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1.
Mol Cancer Ther ; 22(9): 1052-1062, 2023 09 05.
Artigo em Inglês | MEDLINE | ID: mdl-37487000

RESUMO

Pancreatic neuroendocrine tumors (PNET) express high levels of somatostatin receptor type 2 (SSTR2), a unique target for both tumor imaging and therapy. This surface expression is lost in metastatic high-grade PNETs, making patients ineligible for SSTR2-targeted 177 Lutetium (Lu)-DOTATATE peptide receptor radionuclide therapy (PRRT), and represents an unmet clinical need. Here, we aimed to restore SSTR2 expression through the reversal of inhibitory epigenetic gene silencing to improve tumor responsiveness to PRRT. We first assessed human SSTR2 promoter methylation and expression levels in 96 patient samples. We then used three NET cell lines (QGP-1, BON-1, GOT-1) with variable SSTR2 expression profiles for functional in vitro studies using histone deacetylase inhibitors (HDACi). Finally, the QGP-1 xenograft mouse model, with low basal SSTR2 expression, was used to assess the therapeutic efficacy of combined HDACi and 177Lu-DOTATATE therapies. We confirm that SSTR expression is decreased and correlates with SSTR2 promoter methylation in patients with high-grade NETs. When exposed to HDACis, SSTR2 surface expression is increased in three NET cell lines in vitro. In an in vivo PNET xenograft model with low basal SSTR2 expression, our studies demonstrate significantly higher tumor uptake of SSTR2-targeted 177Lu-DOTATATE in animals pretreated with HDACis compared with controls. For the first time, we show that this higher tumor uptake results in significant antitumor response when compared with standard PRRT alone. These preclinical results provide a rationale for utilizing HDACi pretreatment to improve targeted radionuclide therapy in patients with SSTR2-negative, metastatic PNETs.


Assuntos
Tumores Neuroectodérmicos Primitivos , Tumores Neuroendócrinos , Neoplasias Pancreáticas , Humanos , Animais , Camundongos , Regulação para Cima , Tumores Neuroendócrinos/tratamento farmacológico , Tumores Neuroendócrinos/genética , Tumores Neuroendócrinos/radioterapia , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/radioterapia
2.
Diagn Pathol ; 18(1): 31, 2023 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-36829189

RESUMO

BACKGROUND: Carotid body tumors (CBTs) are rare neuroendocrine neoplasms arising near the carotid bifurcation with a reported incidence of 1 to 2 cases in 100,000 patients. Most CBTs are sporadic, benign, slow-growing, and non-secreting, but untreated CBTs can grow locally to compress the nearby blood vessels, esophagus, and airway. Regional metastases can occur in 5% to 10% of cases, but distant metastases are exceedingly rare, occurring in roughly 1-2% of cases. As such, the optimal treatment for metastatic CBTs is not well-defined. We report a rare case of a patient with CBT distant metastases causing spinal cord compression. CASE PRESENTATION: A 40-year-old African American female presented with a right neck mass, headaches, vertigo, tinnitus, hoarseness, and dysphagia. Imaging demonstrated a Shamblin II right neck mass; subsequent transcervical resection and pathology showed a carotid body paraganglioma. The patient recurred locally near the carotid bifurcation, so she underwent Stereotactic Body Radiation Therapy to the recurrent right neck disease. She later re-presented with new onset bilateral lower extremity weakness, dysmetria, and numbness. She was found to have metastatic disease to the thoracic spine causing spinal cord compression. She underwent laminectomy, tumor resection, and posterior fixation followed by adjuvant radiation therapy. She was started on systemic therapy with sunitinib. She eventually progressed with metastatic disease to the right iliac bone, which was treated with palliative radiotherapy. Second line systemic therapy with capecitabine and temozolomide was started. At last follow up, the patient was asymptomatic with stable persistent disease. CONCLUSIONS: Paragangliomas often exhibit a prolonged interval to the development of progression; locoregional recurrences or rare distant metastases have been reported to occur as many as 20 years from diagnosis. The natural course of CBTs in other cases as well as the present case call into question the idea that CBTs are truly benign; instead CBTs may be indolent tumors with metastatic potential. Treatment choices for CBTs include surgical resection, radiation therapy, and systemic therapy, though the optimal treatment regimen for metastatic CBTs is not well-defined. A more advanced understanding of CBT pathophysiology, disease classification, risk stratification, and treatment options is needed to improve outcomes for patients.


Assuntos
Tumor do Corpo Carotídeo , Paraganglioma , Compressão da Medula Espinal , Humanos , Feminino , Adulto , Tumor do Corpo Carotídeo/diagnóstico , Tumor do Corpo Carotídeo/patologia , Tumor do Corpo Carotídeo/cirurgia , Recidiva Local de Neoplasia
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