Detección radioguiada de lesión oculta no palpable (ROLL) en un caso de metástasis abdominal de tumor neuroendocrino / No disponible

Los tumores neuroendocrinos (TNE) son un grupo heterogéneo de neoplasias que tienen origen en tejidos derivados de la cresta neural, que expresan marcadores neuroendocrinos y receptores de somatostatina. Presentamos el caso de una paciente con un TNE de intestino delgado previamente intervenido. En la gammagrafía de receptores de somatostatina (GRS/99mTc-Tektrotyd) se identificó un foco en mesenterio no resecado. Se realizó una segunda intervención con detección radioguiada con sonda gamma y con SPECT-portátil. Permitió detectar una lesión que se confirmó por histología como metástasis ganglionar de TNE y un nódulo de TNE en la anastomosis de la primera intervención quirúrgica

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Will 177Lu-DOTATATE Treatment Become More Effective in Salvage Meningioma Patients, When Boosting Somatostatin Receptor Saturation? A Promising Case on Intra-arterial Administration.

Somatostatin receptor subtype 2 upregulation is very common in meningiomas, and the use of peptide receptor radionuclide therapy (PRRT) is recognized in recent European guidelines, with long-term stable disease and a long overall survival. Treatment efficacy of radionuclide treatments is correlated with tumour radiation absorbed dose. Meningioma patients with low tumour uptake might benefit less from treatment. Thus, a method to increase tumour uptake in these patients is needed. We describe a case treated with both intravenous and intra-arterial PRRT. Tumour uptake after intravenous PRRT was disappointing, and after intra-arterial administration significantly increased tumour uptake was seen. Patient had a partial response on imaging and reduction in tumour-related complaints. Potentially, intra-arterial administration of PRRT could increase treatment efficacy in meningioma patients.Level of Evidence 5 (case report).

Physiological expression of pancreatic somatostatin receptors in 99mTc-HYNIC-TOC scintigraphy

Purpose. To describe the frequency of head and/or pancreas uncinate process uptake of 99mTc-HYNIC-TOC, to study its nature, and analyze its diagnostic value. Materials and methods. Retrospective evaluation of 47 consecutive 99mTc-HYNIC-TOC examinations was conducted. Head and/or pancreas uncinate process uptake was considered to be physiological in patients with normal CT at the same episode and in follow-up. It was analyzed if age or diabetes mellitus was justifying the existence or not of uptake. Results. 32.5% patients showed uptake; 73% of them were mild. 84.6% patients with uptake have no pathology and 4% had neuroendocrine pancreatic disease at CT. Neither the age nor the diabetes mellitus established differences in patients without lesion. Conclusions. Near one-third of patients show physiological uptake by head and/or pancreas uncinate process at 99mTc-HYNIC-TOC scintigraphy. It seems that neither the diabetes nor the ages are factors that determine this physiological uptake (AU)

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Radionuclide Therapy for Neuroendocrine Tumors.

Peptide receptor radionuclide therapy (PRRT) is a form of systemic radiotherapy that allows targeted delivery of radionuclides to tumor cells expressing high levels of somatostatin receptors. The two radiopeptides most commonly used for PRRT, 90Y-DOTATOC and 177Lu-DOTATATE, have been successfully employed for more than a decade for the treatment of advanced neuroendocrine tumors (NETs). Recently, the phase III, randomized NETTER-1 trial has compared 177Lu-DOTATATE versus high-dose octreotide LAR in patients with progressive, metastatic midgut NETs, demonstrating exceptional tolerability and efficacy. This review summarizes recent developments in the field of radionuclide therapy for gastroenteropancreatic and lung NETs and considers possible strategies to further enhance its clinical efficacy.

Somatostatin receptor-targeted radionuclide therapy for progressive meningioma: benefit linked to 68Ga-DOTATATE/-TOC uptake.

BACKGROUND: The prognosis of patients with progressive meningioma after failure of surgery and radiotherapy is poor. METHODS: We retrospectively evaluated the safety and efficacy of somatostatin-receptor (SSTR)-targeted radionuclide therapy (177Lu-DOTATATE [n = 16], 90Y-DOTATOC [n = 3], or both [n = 1]) in patients with progressive, treatment-refractory meningiomas (5 World Health Organization [WHO] grade I, 7 WHO grade II, 8 WHO grade III) and in part multifocal disease (17 of 20 patients). RESULTS: SSTR radionuclide treatment (median of 3 treatment cycles, median administered dose/cycle 7400 MBq) led to a disease stabilization in 10 of 20 patients for a median time of 17 months. Stratification according to WHO grade showed a median progression-free survival (PFS) of 32.2 months for grade I tumors, 7.2 for grade II, and 2.1 for grade III. PFS at 6 months was 100% for grade I, 57% for grade II, and 0% for grade III. Median overall survival was 17.2 months in WHO grade III patients and not reached for WHO I and II at a median follow-up of 20 months. In the analysis of single meningioma lesions, maximal and mean standardized uptake values in pretherapeutic 68Ga-DOTATOC/-TATE PET/CT were significantly higher in those lesions with radiographic stability after 6 months. In line with this, high expression of SSTR via immunohistochemistry was associated with PFS >6 months. CONCLUSIONS: SSTR-targeted radionuclide treatment has activity in a subset of patients with meningioma. Expression of SSTR via immunohistochemistry or radionuclide uptake might serve as a predictive biomarker for outcome to facilitate individualized treatment optimization in patients with uni- and multifocal meningiomas.

[Nuclear medicine in oncotherapy]. / Nukleáris medicina az onkoterápiában.

After a brief historical overview, the basic concept of therapy with radionuclides is summarised. This is followed by a review of the physical and biological features of the different radiopharmaceuticals that are available. A clinical application of the different techniques commences with the treatment of differentiated thyroid cancer using radio-iodine. From the various bone-seeking radiopharmceuticals, we opted for the alpha-emitting 223-RaCl2 for treatment purposes. Due to the increasing prevalence of neuroendocrine tumors nowadays, somatostatin receptor and adrenerg analog radiotherapy are discussed. Next, one of the most promising new techniques is presented along with some radioimmunological applications. Lastly, the importance of multidisciplinary cooperation is analysed from the viewpoint of successful individual oncotherapy and safe radionuclide treatment for the benefit of patients.

Peptide receptor radionuclide therapy in a patient with disabling non-functioning pituitary adenoma.

Non-functioning pituitary adenoma (NFPA) with higher proliferation index (WHO II) are often a therapeutical challenge. Low somatostatin receptor expression in these tumors usually prevents a treatment with somatostatin analogs. In 1996, a 55-year-old patient was referred due to right-sided headache. A pituitary macroadenoma with infiltration into the right cavernous sinus was diagnosed. There was no visual field deficit and the clinical and biochemical work up was consistent with a NFPA. The patient underwent transsphenoidal surgery. Residual adenoma remained in the right cavernous sinus. Histologically, a null-cell adenoma with a high proliferation index was documented (MIB-1: 11.6%, WHO II). Somatostatin receptor autoradiography was performed in the surgical specimen showing a homogenous expression of sst2 receptors. Radiosurgery was completed with stable disease for 8 years. In 2004, the patient was diagnosed with an incomplete palsy of the right oculomotorius nerve and a significant increase in the volume of the adenoma in the right cavernous sinus. After a positive Octreoscan(®) the patient consented to an experimental therapy approach using Lutetium DOTATOC (3 × 200 mCi). The palsy of the oculomotorius nerve improved and remained stable until today (March 2013), the follow-up MRI scans demonstrated stable disease. This is the first case of a patient with a NFPA (WHO II) in whom PRRT successfully improved the local complications of the tumor for more than 8 years after ineffective surgery and gamma knife therapy. The determination of sst2 in vitro using autoradiography and in vivo by Octreoscan was instrumental to administer this therapy in a challenging situation.

Review of functional/anatomical imaging in oncology.

Patient management in oncology increasingly relies on imaging for diagnosis, response assessment, and follow-up. The clinical availability of combined functional/anatomical imaging modalities, which integrate the benefits of visualizing tumor biology with those of high-resolution structural imaging, revolutionized clinical management of oncologic patients. Conventional high-resolution anatomical imaging modalities such as computed tomography (CT) and MRI excel at providing details on lesion location, size, morphology, and structural changes to adjacent tissues; however, these modalities provide little insight into tumor physiology. With the increasing focus on molecularly targeted therapies, imaging radiolabeled compounds with PET and single-photon emission tomography (SPECT) is often carried out to provide insight into a tumor's biological functions and its surrounding microenvironment. Despite their high sensitivity and specificity, PET and SPECT alone are substantially limited by low spatial resolution and inability to provide anatomical detail. Integrating SPECT or PET with a modality capable of providing these (i.e. CT or MR) maximizes their separate strengths and provides anatomical localization of physiological processes with detailed visualization of a tumor's structure. The availability of multimodality (hybrid) imaging with PET/CT, SPECT/CT, and PET/MR improves our ability to characterize lesions and affect treatment decisions and patient management. We have just begun to exploit the truly synergistic capabilities of multimodality imaging. Continued advances in the development of instrumentation and imaging agents will improve our ability to noninvasively characterize disease processes. This review will discuss the evolution of hybrid imaging technology and provide examples of its current and potential future clinical uses.

Clinical molecular imaging with radiotracers: current status.

Molecular imaging is defined as the visualization, characterization, and measurement of biological processes at the molecular and cellular levels in humans and other living systems. Most clinical molecular imaging is currently done using radioisotope-labeled agents to define the activity of various metabolic pathways in vivo or to determine the distribution and density of various receptors relevant to human disease. This paper briefly reviews most of the commonly used radiopharmaceuticals in nuclear medicine, as well as newer agents that are likely to become available in the near future. The metabolic pathways include those relevant to the thyroid, parathyroid, heart, brain, bones, kidneys, liver, pancreas, adrenals and tumor. The receptor systems include agents useful in evaluating movement disorders, dementia, cardiac sympathetic enervation and neoangiogenesis. Receptor systems relevant to tumors include somatostatin receptors (neuroendocrine tumors), prostate-specific membrane antigen, carbonic anhydrase IX (renal cancer), and CD-20 (lymphoma). These agents, and newer agents that are being developed, are likely to become critical in the development of personalized medicine, where it will become increasingly important to determine whether a treatment that is targeted to a specific metabolic pathway or receptor is likely to be successful.

Somatostatin receptors as targets for nuclear medicine imaging and radionuclide treatment.

Radiolabeled peptides have been an important class of compounds in radiopharmaceutical sciences and nuclear medicine for more than 20 years. Despite strong research efforts, only somatostatin-based radiopeptides have a real impact on patient care, diagnostically and therapeutically. [(111)In-diethylenetriaminepentaacetic acid(0)]octreotide is commercially available for imaging. Imaging was highly improved by the introduction of PET radionuclides such as (68)Ga, (64)Cu, and (18)F. Two peptides are successfully used in targeted radionuclide therapy when bound to DOTA and labeled with (90)Y and (177)Lu.

[Somatostatin receptor endoradiotherapy of neuroendocrine tumors: experience in Hungarian patients]. / Neuroendokrin daganatok szomatosztatinreceptor-endoradioterápiája: hazai betegeken szerzett tapasztalatok.

Beside conventional therapies for the treatment of neuroendocrine tumors, a new therapeutical approach, peptide receptor radionuclide therapy has been developed recently. There are two important features which make this therapy feasible: somatostatin receptors are strongly over-expressed in most neuroendocrine tumors resulting in a high tumor-to-background ratio and internalization of the somatostatin-receptor complex in neuroendocrine cells. Due to these features, neuroendocrine tumors can be treated with radiolabelled somatostatin analogues. For peptide receptor radionuclide therapy, somatostatin analogues are conjugated to a chelator that can bind a radionuclide. The most frequently used radionuclides for neuroendocrine tumor treatment are the ß-emitter Yttrium-90 (9°Y) and the ß+γ emitter Lutetium-177 (¹77Lu). Candidates for somatostatin receptor endoradiotherapy are patients with progressive, metastatic, somatostatin-receptor positive neuroendocrine tumors. Many patients have been successively treated with this approach: according to international results major remission can be achieved in 25% of the cases. Although this therapy is still unavailable in Hungary, Hungarian patients can be treated with somatostatin receptor endoradiotherapy with financial support from the National Health Fund in a co-operation with the University of Basel since 2005. During the past 5 years, 51 Hungarian patients have been treated with this therapy. This review briefly summarizes the theoretical background, indications, effectiveness and side effects of somatostatin receptor endoradiotherapy and the authors present the first data obtained from Hungarian patients.

Cirugía radiodirigida de metástasis de tumor carcinoide intestinal. Importancia de la realización de SPECT–TAC / Radioguided surgery of intestinal carcinoid tumor relapse. Role of SPECT–CT

Presentamos un paciente con sospecha de recidiva de tumor carcinoide intestinal confirmada por medio de una gammagrafía con receptores de somatostatina. Se identificó una lesión patológica intraabdominal que mostraba una gran avidez por el trazador, planteándose una extirpación radiodirigida de la misma. Previamente a la intervención se realizó un SPECT-TAC que permitió la detección y localización anatómica de la lesión, facilitando la realización del procedimiento radiodirigido. Además, modificó la planificación de la intervención con los medios físicos y humanos adecuados para prevenir las posibles complicaciones quirúrgicas(AU)

We present a patient with clinical suspicion of intestinal carcinoid relapse confirmed by a somatostatin receptor scintigraphy. A very intense somatostatin avid abdominal lesion was located and radioguided surgery was proposed. Prior to the procedure, we performed a SPECT-CT that made it possible to detect and localize the lesion anatomically, thus facilitating the performance of the radioguided procedure. Furthermore, it modified the planning of the intervention with the adequate physical and human resources to prevent the possible surgical complications(AU)

Enhancement of somatostatin-receptor-targeted (177)Lu-[DOTA(0)-Tyr(3)]-octreotide therapy by gemcitabine pretreatment-mediated receptor uptake, up-regulation and cell cycle modulation.

INTRODUCTION: Clinical studies of patients treated with somatostatin-receptor (sstr)-targeted [DOTA(0)-Tyr(3)]-octreotide (DOTATOC) labeled with (177)Lu and (90)Y have shown overall response rates in the range of 9-33%. This study evaluates the potential for combination therapy with gemcitabine in an effort to improve clinical outcomes. METHODS: Human pancreatic adenocarcinoma Capan-2, rat pancreatic cancer AR42J and human small cell lung cancer NCI-H69 cells were each treated with 1 microg/ml gemcitabine for 4 days followed by replacement of the medium alone for four additional days. Cell cycle and direct receptor-uptake studies were performed with (177)Lu-DOTATOC after the total 8-day treatment as described. Cell viability and apoptosis experiments were performed to study the effects of gemcitabine pretreatment and (177)Lu-DOTATOC radionuclide therapy. Parallel control studies were performed with receptor-non-targeted (177)Lu-DOTA and DOTATOC. RESULTS: Cells treated with gemcitabine for 4 days showed a down-regulation of sstr expression as determined by (177)Lu-DOTATOC uptake. However, after 4 days of additional growth in absence of gemcitabine, the uptake of (177)Lu-DOTATOC was 1.5-3 times greater than that of the untreated control cells. In gemcitabine-pretreated Capan-2 cells, 84% of the cell population was in the G(2)M phase of the cell cycle. Due to sstr up-regulation and cell cycle modulations, synergistic effects of gemcitabine pretreatment were observed in cell viability and apoptosis assays. (177)Lu-DOTATOC resulted in two to three times greater apoptosis in gemcitabine-pretreated Capan-2 cells compared to the untreated cells. CONCLUSION: Gemcitabine pretreatment up-regulates sstr expression and acts as a radiosensitizer through cell cycle modulation. The rational combination of gemcitabine and sstr-targeted radiopharmaceuticals represents a promising chemoradiation therapeutic tool with great potential to improve clinical outcomes and, thus, merits further study.

Preclinical evaluation of the alpha-particle generator nuclide 225Ac for somatostatin receptor radiotherapy of neuroendocrine tumors.

PURPOSE: Peptide receptor radionuclide therapy (PRRT) using somatostatin analogues labeled with beta-particle-emitting isotopes such as 90Y or 177Lu has been a promising treatment strategy for metastasized neuroendocrine tumors. Although remission can be accomplished in a high percentage of neuroendocrine tumors, some tumors do not respond to this treatment. alpha-Emitting isotopes-such as the 10-day half-life alpha-emitting generator nuclide Actinum-225 (225Ac)-are characterized by extremely high cytotoxic activity on the cellular level, and may be superior in the treatment of neuroendocrine tumors not responding to PRRT using beta-emitting isotopes. EXPERIMENTAL DESIGN: Radiolabeling of 225Ac 1,4,7,10-tetra-azacylododecane N,N',N'',N'''-J-tetraacetic acid-Tyr3-octreotide (DOTATOC) was done at pH 5 (60 minutes at 70 degrees C) without further purification. Biodistribution in nude mice bearing AR42J rat pancreas neuroendocrine tumor xenografts were measured for up to 24 hours. Toxicity was tested by weight changes, retention variables (blood urea nitrogen and creatine), and histopathology in mice 7 months after treatment with 10 to 130 kBq (n = 4-5). Therapeutic efficacy was assessed by tumor weighing in animals treated 4 days after xenotransplantation and compared with 177Lu-DOTATOC as a reference. RESULTS: Activities up to 20 kBq had no significant toxic effects in mice. In contrast, activities higher than 30 kBq induced tubular necrosis. Biodistribution studies revealed that 225Ac-DOTATOC effectively accumulated in neuroendocrine xenograft tumors. 225Ac-DOTATOC activities were shown to be nontoxic (12-20 kBq), reduced the growth of neuroendocrine tumors, and showed improved efficacy compared with 177Lu-DOTATOC. CONCLUSIONS: 225Ac might be suitable to improve PRRT in neuroendocrine tumors.

Gamma knife radiosurgery in skull base meningiomas: a possible relationship between somatostatin receptor decrease and early neurological improvement without tumour shrinkage at short-term imaging follow-up.

BACKGROUND: This study investigates a possible relationship between the effects of gamma knife (GK) on meningioma somatostatin receptors (SRs) and the high rate of early neurological improvement without tumour reduction at short-term imaging follow-up. METHODS: From December 1997 to December 2002, somatostatin receptor scintigraphy (SRS) using an 111Indium-labelled somatostatin analogue, Octreotide, was performed both before and 7-12 months after radiosurgery in 20 patients with intracranial meningiomas. Semiquantitative data were calculated as an SRS index. FINDINGS: The pre-GK SRS index was always > 1, averaging 4.44 +/- 3.20. There were no statistically significant differences between the pre-GK average values of primary (4.80 +/- 3.65) and residual (3.75 +/- 1.93) meningiomas. At the first clinical/MRI follow-up, the neurological examination had improved in 15/20 (75%) and had not changed in 5/20 patients. A corresponding slight tumour shrinkage on high-resolution MRI was documented in 3/20 cases only. The post-GK average SRS index was lower than pre-GK values both in primary (3.87 +/- 3.19) and in adjuvant (2.52 +/- 1.14) treatments, but the differences were not significant. However, the subgroup of patients with early neurological improvement showed a higher pre-GK average SRS index (5.21 +/- 3.33) and a more substantial post-GK average SRS index decrease (3.86 +/- 3.00) than the patients whose clinical condition remained stable (2.10 +/- 0.59 and 1.99 +/- 0.55, respectively). The difference between the two subgroups of patients proved to be statistically significant (P < 0.05). CONCLUSIONS: Our preliminary findings suggest a possible relationship between a decrease in the concentration of SRs on meningioma cells at short-term functional imaging follow-up after radiosurgery and early neurological improvement.

Tumor response after [(90)Y-DOTA(0),Tyr(3)]octreotide radionuclide therapy in a transplantable rat tumor model is dependent on tumor size.

UNLABELLED: A promising application of radiolabeled somatostatin analogs is peptide receptor-targeted radionuclide therapy of somatostatin receptor-expressing tumors. A suitable radionuclide is (90)Y, which emits high-energy beta-particles with a pathlength of several millimeters in tissue, making it especially promising for treatment of large tumors. METHODS: We investigated the radiotherapeutic effect of different activities (111 and 370 MBq) of [(90)Y-1,4,7,10-tetraazacyclododecane-N,N',N",N"'-tetraacetic acid (DOTA)(0),Tyr(3)]octreotide in Lewis rats bearing somatostatin receptor-positive rat pancreatic CA20948 tumors of different size (0.08-15 cm(2)) in their flank. RESULTS: Dose-dependent radiotherapeutic effects of (90)Y-labeled octreotide in this rat tumor model were found. Tumor control (100% complete response) was found in animals bearing tumors of 3-9 cm(2) (mean, 7.8 cm(2)) after intravenous injection of the highest activity (370 MBq [(90)Y-DOTA(0),Tyr(3)]octreotide). In rats bearing tumors of < or =1 cm(2) or > or =14 cm(2), the effects were less pronounced (50% and 0% complete response, respectively). In tumors of < or =1 cm(2) the (90)Y radiation energy will not be absorbed completely in the tumor, whereas in tumors of > or =14 cm(2) the increased number of clonogenic and probably hypoxic tumor cells may explain the failure to reach a cure. CONCLUSION: This study shows the ability of [(90)Y-DOTA(0),Tyr(3)]octreotide to control tumor growth, especially in medium-sized tumors. The effect of radionuclide therapy appeared to be dependent on tumor size at the onset of therapy.

Is somatostatin receptor scintigraphy suited to detection of acute infectious disease?

Fast and accurate delineation of acute infectious foci is very important for adequate management of patients. All currently available scintigraphic techniques require a relatively long timespan between referral to the nuclear medicine department and final diagnosis. Small peptides that bind to receptors on cells in the infectious focus might improve the diagnostic possibilities. Since activated leukocytes express somatostatin receptors, 111In-octreotide, a somastostatin analogue, was tested for its usefulness in detecting acute infection in rats with a calf muscle infection caused by Staphylococcus aureus. 111In-octreotide was compared with the much larger protein 111In-labelled human nonspecific immunoglobulin G (111In-IgG). As early as 0.5 h after injection, the 111In-octreotide uptake in the abscess was significantly lower than that of 111In-IgG. Moreover, no 111In-octreotide retention in the abscess over time was noted. In conclusion, somatostatin receptor imaging does not allow scintigraphic detection of an acute infectious lesion. The uptake in an abscess is relatively poor compared to 111In-IgG.