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1.
Cancers (Basel) ; 16(17)2024 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-39272851

RESUMO

Background: Peptide Receptor Radionuclide Therapy (PRRT), a form of Radioligand Therapy (RLT), and Capecitabine/Temozolomide (CAPTEM) are cornerstones of systemic therapy for metastatic pancreatic neuroendocrine tumors (PNETs). Data regarding comparative efficacy are lacking. Herein, we compare the efficacy of PRRT vs. CAPTEM as second-line/beyond regimens and treatment sequencing. Methods: Clinicopathologic, radiographic, and genomic data were captured for metastatic PNETs seen in our multi-disciplinary NET clinic between 2013 and 2023. The primary outcome was progression-free survival (PFS) after progression on a previous line of systemic therapy. The secondary outcomes were objective response rate (ORR), time to response (TTR), and overall survival (OS). Results: Fifty-nine cases were included. PFS was similar in the PRRT (n = 29) and CAPTEM (n = 30) groups (PRRT = 21.90 months vs. CAPTEM = 20.03 months; HR 0.99; p = 0.97). On subgroup analysis, PRRT had longer PFS in cases without extrahepatic metastases (26.47 months vs. 17.67 months; p = 0.03) and cases with a mutation in the MEN1, DAXX, and/or ATRX genes (28.43 months vs. 18.67 months; p = 0.03). PRRT had reduced PFS in patients with grade 3 disease (7.83 months vs. 16.33 months; p = 0.02). ORR did not vary significantly (34.78% vs. 40.91%; p = 0.67). CAPTEM responders showed shorter TTR (6.03 months vs. 11.15 months; p = 0.03). In patients who received both, OS did not vary based on the sequence (HR 1.20; p = 0.75). Conclusions: PFS, ORR, and OS are similar when using PRRT vs. CAPTEM as second-line-and-beyond therapy for patients with metastatic PNETs. However, patients with MEN1, DAXX, and/or ATRX mutations or without extrahepatic metastases might better benefit from PRRT and patients with grade 3 disease from CAPTEM. Candidates for surgical debulking or with tumor-induced symptoms may benefit from initial treatment with CAPTEM due to shorter TTR.

2.
Endocr Relat Cancer ; 2024 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-39093924

RESUMO

Pre-clinical data suggest that mutations in the MEN1, DAXX, and/or ATRX genes may potentially increase radiation efficacy in cancer cells. Herein, we explore the association between response to peptide receptor radionuclide therapy (PRRT) and those mutations in patients with gastroenteropancreatic neuroendocrine tumors (GEP-NETs). We analyzed tissue-based next generation sequencing (NGS) assay results and clinicopathologic data from 28 patients with GEP-NETs treated with PRRT. Findings were correlated with progression-free survival (PFS) and objective response (ORR). Patients with mutations in MEN1, DAXX, and/or ATRX (n = 13) had a longer median PFS (26.47 vs. 12.13 months; p = 0.014) than wildtype (n = 15) patients when adjusted for surgery prior to PRRT, tumor grade, and presence of TP53 mutation. Alterations in MEN1 along with a concurrent mutation in either DAXX or ATRX (n = 6) trended towards longer PFS compared to patients without concurrent mutations (31.53 vs. 17.97 months; p = 0.09). ORR was higher in patients with a mutation in MEN1, DAXX, or ATRX (41.67% vs. 15.38%). In pancreatic NET patients, these target mutations also showed a longer PFS (28.43 vs. 9.83 months; p = 0.04). TP53 alterations showed a shorter PFS than wild-type cases (11.17 vs. 20.47 months; p = 0.009). Mutations in MEN1/DAXX/ATRX are associated with improved PFS in patients with GEP-NETs receiving PRRT and might be used as a biomarker for treatment response.

3.
Surg Clin North Am ; 104(4): 883-890, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38944506

RESUMO

Pancreatic neuroendocrine tumors originate from hormone-producing islet cells and have a propensity to metastasize to the liver once they reach 2 cm in size. Their diagnosis relies upon a combination of computed tomography, MRI, DOTATATE PET, and endoscopic ultrasound with or without tissue biopsy. Biochemical work-up is driven by patient symptoms of hormone excess.


Assuntos
Tumores Neuroendócrinos , Neoplasias Pancreáticas , Humanos , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/diagnóstico por imagem , Tumores Neuroendócrinos/diagnóstico , Tumores Neuroendócrinos/diagnóstico por imagem , Endossonografia/métodos , Tomografia Computadorizada por Raios X/métodos , Imageamento por Ressonância Magnética/métodos
4.
Artigo em Inglês | MEDLINE | ID: mdl-38817124

RESUMO

CONTEXT: Pancreatic neuroendocrine tumors (PNETs) exhibit a wide range of behavior from localized disease to aggressive metastasis. A comprehensive transcriptomic profile capable of differentiating between these phenotypes remains elusive. OBJECTIVE: Use machine learning to develop predictive models of PNET metastatic potential dependent upon transcriptomic signature. METHODS: RNA-sequencing data were analyzed from 95 surgically-resected primary PNETs in an international cohort. Two cohorts were generated with equally balanced metastatic PNET composition. Machine learning was used to create predictive models distinguishing between localized and metastatic tumors. Models were validated on an independent cohort of 29 formalin-fixed, paraffin-embedded samples using NanoString nCounter®, a clinically-available mRNA quantification platform. RESULTS: Gene expression analysis identified concordant differentially expressed genes between the two cohorts. Gene set enrichment analysis identified additional genes that contributed to enriched biologic pathways in metastatic PNETs. Expression values for these genes were combined with an additional 7 genes known to contribute to PNET oncogenesis and prognosis, including ARX and PDX1. Eight specific genes (AURKA, CDCA8, CPB2, MYT1L, NDC80, PAPPA2, SFMBT1, ZPLD1) were identified as sufficient to classify the metastatic status with high sensitivity (87.5% - 93.8%) and specificity (78.1% - 96.9%). These models remained predictive of the metastatic phenotype using NanoString nCounter® on the independent validation cohort, achieving a median AUROC of 0.886. CONCLUSIONS: We identified and validated an eight-gene panel predictive of the metastatic phenotype in PNETs, which can be detected using the clinically-available NanoString nCounter® system. This panel should be studied prospectively to determine its utility in guiding operative versus non-operative management.

5.
J Surg Res ; 298: 88-93, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38593602

RESUMO

INTRODUCTION: Elevated metanephrine and catecholamine levels 3-fold upper limit of normal (ULN) are diagnostic for pheochromocytoma. We sought to determine whether size correlates with biochemical activity or symptoms which could guide timing of surgery. METHODS: Data from consecutive patients undergoing adrenalectomy for pheochromocytoma at our institution over a 10-year period were retrospectively collected. These included maximal lesion diameter on preoperative imaging, plasma/urine metanephrine and/or catecholamine levels, demographic variables and presence of typical paroxysmal symptoms. Receiver operating characteristic curves were used to assess predictive accuracy. RESULTS: Sixty-three patients were included in the analysis (41 females and 22 males). Median age was 56 (43, 69) years. Due to various referring practices, 31 patients had documented 24-h urine metanephrine, 26 had 24-h urine catecholamine, and 52 had fractionated plasma metanephrine levels available for review. Values were converted to fold change compared to ULN and the maximum of all measured values was used for logistic regression. Median tumor size was 3.40 (2.25, 4.55) cm in greatest dimension. Tumor size at which pheochromocytoma produced > 3-fold ULN was ≥2.3 cm (AUC of 0.84). Biochemical activity increased with doubling tumor size (odds ratio = 8, P = 0.0004) or ≥ 1 cm increase in tumor size (odds ratio = 3.03, P = 0.001). 40 patients had paroxysmal symptoms, but there was no significant correlation between tumor size/biochemical activity and symptoms. CONCLUSIONS: In our study, tumor size directly correlated with the degree of biochemical activity and pheochromocytomas ≥2.3 cm produced levels 3 times ULN. These findings may allow clinicians to adjust timing of operative intervention.


Assuntos
Neoplasias das Glândulas Suprarrenais , Adrenalectomia , Metanefrina , Feocromocitoma , Humanos , Feocromocitoma/cirurgia , Feocromocitoma/patologia , Feocromocitoma/sangue , Feminino , Masculino , Pessoa de Meia-Idade , Neoplasias das Glândulas Suprarrenais/cirurgia , Neoplasias das Glândulas Suprarrenais/patologia , Neoplasias das Glândulas Suprarrenais/sangue , Estudos Retrospectivos , Adulto , Idoso , Metanefrina/urina , Metanefrina/sangue , Catecolaminas/urina , Catecolaminas/sangue , Carga Tumoral , Relevância Clínica
6.
Artigo em Inglês | MEDLINE | ID: mdl-38651609

RESUMO

CONTEXT: Medullary thyroid cancer has a historic recurrence rate up to 50%, and surgery remains the only cure. OBJECTIVE: This study aims to assess factors related to recurrence and metastatic spread in MTC. DESIGN: Retrospective chart review was performed from 1990-2023. Descriptive analysis and regression models were used for analysis. SETTING: Single specialized tertiary care referral center. PATIENTS: 68 patients with MTC, who underwent surgery, were included. MAIN OUTCOME MEASURE: Recurrence. RESULTS: Mean age at diagnosis was 54.9years(42.2-64.1), 65%(n=44) females. Lymph node and distant metastases were found in 24%(n=16) and 4%(n=3), respectively. RET mutations were present in 52%(n=35): MTC risk levels Highest 6%, High 7%, and Moderate 39%. Mean tumor size was 1.9cm(1.2-3.2) and mean preoperative calcitonin was 504.4pg/mL(133.2-1833.8). Total thyroidectomy(TT) was performed in 10 patients, TT+central neck dissection(CND) in 28, and TT+CND+lateral neck dissection(LND) in 25. On final pathology, 40% had positive central nodes and 25% had positive lateral nodes. Recurrence was 22%, median follow-up 4.7years(1.2-28.0). Male gender(HR=5.81, p=0.021), positive lateral neck nodes(HR 8.10, p=0.011) and high/highest MTC risk level RET mutations(HR 8.66, p=0.004) were significantly associated with recurrence. Preoperative calcitonin>2,175 pg/mL was a strong predictor for distant metastasis(AUC0.893) and a good predictor for lateral neck disease(AUC0.706). Extent of surgery was not significantly associated with recurrence(p=0.634). CONCLUSION: One of 4 patients undergoing surgery for MTC will recur. Risk factors associated with recurrence are male gender, lateral LN metastasis and high/highest MTC risk level mutations, but not necessarily surgery type. Preoperative calcitonin>2,175 pg/mL is suggestive of advanced disease and should prompt further evaluation.

8.
Am J Surg ; 229: 17-23, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-37802701

RESUMO

BACKGROUND: Reported outcomes after surgical debulking in patients with advanced neuroendocrine tumor liver metastases (NETLM) are sparse. METHODS: NETLM patients that underwent surgical debulking from 2019 to 2021 were reviewed. Trends in perioperative liver function, complications, symptom response, and progression-free survival were examined. RESULTS: 1069 liver lesions were debulked from 53 patients using a combination of parenchymal-sparing resections (PSR) and ultrasound-guided microwave ablations (MWA). Post-operative transaminitis and thrombocytopenia were common, and severity correlated with increasing number of lesions. Laboratory markers for synthetic liver function did not differ according to the number of lesions debulked. 13% of patients sustained a Clavien-Dindo grade 3 or 4 complication which was not associated with the number of lesions targeted. All patients with preoperative symptoms had improvement after surgery. Median time to progression was 10.9 months. CONCLUSIONS: PSR with MWA for large numbers of NETLM is safe and effective for symptom control and does not affect synthetic liver function.


Assuntos
Ablação por Cateter , Neoplasias Hepáticas , Tumores Neuroendócrinos , Humanos , Tumores Neuroendócrinos/cirurgia , Micro-Ondas/uso terapêutico , Hepatectomia , Resultado do Tratamento , Estudos Retrospectivos
9.
Surgery ; 175(1): 234-240, 2024 01.
Artigo em Inglês | MEDLINE | ID: mdl-37907382

RESUMO

BACKGROUND: Molecular testing guides the management of cytologically indeterminate thyroid nodules. We evaluated the real-world clinical benefit of a commercially available thyroid mutation panel plus microRNA risk classifier in classifying RAS-mutated nodules. METHODS: We performed a subgroup analysis of the results of molecular testing of Bethesda III/IV nodules using the ThyGenX/ThyGeNEXT-ThyraMIR platform at 3 tertiary-care centers between 2017 and 2021, defining a positive result as 10% or greater risk of malignancy. RESULTS: We identified 387 nodules from 375 patients (70.7% female, median age 59.3 years) who underwent testing. Positive nodules (32.3%) were associated with increased surgical intervention (74.4% vs 14.9%, P < .0001) and carcinoma on surgical pathology (46.4% vs 3.4%, P < .0001) compared to negative modules. RAS mutations were the most common mutations, identified in 71 of 380 (18.7%) nodules, and were classified as ThyraMIR- (28 of 71; 39.4%) or ThyraMIR+ (43 of 71; 60.6%). Among RAS-mutated nodules, there was no significant difference in operative rate (P = .2212) or carcinoma diagnosis (P = .6277) between the ThyraMIR+ and ThyraMIR- groups, and the sensitivity, specificity, negative predictive value, and positive predictive value of ThyraMIR were 64.7%, 34.8%, 40.0%, and 59.5%, respectively. CONCLUSION: Although testing positive is associated with malignancy in surgical pathology, the ThyraMIR classifier failed to differentiate between benign and malignant RAS-mutated nodules. Diagnostic lobectomy should be considered for RAS-mutated nodules, regardless of microRNA expression status.


Assuntos
Carcinoma , MicroRNAs , Neoplasias da Glândula Tireoide , Nódulo da Glândula Tireoide , Humanos , Feminino , Pessoa de Meia-Idade , Masculino , Nódulo da Glândula Tireoide/diagnóstico , Nódulo da Glândula Tireoide/genética , Nódulo da Glândula Tireoide/cirurgia , MicroRNAs/genética , Neoplasias da Glândula Tireoide/diagnóstico , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/cirurgia , Mutação , Estudos Retrospectivos
10.
J Am Coll Surg ; 237(1): 157-168, 2023 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-37022773

RESUMO

BACKGROUND: Neuroendocrine tumor liver metastases (NELM) are a major source of morbidity and mortality in neuroendocrine tumor patients and can be treated with hepatic debulking surgery (HDS). This study aims to identify variables associated with postoperative morbidity in NELM HDS. STUDY DESIGN: This analysis uses the American College of Surgeons NSQIP targeted hepatectomy-specific Participant User File from 2014 to 2020. Surgeries were grouped by number of hepatic resections performed (1 to 5, 6 to 10, greater than 10). Multivariable logistic regression and matching were used to identify prognostic factors of morbidity. RESULTS: A total of 1,163 patients were included. A total of 1,011 (87%) had 1 to 5 hepatic resections, 101 (8.7%) had 6 to 10 resections, and 51 (4.4%) had greater than 10 resections. The overall complication rate was 35%, and surgical and medical complications reached 30% and 13%, respectively. Mortality occurred in 11 patients (0.9%). Significantly higher rates of any (34% vs 35% vs 53%, p = 0.021) and surgical complications (29% vs 28% vs 49%, p = 0.007) were noted for those undergoing greater than 10 resections (1 to 5 resections, 6 to 10, greater than 10). "Bleeding requiring transfusion" (p < 0.0001) occurred more frequently in the greater than 10 resection group. On multivariable logistic regression, greater than 10 resections were an independent risk factor for any (odds ratio [OR] 2.53, p = 0.002; OR 2.52, p =. 0013) and surgical (OR 2.53, p = 0.003; OR 2.88, p = 0.005) complications compared with 1 to 5 resections and 6 to 10 resections, respectively. Medical complications (OR 2.34, p = 0.020) and length of stay greater than 5 days (OR 1.98, p = 0.032) were also increased with greater than 10 vs 1 to 5 resections. CONCLUSIONS: As reported by NSQIP, NELM HDS were performed safely with low mortality. However, more hepatic resections, especially greater than 10, were associated with increased postoperative morbidity and length of stay.


Assuntos
Neoplasias Hepáticas , Tumores Neuroendócrinos , Cirurgiões , Humanos , Estados Unidos/epidemiologia , Tumores Neuroendócrinos/cirurgia , Procedimentos Cirúrgicos de Citorredução/efeitos adversos , Neoplasias Hepáticas/cirurgia , Hepatectomia , Complicações Pós-Operatórias , Estudos Retrospectivos
11.
Hepatobiliary Surg Nutr ; 12(1): 69-83, 2023 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-36860243

RESUMO

Background and Objective: Pancreatic neuroendocrine tumors (PanNETs) are derived from the islet cells of the pancreas and have been increasing in incidence. Most of these tumors are nonfunctional although some can secrete hormones and lead to hormone-specific clinical syndromes. Surgery is the mainstay of treatment for localized tumors, however, surgical resection is controversial in metastatic PanNETs. This narrative review seeks to summarize the current literature surrounding surgery, specifically in the controversial area of metastatic PanNETs, review current treatment paradigms, and understand the benefits of surgery in this group of patients. Methods: Authors searched PubMed using the terms "surgery pancreatic neuroendocrine tumor", "metastatic neuroendocrine tumor", and "liver debulking neuroendocrine tumor" from January 1990 to June 2022. Only English language publications were considered. Key Content and Findings: There is no consensus among the leading specialty organizations regarding surgery for metastatic PanNETs. When considering surgery for metastatic PanNETs, tumor grade and morphology, location of the primary tumor, extra-hepatic or extra-abdominal disease, as well as liver tumor burden and metastatic distribution should be considered. Because the liver is the most common site of metastasis and liver failure is the most common cause of death in patients with hepatic metastases, attention is centered here on debulking and other ablative techniques. Liver transplantation is rarely used for hepatic metastases but could be beneficial in a small subset of patients. Retrospective studies have demonstrated improvement in survival and symptoms after surgery for metastatic disease, but the lack of prospective randomized control trials significantly limits analysis of surgical benefits in patients with metastatic PanNETs. Conclusions: Surgery is the standard of care for localized PanNETs, while it remains controversial in metastatic disease. Many studies have shown a survival and symptomatic benefit to surgery and liver debulking in select groups of patients. However, most of the studies on which recommendations are based in this population are retrospective in nature and are subject to selection bias. This presents an opportunity for future investigation.

12.
Surg Pathol Clin ; 16(1): 151-161, 2023 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-36739162

RESUMO

Radiolabeled somatostatin analogs are increasingly used in the diagnosis and treatment of neuroendocrine tumors. Diagnostic imaging with 68Ga-DOTATATE PET/CT has demonstrated the improved sensitivity in detecting primary and metastatic neuroendocrine lesions compared with conventional imaging and prior generation somatostatin receptor imaging. Peptide receptor radionuclide therapy with 177Lu-DOTATATE is now frequently included in the management of neuroendocrine neoplasms, with prospective randomized control studies demonstrating its beneficial impact on survival and quality of life. Nonetheless, peptide rector radionuclide therapy is still considered palliative rather than curative and may be accompanied by adverse effects.


Assuntos
Tumores Neuroendócrinos , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Humanos , Estudos Prospectivos , Qualidade de Vida , Tumores Neuroendócrinos/diagnóstico , Tumores Neuroendócrinos/terapia , Tumores Neuroendócrinos/patologia , Radioisótopos/uso terapêutico
13.
Ann Surg ; 276(4): 684-693, 2022 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-35837957

RESUMO

OBJECTIVE: To evaluate the relationship between the use intraoperative neuromonitoring (IONM) during thyroidectomy and the risk of recurrent laryngeal nerve (RLN) injury. BACKGROUND: The role of IONM in reducing RLN injury during thyroidectomy remains controversial. Several studies on this topic apply conventional multivariable regression to adjust for confounding. However, estimates from this method may be biased due to model misspecification, especially with a rare outcome such as RLN injury. METHODS: We used a pooled dataset created by linking the 2016-2019 National Surgical Quality Improvement Project General Participant User File with the corresponding Targeted-Thyroidectomy file. The primary outcome was RLN injury rates, and the secondary outcomes were operating time and postoperative length of stay. A doubly robust (DR) estimator, in the form of an inverse-probability-weighted regression adjustment model, was used to estimate the effect of the use of IONM on the risk of RLN injury. Sensitivity analyses was performed. RESULTS: Twenty-four thousand three hundred seventy patients were evaluated, out of which 15,836 (70%) patients had IONM during thyroidectomy, and RLN injury occurred in 1498 (6.2%) cases. Rates of RLN injury increase with increasing age and BMI and are higher in patients with a cancer diagnosis, previous neck operation, total thyroidectomy, and node dissection. Doubly robust model suggests that the use of IONM was associated with a significant reduction in overall rate of RLN injury [risk ratio 0.77, confidence interval (CI), 0.68-0.87, P <0.001], and postoperative length of stay [-2.5 hours (CI, -4.18 to -0.81 h), P =0.004]. However, IONM use was associated with an increase in operating time [15.41 minutes (CI, 13.29-17.54 minutes), P <0.0001]. Sensitivity analyses revealed that our estimates are largely robust to confounding. CONCLUSION: In a balanced cohort of patients undergoing thyroidectomy from multiple sites and surgeons participating in National Surgical Quality Improvement Project, the use of IONM during thyroidectomy was associated with reduction in RLN injury.


Assuntos
Traumatismos do Nervo Laríngeo Recorrente , Cirurgiões , Estudos de Coortes , Humanos , Monitorização Intraoperatória/métodos , Traumatismos do Nervo Laríngeo Recorrente/epidemiologia , Traumatismos do Nervo Laríngeo Recorrente/etiologia , Traumatismos do Nervo Laríngeo Recorrente/prevenção & controle , Tireoidectomia/efeitos adversos , Tireoidectomia/métodos
14.
J Med Imaging (Bellingham) ; 9(3): 034501, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35692282

RESUMO

Background: Ultrasound (US)-guided fine needle aspiration (FNA) cytology is the gold standard for the evaluation of thyroid nodules. However, up to 30% of FNA results are indeterminate, requiring further testing. In this study, we present a machine-learning analysis of indeterminate thyroid nodules on ultrasound with the aim to improve cancer diagnosis. Methods: Ultrasound images were collected from two institutions and labeled according to their FNA (F) and surgical pathology (S) diagnoses [malignant (M), benign (B), and indeterminate (I)]. Subgroup breakdown (FS) included: 90 BB, 83 IB, 70 MM, and 59 IM thyroid nodules. Margins of thyroid nodules were manually annotated, and computerized radiomic texture analysis was conducted within tumor contours. Initial investigation was conducted using five-fold cross-validation paradigm with a two-class Bayesian artificial neural networks classifier, including stepwise feature selection. Testing was conducted on an independent set and compared with a commercial molecular testing platform. Performance was evaluated using receiver operating characteristic analysis in the task of distinguishing between malignant and benign nodules. Results: About 1052 ultrasound images from 302 thyroid nodules were used for radiomic feature extraction and analysis. On the training/validation set comprising 263 nodules, five-fold cross-validation yielded area under curves (AUCs) of 0.75 [Standard Error (SE) = 0.04; P < 0.001 ] and 0.67 (SE = 0.05; P = 0.0012 ) for the classification tasks of MM versus BB, and IM versus IB, respectively. On an independent test set of 19 IM/IB cases, the algorithm for distinguishing indeterminate nodules yielded an AUC value of 0.88 (SE = 0.09; P < 0.001 ), which was higher than the AUC of a commercially available molecular testing platform (AUC = 0.81, SE = 0.11; P < 0.005 ). Conclusion: Machine learning of computer-extracted texture features on gray-scale ultrasound images showed promising results classifying indeterminate thyroid nodules according to their surgical pathology.

16.
Endocr Relat Cancer ; 29(4): 225-239, 2022 03 21.
Artigo em Inglês | MEDLINE | ID: mdl-35171113

RESUMO

Somatic MEN1 mutations occur in up to 50% of pancreatic neuroendocrine tumors (PanNETs). Clinical studies have shown that radiation therapy (IR) is effective in a subset of PanNETs, but it remains unclear why some patients respond better to IR than others. Herein, we study whether MEN1 loss of function increases radiosensitivity of PanNETs and determine its effect on DNA double-strand break (DSB) repair. After creating a MEN1 knockout PanNET cell line, we confirmed reduced DSB repair capacity in MEN1-deficient cells and linked these findings to a defect in homologous recombination, as well as reduced BRCA2 expression levels. Consistent with this model, we found that MEN1 mutant cells displayed increased sensitivity to the highly trapping poly (ADP-ribose) polymerase (PARP) 1 inhibitor talazoparib in vitro. Our results suggest that combining IR with PARP inhibition may be beneficial in patients with PanNETs and MEN1 loss of function.


Assuntos
Tumores Neuroendócrinos , Neoplasias Pancreáticas , Proteínas Proto-Oncogênicas/metabolismo , Reparo do DNA , Humanos , Tumores Neuroendócrinos/patologia , Neoplasias Pancreáticas/patologia , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Poli(ADP-Ribose) Polimerases/metabolismo
17.
Cancer ; 128(3): 435-446, 2022 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-34735022

RESUMO

Von Hippel-Lindau disease (VHL) is a multineoplasm inherited disease manifesting with hemangioblastoma of the central nervous system and retina, adrenal pheochromocytoma, renal cell carcinoma, pancreatic neuroendocrine tumors and cysts, and neoplasms/cysts of the ear, broad ligament, and testicles. During 2018-2020, the VHL Alliance gathered several committees of experts in the various clinical manifestations of VHL to review the literature, gather the available evidence on VHL, and develop recommendations for patient management. The current report details the results of the discussion of a group of experts in the pancreatic manifestations of VHL along with their proposed recommendations for the clinical surveillance and management of patients with VHL. The recommendations subcommittee performed a comprehensive systematic review of the literature and conducted panel discussions to reach the current recommendations. The level of evidence was defined according to the Shekelle variation of the Grading of Recommendations, Assessment, Development, and Evaluation grading system. The National Comprehensive Cancer Network Categories of Evidence and Consensus defined the committee members' interpretation of the evidence and degree of consensus. The recommendations encompass the main aspects of VHL-related pancreatic manifestations and their clinical management. They are presented in a clinical orientation, including general planning of screening and surveillance for pancreatic neuroendocrine tumors, utility of biochemical biomarkers, the optimal choice for imaging modality, indirect risk stratification, indications for tissue sampling of VHL-related pancreatic neuroendocrine tumors, and interventions. These recommendations are designed to serve as the reference for all aspects of the screening, surveillance, and management of VHL-related pancreatic manifestations.


Assuntos
Neoplasias das Glândulas Suprarrenais , Hemangioblastoma , Neoplasias Renais , Neoplasias Pancreáticas , Feocromocitoma , Doença de von Hippel-Lindau , Neoplasias das Glândulas Suprarrenais/complicações , Neoplasias das Glândulas Suprarrenais/diagnóstico , Neoplasias das Glândulas Suprarrenais/terapia , Feminino , Hemangioblastoma/diagnóstico , Humanos , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/etiologia , Neoplasias Pancreáticas/terapia , Feocromocitoma/diagnóstico , Feocromocitoma/terapia , Proteína Supressora de Tumor Von Hippel-Lindau , Doença de von Hippel-Lindau/complicações , Doença de von Hippel-Lindau/diagnóstico , Doença de von Hippel-Lindau/terapia
18.
Appl Immunohistochem Mol Morphol ; 30(2): e11-e15, 2022 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-34711739

RESUMO

Dysregulation of epigenetic mechanisms, reflected by loss of expression of 5-hydroxymethylcytosine (5-hmC) is being increasingly recognized as a marker of aggressive behavior in several neoplasms; however, the role of such epigenetic modifiers in pancreatic neuroendocrine tumors (PanNETs) has not been studied. Annotated cohort of 60 PanNETs was evaluated for 5-hmC expression using immunohistochemistry. Univariable and multivariable analyses were performed. To determine intratumor heterogeneity of 5-hmC expression, 26 additional synchronous metastatic deposits of PanNETs from 8 patients were evaluated for 5-hmC expression. 5-hmC level showed significant association with the presence of distant metastases (P=0.02), female sex (P=0.04), and Ki-67 proliferation index (P=0.002). A multivariate model created using the stepwise logistic regression analysis showed the presence of nodal metastases (odds ratio=6.15), lymphovascular invasion (odds ratio=4.07) and lack of 5-hmC expression (odds ratio=5.34) were predictive of the risk of distant metastasis in PanNETs with a c-statistic of 0.845. Epigenetic intratumoral heterogeneity of 5-hmC expression was seen in 37.5% cases (3/8). Our work provides evidence that epigenetic regulators are involved in the pathobiology of PanNETs and immunohistochemical analysis of 5-hmC may be able to refine prognostic evaluation of these tumors.


Assuntos
Tumores Neuroendócrinos , Neoplasias Pancreáticas , 5-Metilcitosina/análogos & derivados , Epigênese Genética , Feminino , Humanos , Índice Mitótico , Tumores Neuroendócrinos/metabolismo , Neoplasias Pancreáticas/metabolismo
19.
Ann Surg Oncol ; 28(13): 8532-8543, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34091777

RESUMO

BACKGROUND: Pancreatic neuroendocrine tumors (PanNETs) are increasingly common. Experts debate whether small tumors should be resected. Tumor destruction via injection of cytotoxic agents could offer a minimal invasive approach to this controversy. We hypothesize that a new drug delivery system comprising chondroitin sulfate (CS) hydrogels loaded with sunitinib (SUN) suppresses tumor growth in PanNET cells. METHODS: Injectable hydrogels composed of CS modified with methacrylate groups (MA) were fabricated and loaded with SUN. Loading target was either 200 µg (SUN200-G) or 500 µg (SUN500-G) as well as sham hydrogel with no drug loading (SUN0-G). SUN release from hydrogels was monitored in vitro over time and cytotoxicity induced by the released SUN was evaluated using QGP-1 and BON1 PanNET cell lines. QGP-1 xenografts were developed in 35 mice and directly injected with 25 µL of either SUN200-G, SUN500-G, SUN0-G, 100 µL of Sunitinib Malate (SUN-inj), or given 40 mg/kg/day oral sunitinib (SUN-oral). RESULTS: SUN-loaded CSMA hydrogel retained complete in vitro cytotoxicity toward the QGP-1 PanNET and BON-1 PanNET cell lines for 21 days. Mouse xenograft models with QGP-1 PanNETs showed a significant delay in tumor growth in the SUN200/500-G, SUN-inj and SUN-oral groups compared with SUN0-G (p = 0.0014). SUN500-G hydrogels induced significantly more tumor necrosis than SUN0-G (p = 0.04). There was no difference in tumor growth delay between SUN200/500G, SUN-inj, and SUN-oral. CONCLUSIONS: This study demonstrates that CSMA hydrogels loaded with SUN suppress PanNETs growth. This drug delivery could approach represents a novel way to treat PanNETs and other neoplasms via intratumoral injection.


Assuntos
Tumores Neuroendócrinos , Neoplasias Pancreáticas , Animais , Linhagem Celular Tumoral , Sulfatos de Condroitina/uso terapêutico , Sistemas de Liberação de Medicamentos , Hidrogéis , Camundongos , Tumores Neuroendócrinos/tratamento farmacológico , Neoplasias Pancreáticas/tratamento farmacológico , Sunitinibe/uso terapêutico
20.
Surgery ; 170(1): 106-113, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33814188

RESUMO

BACKGROUND: Small bowel neuroendocrine tumors (SB-NET) frequently metastasize to regional lymphatic or distant sites. Although most prognostication of SB-NET focuses on lymph node involvement, findings from studies of neuroendocrine tumors from other primary sites have suggested that preoperative serum chromogranin-A (CgA) levels may provide a more accurate metric. METHODS: Using the National Cancer Database (2004-2016), we analyzed patients with locoregional SB-NET who underwent curative resection including an adequate lymphadenectomy (n = 1,274). A statistically optimized cut-point was used to dichotomize CgA cohort based on preoperative serum CgA levels. RESULTS: We determined that a CgA ≥139 ng/mL identified patients with significantly shorter estimated mean overall survival (6.6 years vs 7.6 years, log-rank P = .00001). These patients were also older (63 vs 57 years, P < .001) and had higher rates of poorly differentiated tumors (2.1% vs 0.7%, P = .04) or primary tumors >1 cm (88.2% vs 79.2%, P = .001). Clinical features associated with shorter overall survival included preoperative CgA ≥139 ng/mL (HR = 2.19, 95% CI 1.22-3.92; P = .009), age at diagnosis (HR = 1.06, 95% CI 1.03-1.09; P < .001), Charlson-Deyo score ≥2 (HR = 3.93, 95% CI 1.71-9.01; P = .001), and poorly differentiated tumors (HR = 11.22, 95% CI 4.16-30.24; P < .001). Neither lymph node metastasis nor T-stage were independently associated with shorter overall survival in patients with locoregional SB-NET. CONCLUSION: Elevated preoperative serum CgA is an adverse prognostic marker associated with shorter overall survival in patients with locoregional SB-NET.


Assuntos
Cromogranina A/sangue , Neoplasias do Íleo/sangue , Neoplasias do Jejuno/sangue , Tumores Neuroendócrinos/sangue , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Bases de Dados Factuais , Feminino , Humanos , Neoplasias do Íleo/mortalidade , Neoplasias do Íleo/cirurgia , Neoplasias do Jejuno/mortalidade , Neoplasias do Jejuno/cirurgia , Estimativa de Kaplan-Meier , Excisão de Linfonodo , Masculino , Pessoa de Meia-Idade , Tumores Neuroendócrinos/mortalidade , Tumores Neuroendócrinos/cirurgia , Valor Preditivo dos Testes , Período Pré-Operatório , Prognóstico , Adulto Jovem
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