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1.
Cancers (Basel) ; 13(24)2021 Dec 16.
Artigo em Inglês | MEDLINE | ID: mdl-34944946

RESUMO

(1) Background: Neuroendocrine neoplasms of the lung (LNENs, lung carcinoids) are often diagnosed at an advanced stage when they are not surgically curable, and treatment options are limited. One of the approved options for treating inoperable tumors is everolimus-an mTOR inhibitor (mTORi). Activation of mTOR, among many other effects, inhibits autophagy, which is a cell survival mechanism in general, and in tumor cells in particular. Everolimus may paradoxically encourage cancer cell survival. In practice, the drug inhibits tumor development. Chloroquine (CQ) is a known antimalarial compound that inhibits autophagy. Our research is focused on the hypothesis that autophagy plays a key role in the development of tumor resistance to mTORi, and that the addition of autophagy inhibitors to mTORi exerts a synergistic effect on suppressing tumor cell proliferation. We have recently demonstrated that the combination of CQ with different mTORi increases their potency compared with mTORi alone in both in vitro and in vivo models of pancreatic NENs. In this study, we examined the effects of CQ and mTORi on in vitro and in vivo LNEN models. Aims: Testing the effects of CQ together with mTORi on cell proliferation, apoptosis, and autophagy in in vitro and in vivo LNEN models. (2) Methods: The NCI-H727 LNEN cells were treated with CQ ± mTORi. Cells' viability and proliferation were measured using XTT and Ki-67 FACS staining. The effects of the treatments on the mTOR pathway and autophagy were examined using Western blotting. Cytotoxicity was measured using a cytotoxicity kit; apoptosis was measured by PI FACS staining and Western blotting. We further established an LNEN subcutaneous murine xenograft model and evaluated the effects of the drugs on tumor growth. (3) Results: CQ alone suppressed LNEN cells' viability and proliferation and increased their cytotoxicity and apoptosis; these effects were augmented when CQ was added to an mTORi. We also showed the possible mechanisms for these results: on the one hand we could see a decrease in P62 levels and the absence of LC3-II (both inversely related to autophagy) following treatment with the mTORi, and on the other hand we could demonstrate an increase in their levels when CQ was added. The effect was less apparent in the murine xenograft model. (4) Conclusions: By inhibiting autophagy and inducing apoptosis, CQ suppresses tumor cell growth in LNENs. CQ potentiates mTORi effects, implying that further studies are needed in order to elucidate its possible role in tumor inhibition in patients with LNENs.

2.
EJNMMI Phys ; 8(1): 63, 2021 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-34436698

RESUMO

BACKGROUND: Following each cycle of peptide receptor radionuclide therapy (PRRT), absorbed doses by tumors and normal organs are typically calculated from three quantitative single-photon emission computed tomography (SPECT)/computed tomography (CT) studies acquired at t1 = 24 h, t2 = 96 h, t3 = 168 h after the first cycle of treatment and from a single study at t1 after the subsequent cycles. In the present study, we have assessed the feasibility of a single SPECT/CT study after each PRRT cycle using a trained multiple linear regression (MLR) model for absorbed dose calculation and have evaluated its impact on patient management. Quantitative [177Lu]-DOTA-TATE SPECT/CT data after PRRT of seventy-two consecutive metastatic neuroendocrine tumors patients were retrospectively evaluated. A set of 40 consecutive studies was used to train the MLR model. The two independent variables of the model included the time of imaging after administration of the treatment and the radiopharmaceutical activity concentration in a given  organ/tumor. The dependent variable was the dose absorbed by the organ/tumor obtained with the standard protocol. For bone marrow dosimetry, the independent variables included the time of imaging, and the blood and remainder of the body activity concentration. The model was evaluated in 32 consecutive patients. Absorbed doses were assessed for kidneys, bone marrow, liver, spleen and tumor sites. RESULTS: There was no difference in management decisions, whether PRRT can be safely continued or not because unsafe absorbed dose to risk organs between the standard and the MLR model-based protocol using a single SPECT/CT study performed at t3 = 168 h after the first cycle and at t1 = 24 h after the subsequent cycles. Cumulative absorbed doses were obtained with mean relative differences of - 0.5% ± 5.4%, 1.6% ± 15.1%, - 6.2% ± 7.3%, - 5.5% ± 5.8% and 2.9% ± 12.7% for kidneys, bone marrow, liver, spleen and tumors, respectively (Pearson's r correlation coefficient 0.99, 0.91, 0.99, 0.99 and 0.97, respectively). CONCLUSION: Dosimetry calculations using a MLR model with a single SPECT/CT study are in good agreement with the standard protocol, while avoiding the use of dosimetry software and enabling improved patient comfort and reduced scanner and staff time.

4.
J Nucl Med ; 2021 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-34049983

RESUMO

To assess the efficacy and safety of 177Lu-DOTATATE in patients with somatostatin receptor (SSR) positive lung neuroendocrine tumor (NET). Methods: This is a retrospective review of the outcome of patients with typical carcinoid (TC) and atypical carcinoid (AC), treated with 177Lu-DOTATATE at two ENETS Centres of Excellence. Morphological imaging (RECIST 1.1) and 68Ga-DOTATATE PET/CT responses were assessed at 3 months after completion of 177Lu-DOTATATE. Concordance between two response assessment methods was evaluated by Kappa statistics. Progression-free survival (PFS) and overall survival (OS) was estimated by Kaplan-Meier analysis and compared by Log-rank test. Treatment-related adverse events (AEs) were graded based on CTCAE version 5. Results: Of 48 patients (median age, 63 years, 13 female), 43 (90%) had AC and 5 (10%) TC. Almost all patients (47, 98%) were treated due to progression. Majority (40, 83%) received somatostatin analogs and 10 patients (20%) had prior everolimus, chemotherapy or both. All patients had high SSR expression (≥ modified Krenning score 3) on pre-treatment 68Ga-DOTATATE PET/CT. Patients received a median 4 (range 1-4) cycles of 177Lu-DOTATATE (33% with concurrent radiosensitizing chemotherapy) to a median cumulative activity of 27GBq (range 6-43GBq). At median follow-up of 42 months, the median PFS and OS were 23 months (95% CI 18-28 months) and 59 months (95% CI 50-not reached [NR]), respectively. Of 40 patients with RECIST-measurable disease and 39 patients with available 68Ga-DOTATATE PET/CT response categories were: partial response, 20% (95% CI 10-35%) and 44% (95% CI 30-59%); stable disease, 68% (95% CI 52-80%) and 44% (95% CI 30-59%) and progressive disease 12% (95% CI 5-27%) by both, respectively. There was a moderate concordance between response categories by RECIST and 68Ga-DOTATATE PET/CT, weighted Kappa of 0.51 (95% CI 0.21-0.68). Of patients with stable disease by RECIST, those with partial response on 68Ga-DOTATATE PET/CT had longer OS compared to those with no response, NR vs 52 months (95% CI 28-64), HR 0.2 (95% CI 0.1-0.6), p 0.001. Most grade 3/4 AEs were reversible and the most common was lymphopenia (14%) with no incidence of myelodysplasia/leukemia. Conclusion: In patients with advanced progressive lung NET and satisfactory SSR expression, 177Lu-DOTATATE is effective and safe with a high disease control rate and encouraging PFS and OS.

5.
Acad Pathol ; 8: 23742895211002816, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33889716

RESUMO

This article presents findings from a 4-year series of surveys of new-in-practice pathologists, and a survey of physician employers of new pathologists, assessing how pathology graduate medical education prepares its graduates for practice. Using the methodology described in our previous study, we develop evidence for the importance of residency training for various practice areas, comparing findings over different practice settings, sizes, and lengths of time in practice. The principal findings are (1) while new-in-practice pathologists and their employers report residency generally prepared them well for practice, some areas-billing and coding, laboratory management, molecular pathology, and pathology informatics-consistently were identified as being important in practice but inadequately prepared for in residency; (2) other areas-autopsy pathology, and subspecialized apheresis and blood donor center blood banking services-consistently were identified as relatively unimportant in practice and excessively prepared for in residency; (3) the notion of a single comprehensive model for categorical training in residency is challenged by the disparity between broad general practice in some settings and narrower subspecialty practice in others; and (4) the need for preparation in some areas evolves during practice, raising questions about the appropriate mode and circumstance for training in these areas. The implications of these findings range from rebalancing the emphasis among practice areas in residency, to reconsidering the structure of graduate medical education in pathology to meet present and evolving future practice needs.

6.
EJNMMI Phys ; 8(1): 13, 2021 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-33580359

RESUMO

BACKGROUND: Image quality and quantitative accuracy of positron emission tomography (PET) depend on several factors such as uptake time, scanner characteristics and image reconstruction methods. Ordered subset expectation maximization (OSEM) is considered the gold standard for image reconstruction. Penalized-likelihood estimation (PL) algorithms have been recently developed for PET reconstruction to improve quantitation accuracy while maintaining or even improving image quality. In PL algorithms, a regularization parameter ß controls the penalization of relative differences between neighboring pixels and determines image characteristics. In the present study, we aim to compare the performance of Q.Clear (PL algorithm, GE Healthcare) and OSEM (3 iterations, 8 subsets, 6-mm post-processing filter) for 68Ga-DOTATATE (68Ga-DOTA) PET studies, both visually and quantitatively. Thirty consecutive whole-body 68Ga-DOTA studies were included. The data were acquired in list mode and were reconstructed using 3D OSEM and Q.Clear with various values of ß and various acquisition times per bed position (bp), thus generating images with reduced injected dose (1.5 min/bp: ß = 300-1100; 1.0 min/bp: ß = 600-1400 and 0.5 min/bp: ß = 800-2200). An additional analysis adding ß values up to 1500, 1700 and 3000 for 1.5, 1.0 and 0.5 min/bp, respectively, was performed for a random sample of 8 studies. Evaluation was performed using a phantom and clinical data. Two experienced nuclear medicine physicians blinded to the variables assessed the image quality visually. RESULTS: Clinical images reconstructed with Q.Clear, set at 1.5, 1.0 and 0.5 min/bp using ß = 1100, 1300 and 3000, respectively, resulted in images with noise equivalence to 3D OSEM (1.5 min/bp) with a mean increase in SUVmax of 14%, 13% and 4%, an increase in SNR of 30%, 24% and 10%, and an increase in SBR of 13%, 13% and 2%. Visual assessment yielded similar results for ß values of 1100-1400 and 1300-1600 for 1.5 and 1.0 min/bp, respectively, although for 0.5 min/bp there was no significant improvement compared to OSEM. CONCLUSION: 68Ga-DOTA reconstructions with Q.Clear, 1.5 and 1.0 min/bp, resulted in increased tumor SUVmax and in improved SNR and SBR at a similar level of noise compared to 3D OSEM. Q.Clear with ß = 1300-1600 enables one-third reduction of acquisition time or injected dose, with similar image quality compared to 3D OSEM.

7.
Eur J Surg Oncol ; 46(11): 2023-2028, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32389525

RESUMO

INTRODUCTION: The lymph node ratio (LNR), which represents the proportion of metastatic lymph nodes resected, has been found to be a prognostic variable in several cancers, but data for Medullary thyroid carcinoma (MTC) are sparse. The aim of this study was to determine the value of the LNR in predicting outcome in patients with MTC. MATERIALS AND METHODS: A retrospective multicenter study design of 107 patients with MTC who underwent total thyroidectomy with neck dissection between 1984 and 2016. The association of LNR with patient and tumor characteristics and prognostic factors was evaluated. RESULTS: Study population consisted of 53.3% female, mean age at diagnosis was 50.3 ± 18.4 years; 16.8% had inherited MTC. LNR was positively correlated with tumor size (p = 0.018) and inversely correlated with age at diagnosis (p = 0.024). A higher LNR was associated with extrathyroidal extension (p < 0.001), multifocality (p = 0.001), bilateral tumor (p = 0.002), distant metastases (p < 0.001), and tumor recurrence (OR = 14.7, p < 0.001). LNR was also correlated to postoperative calcitonin levels (p < 0.001) and carcinoembryonic antigen (p = 0.011). LNR >0.1 was associated with shorter disease-specific survival in patients at risk: tumor larger than 20 mm at diagnosis (p = 0.013), sporadic MTC (p = 0.01), and age above 40 years at diagnosis (p = 0.004). Cox multivariate survival analysis revealed LNR as the only significant independent factor for disease free survival (p = 0.005). CONCLUSIONS: This study showed that LNR correlates well with patient and tumor characteristics and prognostic variables. We suggest that LNR should be considered an important parameter for predicting outcome in MTC.


Assuntos
Carcinoma Neuroendócrino/patologia , Linfonodos/patologia , Esvaziamento Cervical , Neoplasias da Glândula Tireoide/patologia , Tireoidectomia , Adulto , Fatores Etários , Idoso , Calcitonina/sangue , Antígeno Carcinoembrionário/sangue , Carcinoma Neuroendócrino/sangue , Carcinoma Neuroendócrino/mortalidade , Carcinoma Neuroendócrino/cirurgia , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Fatores de Risco , Neoplasias da Glândula Tireoide/sangue , Neoplasias da Glândula Tireoide/mortalidade , Neoplasias da Glândula Tireoide/cirurgia , Carga Tumoral
8.
Chest ; 158(1): 401-405, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32059961

RESUMO

BACKGROUND: Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) is a rare lung disease associated with proliferation of neuroendocrine cells in the lung and multifocal neuroendocrine tumorlets/tumors. Although usually considered an indolent condition, DIPNECH causes chronic, progressive cough and dyspnea which can adversely impact quality of life. There is very limited information on the treatment of this condition. The objective of this study was to assess changes in symptoms and pulmonary function tests (PFTs) in response to somatostatin analog (SSA) treatment. METHODS: Patients with clinical and/or pathologic diagnosis of DIPNECH and chronic respiratory symptoms were treated with SSAs at the H. Lee Moffitt Cancer Center and Research Institute, Hadassah-Hebrew University Medical Center, and Mayo Clinic Cancer Center. Their charts were reviewed to assess changes in symptoms and PFTs. RESULTS: Forty-two patients were identified who had either chronic cough or dyspnea because of proven or suspected DIPNECH and who had received treatment with an SSA. Thirty-three patients experienced symptomatic improvement. Additionally, 14 of 15 patients in whom PFTs were checked were noted to have an improvement in FEV1 after treatment. CONCLUSIONS: SSA treatment can improve chronic respiratory symptoms and PFTs in patients with DIPNECH.


Assuntos
Pneumopatias/complicações , Pneumopatias/tratamento farmacológico , Células Neuroendócrinas/patologia , Octreotida/uso terapêutico , Peptídeos Cíclicos/uso terapêutico , Somatostatina/análogos & derivados , Idoso , Antineoplásicos/uso terapêutico , Feminino , Humanos , Hiperplasia , Pneumopatias/patologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Somatostatina/uso terapêutico , Resultado do Tratamento
9.
Endocrine ; 68(1): 222-229, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32036501

RESUMO

PURPOSE: The decreased life expectancy of MEN-1 patients is mainly related to pancreatic neuroendocrine tumors (pNETs). At best, limited data is available on the natural history of MEN-1-associated pNETs, as these tumors are rare and have a wide range of biologic behavior. Our study aims to explore the clinical course of patients with MEN-1-associated pNETs and the long-term outcomes. METHODS: This longitudinal study was conducted on the MEN-1 cohort treated at our referral center over a 22-year period (1996-2018). Relevant clinical data were retrospectively analysed. RESULTS: Among the 33 MEN-1 patients included in our study, pNETs were identified in 21 subjects with a penetrance of 48% by the age of 50. Non-functioning and functioning pNETs were diagnosed in sixteen (76%) and five (24%) patients, respectively. Two-thirds of the patients had multifocal tumors. The median number of pancreatic macroscopic lesions per individual was 4.0 ± 3.9 (range 1-8) with a mean size of 1.3 ± 2.1 cm (range 0.5-10). The metastatic rate according to the dominant pNET lesion reached 100%, 62% and 6% for tumors sized > 4 cm, 2.1-4 cm, and 1-2 cm, respectively. Over the study period, one or more therapeutic interventions for pNETs were required in 20 out of the 21 patients. pNET-related metastatic complication was the main cause of death within this MEN-1 cohort. The overall survival rate for the pNETs patients was 86% during a mean follow-up period of 8.0 ± 4.6 years. CONCLUSIONS: In our MEN-1 cohort, non-functioning pNETs were the most frequent type of pancreaticoduodenal tumor, and the tumor size correlated with the risks of metastasis and death. Increased awareness, early diagnosis, and a multidisciplinary approach may improve the associated morbidity and mortality in these patients.


Assuntos
Neoplasia Endócrina Múltipla Tipo 1 , Tumores Neuroendócrinos , Neoplasias Pancreáticas , Humanos , Estudos Longitudinais , Neoplasia Endócrina Múltipla Tipo 1/terapia , Tumores Neuroendócrinos/epidemiologia , Tumores Neuroendócrinos/terapia , Neoplasias Pancreáticas/epidemiologia , Neoplasias Pancreáticas/terapia , Estudos Retrospectivos
10.
EJNMMI Phys ; 7(1): 5, 2020 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-31975156

RESUMO

BACKGROUND: After each cycle of [177Lu]-DOTA-TATE peptide receptor radionuclide therapy (PRRT) dosimetry is performed to enable precise calculation of the radiation-absorbed dose to tumors and normal organs. Absorbed doses are routinely calculated from three quantitative single-photon emission computed tomography (SPECT) studies corrected by computed tomography (CT) acquired at t1 = 24 h, t2 = 96 h, and t3 = 168 h after the first cycle of treatment. After following cycles, a single SPECT/CT study is performed. The aim of the present study is to assess the feasibility of a "two time point" quantitative SPECT/CT protocol after the first PRRT cycle and its impact on patient management. Quantitative SPECT/CT data of 25 consecutive patients with metastatic neuroendocrine tumors after PRRT were retrospectively analyzed. Radiation-absorbed doses calculated using the standard protocol with three SPECT/CT studies acquired at (t1, t2, t3) were compared to those obtained from three different "two time point" protocols with SPECT/CT studies performed at (t1, t2), (t1, t3), or (t2, t3). RESULTS: The best agreement for the cumulative doses absorbed by the kidneys, bone marrow, liver, spleen, and tumors with the conventional protocol was obtained with the (t1, t3) protocol with mean relative differences of - 1.0% ± 2.4%, 0.4% ± 3.1%, - 0.9% ± 4.0%, - 0.8% ± 1.1%, and - 0.5% ± 2.0%, respectively, and correlation coefficients of r = 0.99 for all. In all patients, there was no difference in the management decision of whether or not to stop PRRT because of unsafe absorbed dose to risk organs using either the standard protocol or the (t1, t3) protocol. CONCLUSION: These preliminary results demonstrate that dosimetry calculations using two quantitative SPECT/CT studies acquired at 24 and 168 h after the first PRRT cycle are feasible and are in good agreement with the standard imaging protocol with no change in patient management decisions, while enabling improved patient comfort and reduced scanner and staff time.

11.
Arch Pathol Lab Med ; 144(4): 420-426, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31971466

RESUMO

CONTEXT.­: Disagreement exists within the pathology community about the status of the job market for pathologists. Although many agree that jobs in pathology were harder to come by earlier this decade, recent evidence suggests improvement is occurring. OBJECTIVE.­: To assess the state of the job market for pathologists. DESIGN.­: We analyzed data from the 2018 College of American Pathologists Practice Leader Survey. This survey contains data from 253 practice leaders on practices' hiring (and retrenchments) in 2017, the skills and level of experience being sought, success in filling those positions, and expectations for hiring in the next 3 years. RESULTS.­: Among the surveyed practice leaders, 115 (45.5%) sought to hire at least 1 pathologist in 2017, and together tried to fill 246 full-time equivalent positions that year, of which 93.5 full-time equivalents (38%) were newly created. This hiring was not limited to larger, academic-based practices, but also occurred among smaller practices and practices based in nonacademic hospitals, independent laboratories, and other settings. Although some practices retrenched (60 full-time equivalents in 2017), the net increase was a healthy 187 full-time equivalents. Practices most frequently sought pathologists who had at least 2 years of experience, but the level of experience identified with the "optimal" candidate varied by desired areas of subspecialty expertise. Practice leaders also reported expected growth in hiring, with the number of positions they hope to fill in the next 3 years exceeding those vacated by retirement. CONCLUSIONS.­: Our findings support the proposition that the demand for pathologists is strong, at least at the current time.


Assuntos
Patologistas/provisão & distribuição , Patologia Clínica/tendências , Escolha da Profissão , Mobilidade Ocupacional , Emprego/estatística & dados numéricos , Humanos , Seleção de Pessoal/estatística & dados numéricos , Inquéritos e Questionários
12.
Endocr Pract ; 26(10): 1131-1142, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33471715

RESUMO

OBJECTIVE: Von Hippel-Lindau (VHL) syndrome is a rare and complex disease. In 1996, we described a 3 generation VHL 2A kindred with 11 mutation carriers. We aim to share our experience regarding the long-term follow-up of this family and the management of all our other VHL patients focusing on frequently encountered neuroendocrine neoplasms: pheochromocytoma/paraganglioma and pancreatic neuroendocrine neoplasms (PNEN). METHODS: All VHL patients in follow-up at our tertiary center from 1980 to 2019 were identified. Clinical, laboratory, imaging, and therapeutic characteristics were retrospectively analyzed. RESULTS: We identified 32 VHL patients in 16 different families, 7/16 were classified as VHL 2 subtype. In the previously described family, the 4 initially asymptomatic carriers developed a neuroendocrine tumor; 7 new children were born, 3 of them being mutation carriers; 2 patients died, 1 due to metastatic PNEN-related liver failure. Pheochromocytoma was frequent (22/32), bilateral (13/22;59%), often diagnosed in early childhood when active screening was timely performed, associated with paraganglioma in 5/22, rarely malignant (1/22), and recurred after surgery in some cases after more than 20 years. PNEN occurred in 8/32 patients (25%), and was metastatic in 3 patients. Surgery and palliative therapy allowed relatively satisfactory outcomes. Severe disabling morbidities due to central-nervous system and ophthalmologic hemangiomas, and other rare tumors as chondrosarcoma in 2 patients and polycythemia in 1 patient were observed. CONCLUSION: A multidisciplinary approach and long-term follow-up is mandatory in VHL patients to manage the multiple debilitating morbidities and delay mortality in these complex patients.


Assuntos
Neoplasias das Glândulas Suprarrenais , Tumores Neuroendócrinos , Neoplasias Pancreáticas , Doença de von Hippel-Lindau , Neoplasias das Glândulas Suprarrenais/epidemiologia , Neoplasias das Glândulas Suprarrenais/terapia , Criança , Pré-Escolar , Humanos , Recidiva Local de Neoplasia , Tumores Neuroendócrinos/epidemiologia , Tumores Neuroendócrinos/terapia , Neoplasias Pancreáticas/epidemiologia , Neoplasias Pancreáticas/terapia , Estudos Retrospectivos , Proteína Supressora de Tumor Von Hippel-Lindau , Doença de von Hippel-Lindau/epidemiologia , Doença de von Hippel-Lindau/genética
13.
Curr Treat Options Oncol ; 20(9): 70, 2019 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-31286272

RESUMO

OPINION STATEMENT: Carcinoid syndrome (CS) is a complex disorder caused by functional neuroendocrine tumors (NETs). This debilitating disease is characterized by hyper-secretion of biologically active substances eliciting major hormonal symptoms burden and fibrotic changes that are often challenging for management. There have been a number of insights that have substantially advanced treatments since the introduction of somatostatin analogs (SSAs). Second-line treatments are needed in a substantial proportion of patients with advanced disease that have uncontrolled hormone secretion on the highest labeled doses of SSAs. International guidelines suggest several available options including dose escalation of SSAs, interferon alpha, everolimus, radionuclide therapy, liver-directed therapies, and the novel tryptophan hydroxylase 1 inhibitor, telotristat ethyl. The clear preference of one second-line therapy over the other is not stated since their relative and long-term efficacy are largely unknown, and standardized approach of hormonal response assessment is lacking in the literature. In the clinical setting, the treatment of CS is guided in conjunction with patients' performance status, tumor origin, grade, stage, and growth rate, with regard to both anti-hormonal, as well as anti-proliferative effect. There is an unmet need for further well-designed randomized placebo-controlled and head-to-head studies that systematically assess CS symptom control and biochemical response following a specific intervention.


Assuntos
Síndrome do Carcinoide Maligno/terapia , Algoritmos , Ensaios Clínicos como Assunto , Terapia Combinada/métodos , Gerenciamento Clínico , Humanos , Síndrome do Carcinoide Maligno/diagnóstico , Síndrome do Carcinoide Maligno/epidemiologia , Síndrome do Carcinoide Maligno/etiologia , Resultado do Tratamento
14.
J Clin Endocrinol Metab ; 104(7): 2637-2647, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-31102458

RESUMO

CONTEXT: Endoscopic ultrasound-guided radiofrequency ablation (EUS-RFA) is rapidly emerging as feasible therapy for patients with pancreatic neuroendocrine tumors (pNETs) in selected cases, as a result of its favorable safety profile. OBJECTIVE: To assess the feasibility, safety, and efficacy of EUS-RFA in a cohort of patients with functional and nonfunctional pNETs (NF-pNETs). DESIGN: Data on pNET patients treated with EUS-RFA between March 2017 and October 2018 at two tertiary centers was retrospectively analyzed. RESULTS: The cohort included 18 adults (eight women, 10 men), aged 60.4 ± 14.4 years (mean ± SD), seven insulinoma patients, and 11 patients with NF-pNETs. Twenty-seven lesions with a mean diameter of 14.3 ± 7.3 mm (range 4.5 to 30) were treated. Technical success defined as typical postablative changes on a surveillance imaging was achieved in 26 out of 27 lesions. Clinical response with normalization of glucose levels was observed in all (seven of seven) insulinoma cases within 24 hours of treatment. Overall, there were no major complications 48 hours postprocedure. No clinically significant recurrences were observed during mean follow-up of 8.7 ± 4.6 months (range 2 to 21 months). CONCLUSIONS: EUS-guided RFA of pNETs is a minimally invasive, safe, and technically feasible procedure for selected patients.


Assuntos
Ablação por Cateter/métodos , Insulinoma/cirurgia , Recidiva Local de Neoplasia/prevenção & controle , Tumores Neuroendócrinos/cirurgia , Neoplasias Pancreáticas/cirurgia , Idoso , Glicemia/análise , Ablação por Cateter/efeitos adversos , Endossonografia , Estudos de Viabilidade , Feminino , Seguimentos , Humanos , Insulinoma/sangue , Insulinoma/diagnóstico por imagem , Insulinoma/patologia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/epidemiologia , Tumores Neuroendócrinos/sangue , Tumores Neuroendócrinos/diagnóstico por imagem , Tumores Neuroendócrinos/patologia , Pâncreas/diagnóstico por imagem , Pâncreas/patologia , Pâncreas/cirurgia , Neoplasias Pancreáticas/sangue , Neoplasias Pancreáticas/diagnóstico por imagem , Neoplasias Pancreáticas/patologia , Estudos Retrospectivos , Resultado do Tratamento , Ultrassonografia de Intervenção
15.
Eur J Endocrinol ; 181(1): 13-21, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31048559

RESUMO

Objective: Multiple clinical, pathological and biochemical variables, including the response to initial treatment, are associated with medullary thyroid carcinoma (MTC) prognosis. Studies that include separate analyses of familial and sporadic MTC patients followed for long period are scarce. This study evaluated the association between baseline clinico-pathologic variables and response to initial treatment and short- and long-term disease outcomes in sporadic and familial MTC. Methods: Patients treated for MTC at four tertiary medical centers were retrospectively analyzed. Clinical and pathological data were collected. The outcomes measured included disease persistence 1 year after diagnosis, disease persistence at last follow-up, disease-related mortality (DRM) and all-cause mortality. Results: The study enrolled 193 patients (mean age: 48.9 ± 18.7, 44.7% males), of whom 18.1% were familial cases. The mean follow-up period was 10.1 ± 9.4 years (8.5 ± 8.1 in sporadic and 16.9 ± 11.6 in familial MTC). Disease persistence 1-year after diagnosis and at last follow-up was detected in 56.1 and 60.4% patients, respectively. All-cause and DRM were 28.5 and 12.6%, respectively. Extra-thyroidal extension (ETE) and distant metastases (DM) were associated with disease persistence at last follow-up. ETE and DM were also significantly associated with DRM. Complete remission 1 year after diagnosis had high correlation with no evidence of disease at last follow-up (Cramer's V measure of association 0.884, P < 0.001) and with 100% disease-specific survival (Cramer's V measure of association 0.38, P < 0.001). Conclusions: Apart from clinico-pathologic parameters, close correlation was found between 1-year status and long-term prognosis. These results underscore the importance of combining classical and dynamic factors for both sporadic and familial MTC prognostication and treatment decision making.


Assuntos
Carcinoma Medular/congênito , Carcinoma Neuroendócrino/terapia , Neoplasia Endócrina Múltipla Tipo 2a/terapia , Esvaziamento Cervical , Radioterapia Adjuvante , Neoplasias da Glândula Tireoide/terapia , Tireoidectomia , Adolescente , Adulto , Idoso , Carcinoma Medular/mortalidade , Carcinoma Medular/patologia , Carcinoma Medular/terapia , Carcinoma Neuroendócrino/mortalidade , Carcinoma Neuroendócrino/patologia , Causas de Morte , Intervalo Livre de Doença , Feminino , Humanos , Israel , Masculino , Pessoa de Meia-Idade , Mortalidade , Neoplasia Endócrina Múltipla Tipo 2a/mortalidade , Neoplasia Endócrina Múltipla Tipo 2a/patologia , Invasividade Neoplásica , Metástase Neoplásica , Prognóstico , Estudos Retrospectivos , Neoplasias da Glândula Tireoide/mortalidade , Neoplasias da Glândula Tireoide/patologia , Carga Tumoral , Adulto Jovem
16.
Endocrine ; 64(3): 690-701, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30635793

RESUMO

PURPOSE: To study the evolution and optimal management of metastatic bone disease (mBD) in patients with neuroendocrine neoplasms (NENs). METHODS: Seventy-four patients were recruited from four NEN centers in this observational multicenter study. RESULTS: Pancreas and small bowel were the most common primaries (30 and 27%, respectively). Almost all gastrointestinal (GI)-NENs were grades 1 and 2, whereas bronchopulmonary-thymic were atypical carcinoids. Thirty-two (43%) patients had synchronous metastatic bone disease (mBD) and three patients reported bone-specific symptoms; metachronous mBD developed at a median of 35 (range: 4-395) months. Thirty-six (86%) of patients with metachronous mBD had stage IV disease at diagnosis. Somatostatin receptor functional imaging and computed tomography were the modalities mostly used for mBD identification. Fifty-two patients received assessable bone-related therapy (bisphosphonates, denosumab, local radiotherapy, and radionuclide treatment). Improvement in mBD was seen in 5, stable disease in 22, and deterioration in 25 patients. The presence of synchronous mBD and the negative outcome of bone-related therapy negatively affected overall survival (OS). In the multivariate analysis, the stronger predictor of OS was the outcome of bone-related therapy (HR: 4.753; 95% CI: 1.589-14.213). Bisphosphonates therapy was the mostly used bone-specific treatment but its monthly administration did not affect OS. At last follow-up, 39 patients were alive with OS 50 (14-463) months. CONCLUSIONS: Early investigation for mBD offers a prognostic marker of patients with NENs, since synchronous mBD has a negative impact on survival. The outcome of bone-related therapy affects OS but the monthly administration of bisphosphonates did not show a benefit over less intense schemes.


Assuntos
Neoplasias Ósseas/terapia , Difosfonatos/uso terapêutico , Neoplasias Intestinais/terapia , Tumores Neuroendócrinos/terapia , Neoplasias Pancreáticas/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Ósseas/diagnóstico por imagem , Neoplasias Ósseas/secundário , Gerenciamento Clínico , Feminino , Humanos , Neoplasias Intestinais/diagnóstico por imagem , Neoplasias Intestinais/patologia , Masculino , Pessoa de Meia-Idade , Tumores Neuroendócrinos/diagnóstico por imagem , Tumores Neuroendócrinos/secundário , Neoplasias Pancreáticas/diagnóstico por imagem , Neoplasias Pancreáticas/patologia , Prognóstico , Tomografia Computadorizada por Raios X , Adulto Jovem
17.
Arch Pathol Lab Med ; 143(5): 610-620, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30398912

RESUMO

CONTEXT.­: As part of its value-based care initiative, the College of American Pathologists has pursued research to better understand the role pathologists can have in population health. OBJECTIVES.­: To answer the following questions: (1) what is the impact of population health and population health management on pathologists; (2) what roles are pathologists playing in population health management; (3) is population health something that pathologists in both larger and smaller settings can engage in; (4) are pathologists in a position to analyze laboratory data for population health, and, if so, what are the key information sources those pathologists must access; and (5) what steps can a pathologist take to become involved in population health? DESIGN.­: We conducted 10 semistructured interviews with pathologists and other medical laboratory leaders who have been active in population health. These interviews were supplemented with a review of the medical literature. RESULTS.­: Pathologists have demonstrated that laboratory data can provide unique value-added contributions to improving the health of populations. These contributions are not limited to pathologists in large, integrated settings. However, pathologists need to be proactive to contribute to health systems' population health efforts and may need to both enhance their own skills and the quality of their data to maximize the value of their contributions. CONCLUSIONS.­: Although not necessarily a definitive summary of the roles that pathologists are playing in population health, this article identifies some of the promising and innovative activities occurring among pathologists and laboratorians.


Assuntos
Patologistas , Patologia Clínica/métodos , Saúde da População , Humanos
18.
Eur J Nucl Med Mol Imaging ; 46(3): 718-727, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30343432

RESUMO

PURPOSE: Rectal neuroendocrine neoplasia (NEN) is more common than other NEN origins, but is less commonly metastatic. However, when present, distant disease carries a particularly poor prognosis. Evidence guiding optimal treatment of such patients is lacking. We assessed PRRT outcomes in patients with somatostatin receptor (SSTR) positive metastatic rectal NEN from two referral centres. METHODS: Patients treated with PRRT were retrospectively reviewed. Morphologic (RECIST 1.1), SSTR imaging responses and toxicity were assessed 3 months post-PRRT. Kaplan-Meier estimate was used to determine progression-free survival (PFS) and overall survival (OS) from start of PRRT. RESULTS: Twenty-seven consecutive patients (M = 20, age 31-81 years) were reviewed. The majority (70%) had ENETs grade 2 disease (19 patients), three had Grade 3, one Grade 1, and four not documented. Overall, 63% (10/16 patients with available FDG PET/CT) had FDG avid disease. Twenty-six patients were treated for disease progression. Most had 177Lu-DOTA-octreotate with median cumulative activity of 30 GBq, median four cycles. 14 patients had radiosensitising chemotherapy (5FU or capecitabine). At 3 months post-PRRT, CT disease control rate (DCR) was 96%: partial response was observed in 70% (19/27) and stable disease in 26%. All but one had partial SSTR imaging response. The median PFS was 29 months. Ten patients died, with median overall survival 81 months with a median follow-up of 67 months. Seventeen patients had further treatments after initial PRRT (10 had further cycles of PRRT). Three patients had grade 3 lymphopenia, without significant renal toxicity, MDS or leukaemia. CONCLUSION: Our results indicate high efficacy and morphologic responses with minimal toxicity and very encouraging survival from PRRT in patients with metastatic rectal NEN despite the adverse prognostic features of this cohort. Further prospective PRRT trials are warranted in this subgroup.


Assuntos
Tumores Neuroendócrinos/patologia , Tumores Neuroendócrinos/radioterapia , Receptores de Somatostatina/metabolismo , Neoplasias Retais/patologia , Neoplasias Retais/radioterapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Tumores Neuroendócrinos/diagnóstico por imagem , Tumores Neuroendócrinos/metabolismo , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Neoplasias Retais/diagnóstico por imagem , Neoplasias Retais/metabolismo , Estudos Retrospectivos , Resultado do Tratamento
19.
EJNMMI Phys ; 5(1): 36, 2018 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-30535780

RESUMO

BACKGROUND: The aim of this study was to evaluate the predictive power of the absorbed dose to kidneys after the first course of treatment with [177Lu]-DOTA-TATE for neuroendocrine tumors (NETs) on the cumulative kidney absorbed dose after 3 or 4 cycles of treatment. Post-treatment scans (PTS) are acquired after each cycle of peptide receptor radionuclide therapy (PRRT) with [177Lu]-DOTA-TATE for personalized radiation dosimetry in order to ensure a cumulative absorbed dose to kidneys under a safety threshold of 25 Gy. One hundred eighty-seven patients who completed treatment with [177Lu]-DOTA-TATE and underwent PTS for dosimetry calculation were included in this retrospective study. The correlation between the cumulative absorbed dose to kidneys after the completion of treatment and the absorbed dose after the first cycle(s) was studied. Multilinear regression analysis was done to predict the cumulative absorbed dose to the kidneys of the subsequent cycles, and an algorithm for the follow up of kidney absorbed dose is proposed. RESULTS: Patients whose absorbed dose to kidneys after the first cycle of treatment is below 5.6 Gy can receive four cycles of treatment with a cumulative dose less than 25 Gy (p < 0.1). For the other patients, the cumulative absorbed dose after 3 or 4 cycles of treatment can be predicted after the second cycle of treatment to allow for an early decision regarding the number of cycles that may be given. CONCLUSIONS: The follow up of kidney absorbed dose after PRRT can be simplified with the algorithm presented in this study, reducing by one-third the number of post-treatment scans and reducing hospitalization time for more than half of the treatment cycles.

20.
Eur Thyroid J ; 7(5): 267-271, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30374431

RESUMO

Background: Multiple endocrine neoplasia (MEN) 2A is an autosomal dominant disorder that results from a mutation in the RET proto-oncogene on chromosome 10. Almost all of the affected patients develop medullary thyroid carcinoma (MTC). The American Thyroid Association recommends prophylactic thyroidectomy in MEN 2A pediatric patients, with the age of the recommended thyroidectomy varying according to the codon mutation present. Objectives: This report questions the reliability of the currently placed guidelines and whether the age threshold for prophylactic thyroidectomy in patients with known codon 634 mutations should be lowered, in parallel with an earlier evaluation of calcitonin levels in the serum. Methods: We report the preoperative diagnosis as well as operative and postoperative course of a 3-year-old female patient with MEN 2A (codon 634 mutation) who underwent prophylactic thyroidectomy. The postoperative histopathologic findings are presented and discussed. Results: Despite the prophylactic nature of the operation, in parallel with a borderline calcitonin increase in the serum, bilateral MTC was discovered on pathology. Conclusion: It is likely that the current guidelines should be revised to recommend calcitonin screening and prophylactic thyroidectomy at an earlier age for MEN 2A patients with known codon 634 mutations.

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