Spatial and temporal expression pattern of somatostatin receptor 2 in mouse / 生物工程学报

Somatostatin (SST) is an inhibitory polypeptide hormone that plays an important role in a variety of biological processes. Somatostatin receptor 2 (SSTR2) is the most widely expressed somatostatin receptor. However, the specific cell types expressing Sstr2 in the tissues have not been investigated. In this study, we detected the expression pattern of SSTR2 protein in mouse at different development stages, including the embryonic 15.5 days and the postnatal 1, 7, 15 days as well as 3 and 6 months, by multicolour immunofluorescence analyses. We found that Sstr2 was expressed in some specific cells types of several tissues, including the neuronal cells and astrocytes in the brain, the mesenchymal cells, the hematopoietic cells, the early hematopoietic stem cells, and the B cells in the bone marrow, the macrophages, the type Ⅱ alveolar epithelial cells, and the airway ciliated cells in the lung, the epithelial cells and the neuronal cells in the intestine, the hair follicle cells, the gastric epithelial cells, the hematopoietic stem cells and the nerve fibre in the spleen, and the tubular epithelial cells in the kidney. This study identified the specific cell types expressing Sstr2 in mouse at different developmental stages, providing new insights into the physiological function of SST and SSTR2 in several cell types.

Eficacia de lutecio-177 DOTATATE/TOC en pacientes con tumores neuroendocrinos bien diferenciados en estado avanzado. Ensayo clínico fase II / Efficacy of Lutetium-177 DOTATATE/TOC in Advanced Neuroendocrine Tumors

Resumen Introducción: En 2009, el Instituto Nacional de Cancerología (INC) elaboró el 177Lu-DOTATATE/TOC. El propósito del estudio fue demostrar la eficacia de estos radiopéptidos en el tratamiento paliativo de pacientes con tumores neuroendocrinos (TNE) avanzados inoperables (metastásicos o localmente avanzados) y en progresión. Métodos: Ensayo clínico abierto fase II de un solo brazo en 13 pacientes adultos con TNE grado 1 o 2, con expresión de receptores de somatostatina en lesiones blanco demostrada por captación Krenning 3 o 4 en 99mTc-HYNIC TOC. Los pacientes fueron tratados con 177Lu-DOTATATE o 177Lu-DOTATOC (según disponibilidad) a una actividad acumulativa proyectada de 600-800 mCi dividida en 3-4 dosis cada 6-9 semanas comenzando siempre con una actividad fija de 200 mCi y dosimetría con la primera dosis. El desenlace primario fue la respuesta objetiva calculada 6 y 12 meses después de la última dosis del tratamiento. Resultados: Se incluyeron 13 pacientes (7 mujeres) de 63 ± 11,6 años con TNE avanzado inoperable y en progresión. La actividad final administrada fue de 800 mCi, 600 mCi, 400 mCi y 200 mCi en 4, 7, 1 y 1 pacientes, respectivamente. La tasa de control de enfermedad a 6 y 12 meses fue de 69,2% y 45,5%, respectivamente, logrando únicamente enfermedad estable. Fallecieron 7 pacientes, 2 de ellos en los primeros 6 meses. La mediana de supervivencia global a partir de la última dosis del radiopéptido fue de 15,7 meses. Conclusiones: Se corroboró la eficacia y la seguridad del tratamiento con los radiopéptidos en NETs avanzados.

Abstract Objectives: The National Cancer Institute first elaborated 177Lu-DOTATATE/TOC in 2009. The purpose of this study was to prove the efficacy of these radiopeptides in the palliative treatment of patients with progressive advanced inoperable neuroendocrine tumors (NETs). Methods: A single-phase phase II open clinical trial was conducted in 13 adult patients with grade 1 y 2 NETs, with expression of somatostatin receptors in target lesions proven by Krenning Score 3 or 4 uptake in 99mTc-HYNIC TOC. Patients were treated with 177Lu-DOTATATE or 177Lu-DOTATOC (depending upon availability) at a projected acumulative activitiy of 600-800 mCi divided into 3-4 doses every 6-9 weeks always beginning with a fixed activity of 200 mCi and dosimetry during the first dose. The primary outcome was objective response to therapy. Results: 13 patients (7 women) aged 63 ± 11.6 years with inoperable advanced NETs were included. The final therapeutic administered activity was 800 mCi, 600 mCi, 400 mCi and 200 mCi in 4, 7, 1 and 1 patients, respectively. The disease control rate at 6 and 12 months was 69.2% and 45.5%, respectively, only obtaining stable disease. Six patients died, 2 of them in the first 6 months. Median overall survival was 15.7 months from the last treatment dose. Conclusions: The efficacy of the treatment with 177Lu-DOTATATE or 177Lu-DOTATOC radiopeptides elaborated in-house was confirmed, becoming a management alternative for patients with advanced NETs.

Therapeutic Effect of a Novel Chimeric Molecule Targeting Both Somatostatin and Dopamine Receptors on Growth Hormone-Secreting Pituitary Adenomas

BACKGROUND: Acromegaly is a rare disease primarily caused by growth hormone (GH)-secreting pituitary adenomas, and its treatment is costly. Moreover, some patients are unresponsive to treatment. Hence, there are increasing efforts to develop new drugs with improved effectiveness for this disease. BIM23B065 is a novel chimeric molecule that acts on both somatostatin and dopamine receptors. This study aimed to investigate the effects of BIM23B065 compared with those of a somatostatin receptor analog and a dopamine agonist.METHODS: The effects of BIM23B065 on the proliferation, GH and insulin-like growth factor-1 (IGF-1) levels, and extracellular signal-regulated kinase (ERK) 1/2 and cyclic AMP response element binding (CREB) phosphorylation of GH3 cells were investigated with MTS assay, enzyme-linked immunosorbent assay, and Western blotting, respectively. The dosage and treatment duration of BIM23B065 were tested in animal models of GH-secreting pituitary adenoma. The effect of BIM23B065 (3 mg/kg/day) on changes in IGF-1 levels before and after treatment was further investigated.RESULTS: In vitro, BIM23B065 treatment decreased GH release in the culture media and downregulated ERK 1/2 and CREB phosphorylation to 22% and 26%, respectively. In vivo, IGF-1 expression decreased to 50 % after 4 weeks of treatment with BIM23B065 using an osmotic pump implant. Moreover, magnetic resonance imaging results showed that the tumor size decreased significantly following treatment with BIM23B065 for 4 weeks.CONCLUSION: The novel chimeric molecule was effective in decreasing IGF-1 and GH levels and may serve as an effective therapeutic agent for acromegaly.

The position of combined medical treatment in acromegaly

ABSTRACT Advances in combination medical treatment have offer new perspectives for acromegaly patients with persistent disease activity despite receiving the available medical monotherapies. The outcomes of combination medical treatment may reflect both additive and synergistic effects. This review focuses on combination medical treatment and its current position in acromegaly, based on clinical studies evaluating the efficacy and safety of combined medical treatment(s) and our own experiences with combination therapy. Arch Endocrinol Metab. 2019;63(6):646-52

Brazilian multicenter study on pegvisomant treatment in acromegaly

ABSTRACT Objective Investigate the therapeutic response of acromegaly patients to pegvisomant (PEGV) in a real-life, Brazilian multicenter study. Subjects and methods Characteristics of acromegaly patients treated with PEGV were reviewed at diagnosis, just before and during treatment. All patients with at least two IGF-I measurements on PEGV were included. Efficacy was defined as any normal IGF-I measurement during treatment. Safety data were reviewed. Predictors of response were determined by comparing controlled versus uncontrolled patients. Results 109 patients [61 women; median age at diagnosis 34 years; 95.3% macroadenomas] from 10 Brazilian centers were studied. Previous treatment included surgery (89%), radiotherapy (34%), somatostatin receptor ligands (99%), and cabergoline (67%). Before PEGV, median levels of GH, IGF-I and IGF-I % of upper limit of normal were 4.3 µg/L, 613 ng/mL, and 209%, respectively. Pre-diabetes/diabetes was present in 48.6% and tumor remnant in 71% of patients. Initial dose was 10 mg/day in all except 4 cases, maximum dose was 30 mg/day, and median exposure time was 30.5 months. PEGV was used as monotherapy in 11% of cases. Normal IGF-I levels was obtained in 74.1% of patients. Glycemic control improved in 56.6% of patients with pre-diabetes/diabetes. Exposure time, pre-treatment GH and IGF-I levels were predictors of response. Tumor enlargement occurred in 6.5% and elevation of liver enzymes in 9.2%. PEGV was discontinued in 6 patients and 3 deaths unrelated to the drug were reported. Conclusions In a real-life scenario, PEGV is a highly effective and safe treatment for acromegaly patients not controlled with other therapies.

Orbital IgG4 Disease: Imaging Findings on 68Ga-DOTANOC PET/CT / 대한핵의학회잡지

Immunoglobulin G4 (IgG4)–related diseases are a spectrum of systemic inflammatory conditions of unknown etiology, which are characterized by infiltration of tissues by IgG4 plasma cells and sclerosing inflammation (Cheuk and Chan Adv Anat Pathol 17:303-32, 2010). Although this condition was initially described in relation to autoimmune pancreatitis, now it has been reported in almost every organ system of body (Zen and Nakanuma Am J Surg Pathol 34:1812-9, 2010, Masaki et al. Ann Rheuma Dis 68:1310-5, 2009). Orbital involvement by IgG4 disease can involve extraocular muscles (EOM), lacrimal glands, conjunctiva, eyelids, infraorbital nerve, orbital fat, and nasolacrimal system (McNab and McKelvie. Ophthal Plast Reconstr Surg 31:167-78, 2015, Katsura et al. Neuroradiology 54:873-82, 2012). The basis of using ⁶⁸Ga-DOTANOC PET/CT in IgG4 orbital disease is the known expression of somatostatin receptors in chronic inflammatory cells (Cuccurullo et al. Indian J Radiol Imaging 27:509-16, 2017) and also avidity shown previously in other IgG4-related diseases (Cheng et al. Clin Nucl Med 43:773-6, 2018).

Perspectives in Radiomics for Personalized Medicine and Theranostics / 대한핵의학회잡지

Radiomics handles imaging biomarker from high-throughput feature extraction through complex pattern recognition that is difficult for human to process. Recent medical paradigms are rapidly changing to personalized medicine, including molecular targeted therapy, immunotherapy, and theranostics, and the importance of biomarkers for these is growing day by day. Even though biopsy continues to gold standard for tumor assessment in personalized medicine, imaging is expected to complement biopsy because it allows whole tumor evaluation, whole body evaluation, and non-invasive and repetitive evaluation. Radiomics is known as a useful method to get imaging biomarkers related to intratumor heterogeneity in molecular targeted therapy as well as one-size-fits-all therapy. It is also expected to be useful in new paradigms such as immunotherapy and somatostatin receptor (SSTR) or prostate-specific membrane antigen (PSMA)-targeted theranostics. Radiomics research should move to multimodality (CT, MR, PET, etc.), multicenter, and prospective studies from current single modality, single institution, and retrospective studies. Image-quality harmonization, intertumor heterogeneity, and integrative analysis of information from different scales are thought to be important keywords in future radiomics research. It is clear that radiomics will play an important role in personalized medicine.

Lu-177-Based Peptide Receptor Radionuclide Therapy for Advanced Neuroendocrine Tumors / 대한핵의학회잡지

Peptide receptor radionuclide therapy (PRRT) is a systemic cytotoxic radiation therapy using a compound of β-emitting radionuclide chelated to a peptide for the treatment of tumor with overexpressed specific cell receptor such as somatostatin receptor subtype 2 (SSTR2) of neuroendocrine tumor (NET). Surgical resection should be performed for the curative treatment for NETs when it is feasible; however, a multi-disciplinary approach is needed when locally advanced or metastasized disease. PRRT with lutetium-177 (Lu-177)-labeled somatostatin analogues, as a new treatment modality targeting metastatic or inoperable NETs expressing the SSTR2, have been developed and successfully used for the past two decades. As Lu-177 emits both β- and γ-radiation, it has the ability as a theragnostic agent for NETs compared with only β-emitting yttrium-90 labeled PRRT. Several recent studies reported that Lu-177 gave an overall positive response and improved the patients' quality of life. To fully exploit its potential, large comparative studies are needed for the assessment of distinct efficacies of Lu-177 labeled PRRT. Additionally, for extending the indications and developing new regimens of Lu-177-based PRRT, more dedicated clinical research is required.

Incidental Detection of Parathyroid Adenoma on Somatostatin Receptor PET/CT and Incremental Role of ¹⁸F-Fluorocholine PET/CT in MEN1 Syndrome / 대한핵의학회잡지

Multiple endocrine neoplasia type 1 (MEN1) syndrome is characterized by combined occurrence of tumors of endocrine glands including the parathyroid, the pancreatic islet cells, and the anterior pituitary gland. Parathyroid involvement is the most common manifestation and usually the first clinical involvement inMEN1 syndrome, followed by gastroentero-pancreatic neuroendocrine tumors (NETs). Here we present a case where the patient initially presented with metastatic gastric NET and a single parathyroid adenoma was detected incidentally on ⁶⁸Ga-DOTANOC PET/CT done as part of post ¹⁷⁷Lu-DOTATATE therapy (PRRT) follow-up. Further ¹⁸F-fluorocholine PET/CT showed four adenomas for which the patient subsequently underwent subtotal parathyroidectomy.

Patologías benignas y variantes que captan 68Ga-DOTATATE en PET/TC / Benign Pathology And Variants With Uptake In 68ga-Dotatate Pet/Ct Studies

Objetivos: Valorar las variantes fisiológicas, anatómicas y lesiones benignas en estudios por tomografía computada por emisión de positrones (PET/TC) con Galio 68 (68Ga)-DOTATATE. Materiales y métodos: Se revisaron en forma retrospectiva los informes de PET/TC con 68Ga-DOTATATE y se seleccionaron aquellos en los cuales se mencionaran palabras en el reporte relacionadas a variantes anatómicas, fisiológicas y tumores benignos. El grado de captación del 68Ga-DOTATATE fue evaluado de forma cualitativa y cuantitativa mediante la medición del valor estandarizado de captación máximo (SUVmax). Se consignó la localización del hallazgo, el valor de SUVmax y la imagen morfológica por tomografía computada (TC). Todos los casos fueron controlados mediante evolución clínica y hallazgos imagenológicos. Resultados: De un total de 772 informes de PET/TC se obtuvo un total de 28 pacientes con 33 variantes o tumores benignos, 14 mujeres y 14 hombres con edad promedio de 63 años. Las captaciones se clasificaron en cuatro grupos: variantes anatómicas y/o fisiológicas (n = 15), dependientes de la actividad osteoblástica (n=4), dependientes de actividad inflamatoria (n = 10) y tumores benignos no neuro-endócrinos (n = 4). Discusión: Los receptores de somatostatina se localizan no sólo en el sistema neuroendócrino sino también en otros tejidos. Las variantes fisiológicas, anatómicas y tumores benignos que expresan estos receptores pueden inducir a un error diagnóstico. Conclusión: Las variantes fisiológicas y lesiones benignas (tumorales e inflamatorias) pueden captar 68Ga-DOTATATE ya que sus tejidos pueden expresar receptores de somatostatina. El análisis semiológico del componente tomográfico de este método de imágenes híbrido, permite la orientación diagnóstica, optimizando el rendimiento del estudio PET/TC.

Purpose: To evaluate the physiological, anatomical variants and benign lesions in positrón emission computed tomography (PET/CT) studies with 68Ga-DOTATATE. Materials and methods: We retrospectively reviewed PET/CT reports scanned with 68Ga-DOTATATE and selected those that contained words in the report related to anatomical, physiological variants and benign tumors. The degree of 68Ga-DOTATATE uptake was evaluated qualitatively and quantitatively by measuring the standarized uptake max value (SUVmax value). The anatomical location, SUVmax value and morphological CT image findings were recorded. All cases had clinical and imaging follow-up. Results: From a total of 772 PET/CT reports, 28 patients were obtained with 33 benign variants or tumors, 14 females and 14 males with a median age of 63 years. Uptake patterns were classified into four groups: anatomic and physiological variants (15), dependent on osteoblastic activity (4), dependent on inflammatory activity (10) and non-neuro-endocrine benign tumors (4). Discussion: Somatostatin receptors are overexpressed not only in the neuroendocrine system but also in other tissues. Physiological, anatomical variants and benign tumors expressing these receptors may be misleading. In the present work the frequency of this finding is 5.1%. Conclusion: Physiological variants and benign lesions (tumor and inflammatory) can accumulate 68Ga-DOTATATE since their tissues can express somatostatin receptors. The semiologic analysis of the tomographic component of this hybrid method enhances the diagnostic efficacy, optimizing PET/CT study performance.

Treatment of acromegaly patients at the Federal University of Triângulo Mineiro (UFTM): Experience Report

OBJECTIVE: To evaluate the effectiveness of the treatment of acromegaly patients at the Federal University of Triangulo Mineiro. METHODS: Cross-sectional and retrospective study of thirty cases treated over a period of two decades. RESULTS: 17 men (56.7%) aged 14-67 years and 13 women aged 14-86 years were analyzed. Twenty-one patients underwent transphenoidal surgery, whichwas associated with somatostatin receptor ligands in 11 patients (39.3%), somatostatin receptor ligands + radiotherapyin 5 patients (17.8%), radiotherapy in 3 patients (10.7%), and radiotherapy + somatostatin receptorligands + cabergoline in 1 patient (3.6%). Additionally, 2 patients underwent radiotherapy and surgeryalone. Six patients received somatostatin receptor ligands before surgery, and 2 were not treated due to refusal and death. Nine patients have died, and 20 are being followed; 13 (65%) have growth hormonelevels o1 ng/mL, and 11 have normal insulin-like growth factor 1 levels. CONCLUSION: The current treatment options enable patients seen in regional reference centers to achieve strict control parameters, which allows them to be treated close to their homes.

Terapia con [ 177 Lu - Dota0 - Tyr 3 ]-Octreotate ( 177 Lu-Dotatate) en pacientes con tumores avanzados de origen neuroendocrino: experiencia inicial y resultados preliminares / Therapy with [ 177 Lu - Dota0 - Tyr 3 ]-Octreotate ( 177 Lu-Dotatate) in Patients with Advanced Neuroendocrine Tumors: Initial Experience and Preliminary Results / Terapia com [ 177 Lu - Dota0 - Tyr 3 ]-Octreotate ( 177 Lu-Dotatate) em Pacientes com Tumores Avançados de Origem Neuroendócrino: Experiência Inicial e Resultados Preliminares

Resumen Objetivo: Mostrar la experiencia inicial y los resultados preliminares de la terapia con [177Lu -Dota0 - Tyr3] - Octreotate (177Lu-Dotatate) en pacientes tratados en la Fundación Cardioinfantil - Instituto de Cardiología (FCI-IC) debido a que la experiencia derivada de esta práctica en países latinoamericanos es poco conocida. Materiales y métodos: Se realizó un análisis descriptivo y retrospectivo en pacientes a los que se les realizó terapia con 177Lu-Dotatate con al menos una dosis y un año de seguimiento. Se incluyeron 8 pacientes (4 mujeres y 4 hombres) de edad media: 57 años (50-63). Se administraron 24 dosis en total, 3 dosis en promedio por paciente, 187 GBq totales y 23,5 GBq dosis/paciente. Se valoró la respuesta al tratamiento y la presencia de efectos adversos. Resultados: El tiempo medio de seguimiento fue de 46 meses (26-72 meses). 5/8 pacientes tenían diagnóstico de tumores neuroendocrinos (TNE) de origen pancreático, 2/8 de origen gástrico y 1/8 de yeyuno. 7/8 pacientes tenían compromiso metastásico; 1/8, a pesar de no tener afectación metastásica, fue considerado irresecable. 7/8 pacientes presentaron síntomas posterapia leves y 1/8 eventos adversos serios. 2/8 pacientes tuvieron respuesta parcial, 4/8 enfermedad estable y 2/8 respuesta completa. Sin embargo, al final del seguimiento un paciente que tuvo respuesta completa presentó recaída y otro, respuesta parcial con posterior progresión y muerte. Conclusiones: En la institución, la terapia con 177Lu-Dotatate ha sido segura y eficaz en pacientes con TNE como alternativa terapéutica con adecuados niveles de respuesta y control de la enfermedad con eventos adversos leves, esperables y eventos serios mínimos autolimitados.

Abstract Objective: To Show the initial experience and preliminary results of therapy with [177Lu -Dota0 - Tyr3] - Octreotate (177 Lu-Dotatate) in patients with neuroendocrine tumors (NET) treated in our institution, because the experience gained from this practice in Latin American countries is poorly known. Materials and methods: A descriptive and retrospective analysis in patients who have undergone therapy with 177 Lu-Dotatate with at least one dose and at least one year of follow-up was performed. 8 patients (4 women and 4 men) with a mean age of 57 years (50-63) were included. A total of 24 doses were given, an average of 3 doses per patient. A total of 187 GBq were administered, equivalent to 23.5 GBq / patient. Response to therapy and the presence of adverse short and long term effects were assessed. Results: The average follow-up time was 46 months (26-72 months). 5/8 patients were diagnosed with pancreatic net, 2/8 of gastric origin and 1/8 of small bowel origin. 7/8 patients had metastatic involvement and 1/8 patient despite not having metastasis was considered unresectable. 6/8 patients had mild post-therapy symptoms and 1/8 serious adverse events. 2/8 patients had partial response, 4/8 stable disease and 2/8 had a complete response. At the end of follow-up, however, one patient who had a complete response presented with recurrence and one with partial response showed progression and death. Conclusions: In our experience, therapy with 177 Lu-Dotatate was safe and effective in patients with net as an alternative therapy with appropriate levels of response and disease control and with mild expected adverse events and self-limiting minimum serious events.

Resumo Objetivo: Mostrar a experiência inicial e os resultados preliminares da terapia com [177Lu - Dota0 - Tyr3] -Octreotate (177Lu-Dotatate) em pacientes tratados na nossa instituição, devido a que a experiência derivada desta prática em países latino-americanos é pouco conhecida. Materiais e métodos: Se realizou uma análise descritiva e retrospectiva em pacientes aos que se lhes tem realizado terapia com 177Lu-Dotatate com ao menos uma dose e ao menos um ano de seguimento. Incluíram-se 8 pacientes, idade média de 57 anos (50-63). Administraram-se: 24 doses em total, 3 doses em média por paciente, 187 GBq totais administrados e 23.5 GBq doses/paciente. Valorou-se a resposta ao tratamento e a presença de efeitos adversos. Resultados: O tempo médio de seguimento foi de 45 meses (26-72 meses). 5/8 tinham diagnóstico de TNE de origem pancreática, 2/8 de origem gástrica e 1/8 de jejuno. 7/8 pacientes tinham compromisso metastático e 1/8 paciente apesar de não ter afetação metastática foi considerado irressecável. 6/8 pacientes apresentaram sintomas pós-terapia leves e 1/8 eventos adversos sérios. 2/8 pacientes tiveram resposta parcial, 4/4 doença estável e 2/8 resposta completa. No entanto, no final do seguimento um paciente que teve resposta completa apresentou recaída e outro resposta parcial com posterior progressão e morte. Conclusões: no nosso meio a terapia com 177Lu-Dotatate tem sido segura e eficaz em pacientes com TNE como alternativa terapêutica com adequados níveis de resposta e controle da doença com eventos adversos leves esperáveis e eventos sérios mínimos autolimitados.

Short-term Preoperative Octreotide for Thyrotropin-secreting Pituitary Adenoma / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Thyrotropin-secreting pituitary adenomas (TSHomas) are a rare cause of hyperthyroidism. Somatostatin (SST) analogs work by interacting with somatostatin receptors (SSTRs). This study aimed to evaluate short-term preoperative octreotide (OCT) use in TSHoma patients and to investigate SSTR2 and SSTR5 expression and observe structural changes in tumor tissue.</p><p><b>METHODS</b>We reviewed records and samples from eight TSHoma patients treated between July 2012 and July 2015. We tested immunohistochemically for SSTR2/5 expression and examined TSHoma cells for morphological changes. Signed rank sum test was used to compare the efficacy of short-term preoperative OCT treatment.</p><p><b>RESULTS</b>OCT treatment (median time: 7.9 days, range: 3-16 days; median total dose: 1.8 mg, range: 0.9-4.2 mg) led to significant decrease in all patients' thyroid hormone levels (FT3 [nmol/L]: 8.33 [7.02, 12.29] to 4.67 [3.52, 5.37] [P = 0.008]; FT4 [pmol/L]: 25.36 [21.34, 28.99] to 16.66 [14.88, 21.49] [P = 0.016]; and TSH [μU/ml]: 5.80 [4.37, 6.78] to 0.57 [0.19, 1.24] [P = 0.008]). All the eight tumor specimens expressed high SSTR2 protein levels; 5/8 expressed high SSTR5, but 3/8 that expressed low SSTR5 presented a significantly higher TSH suppression rate (P = 0.036). Electron microscopy showed subcellular level impairments, including clumped nuclear chromatin and reduced cytoplasmic volume. Golgi complexes were observed in the OCT-treated TSHoma specimens.</p><p><b>CONCLUSIONS</b>OCT can control hormone levels and damage the ultrastructure of tumor cells and organelles. Short-term response to OCT may be related to SSTR5 expression. Preoperative SST analog treatment for TSHoma could be considered as a combination therapy.</p>

Diagnosis of Pancreatic Neuroendocrine Tumors

Pancreatic neuroendocrine tumors (PNETs) are relatively rare; however, the incidence has increased over the last few decades. They are classified as functional or non-functional tumors according to the presence of associated clinical symptoms. The majority are non-functional tumors. For classification and staging, the World Health Organization 2010 classification system is the most commonly accepted. Chromogranin A is the most sensitive marker but has insufficient specificity. In general, PNETs are hypervascular tumors, and multiphasic contrast-enhanced computed tomography is considered the first choice for imaging study. Multiphasic magnetic resonance imaging can detect PNETs smaller than 2 cm and small liver metastasis compared with other modalities. Somatostatin receptor scintigraphy is often used in cases where functional PNETs are suspected. Positron emission tomography (PET) scan with 18F-fluorodeoxyglucose cannot visualize PNETs, but PET with 68-Ga DOTATATE can. Endoscopic ultrasonography can characterize smaller PNETs using contrast and confirm histology through fine needle aspiration or biopsy. In this article, we review the characteristics of grading systems and diagnostic modalities commonly used for PNETs.

Uso del análogo de somatostatina 99m TC-HYNIC-TYR-3-Octreotida 20 µg en gammagrafias de receptores de somatostatina para la detección de tumores neuroendocrinos / Use of the somatostatin 99m TC-HYNIC-TYR-3-Octreotide analogue 20 µg in somatostatin receptor scans for the detection of neuroendocrine tumors

INTRODUCCIÓN: Antecedentes: El presente dictamen expone la evaluación de tecnología del uso del análogo de somatostatina 99m TC-HYNIC-TYR-3-Octreotida (99mTc-HYNIC-TOC) em gammagrafias de receptores de somatostatina para la detección de tumores neuroendocrinos.Aspectos Generales: Los tumores neuroendocrinos (TNE) surgen a partir de células neurales, las cuales pueden diferenciarse de cualquier otro tipo de célula, llegando así a distribuirse en todo el cuerpo. Este tipo de neoplasias es poco común ya que constituyen menos del 5% de todos los carcinomas de sitio primario desconocido. Este grupo de neoplasias es considerablemente heterogéneo, ya que incluye varios sub-tipos, los cuales difieren en sintomatologia, apariencia histológica y respuesta a tratamiento. Los subtipos incluyen, por ejemplo, los TNE bien diferenciados del tracto gastrointestinal, pancreáticos, tumores medulares de la tiroides y cáncer de pulmón de células pequeñas. Tecnología Sanitaria de Interés: El Tecnecio-99m es un isótopo radioactivo que posee menor energia de radiación que In-11, el cual al unirse con un análogo de somatostaina (i.e.: Octreotida) constituye un radiofármaco que es adminitrado vía intravenosa para la realización de pruebas por imágenes diagnósticas tales como PET, SPECT, RMN entre otras. METODOLOGÍA: Estratégia de Búsqueda: Se realizó una estratégia de búsqueda sistemática de la evidencia científica con respecto al uso del análogo de somatostatina 99mTC-HYNIC-TYR-3-Octreotida (99mTC-HYNIC-TOC) en gammagrafías de receptores de somatostatina para la detección de tumores neuroendocrinos. Para la búsqueda primaria se revisó la información disponible por entes reguladoras y normativas como la Food and Drug Administration (FDA), y la Dirección General de Medicamentos y Drogas (DIGEMID). Posteriormente se buscaron Guías de Práctica Clínica a través de los metabuscadores: Translating Research into Practice (TRIPDATABASE)< National Library of Medicine (Pubmed-Medline), The National Guideline of Clearinghouse, y Helath Systems Evidence. Finalmente, se realizo una búsqueda dentro de la información generada por grupos internacionales que realizan revisiones sistemáticas, evaluación de tecnologías sanitarias y guías de práctica clínica, tales como The Cochrane Library, The National Institute for Health and Care Excellence (NICE), The Canadian Agency for Drugs and Technologies en Health (CADTH), The Scottish Medicines Consortium (SMC), que a su vez fue complementada con una búsqueda em www.clinicaltrials.gov, para indentificar estudios primarios en elaboración o que no hayan sido publicados aún. Se realizó además una búsqueda manual con una estrategia de "bola de nieve" mediante revisión de listas de referencias de las guías, evaluaciones de tecnologías, estudios primarios y revisiones narrativas seleccionados. RESULTADOS: Tras la búsqueda se encontró evidencia científica acerca del uso del análogo de somatostatina 99mTC-HYNIC-TOC en gammagrafias de receptores de somatostatina para la detección de tumores neuroendocrinos. Sinopsis de la Evidencis: A continuación, se detalla la evidencia científica encontrada acerca del uso del análogo de somatostatina 99mTC-HYNIC-TOC en gammagrafias de receptores de somatostatina para la detección de tumores neuroendocrinos. No se encontraron Guías de Práctica Clínica (GPC), Evaluaciones de Tecnología Sanitarias (ETS), Revisiones Sistemáticas que respondan a la pregunta PICO de interés. CONCLUSIONES: La presente evaluación de tecnología sanitaria presenta la evidencia científica encontrada acerca del uso de análogo de somatostatina 99mTC-HYNIC-TYR-3-Octreotida (99mTC-HYNIC-TOC) en gammagrafías de receptores de somatostatina para la detección de tumores neuroendocrinos (TNE). El 99mTC-HYNIC-TYR-3-Octreotida es la única alternativa disponible en el mercado peruano para la realización de gammagrafías de tumores neuroendocrinos. A diferencia de otro tipo de células oncológicas, las neuroendocrinas, carecen de alta actividad metabólica y expresan en su lugar, receptores de somatostaina, siendo necesario el uso de radiofármacos análogos de somatostatina com el 99mTC-HYNIC-TYR-3-Octreotida para la oportuna detección de TNE. El Instituto de Evaluación de Tecnologías en Salud e Investigación-IETSI, aprueba el uso del análogo de somatostatina 99mTC-HYNIC-TYR-3-Octreotida en gammagrafias de receptores de somatostatina para la detección de tumores neuroendocrinos. El presente Dictamen Preliminar tiene una vigencia de dos años a partir de la fecha de publicación.

Interpretation of the latest guidelines in the treatment of gastrointestinal neuroendocrine neoplasms / 中华胃肠外科杂志

Neuroendocrine neoplasms(NEN) is a rare group of tumors with gastrointestinal tract as one of the most common primary locations. The most commonly used guidelines are proposed by European Neuroendocrine Tumor Society (ENETS) and National Comprehensive Cancer Network(NCCN) respectively, while the management of gastrointestinal NEN is generally identical in these two guidelines. Surgery is still the sole curative method which should be considered as the first choice of locoregional NEN. Otherwise, 40% to 50% of patients manifests metastatic disease when diagnosed. Hence, somatostatin analogs, targeted drugs, chemotherapy, and peptide receptor radionuclide therapy should be used comprehensively, especially for unresectable lesions. Therapeutic decision making should be based on the tumor location, functional status, tumor grade, tumor stage, somatostatin receptor status and adverse effect of drugs, etc.

Preclinical studies of [68]Ga-DOTATOC: biodistribution assessment in Syrian rats and evaluation of absorbed dose in human organs

Objective[s]: Gallium-68 DOTA-DPhe[1]-Tyr[3]-Octreotide [[68]Ga-DOTATOC] has been applied by several European centers for the treatment of a variety of human malignancies. Nevertheless, definitive dosimetric data are yet unavailable. According to the Society of Nuclear Medicine and Molecular Imaging, researchers are investigating the safety and efficacy of this radiotracer to meet Food and Drug Administration requirements. The aim of this study was to introduce the optimized procedure for [68]Ga-DOTATOC preparation, using a novel germanium-68 [[68]Ge]/[68]Ga generator in Iran and evaluate the absorbed doses in numerous organs with high accuracy

Methods: The optimized conditions for preparing the radiolabeled complex were determined via several experiments by changing the ligand concentration, pH, temperature and incubation time. Radiochemical purity of the complex was assessed, using high-performance liquid chromatography and instant thin-layer chromatography. The absorbed dose of human organs was evaluated, based on biodistribution studies on Syrian rats via Radiation Absorbed Dose Assessment Resource Method

Results: [68]Ga-DOTATOC was prepared with radiochemical purity of >98% and specific activity of 39.6 MBq/nmol. The complex demonstrated great stability at room temperature and in human serum at 37[degree]C at least two hours after preparation. Significant uptake was observed in somatostatin receptor-positive tissues such as pancreatic and adrenal tissues [12.83%ID/g and 0.91%ID/g, respectively]. Dose estimations in human organs showed that the pancreas, kidneys and adrenal glands received the maximum absorbed doses [0.105, 0.074 and 0.010 mGy/MBq, respectively]. Also, the effective absorbed dose was estimated at 0.026 mSv/MBq for [68]Ga-DOTATOC

Conclusion: The obtained results showed that [68]Ga-DOTATOC can be considered as an effective agent for clinical PET imaging in Iran

Prognostic Value of Soluble ST2 During Hospitalization for ST-Segment Elevation Myocardial Infarction

BACKGROUND: Studying the role of soluble ST2 (sST2) during hospitalization for myocardial infarction (MI) can be helpful for predicting the course of the hospitalization and development of complications. METHODS: We included 88 patients with MI (median age, 58 yr). Depending on the course of the hospitalization, the patients were divided into two groups: the favorable (n=58) and unfavorable (n=30) outcome groups. On days 1 and 12 after MI, serum sST2 and N-terminal pro-brain natriuretic peptide (NT-proBNP) were measured by ELISA. RESULTS: On day 1, the concentrations of sST2 and NT-proBNP increased 2.4- and 4.5-fold, compared with the controls. Measurements on day 12 showed a significant decrease in the sST2 level (P=0.001), whereas the NT-proBNP level did not change. On day 1, the sST2 level in the unfavorable outcome group was 2-fold higher than that in the favorable outcome group and 3.7-fold higher than in the controls. On day 12, the marker level decreased in both groups. On day 1, the NT-proBNP level in the unfavorable outcome group was 6.8-fold higher than in the controls and 1.8-fold higher than in the favorable outcome group. On day 12, the level of NT-proBNP remained elevated in both groups. Determining the levels of both sST2 and NT-proBNP increases their diagnostic significance (odds ratio [OR], 1.92; 95% confidence interval [CI], 1.7-3.2; areas under curve [AUC] 0.89; P=0.004). CONCLUSIONS: The level of sST2 is a more sensitive indicator during MI hospitalization than NT-proBNP.

Inhibitory effect of octreotide on the cross excitation of adjacent segment of spinal nerve in rat / 生理学报

This study was to observe the effect and possible mechanism of somatostatin analogue octreotide (OCT) on cross excitation of adjacent segment of spinal nerve in rat. Cutaneous branches of T9-T13 spinal dorsal rami were chosen and dissected free for the following recording and stimulation. Only single unit fiber was used for recording, and the adjacent segment of nerve stem was used for antidromic electrical stimulation. To investigate the change of discharge rate and mechanical threshold, OCT and (or) somatostatin receptor antagonist cyclo-somatostatin (c-SOM) were applied to the receptive field following the antidromic electrical stimulation. The result showed that injection of OCT inhibited the increase of discharge rate and the decrease of mechanical threshold induced by the electrical stimulation (cross excitation); c-SOM reversed the effects of OCT. Application of c-SOM alone enhanced the cross excitation effects. The results suggest local application of somatostatin analogue OCT can inhibit the cross excitation between the two segments of spinal nerve by somatostatin receptor.

Neuroendocrine Tumors / 대한내과학회지

Neuroendocrine tumors (NETs) are rare. However, several data showed the incidence is increased in the past 30 years. NETs can be both functional and non-functional, and may be undetected for years without obvious signs or symptoms. NET are classified as G1 (carcinoid), G2, G3 (large cell or small cell type), mixed adenoneuroendocrine carcinoma (MANEC), hyperplastic and preneoplastic lesions according to WHO classification 2010. NETs are often advanced at the time of diagnosis and is a progressive disease. Outcomes in patients with locally inoperable or metastatic NETs are poor, survival is also associated with tumor grade. Diagnosing NETs is the systematic approach. History taking and physical examiantion are essential and biochemical markers are useful. Imaging studies, somatostatin-receptor scintigraphy (Octreoscan(TM)), CT scan, MRI and/or PET scan can be used. Somatostatin receptor analogues showed symptomatic, biochemical and disease control. Targeted agents such as everolimus and sunitinib also showed benefit for advanced pancreatic NETs. Other treatments including peptide receptor radionuclide therapy (PRRT), hepatic regional therapy for liver metastases (arterial embolization, chemoembolization), or ablative therapy can be used. Chemotherapy, such as streptozotocin, 5-fluorouracil, doxorubicin, dacarbazin, etoposide, cisplatin, temozolomide, capecitabine is another option for the treatment of NETs. In conclusion, NETs are no longer rare disease. If we raise the index of suspicion for NETs, we can detect these tumors as earlier as possible. Local treatment is unique option for cure in earlier stage. The treatment for patients with advanced NETs, symptom and disease control is important with multidisciplinary team approaches.