Overexpression Of Somatostatin Receptors Research Articles

Neuroblastoma xenograft models demonstrate the therapeutic potential of 177Lu-octreotate

BackgroundNeuroblastoma (NB) is one of the most frequently diagnosed tumors in infants. NB is a neuroendocrine tumor type with various characteristics and features, and with diverse outcome. The most malignant NBs have a 5-year survival rate of only 40–50%, indicating the need for novel and improved treatment options. 177Lu-octreotate is routinely administered for treatment of neuroendocrine tumors overexpressing somatostatin receptors (SSTR). The aim of this study was to examine the biodistribution of 177Lu-octreotate in mice bearing aggressive human NB cell lines, in order to evaluate the potential usefulness of 177Lu-octreotate for treatment of NB.MethodsBALB/c nude mice bearing CLB-BAR, CLB-GE or IMR-32 tumor xenografts (n = 5–7/group) were i.v. injected with 0.15 MBq, 1.5 MBq or 15 MBq 177Lu-octreotate and sacrificed 1 h, 24 h, 48 h and 168 h after administration. The radioactivity concentration was determined for collected tissue samples, tumor-to-normal-tissue activity concentration ratios (T/N) and mean absorbed dose for each tissue were calculated. Immunohistochemical (IHC) staining for SSTR1–5, and Ki67 were carried out for tumor xenografts from the three cell lines.ResultsHigh 177Lu concentration levels and T/N values were observed in all NB tumors, with the highest for CLB-GE tumor xenografts (72%IA/g 24 h p.i.; 1.5 MBq 177Lu-octreotate). The mean absorbed dose to the tumor was 6.8 Gy, 54 Gy and 29 Gy for CLB-BAR, CLB-GE and IMR-32, respectively, p.i. of 15 MBq 177Lu-octreotate. Receptor saturation was clearly observed in CLB-BAR, resulting in higher concentration levels in the tumor when lower activity levels where administered. IHC staining demonstrated highest expression of SSTR2 in CLB-GE, followed by CLB-BAR and IMR-32.ConclusionT/N values for all three human NB tumor xenograft types investigated were high relative to previously investigated neuroendocrine tumor types. The results indicate a clear potential of 177Lu-octreotate as a therapeutic alternative for metastatic NB.

Peptide receptor radionuclide therapy in patients with metastatic progressive pheochromocytoma and paraganglioma: long-term toxicity, efficacy and prognostic biomarker data of phase II clinical trials

BackgroundPheochromocytoma and paraganglioma (PPGL) have currently only limited treatment options available for patients in the metastatic phase (mPPGL) in either post-surgery or inoperable settings. However, these rare tumors overexpress somatostatin receptors and can thus be treated with peptide receptor radionuclide therapy (PRRT). We present data about our 10-year experience treating 46 consecutive mPPGL patients with 90Y-DOTATOC or 177Lu-DOTATATE.Patients and methodsAll patients (20 men and 26 women, median age 52 years) showed positive scintigraphic imaging at 111In-octreotide or 68Ga-DOTATOC positron emission tomography/computed tomography (PET/CT). 90Y-DOTATOC was administered in 12 patients, with cumulative dosages ranging from 7.4 to 11 GBq, while 34 patients received 18.5 or 27.5GBq of 177Lu-DOTATATE. We used Southwest Oncology Group Response Evaluation Criteria in Solid Tumors criteria to evaluate treatment efficacy and Common Terminology Criteria for Adverse Events criteria to assess toxicity. The prognostic role of primary tumor site, hormone secretion, succinate dehydrogenase (SDHx) mutation, and metastatic involvement was also evaluated.ResultsBoth 90Y-DOTATOC and 177Lu-DOTATATE PRRT were well tolerated by patients without significant renal or bone marrow toxicity. The median follow-up was 73 months (range 5-146 months). The overall disease control rate (DCR) was 80% [95% confidence interval (CI) 68.9% to 91.9%] with a mean five cycles of therapy. However, 177Lu-DOTATATE patients showed a longer median overall survival (mOS) than those receiving 90Y-Dotatoc and a better DCR when higher dosages were administered, even if a direct comparison was not carried out. Syndromic patients had a poorer mOS. SDHx mutations did not interfere with treatment efficacy.ConclusionsPRRT is safe and effective for the treatment of patients with progressive mPPGL, especially at higher dosages. The longer mOS of 177Lu-DOTATATE-treated patients in our protocols indicates the former radiopharmaceutical as the better candidate for further clinical application.

Doing Great With DOTATATE: Update on GA-68 DOTATATE Positron Emission Tomography/Computed Tomography and Magnetic Resonance Imaging for Evaluation of Sinonasal Tumors.

Sinonasal tumors are relatively rare and radiographically challenging to evaluate due to their wide variety of pathologies and imaging features. However, sinonasal tumors possessing somatostatin receptor overexpression have the benefit of utilizing a multimodality anatomic and functional imaging for a more comprehensive evaluation. This is particularly evident with esthesioneuroblastoma, with computed tomography and magnetic resonance imaging defining the anatomic extent of the tumor, whereas somatostatin receptor imaging, particularly with gallium-68 DOTATATE positron emission tomography/computed tomography, is used to assess the presence of metastatic disease for staging purposes as well as in the surveillance for tumor recurrence. In addition, areas which accumulate gallium-68 DOTATATE are potentially amenable to treatment with peptide receptor radionuclide therapy. In this manner, a combined approach of anatomic and functional imaging is critical for optimal imaging evaluation and treatment strategy of patients with sinonasal tumors.

Ectopic ACTH-Producing Pheochromocytoma as a Rare Cause for Rapid Progressing Cushing Syndrome: A Case Report

Background: Cushing syndrome due to ectopic CRH or ACTH secretion can be rarely caused by pheochromocytoma, commonly as part of genetic conditions. Case: A 21 year-old male, previously healthy, with no usual medication, went to the physician assistant for hematuria. The kidney US revealed, besides lithiasis, a highly vascularized mass in the right adrenal gland with 10 cm. In his first evaluation the patient had no complaints or pheochromocitoma/hypercortisolism stigmata, other than hand tremor and slight rounding of the face. Blood pressure was 149/88 mmHg, and heart rate 86 bpm. There was no family history of endocrine disease. He rapidly developed increased appetite, insomnia, and severe myalgias, with filling of supraclavicular fossae, facial plethora, and cervical and truncal acne. Laboratory analysis showed abnormal overnight dexamethasone suppression test (57.4 µg/dL, N < 1.8), elevated ACTH 378 pg/mL (N 9.0–52.0), 24h-urinary free cortisol (UFC) (5334.0 µg/24h, N 4.3–176.0), and late-night salivar cortisol (1.44 µg/dL, N < 0.32), hypokalemia (2.8 mEq/L, N 3.8–5.0), and leukocytosis (22.4*109/L, N 4.0–11.0); DHEA-S 962 µg/dL (N 80–560), 4-androstenedione 380 ng/dL (N 70–360), 17-OH progesterone 4.5 ng/mL (N 0.59–3.44), cromogranine A 6063 ng/mL (N 0–100), and markedly elevated urinary amines (adrenaline 173 nmol/24h, N 0–109; noradrenaline 5033 nmol/24h, N 89–473; normetanephrine 334605 nmol/24h, N 480–2424; metanephrine 15998 nmol/24h, N 264–1729; dopamine 4808 nmol/24h, N 424–2612). Hypercalcemia with hypophosphatemia and supressed PTH level was also detected. 68Ga-DOTANOC PET revealed a mass of the right adrenal gland with overexpression of somatostatin receptors (likely pheochromocytoma), without evidence of other tumor lesions of neuroendocrine origin. Pituitary MRI showed normal pituitary gland. Potassium supplementation, alpha-blockade with phenoxybenzamine, and metyrapone were initiated. Due to severe back pain, a CT scan of the spine was performed detecting compressive osteoporotic fractures in the mid dorsal and low dorsal segments. The patient was submitted to right adrenalectomy. Histology revealed pheochromocytoma with 11.2*9mm, with capsular and vascular invasion, extra-adrenal extension, necrosis, and atypical mitosis, with Ki67 of 9.5% and PASS score of 16. Postoperative analysis showed ACTH 45.6 pg/mL (N 7.2-63,3), late-night salivar cortisol < 0,0544 µg/dL (N < 0,32) and free urinary cortisol 41.4 µg/24h (N 4.3–176.0). Discussion: Ectopic cushing syndrome caused by pheochromocytoma is a rarely described entity. In this young patient, it caused rapid clinical progression of hypercortisolism with important hydroelectrolytic disturbances and compressive vertebral fractures, requiring prompt surgical intervention for clinical remission and improvement.

On the production of pharmaceutical grade indium-111-chloride in the medical cyclotron from natural cadmium target and its use in formulation of diagnostic patient dose of 111In-pentetreotide for imaging somatostatin receptor overexpression

On the production of pharmaceutical grade indium-111-chloride in the medical cyclotron from natural cadmium target and its use in formulation of diagnostic patient dose of 111In-pentetreotide for imaging somatostatin receptor overexpression

Cirugía radioguiada con análogos de somatostatina radiomarcados en tumores neuroendocrinos: reporte de caso

Introducción: el mejor tratamiento para los tumores neuroendocrinos es la resección completa del tumor, los ganglios, e inclusive en casos seleccionados, las metástasis a distancia. En ocasiones, el tumor primario es pequeño y de difícil localización preoperatoria o sus recaídas pueden ser difíciles de localizar en el terreno de fibrosis por cirugías o tratamientos previos. La cirugía radioguíada ofrece una opción adicional de localización intraoperatoria que hasta ahora no ha sido muy utilizada en tumores neuroendocrinos. Presentación del caso: paciente de 59 años con antecedente de resección atípica de duodeno y páncreas por tumor neuroendocrino grado 2 del duodeno un año antes. En la tomografía por emisión de positrones/tomografía computarizada (PET/CT) 68Ga-DOTANOC se encontró un ganglio con sobreexpresión de receptores de somatostatina en el mesenterio, sin otras lesiones a distancia. Por los antecedentes quirúrgicos y la dificultad de visualizar la lesión en las imágenes anatómicas (resonancia magnética [RM]) se decidió realizar la cirugía radioguíada. En el preoperatorio se administraron 15 mCi de tecnecio 99 metaestable-hidrazinonicotinilo-Tyr3-octreotida (99mTc-HYNIC-TOC) y se verificó la buena captación en el ganglio. En cirugía, luego de la disección inicial se utilizó la sonda gamma, que detectó una actividad 5 veces mayor en el ganglio, comparado con los tejidos vecinos, lo que permitió su localización y resección. La evolución fue adecuada y un año después no hay evidencia de recaídas. Conclusión: la cirugía radioguíada no ha sido muy utilizada en la localización intraoperatoria de tumores neuroendocrinos, pero es una buena alternativa en casos seleccionados, como el presentado en este artículo, y permite la detección intraoperatoria y su resección completa.

Somatostatin Receptors and Analogs in Pheochromocytoma and Paraganglioma: Old Players in a New Precision Medicine World.

Neuroendocrine tumors overexpress somatostatin receptors, which serve as important and unique therapeutic targets for well-differentiated advanced disease. This overexpression is a well-established finding in gastroenteropancreatic neuroendocrine tumors which has guided new medical therapies in the administration of somatostatin analogs, both “cold”, particularly octreotide and lanreotide, and “hot” analogs, chelated to radiolabeled isotopes. The binding of these analogs to somatostatin receptors effectively suppresses excess hormone secretion and tumor cell proliferation, leading to stabilization, and in some cases, tumor shrinkage. Radioisotope-labeled somatostatin analogs are utilized for both tumor localization and peptide radionuclide therapy, with 68Ga-DOTATATE and 177Lu-DOTATATE respectively. Benign and malignant pheochromocytomas and paragangliomas also overexpress somatostatin receptors, irrespective of embryological origin. The pattern of somatostatin receptor overexpression is more prominent in succinate dehydrogenase subunit B gene mutation, which is more aggressive than other subgroups of this disease. While the Food and Drug Administration has approved the use of 68Ga-DOTATATE as a radiopharmaceutical for somatostatin receptor imaging, the use of its radiotherapeutic counterpart still needs approval beyond gastroenteropancreatic neuroendocrine tumors. Thus, patients with pheochromocytoma and paraganglioma, especially those with inoperable or metastatic diseases, depend on the clinical trials of somatostatin analogs. The review summarizes the advances in the utilization of somatostatin receptor for diagnostic and therapeutic approaches in the neuroendocrine tumor subset of pheochromocytoma and paraganglioma; we hope to provide a positive perspective in using these receptors as targets for treatment in this rare condition.

Chemotherapy-Induced Upregulation of Somatostatin Receptor-2 Increases the Uptake and Efficacy of 177Lu-DOTA-Octreotate in Neuroendocrine Tumor Cells.

Simple SummaryThe peptide receptor radionuclide therapy (PRRT) with 177Lu-DOTA-octreotate (LuTate) is recommended for neuroendocrine tumors (NETs) which overexpress somatostatin receptors (SSTR). A combination of LuTate with chemotherapy improves its objective response in NET patients, and here we characterized chemotherapy-induced upregulation of SSTR2 receptors as a cause for this improved response to LuTate. Using multiple NET and non-NET cell lines, we examined the SSTR2 expression for up to 7 days after exposure to drugs and its effect on LuTate uptake and cell proliferation. We report that the exposure to varying doses of chemotherapeutic drugs such as temozolomide for 24 h or 5 days results in upregulation of SSTR2 receptors between 3–7 days. This effect is more pronounced in low SSTR2 expressing BON-1 cells than in high SSTR2 expressing NCI-H727 or non-NET cancer or non-cancer cells. Thus, a properly-timed pre-treatment with low doses of chemotherapy could improve therapeutic efficacy of LuTate in NET patients.The peptide receptor radionuclide therapy (PRRT) with 177Lu-DOTA-octreotate (LuTate) is recommended for different types of neuroendocrine tumors (NETs) which overexpress somatostatin receptors (SSTR). A combination with chemotherapy improves objective response to LuTate in NET patients and here we characterized chemotherapy-induced upregulation of SSTR2 receptors as a cause for this improved response to LuTate. The NET cell lines with low (BON-1) or relatively high (NCI-H727) SSTR2-expression levels, and non-NET cancer and normal cells were treated with chemotherapeutic drugs and assessed for upregulation of SSTR2. We report that an exposure to low or high doses of drugs, such as temozolomide for 24 h or 5 day results in upregulation of SSTR2 between 3–7 days, increased LuTate uptake and decreased rate of cell proliferation. This effect is at the level of SSTR2-mRNA and is more pronounced in low SSTR2 expressing BON-1 than in high SSTR2 expressing NCI-H727 or non-NET cancer or normal cells. Thus, a properly timed pre-treatment with low-dose chemotherapy could not only improve therapeutic efficacy of LuTate in NET patients who are presently eligible for PRRT, but also allow PRRT to be administered to patients with low SSTR-expressing NETs, who would otherwise not respond to this modality because of insufficient radiation delivery.

Differentiation of insulinoma from accessory spleen by 99mTc-labelled heat-denaturated red blood cell scintigraphy: case report

BackgroundNeuroendocrine tumors (NETs) are rare tumors harboring overexpression of somatostatin receptors (SSTRs) on their cell membrane. Because some organs, such as the spleen, adrenal glands and liver, physiologically express SSTR, it might be challenging to distinguish some pancreatic NETs located in the pancreatic tail from the accessory spleen next to the splenic hilum. In this manuscript, we report a case with hypoglycemia attack and 2 different masses displayed by Gallium 68-tetraazacyclododecane tetraacetic acid-octreotate (68Ga-DOTATATE) positron emission tomography/computed tomography (PET/CT).Case presentationA 63-year-old woman presented to the hospital with confusion and profuse sweating. Biochemical diagnosis of insulinoma was established. 68Ga-DOTATATE PET/CT revealed two masses with increased tracer uptake located adjacent to the splenic hilum and inferior pole of the spleen which were initially reported as two separate accessory spleens. Then, 99mTc-labelled heat-denaturated red blood cell (99mTc-HDRBC) scintigraphy-single-photon emission computed tomography (SPECT)/CT was performed to distinguish a NET in the pancreatic tail from accessory spleen at the splenic hilum. Enhanced tracer uptake remained in the inferior pole of spleen, but not in the splenic hilum. The lesions were suggestive of insulinoma in the pancreatic tail and an accessory spleen adjacent to the inferior pole of the spleen.ConclusionApproximately 10% of the population have an accessory spleen which can show similar imaging characteristics with pancreatic NETs, especially if located in the pancreatic tail. In our presented case, 99mTc-HDRBC scintigraphy-SPECT/CT is a useful nuclear medicine method to differentiate a NET in the pancreatic tail from accessory spleen at the splenic hilum which may avoid unnecessary surgeries in the presence of enhanced tracer uptake or vice versa.

68Ga-DOTATOC.

The radiopharmaceutical 68Ga-DOTATOC represents the latest radiopharmaceutical in the diagnosis of a neuroendocrine tumor with somatostatin receptor overexpression. Technological and economic difficulties of preparing and quality control of the radiopharmaceutical limit its use to specialised departments. Background of the department with rich experience with radiopharmaceuticals for positron emission tomography allows handling more difficult 68Ga-radiopharmacy and may increase and improve the care of oncology patients.

99mTc-EDDA/HYNIC-TOC is a New Opportunity in Neuroendocrine Tumors of the Lung (and in other Malignant and Benign Pulmonary Diseases).

Neuroendocrine tumors (NETs) consist of a relatively rare spectrum of malignancies that can arise from neuroendocrine cells; lung NETs (L-NETs) represent about 25% of primary lung neoplasm and 10% of all carcinoid tumors. Diagnostic algorithm usually takes into consideration chest X-ray, contrast-enhanced CT and MRI. Nuclear medicine plays a crucial role in the detection and correct assessment of neoplastic functional status as it provides in vivo metabolic data related to the over-expression of Somatostatin Receptors (SSTRs) and also predicting response to peptide receptor radionuclide therapy (PRRT). 111In-Pentreotide (Octreoscan®) is commercially available for imaging of neuroendocrine tumors, their metastases and the management of patients with NETs. More recently, 99mTc-EDDA/HYNIC-TOC(Tektrotyd®) was introduced into the market and its use has been approved for imaging of patients with L-NETs and other SSTR-positive tumors. 99mTc-EDDA/HYNIC-TOC could also represent a good alternative to 68Ga-DOTA-peptides (DOTA-TOC, DOTA-NOC, DOTA-TATE) in hospitals or centers where PET/CT or 68Ge/68Ga generators are not available. When compared to 111In-Pentetreotide, Tektrotyd® showed slightly higher sensitivity, in the presence of higher imaging quality and lower radiation exposure for patients. Interesting perspectives depending on the kinetic analysis allowed by Tektrotyd® may be obtained in differential diagnosis of non-small cells lung cancer (NSCLC) versus small cells lung cancer (SCLC) and NETs. An interesting perspective could be also associated with a surgery radio-guided by Tektrotyd® in operable lung tumors, including either NETs and NSCLC.

Clinical impact of Ga68-DOTATOC PET/CT on neuroendocrine tumors. A preliminary experience

Ga-68-DOTATOC PET/CT is a recently introduced imaging technique for the diagnosis and follow-up of neuroendocrine tumors.A prospective observational study was conducted in seven patients who underwent a Ga-68-DOTATOC PET/CT study. They were suspected of active neuroendocrine tumor lesions, either on initial diagnosis or as a possible recurrence and/or progression of already known tumors. The results of prior imaging studies (MRI, thoracoabdominal CT scan, octreotide…), had been negative or inconclusive.All positive Ga-68-DOTATOC PETs were true positives, confirmed by pathological examination. There were no false positive results. Only one false negative result was found.Ga-68-DOTATOC PET/CC is more sensitive and specific for the detection of primary neuroendocrine tumor lesions, allows for a more complete extension study, and detects recurrences in earlier stages, conditioning changes in staging and surgical treatment. It provides additional information on somatostatin receptor overexpression, which is essential for the indication of PRRT (peptide receptor radionuclide therapy) with Lu177 dotatate.

Prevention and Management of Hormonal Crisis during Theragnosis with LU-DOTA-TATE in Neuroendocrine Tumors. A Systematic Review and Approach Proposal.

Neuroendocrine tumors (NETs) frequently overexpress somatostatin receptors (SSTR) on their cell surface. The first-line pharmacological treatment for inoperable metastatic functioning well-differentiated NETs are somatostatin analogs. On second line, Lu-DOTA-TATE (177Lu-DOTA0 Tyr 3 octreotate) has shown stabilization of the disease and an increase in progression free survival, as well as effectiveness in controlling symptoms and increasing quality of life. The management of functional NETs before and during LU-DOTA-TATE treatment is specially challenging, as several complications such as severe carcinoid and catecholamine crisis have been described. The aim of this review is to establish practical guidance for the management and prevention of the most common hormonal crises during radionuclide treatment with Lu-DOTA-TATE: carcinoid syndrome (CS) and catecholamine hypersecretion, as well as to provide a brief commentary on other infrequent metabolic complications. To establish a practical approach, a systematic review was performed. This systematic review was developed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement and conducted using MEDLINE (accessed from PubMed), Google Scholar and ClinicalTrials.gov. Literature searches found 449 citations, and finally nine were considered for this systematic review.

Targeting vulnerable atherosclerotic plaque via PET-tracers aiming at cell-surface overexpression of somatostatin receptors.

Cardiovascular disease (CD) is the leading cause of death in the developed world, with major atherothrombotic events, being mainly attributed to the rupture of unstable, vulnerable atherosclerotic lesions, leading to blood flow obstruction. Since unstable atherosclerotic plaques frequently do not cause hemodynamically significant blood flow restriction, conventional stress imaging tests cannot depict the vulnerable, high-risk for rupture atherosclerotic lesions. Therefore, molecular imaging techniques targeting specific pathophysiologic features related to atherosclerotic plaque rupture mechanism, hold promise for precise and individualized treatment strategies of CD. In the current report, we describe in a patient diagnosed with pancreatic neuroendocrine tumor, the selective uptake of 68Ga-DOATATE by an atherosclerotic lesion in the thoracic aorta. This data indicates that 68Ga-DOTATATE, which is a positron emitting tomography tracer, targeting the recruitment of macrophages taking place in the vulnerable plaque, could potentially serve as an imaging probe for the detection of high-risk, prone to rupture plaques.

Impacto clínico del PET/TC Ga68-DOTATOC en tumores de origen neuroendocrino. Experiencia preliminar

Ga-68-DOTATOC PET/CT is a recently introduced imaging technique for the diagnosis and follow-up of neuroendocrine tumors.A prospective observational study was conducted in seven patients who underwent a Ga-68-DOTATOC PET/CT study. They were suspected of active neuroendocrine tumor lesions, either on initial diagnosis or as a possible recurrence and/or progression of already known tumors. The results of prior imaging studies (MRI, thoracoabdominal CT scan, octreotide...), had been negative or inconclusive.All positive Ga-68-DOTATOC PETs were true positives, confirmed by pathological examination. There were no false positive results. Only one false negative result was found.Ga-68-DOTATOC PET/CC is more sensitive and specific for the detection of primary neuroendocrine tumor lesions, allows for a more complete extension study, and detects recurrences in earlier stages, conditioning changes in staging and surgical treatment. It provides additional information on somatostatin receptor overexpression, which is essential for the indication of PRRT (peptide receptor radionuclide therapy) with Lu177 dotatate.

Treatment-related changes in neuroendocrine tumors as assessed by textural features derived from 68Ga-DOTATOC PET/MRI with simultaneous acquisition of apparent diffusion coefficient

BackgroundNeuroendocrine tumors (NETs) frequently overexpress somatostatin receptors (SSTRs), which is the molecular basis for 68Ga-DOTATOC positron-emission tomography (PET) and radiopeptide therapy (PRRT). However, SSTR expression fluctuates and can be subject to treatment-related changes. The aim of this retrospective study was to assess, which changes in PET and apparent diffusion coefficient (ADC) occur for different treatments and if pre-therapeutic 68Ga-DOTATOC-PET/MRI was able to predict treatment response to PRRT.MethodsPatients with histopathologically confirmed NET, at least one liver metastasis > 1 cm and at least two 68Ga-DOTATOC-PET/MRI including ADC maps were eligible. 68Ga-DOTATOC-PET/MRI of up to 5 liver lesions per patients was subsequently analyzed. Extracted features comprise conventional PET parameters, such as maximum and mean standardized uptake value (SUVmax and SUVmean) and ADC values. Furthermore, textural features (TFs) from both modalities were extracted. In patients with multiple 68Ga-DOTATOC-PET/MRI a pair of 2 scans each was analyzed separately and the parameter changes between both scans calculated. The same image analysis was performed in patients with 68Ga-DOTATOC-PET/MRI before PRRT. Differences in PET and ADC maps parameters between PRRT-responders and non-responders were compared using Mann-Whitney test to test differences among groups for statistical significance.Results29 pairs of 68Ga-DOTATOC-PET/MRI scans of 18 patients were eligible for the assessment of treatment-related changes. In 12 cases patients were treated with somatostatin analogues between scans, in 9 cases with PRRT and in 2 cases each patients received local treatment, chemotherapy and sunitinib. Treatment responders showed a statistically significant decrease in lesion volume and a borderline significant decrease in entropy on ADC maps when compared to non-responders. Patients treated with standalone SSA showed a borderline significant decrease in mean and maximum ADC, compared to patients treated with PRRT. No parameters were able to predict treatment response to PRRT on pre-therapeutic 68Ga-DOTATOC-PET/MRI.ConclusionsPatients responding to current treatment showed a statistically significant decrease in lesion volume on ADC maps and a borderline significant decrease in entropy. No statistically significant changes in PET parameters were observed. No PET or ADC maps parameters predicted treatment response to PRRT. However, the sample size of this preliminary study is small and further research needed.

Textural analysis of hybrid DOTATOC-PET/MRI and its association with histological grading in patients with liver metastases from neuroendocrine tumors.

Neuroendocrine tumors (NETs) are known to overexpress somatostatin receptors (SSTR), which can be visualized by DOTATOC-PET. Reduced SSTR expression on the other hand may indicate dedifferentiation. The aim of this retrospective study was to assess, if conventional PET parameters and textural features (TF) derived from simultaneous PET and MRI including apparent diffusion coefficient (ADC) are associated with the proliferative activity of NETs, potentially allowing non-invasive tumor grading. Our institutional database was screened for patients with NET and liver metastases >1 cm. We assessed conventional PET parameters, such as maximum and mean standardized uptake value and more elaborate TF parameters from PET and ADC-MRI (including entropy and homogeneity) from up to the five largest liver lesions per patient. The association of proliferative activity as measured by Ki67-/MIB1-index with the aforementioned parameters was analyzed. One hundred patients with NET/NECs were eligible with a Ki67-index ranging from <1% to 30%. Overall, 304 liver lesions were analyzed. Conventional PET parameters, entropy, homogeneity of PET and ADC maps differed significantly between G1 and G2 NETs. However, Spearman's test showed a weak association (r = -0.23 to 0.31). In our study cohort, conventional PET parameters and TF of PET and ADC-MRI showed only a weak correlation with Ki67. This indicates that in patients with a Ki67-index of up to 30% TF analysis of combined PET/MRI may not be reliably used for accurate non-invasive tumor grading. On the other hand, DOTATOC-PET might be a suitable staging tool in some higher grade NET/NECs.

64Cu-DOTATATE PET/CT and Prediction of Overall and Progression-Free Survival in Patients with Neuroendocrine Neoplasms.

Overexpression of somatostatin receptors (SSTRs) in patients with neuroendocrine neoplasms (NENs) is used for both diagnosis and treatment. Receptor density may reflect tumor differentiation and thus be associated with prognosis. Noninvasive visualization and quantification of SSTR density is possible by SSTR imaging (SRI) using PET. Recently, we introduced 64Cu-DOTATATE for SRI, and we hypothesized that uptake of this tracer could be associated with overall survival (OS) and progression-free survival (PFS). Methods: We evaluated patients with NENs who underwent 64Cu-DOTATATE PET/CT SRI in 2 prospective studies. Tracer uptake was determined as the maximal SUV (SUVmax) for each patient. Kaplan-Meier analysis with log-rank was used to determine the predictive value of 64Cu-DOTATATE SUVmax for OS and PFS. Specificity, sensitivity, and accuracy were calculated for prediction of outcome at 24 mo after 64Cu-DOTATATE PET/CT. Results: In total, 128 patients with NENs were included and followed for a median of 73 mo (range, 1-112 mo). During follow-up, 112 experienced disease progression, and 69 died. The optimal cutoff for 64Cu-DOTATATE SUVmax was 43.3 for prediction of PFS, with a hazard ratio of 0.56 (95% confidence interval, 0.38-0.84) for patients with an SUVmax of more than 43.3. However, no significant cutoff was found for prediction of OS. In multiple Cox regression adjusted for age, sex, primary tumor site, and tumor grade, the SUVmax cutoff hazard ratio was 0.50 (range, 0.32-0.77) for PFS. The accuracy was moderate for predicting PFS (57%) at 24 mo after 64Cu-DOTATATE PET/CT. Conclusion: In this first study to report the association of 64Cu-DOTATATE PET/CT and outcome in patients with NENs, tumor SSTR density as visualized with 64Cu-DOTATATE PET/CT was prognostic for PFS but not OS. However, the accuracy of prediction of PFS at 24 mo after 64Cu-DOTATATE PET/CT SRI was moderate, limiting the value on an individual-patient basis.

Influence of pretreatment with everolimus or sunitinib on the subacute hematotoxicity of 177Lu-DOTATATE PRRT

Background: Peptide receptor radionuclide therapy (PRRT) is a validated treatment for somatostatin receptor overexpressing neuroendocrine tumors (NETs). The NETTER-1 trial demonstrated a pronounced positive effect on progression-free-survival compared to high dose somatostatin analogs (SSAs), with a strong tendency toward overall survival benefit. Our aim was to investigate the influence of pretreatment with everolimus and/or sunitinib on subacute hematotoxicity of PRRT. To assess the influence of prior treatment with everolimus/sunitinib might be of clinical relevance due to the link between short-term hematotoxicity and increased incidence of late hematotoxicity.Material and methods: Our single-center retrospective study enrolled all patients treated with 177Lu-DOTATATE PRRT (1–4 cycles of 7.4 GBq), between November 2013 and July 2018. Patients were assigned to two groups according to their pretreatment: no targeted agents (N = 41), or targeted agents (everolimus, sunitinib or both; N = 41). The end point was subacute hematotoxicity, defined as the nadir value between the first administration until 3 months after the last administration, using the CTCAE 4.03 classification. The impact of splenectomy was also explored.Results: Eighty percent of patients had a primary gastroenteropancreatic NET. No statistically significant differences in severe subacute hematotoxicity were seen in the pretreated group vs. the naive group for hemoglobin (grade 3/4: 12% vs. 22%), neither for leucocytes (grade 3/4: 10% vs. 7%), neutrophils (grade 3/4: 5% vs. 7%), lymphocytes (grade 3/4: 49% vs. 37%) and platelets (grade 3/4: 15% vs. 15%). Furthermore, we observed significantly lower toxicity for total white blood cells, lymphocytes and platelets in the subgroup that had splenectomy (N = 12). Limitations of this study include the potential bias in lack of use of targeted agents in patients more susceptible to toxicity, and the limited number of patients and events.Conclusions: In a patient cohort with NET pretreated with everolimus and/or sunitinib, we could not demonstrate a significant effect of prior/pretreatment with everolimus and/or sunitinib on the subacute hematotoxicity of 177Lu-DOTATATE PRRT.

Multifocal meningioma recurrence detected on Ga68-DOTANOC scan

Meningiomas arise from meningothelial cells of the arachnoid membranes. They are classified into three grades according to the WHO criteria, Grade I (Benign), Grade II (atypical), and Grade III (anaplastic). Radiological and structural imaging computed tomography (CT) and magnetic resonance imaging are done routinely for defining the location, extent, and follow-up. However, these imaging techniques have their limitations. Since meningiomas have overexpression of somatostatin receptor 2, DOTANOC positron-emission tomography (PET)/CT scan is suggested for their delineation and distinguish postradiotherapy necrosis from recurrence. Here, we present a case where DOTANOC PET/CT scan helped in confirming recurrence postsurgery and radiotherapy.