approach and further research will be critical in developing more effective treatment strategies in the future.
Assuntos
Neoplasias dos Ductos Biliares , Carcinoma Neuroendócrino , Humanos , Carcinoma Neuroendócrino/patologia , Carcinoma Neuroendócrino/cirurgia , Carcinoma Neuroendócrino/tratamento farmacológico , Carcinoma Neuroendócrino/terapia , Feminino , Quimioterapia Adjuvante/métodos , Pessoa de Meia-Idade , Idoso , Masculino , Neoplasias dos Ductos Biliares/cirurgia , Neoplasias dos Ductos Biliares/patologia , Carcinoma de Células Grandes/cirurgia , Carcinoma de Células Grandes/patologia , Carcinoma de Células Grandes/tratamento farmacológico , Carcinoma de Células Grandes/terapia , Evolução Fatal , Hepatectomia/métodos , Pancreaticoduodenectomia/métodos , Ductos Biliares Extra-Hepáticos/patologia , Ductos Biliares Extra-Hepáticos/cirurgia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêuticoRESUMO
INTRODUCTION: Lurbinectedin is FDA approved for treatment of metastatic small cell lung cancer (SCLC) following progression on or after platinum-based chemotherapy. Prostatic small cell or neuroendocrine carcinoma (SC/NEPC) behaves like SCLC; however, no safety or efficacy data for lurbinectedin in SC/NEPC exists. PATIENTS AND METHODS: All SC/NEPC patients treated with lurbinectedin across 4 academic oncology centers were identified. Baseline patient data and lurbinectedin outcomes including radiographic responses (complete response [CR], partial response [PR], stable disease [SD], progressive disease [PD]), progression free survival (PFS), overall survival (OS), and treatment-related adverse events (trAEs) were described. Clinical benefit rate (CBR) included CR, PR, or SD on imaging. Descriptive statistics were performed. RESULTS: At first lurbinectedin dose, all 18 patients had metastatic disease. Median age was 63.5 (Range: 53-84), number of prior systemic therapies was 4 (Range: 2-7), and lurbinectedin cycles completed was 5 (Range: 1-10). ADT was administered during lurbinectedin treatment in 9/18 patients. CBR was 9/16 (56%). The most common trAEs were fatigue and anemia. Median OS and PFS were 6.01 (0.23-16.69) and 3.35 (0.16-7.79) months. CONCLUSIONS: Lurbinectedin showed modest but significant clinical benefit in some patients with SC/NEPC and demonstrated an acceptable toxicity profile with no hospitalizations from trAEs. SC/NEPC is an aggressive disease with a poor prognosis for which more treatment options are needed. Evidence for subsequent treatments after platinum-based chemotherapy is lacking. Lurbinectedin is an active treatment option for SC/NEPC; however, larger confirmatory studies are needed.
Assuntos
Carbolinas , Carcinoma Neuroendócrino , Compostos Heterocíclicos de 4 ou mais Anéis , Neoplasias da Próstata , Humanos , Masculino , Carbolinas/administração & dosagem , Carbolinas/uso terapêutico , Carbolinas/efeitos adversos , Idoso , Carcinoma Neuroendócrino/tratamento farmacológico , Carcinoma Neuroendócrino/patologia , Compostos Heterocíclicos de 4 ou mais Anéis/uso terapêutico , Compostos Heterocíclicos de 4 ou mais Anéis/administração & dosagem , Compostos Heterocíclicos de 4 ou mais Anéis/efeitos adversos , Pessoa de Meia-Idade , Idoso de 80 Anos ou mais , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/patologia , Resultado do Tratamento , Carcinoma de Células Pequenas/tratamento farmacológico , Carcinoma de Células Pequenas/patologia , Antineoplásicos/uso terapêutico , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Estudos Retrospectivos , Intervalo Livre de ProgressãoRESUMO
Large cell neuroendocrine carcinoma (LCNEC) of lung is a rare neuroendocrine carcinoma subtype with difficulty in early diagnosis and poor prognosis which is treated with standard strategies of small cell lung cancer and non-small cell lung cancer. In recent years, the precise types of LCNEC and its response to therapy have been identified by next-generation sequencing. Some researches have also found the correlation between different subtypes of LCNEC and the efficacy of chemotherapy regimens. However, there is no consensual agreement of its therapy. Recently, immune checkpoint inhibitors (ICIs) has provided a new option for LCNEC patients based on some retrospective research data and case reports. In this review, we aimed to summarize the epidemiological characteristics, standard therapy, the advances of molecular subtypes and clinical applications of ICIs of LCNEC, so as to provide optimal systemic clinical decision-making for LCNEC patients.â©.
Assuntos
Carcinoma Neuroendócrino , Neoplasias Pulmonares , Humanos , Carcinoma Neuroendócrino/tratamento farmacológico , Carcinoma Neuroendócrino/genética , Carcinoma Neuroendócrino/patologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/terapia , Neoplasias Pulmonares/diagnóstico , Carcinoma de Células Grandes/tratamento farmacológico , Carcinoma de Células Grandes/terapia , Carcinoma de Células Grandes/patologia , Carcinoma de Células Grandes/genética , Inibidores de Checkpoint Imunológico/uso terapêuticoRESUMO
Medullary thyroid carcinoma (MTC) is a rare type of thyroid malignancy that accounts for approximately 1-2% of all thyroid cancers (TCs). MTC include hereditary and sporadic cases, the former derived from a germline mutation of rearrangement during transfection (RET) proto-oncogene, whereas somatic RET mutations are frequently present in the latter. Surgery is the standard treatment for early stage MTC, and the 10-year survival rate of early MTC is over 80%. While for metastatic MTC, chemotherapy showing low response rate, and there was a lack of effective systemic therapies in the past. Due to the high risk (ca. 15-20%) of distant metastasis and limited systemic therapies, the 10-year survival rate of patients with advanced MTC was only 10-40% from the time of first metastasis. Over the past decade, targeted therapy for RET has developed rapidly, bringing hopes to patients with advanced and progressive MTC. Two multi-kinase inhibitors (MKIs) including Cabozantinib and Vandetanib have been shown to increase progression-free survival (PFS) for patients with metastatic MTC and have been approved as choices of first-line treatment. However, these MKIs have not prolonged overall survival (OS) and their utility is limited due to high rates of off-target toxicities. Recently, new generation TKIs, including Selpercatinib and Pralsetinib, have demonstrated highly selective efficacy against RET and more favorable side effect profiles, and gained approval as second-line treatment options. Despite the ongoing development of RET inhibitors, the management of advanced and progressive MTC remains challenging, drug resistance remains the main reason for treatment failure, and the mechanisms are still unclear. Besides, new promising therapeutic approaches, such as novel drug combinations and next generation RET inhibitors are under development. Herein, we overview the pathogenesis, molecular genetics and current management approaches of MTC, and focus on the recent advances of RET inhibitors, summarize the current situation and unmet needs of these RET inhibitors in MTC, and provide an overview of novel strategies for optimizing therapeutic effects.
Assuntos
Carcinoma Neuroendócrino , Resistencia a Medicamentos Antineoplásicos , Inibidores de Proteínas Quinases , Proto-Oncogene Mas , Proteínas Proto-Oncogênicas c-ret , Neoplasias da Glândula Tireoide , Humanos , Neoplasias da Glândula Tireoide/tratamento farmacológico , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/patologia , Proteínas Proto-Oncogênicas c-ret/genética , Proteínas Proto-Oncogênicas c-ret/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-ret/metabolismo , Carcinoma Neuroendócrino/genética , Carcinoma Neuroendócrino/tratamento farmacológico , Carcinoma Neuroendócrino/patologia , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , AnimaisRESUMO
This study reports a significant clinical outcome following the use of bronchoscopic interventional therapy combined with pembrolizumab for treating pulmonary large cell neuroendocrine carcinoma (LCNEC), showcasing a novel approach in managing this aggressive cancer.
Assuntos
Anticorpos Monoclonais Humanizados , Broncoscopia , Carcinoma Neuroendócrino , Neoplasias Pulmonares , Humanos , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais Humanizados/administração & dosagem , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/terapia , Carcinoma Neuroendócrino/tratamento farmacológico , Carcinoma Neuroendócrino/patologia , Carcinoma Neuroendócrino/terapia , Broncoscopia/métodos , Masculino , Resultado do Tratamento , Carcinoma de Células Grandes/tratamento farmacológico , Carcinoma de Células Grandes/patologia , Carcinoma de Células Grandes/terapia , Antineoplásicos Imunológicos/uso terapêutico , Antineoplásicos Imunológicos/administração & dosagem , Pessoa de Meia-Idade , Terapia Combinada/métodos , Tomografia Computadorizada por Raios X/métodos , IdosoRESUMO
Highly selective RET inhibitor selpercatinib has demonstrated notable efficacy in advanced/progressive RET-mutant medullary thyroid cancer (MTC) patients. However, despite a more tolerable toxicity profile than multikinase inhibitors, peculiar adverse events (AEs) have been described. Obliterative bronchiolitis (OB) is a respiratory disease characterized by inflammation and fibrosis in small conducting airways. We evaluated a 70-year-old man with advanced RET-mutant MTC who developed OB during treatment with selpercatinib. Radiological features of OB occurred early and persisted during selpercatinib treatment, with a waxing and waning pattern. Notably, a partial response of MTC was achieved during the treatment, and selpercatinib was never reduced or interrupted. The almost complete absence of symptoms and the fluctuating trend, without specific treatment for OB, suggested that it is necessary to carefully evaluate the risks mediated by this AE with the risks of modifying or discontinuing the anti-cancer therapy.
Assuntos
Bronquiolite Obliterante , Carcinoma Neuroendócrino , Proteínas Proto-Oncogênicas c-ret , Pirazóis , Neoplasias da Glândula Tireoide , Humanos , Masculino , Neoplasias da Glândula Tireoide/tratamento farmacológico , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/patologia , Idoso , Proteínas Proto-Oncogênicas c-ret/genética , Proteínas Proto-Oncogênicas c-ret/antagonistas & inibidores , Carcinoma Neuroendócrino/tratamento farmacológico , Carcinoma Neuroendócrino/genética , Carcinoma Neuroendócrino/patologia , Bronquiolite Obliterante/induzido quimicamente , Bronquiolite Obliterante/patologia , Pirazóis/efeitos adversos , Pirazóis/uso terapêutico , Mutação , Piridinas/efeitos adversos , Piridinas/uso terapêutico , Piridinas/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/uso terapêutico , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêuticoRESUMO
Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.LIBRETTO-001 is a registrational phase I/II, single-arm, open-label study of selpercatinib in patients with RET (REarranged during Transfection)-activated cancers (ClinicalTrials.gov identifier: NCT03157128). We present long-term safety and efficacy from LIBRETTO-001 in patients with RET-mutant medullary thyroid cancer (MTC; n = 324) and RET fusion-positive thyroid cancer encompassing different histological subtypes (TC; n = 66). At the data cutoff of January 2023, the objective response rate was 82.5% among patients with cabozantinib/vandetanib-naïve MTC and 95.8% among patients with treatment-naïve TC. At a median follow-up time of 42.4 and 44.0 months in patients with cabozantinib/vandetanib-naïve and pretreated MTC, the median progression-free survival (PFS) was not reached and 41.4 months, respectively. At a median follow-up time of 24.9 and 30.4 months in patients with treatment-naïve and pretreated TC, the median PFS was not reached and 27.4 months, respectively. Three-year PFS rates were 75.2% and 87.3% among patients with cabozantinib/vandetanib-naïve MTC and treatment-naïve TC, respectively. Median PFS was similar to median duration of response for each patient group. The safety profile of selpercatinib was consistent with previous reports. With an additional follow-up of 37 months and 228 more patients from the last disclosure, selpercatinib continued to provide durable and robust responses in treatment-naïve and previously treated patients with RET-mutant MTC and RET fusion-positive TC.
Assuntos
Proteínas Proto-Oncogênicas c-ret , Pirazóis , Piridinas , Neoplasias da Glândula Tireoide , Humanos , Proteínas Proto-Oncogênicas c-ret/genética , Neoplasias da Glândula Tireoide/tratamento farmacológico , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/patologia , Masculino , Pessoa de Meia-Idade , Feminino , Adulto , Idoso , Pirazóis/uso terapêutico , Pirazóis/efeitos adversos , Piridinas/uso terapêutico , Piridinas/efeitos adversos , Carcinoma Neuroendócrino/tratamento farmacológico , Carcinoma Neuroendócrino/genética , Carcinoma Neuroendócrino/patologia , Adulto Jovem , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/efeitos adversos , Idoso de 80 Anos ou mais , Intervalo Livre de Progressão , Mutação , AnilidasRESUMO
N-Myc is a key driver of neuroblastoma and neuroendocrine prostate cancer (NEPC). One potential way to circumvent the challenge of undruggable N-Myc is to target the protein homeostasis (proteostasis) system that maintains N-Myc levels. Here, we identify heat shock protein 70 (HSP70) as a top partner of N-Myc, which binds a conserved "SELILKR" motif and prevents the access of E3 ubiquitin ligase, STIP1 homology and U-box containing protein 1 (STUB1), possibly through steric hindrance. When HSP70's dwell time on N-Myc is increased by treatment with the HSP70 allosteric inhibitor, STUB1 is in close proximity with N-Myc and becomes functional to promote N-Myc ubiquitination on the K416 and K419 sites and forms polyubiquitination chains linked by the K11 and K63 sites. Notably, HSP70 inhibition significantly suppressed NEPC tumor growth, increased the efficacy of aurora kinase A (AURKA) inhibitors, and limited the expression of neuroendocrine-related pathways.
Assuntos
Proteínas de Choque Térmico HSP70 , Neoplasias da Próstata , Proteostase , Ubiquitina-Proteína Ligases , Ubiquitinação , Masculino , Humanos , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/patologia , Neoplasias da Próstata/genética , Proteínas de Choque Térmico HSP70/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitina-Proteína Ligases/genética , Ubiquitinação/efeitos dos fármacos , Linhagem Celular Tumoral , Animais , Aurora Quinase A/metabolismo , Aurora Quinase A/genética , Aurora Quinase A/antagonistas & inibidores , Proteína Proto-Oncogênica N-Myc/metabolismo , Proteína Proto-Oncogênica N-Myc/genética , Camundongos , Carcinoma Neuroendócrino/metabolismo , Carcinoma Neuroendócrino/genética , Carcinoma Neuroendócrino/tratamento farmacológico , Carcinoma Neuroendócrino/patologia , Tumores Neuroendócrinos/metabolismo , Tumores Neuroendócrinos/tratamento farmacológico , Tumores Neuroendócrinos/genética , Tumores Neuroendócrinos/patologiaRESUMO
RATIONALE: Neuroendocrine neoplasms (NENs) originating from neuroendocrine cells occur in the thyroid, respiratory, and digestive systems, with Gallbladder Neuroendocrine Carcinoma (GB-NEC) accounting for only 0.5% of all NENs and 2.1% of gallbladder cancers. Due to its rarity, little is known about GB-NEC's clinical presentation and treatment. PATIENT CONCERNS: We report a case of a 52-year-old male presenting with acute upper right abdominal pain, leading to further investigation. DIAGNOSES: Initial diagnostic workup, including abdominal ultrasound and contrast-enhanced CT, suggested gallbladder malignancy. Post-surgical pathology confirmed GB-NEC, with immunohistochemistry supporting the diagnosis. INTERVENTIONS: The patient underwent radical cholecystectomy, followed by etoposide plus cisplatin chemotherapy. After disease progression indicated by CT, the patient received additional cycles of chemotherapy with cisplatin and irinotecan, plus targeted therapy with anlotinib and immunotherapy with paimiplimab. OUTCOMES: The patient showed a partial response to initial treatment. Subsequent liver biopsy confirmed NEC, consistent with small cell carcinoma. With continued treatment, the patient maintains a good survival status. LESSONS: GB-NEC is associated with poor prognosis, emphasizing the importance of early detection and multimodal treatment strategies. Our case underlines the potential benefit of a comprehensive treatment plan, including aggressive surgery and chemotherapy, with further research needed to standardize treatment for this rare condition.
Assuntos
Carcinoma Neuroendócrino , Colecistectomia , Neoplasias da Vesícula Biliar , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias da Vesícula Biliar/patologia , Neoplasias da Vesícula Biliar/diagnóstico , Carcinoma Neuroendócrino/patologia , Carcinoma Neuroendócrino/terapia , Carcinoma Neuroendócrino/diagnóstico , Carcinoma Neuroendócrino/tratamento farmacológico , Colecistectomia/métodos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Cisplatino/uso terapêutico , Cisplatino/administração & dosagem , Etoposídeo/uso terapêutico , Etoposídeo/administração & dosagemRESUMO
Resistance to the current Androgen Receptor Signaling Inhibitor (ARSI) therapies has led to higher incidences of therapy-induced neuroendocrine-like prostate cancer (t-NEPC). This highly aggressive subtype with predominant small-cell-like characteristics is resistant to taxane chemotherapies and has a dismal overall survival. t-NEPCs are mostly treated with platinum-based drugs with a combination of etoposide or taxane and have less selectivity and high systemic toxicity, which often limit their clinical potential. During t-NEPC transformation, adenocarcinomas lose their luminal features and adopt neuro-basal characteristics. Whether the adaptive neuronal characteristics of t-NEPC are responsible for such taxane resistance remains unknown. Pathway analysis from patient gene-expression databases indicates that t-NEPC upregulates various neuronal pathways associated with enhanced cellular networks. To identify transcription factor(s) (TF) that could be important for promoting the gene expression for neuronal characters in t-NEPC, we performed ATAC-Seq, acetylated-histone ChIP-seq, and RNA-seq in our NE-like cell line models and analyzed the promoters of transcriptionally active and significantly enriched neuroendocrine-like (NE-like) cancer-specific genes. Our results indicate that Pax5 could be an important transcription factor for neuronal gene expression and specific to t-NEPC. Pathway analysis revealed that Pax5 expression is involved in axonal guidance, neurotransmitter regulation, and neuronal adhesion, which are critical for strong cellular communications. Further results suggest that depletion of Pax5 disrupts neurite-mediated cellular communication in NE-like cells and reduces surface growth factor receptor activation, thereby, sensitizing them to docetaxel therapies. Moreover, t-NEPC-specific hydroxymethylation of Pax5 promoter CpG islands favors Pbx1 binding to induce Pax5 expression. Based on our study, we concluded that continuous exposure to ARSI therapies leads to epigenetic modifications and Pax5 activation in t-NEPC, which promotes the expression of genes necessary to adopt taxane-resistant NE-like cancer. Thus, targeting the Pax5 axis can be beneficial for reverting their taxane sensitivity.
Assuntos
Docetaxel , Resistencia a Medicamentos Antineoplásicos , Fator de Transcrição PAX5 , Neoplasias da Próstata , Humanos , Masculino , Docetaxel/farmacologia , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Neoplasias da Próstata/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Linhagem Celular Tumoral , Fator de Transcrição PAX5/metabolismo , Fator de Transcrição PAX5/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Antineoplásicos/farmacologia , Carcinoma Neuroendócrino/metabolismo , Carcinoma Neuroendócrino/tratamento farmacológico , Carcinoma Neuroendócrino/patologia , Carcinoma Neuroendócrino/genética , Regiões Promotoras Genéticas/genética , Receptores Androgênicos/metabolismo , Receptores Androgênicos/genéticaRESUMO
BACKGROUND: Neuroendocrine Carcinomas (NECs) prognosis is poor.No standard second-line therapy is currently recognized after failure of platinum-based first-line treatment. FOLFIRI and CAPTEM regimens have shown promising activity in preliminary studies. We aimed to evaluate these regimens in metastatic NEC patients. METHODS: This is an open-label, multicenter, randomized non-comparative phase II trial to evaluate the activity and safety of FOLFIRI or CAPTEM in metastatic NEC patients. Primary endpoints were the 12 weeks-Disease Control Rate (12w-DCR) by investigator assessment per RECIST v1.1 and safety per CTCAE v5.0. Additional endpoints included overall response rate (ORR), progression-free survival (PFS) and overall survival (OS). Patients' serum samples were subject to NGS miRNome profiling in comparison with healthy donors to reveal differentially expressed miRNAs as candidate circulating biomarkers. RESULTS: The study was halted for futility at interim analysis, as the minimum 12w-DCR threshold of 10 out of 25 patients required for the first step was not reached. From 06/03/2017 to 18/01/2021, 53 out of 112 patients were enrolled. Median follow-up was 22.6 months (range: 1.4-60.4). The 12w-DCR was 39.1 % in the FOLFIRI arm and 28.0 % in the CAPTEM arm. In the FOLFIRI subgroup the 12-months OS rate was 28.4 % (95 % CI: 12.7-46.5) while in the CAPTEM subgroup it was 32.4 % (95 % CI: 14.9-51.3). The most common G3-G4 side effects were neutropenia (n = 5, 18.5 %) and anemia (n = 2, 7.4 %) for FOLFIRI and G3-G4 thrombocytopenia (n = 2, 8.0 %), G4 nausea/vomiting (n = 1, 4.0 %) for CAPTEM. Three microRNAs emerged as NEC independent predictors. High expression values were found to be significantly associated with decreased PFS and OS. CONCLUSION: The safety profile of FOLFIRI and CAPTEM was manageable. FOLFIRI and CAPTEM chemotherapy showed comparable activity in the second-line setting after progression on etoposide/platinum. GOV IDENTIFIER: NCT03387592.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Camptotecina , Carcinoma Neuroendócrino , Fluoruracila , Leucovorina , Humanos , Masculino , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Feminino , Pessoa de Meia-Idade , Leucovorina/uso terapêutico , Leucovorina/efeitos adversos , Fluoruracila/uso terapêutico , Fluoruracila/efeitos adversos , Idoso , Carcinoma Neuroendócrino/tratamento farmacológico , Carcinoma Neuroendócrino/sangue , Carcinoma Neuroendócrino/patologia , Carcinoma Neuroendócrino/mortalidade , Adulto , Camptotecina/análogos & derivados , Camptotecina/uso terapêutico , Camptotecina/efeitos adversos , Etoposídeo/uso terapêutico , Etoposídeo/efeitos adversos , Etoposídeo/administração & dosagem , Temozolomida/uso terapêutico , Temozolomida/efeitos adversos , Intervalo Livre de ProgressãoRESUMO
Background: Nintedanib is a triple-angiokinase inhibitor with potential activity in patients with advanced thyroid cancers, as radioiodine refractory differentiated thyroid cancer (RAIR DTC) and medullary thyroid cancer (MTC). Design: EORTC-1209 (NCT01788982) was a double-blind randomized (2:1 ratio) placebo-controlled phase II, multi-cohort study exploring the efficacy and safety of nintedanib in patients with progressive, locally advanced, and/or metastatic RAIR DTC and MTC. The primary endpoint was progression-free survival (PFS) in the per-protocol (PP) population for both cohorts. Secondary endpoints included response rate, duration of response, overall survival (OS), and safety. Results: RAIR DTC cohort: Seventy out of the 75 planned patients with RAIR DTC (median age, 66 years; 39 women) who had progressed after one (76%) or two lines (24%) of previous systemic therapy were randomized to receive either nintedanib (N = 45) or placebo (N = 25). Of these, 69 patients started treatment and 56 met all inclusion criteria (PP). At data cutoff, the median duration of follow-up was 26.3 months in the nintedanib arm and 19.8 months in the placebo arm. In the PP population, the median PFS was 3.7 months [80% confidence interval (CI), 1.9-6.5] in the nintedanib arm and 2.9 months (80% CI, 2.0-5.6) in the placebo arm (HR = 0.65; 80% CI, 0.42-0.99; one-sided log-rank test P = 0.0947). No objective response was observed. The median OS was 29.6 months [80% CI, 15.2-not reached (NR)] in the nintedanib arm and not reached in the placebo arm. Grade 3-4 adverse events of any attribution occurred in 50% of patients receiving nintedanib and in 36% of patients receiving placebo. MTC cohort: Thirty-one out of the 67 planned patients with MTC (median age, 57 years; eight women) who had progressed after one (68%) or two (32%) lines of previous systemic therapy were randomized to receive either nintedanib (N = 22) or placebo (N = 9). Of these, 20 patients (15 in the nintedanib arm and five in the placebo arm) started treatment and met all inclusion criteria (PP). The median PFS was 7.0 months (80% CI, 1.9-8.7) in the nintedanib arm and 3.9 months (80% CI, 3.0-5.5) in the placebo arm (HR = 0.49; 95% CI, 0.16-1.53). No objective response was reported. The median OS was 16.4 months (80% CI, 12.1-24.9) in the nintedanib arm and 12.3 months (80% CI, 7.1-NR) in the placebo arm. Grade 3-4 adverse events of any attribution during the blinded period occurred in 59.1% of patients receiving nintedanib and in 33.3% of patients receiving placebo. Conclusion: This study did not suggest a clinically significant improvement of PFS with nintedanib over placebo in patients with pretreated RAIR DTC and MTC.
Assuntos
Carcinoma Neuroendócrino , Indóis , Neoplasias da Glândula Tireoide , Humanos , Neoplasias da Glândula Tireoide/tratamento farmacológico , Neoplasias da Glândula Tireoide/patologia , Feminino , Masculino , Indóis/uso terapêutico , Indóis/efeitos adversos , Indóis/administração & dosagem , Pessoa de Meia-Idade , Idoso , Método Duplo-Cego , Carcinoma Neuroendócrino/tratamento farmacológico , Carcinoma Neuroendócrino/patologia , Adulto , Progressão da Doença , Idoso de 80 Anos ou mais , Antineoplásicos/uso terapêutico , Antineoplásicos/efeitos adversos , Resultado do TratamentoRESUMO
Medullary thyroid carcinoma (MTC) is a neuroendocrine tumor derived from parafollicular thyroid gland cells. In both hereditary MTC and sporadic forms, genetic changes result in fundamental changes, and prognosis and mutational status are highly correlated. In this work, biomarker genes (DEGs and DEmiRNAs) for MTC will be computationally identified in order to help in their diagnosis and treatment. The gene expression profiles of two different types of studies, namely without-treatment (wo-trt) and with-treatment (w-trt), are considered for discovering biomarkers. The datasets were retrieved from the GEO database, and the DEGs and DEmiRNAs were analyzed using ExpressAnalyst and GEO2R. The functional analysis of DEGs and DEmiRNAs was performed, and most of the pathways enriched related to thyroid oncological pathways such as MAPK pathway,mTOR pathway, and PI3K-AKT Signaling pathway. Through this conclusion, the RET gene was upregulated wo-trt; the dinaciclib treatment RET gene was down-regulated computationally. To optimize the therapeutic targeting of RET, greater research into the mechanisms regulating RET transcription is necessary.
Assuntos
Biomarcadores Tumorais , Carcinoma Neuroendócrino , Biologia Computacional , Neoplasias da Glândula Tireoide , Humanos , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/metabolismo , Neoplasias da Glândula Tireoide/tratamento farmacológico , Neoplasias da Glândula Tireoide/patologia , Carcinoma Neuroendócrino/genética , Carcinoma Neuroendócrino/metabolismo , Carcinoma Neuroendócrino/tratamento farmacológico , Carcinoma Neuroendócrino/patologia , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Transcriptoma , Perfilação da Expressão Gênica , Proteínas Proto-Oncogênicas c-ret/genética , Proteínas Proto-Oncogênicas c-ret/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacosRESUMO
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
BACKGROUND: Chemotherapy has limited efficacy in advanced digestive high-grade neuroendocrine neoplasms (HG-NEN) and prognosis is dismal. Predictive markers for palliative chemotherapy are lacking, and prognostic markers are limited. METHODS: Digestive HG-NEN patients (n = 229) were prospectively included 2013-2017. Pathological re-assessment revealed 188 neuroendocrine carcinomas (NEC) and 41 neuroendocrine tumours (NET G3). Tumour-DNA was sequenced across 360 cancer-related genes, assessing mutations (mut) and copy number alterations. We linked sequencing results to clinical information and explored potential markers for first-line chemotherapy efficacy and survival. RESULTS: In NEC given cis/carboplatin and etoposide (PE), TP53mut predicted inferior response rate in multivariate analyses (p = 0.009) and no BRAFmut NEC showed response. In overall assessment of PE-treated NEC, no genetic alterations were prognostic for OS. For small-cell NEC, TP53mut were associated with longer OS (p = 0.011) and RB1 deletions predicted lack of immediate-progression (p = 0.003). In non-small cell NEC, APC mut were associated with immediate-progression and shorter PFS (p = 0.008/p = 0.004). For NET G3, ATRXmut, ARID1A- and ERS1 deletions were associated with shorter PFS. CONCLUSION: Correlations between genetic alterations and response/immediate-progression to PE were frequent in NEC but affected PFS or OS only when subdividing for cell-type. The classification of digestive NEC into large- and small-cell seems therefore molecularly and clinically relevant.
Assuntos
Mutação , Tumores Neuroendócrinos , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Tumores Neuroendócrinos/genética , Tumores Neuroendócrinos/patologia , Tumores Neuroendócrinos/tratamento farmacológico , Adulto , Resultado do Tratamento , Prognóstico , Idoso de 80 Anos ou mais , Etoposídeo/administração & dosagem , Variações do Número de Cópias de DNA , Estudos Prospectivos , Gradação de Tumores , Carcinoma Neuroendócrino/genética , Carcinoma Neuroendócrino/patologia , Carcinoma Neuroendócrino/tratamento farmacológico , Carboplatina/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Adulto Jovem , Proteína Supressora de Tumor p53/genéticaRESUMO
Neuroendocrine carcinoma arising from the urachus is extremely rare. We describe a case of a 33-year-old gentleman who presented with hematuria and diagnosed to have a composite adenocarcinoma and small cell neuroendocrine carcinoma arising from the urachus. The patient also had widespread metastasis at the time of presentation, therefore, he was referred for chemotherapy. However, the disease showed progression despite treatment. Recognition of neuroendocrine carcinoma component in urachal tumors, although rare, is very essential as this histologic type carries poor prognosis with aggressive clinical outcome.
Assuntos
Adenocarcinoma , Carcinoma Neuroendócrino , Resistencia a Medicamentos Antineoplásicos , Neoplasias da Bexiga Urinária , Humanos , Masculino , Adulto , Carcinoma Neuroendócrino/tratamento farmacológico , Carcinoma Neuroendócrino/patologia , Carcinoma Neuroendócrino/secundário , Neoplasias da Bexiga Urinária/patologia , Neoplasias da Bexiga Urinária/tratamento farmacológico , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/secundário , Adenocarcinoma/patologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Evolução Fatal , Neoplasias Complexas Mistas/patologia , Neoplasias Complexas Mistas/tratamento farmacológico , Carcinoma de Células Pequenas/tratamento farmacológico , Carcinoma de Células Pequenas/patologia , Carcinoma de Células Pequenas/secundárioRESUMO
With the widespread use of anti-androgen therapy, such as abiraterone and enzalutamide, the incidence of neuroendocrine prostate cancer (NEPC) is increasing. NEPC is a lethal form of prostate cancer (PCa), with a median overall survival of less than one year after diagnosis. In addition to the common bone metastases seen in PCa, NEPC exhibits characteristics of visceral metastases, notably liver metastasis, which serves as an indicator of a poor prognosis clinically. Key factors driving the neuroendocrine plasticity of PCa have been identified, yet the underlying mechanism behind liver metastasis remains unclear. In this study, we identified PROX1 as a driver of neuroendocrine plasticity in PCa, responsible for promoting liver metastases. Mechanistically, anti-androgen therapy alleviates transcriptional inhibition of PROX1. Subsequently, elevated PROX1 levels drive both neuroendocrine plasticity and liver-specific transcriptional reprogramming, promoting liver metastases. Moreover, liver metastases in PCa induced by PROX1 depend on reprogrammed lipid metabolism, a disruption that effectively reduces the formation of liver metastases.
Assuntos
Proteínas de Homeodomínio , Neoplasias Hepáticas , Neoplasias da Próstata , Proteínas Supressoras de Tumor , Masculino , Humanos , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo , Animais , Neoplasias da Próstata/patologia , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Antagonistas de Androgênios/farmacologia , Antagonistas de Androgênios/uso terapêutico , Camundongos , Metabolismo dos Lipídeos/efeitos dos fármacos , Plasticidade Celular/efeitos dos fármacos , Tumores Neuroendócrinos/patologia , Tumores Neuroendócrinos/genética , Tumores Neuroendócrinos/metabolismo , Tumores Neuroendócrinos/tratamento farmacológico , Carcinoma Neuroendócrino/genética , Carcinoma Neuroendócrino/patologia , Carcinoma Neuroendócrino/metabolismo , Carcinoma Neuroendócrino/tratamento farmacológico , Carcinoma Neuroendócrino/secundárioRESUMO
INTRODUCTION: Neuroendocrine neoplasms (NENs) are a rare group of tumors originating from neuroendocrine cells in various organs. They include neuroendocrine tumors (NETs) and neuroendocrine carcinomas (NECs), which differ in biological behavior and prognosis. NETs are usually well-differentiated and slow-growing, while NECs are poorly differentiated and more aggressive. Management of NETs often involves somatostatin analogs like octreotide and lanreotide to control tumor growth and alleviate symptoms, especially in well-differentiated NETs. Lanreotide is used to control tumor growth, and both lanreotide and octreotide alleviate symptoms. Treatment approaches may vary depending on the specific type and grade of the neuroendocrine neoplasm. AREAS COVERED: This review provides an update on the safety of lanreotide autogel in treating patients with NETs, through a comprehensive review of clinical trials, post-marketing surveillance, real-world evidence, and its safety profile. Specific adverse events, side effects, and potential risks associated with lanreotide autogel are discussed, along with risk mitigation strategies and recommendations for patient monitoring. EXPERT OPINION: The findings highlight the overall safety of lanreotide autogel in managing NETs, focusing on its efficacy in controlling hormone secretion, tumor progression, and symptom management. New safety concerns and precautions are also addressed to help healthcare providers make informed decisions when prescribing lanreotide autogel.
Assuntos
Antineoplásicos , Tumores Neuroendócrinos , Peptídeos Cíclicos , Somatostatina , Humanos , Somatostatina/análogos & derivados , Somatostatina/administração & dosagem , Somatostatina/efeitos adversos , Peptídeos Cíclicos/administração & dosagem , Peptídeos Cíclicos/efeitos adversos , Tumores Neuroendócrinos/tratamento farmacológico , Tumores Neuroendócrinos/patologia , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacologia , Carcinoma Neuroendócrino/tratamento farmacológico , Carcinoma Neuroendócrino/patologia , Géis , Progressão da DoençaRESUMO
Selpercatinib, a selective RET kinase inhibitor, has demonstrated remarkable efficacy in treating patients with advanced medullary (MTC) and differentiated thyroid cancer with RET alterations. Primary resistance to selpercatinib is a very uncommon situation, and its underlying mechanisms are poorly understood. We report the case of a 42-year-old female with advanced MTC harboring a somatic M918T RET mutation who exhibited a primary resistance to selpercatinib. Despite prompt treatment initiation after the diagnosis of progressive disease, the patient continued experiencing rapid spread of disease, characterized by the appearance of new metastatic lesions and increased tumor burden. Genomic analysis revealed no additional mutations associated with on-target or off-target resistance. This case highlights a rare clinical scenario of primary resistance to selpercatinib in advanced MTC. While secondary resistance mechanisms have been well-documented, primary resistance remains poorly understood. Possible explanations include tumor heterogeneity and activation of alternative signaling pathways that stills need to be elucidated. Emerging therapies targeting resistance mechanisms and next-generation RET inhibitors offer promising avenues for further investigation.
Assuntos
Carcinoma Neuroendócrino , Resistencia a Medicamentos Antineoplásicos , Proteínas Proto-Oncogênicas c-ret , Neoplasias da Glândula Tireoide , Humanos , Feminino , Neoplasias da Glândula Tireoide/tratamento farmacológico , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/patologia , Adulto , Carcinoma Neuroendócrino/tratamento farmacológico , Carcinoma Neuroendócrino/genética , Carcinoma Neuroendócrino/patologia , Resistencia a Medicamentos Antineoplásicos/genética , Proteínas Proto-Oncogênicas c-ret/genética , Proteínas Proto-Oncogênicas c-ret/antagonistas & inibidores , Pirazóis/uso terapêutico , Piridinas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Antineoplásicos/uso terapêuticoRESUMO
A 74-year-old man with obstructive jaundice presented with a thickened distal bile duct wall. A transpapillary forceps biopsy revealed an adenocarcinoma; however, because the tumor image was different from that of a typical cholangiocarcinoma, endoscopic ultrasound-guided fine-needle aspiration was performed on the tumor and enlarged lymph nodes. The tumor cells were positive for synaptophysin and CD56 with a Ki67 labeling index of 95%, and he was diagnosed with small cell neuroendocrine carcinoma. We diagnosed a bile duct tumor with neuroendocrine carcinoma component with lymph node metastasis. Preoperative chemotherapy for neuroendocrine carcinoma was administered because R0 resection was difficult and the risk of postoperative recurrence was high. Three courses of chemotherapy with carboplatin and etoposide resulted in marked tumor shrinkage, and radical resection was performed 3 months after diagnosis. Postoperative pathology revealed adenocarcinoma in the mucosal epithelium and small cell neuroendocrine carcinoma in the submucosa, most of which resolved with chemotherapy. Carboplatin and etoposide were resumed as adjuvant chemotherapy, and 67 months of recurrence-free survival were achieved after surgery.