Radiolabeled Somatostatin Analogs Research Articles

Peptide Receptor Radionuclide Therapy With 177Lu-Octreotate in Patients With Somatostatin Receptor Expressing Neuroendocrine Tumors: Six Years' Assessment.

Peptide receptor radionuclide therapy (PRRT) with radiolabeled somatostatin analogues is a promising treatment for patients with inoperable, well to moderately differentiated metastatic neuroendocrine tumors (NETs). In continuation of our novel study with the radionuclide lutetium Lu, we now present further results of Lu DOTATATE therapy in managing NETs and other somatostatin receptor-expressing tumors in a larger and more diverse patient group. One hundred forty-four consecutive patients (85 men and 59 women; age range, 11-87 years; mean age, 58.5 years) with histologically confirmed NET were enrolled. One hundred forty-three patients received at least 1 cycle of treatment. Among them, 132 were deemed evaluable by having at least 1 cycle of treatment and a posttreatment MRI or CT scan for assessment based on modified Response Evaluation Criteria in Solid Tumors. Response to therapy was evaluated in terms of progression-free survival, overall survival, as well as radiologic, biochemical, and clinical responses. Further, analysis of symptoms was reviewed during therapy and also in subsequent follow-ups for safety evaluation. Renal, gastrointestinal (GI), hepatic, and hematological adverse events were evaluated using National Cancer Institute common toxicities criteria V4.03, through full blood panels, as well as consultation with patients for any symptoms and/or adverse events. As of July 2016, median progression-free survival was about to be reached. Of 28 patients who have completed Lu DOTATATE therapy (completion of 4 or more cycles of treatment and all designated follow-ups), no patient showed complete response (CR), 8 patients (28.57%) showed partial response (PR), 16 patients (57.14%) showed stable disease (SD), and progressive disease (PD) was observed in 4 patients (14.28%). The objective response rate (CR + PR) of this group was 28.57% (n = 8) with a cumulative disease control (CR + PR + SD) of 85.71% (n = 24).Among 132 evaluable patients, assessment of treatment response using modified Response Evaluation Criteria in Solid Tumors criteria revealed CR in none of the patients, PR in 12 patients (9.09%), SD in 66 patients (50%), whereas PD, which included patients who passed away, was observed in 54 patients (40.90%), yielding an objective response rate of 9.09% (n = 12) and a cumulative disease control rate of 59.09% (n = 78).Symptoms including abdominal pain, diarrhea, flushing, and fatigue improved in over 50% of the patients, whereas weight loss improved in 28.26% of the patients. No grade 3 or grade 4 renal toxicities were found, though eleven grade 3 and five grade 4 hematological as well as three grade 3 hepatotoxicities were reported. Grade 3 hematotoxicity lasted an average of 2.7 months, and grade 4 lasted for only 0.9 months, whereas grade 3 hepatotoxicity lasted an average of 3.1 months. Lu-octreotate peptide receptor radionuclide therapy has shown promising potential as a safe and effective targeted therapy in inoperable, well to moderately differentiated metastatic neuroendocrine cancers. The results of the multicenter randomized clinical trial conducted in United States and Europe are concordant with current study.

Targeted radiopeptide therapy Re188-P2045 to treat neuroendocrine lung cancer.

e20016 Background: : Despite the recent success of checkpoint inhibitors, there continues to be a significant medical need for lung cancer therapies that can be directed to the patients most likely to respond. Somatostatin receptor subtype 2 (SSTR2) is the most widely up-regulated subtype in both small and non-small cell lung cancers and is also expressed in tumoral (but not mature) blood vessels. Peptide targeted radiotherapy has advantages over traditional targeted therapies in that targeted tumor cells as well as surrounding cancer cells and supporting stroma are selectively killed. This study was conducted to determine the ability of Rhenium Re 188 P2045, a radiolabeled somatostatin analog specific for SSTR2 to both image (to select the most appropriate patients) and treat lung cancer patients who over-express somatostatin receptors. Methods: In an open label, single arm study, refractory lung cancer patients to standard of care therapy were identified by image analysis using Rhenium Re 188 P2045, a radiolabeled somatostatin analog. 25 Patients received the imaging dose of 10uCi of Re188 and 265ng of peptide by intravenous injection. Three patients were selected based on high SSTR expression levels to receive 30uCi of Re188 P2045 as a therapeutic dose 14 days after imaging. Patients were followed for 8 weeks post treatment. Results: The imaging study revealed a high density of expression of the somatostatin receptor in the lungs of patients. Patients in the imaging and therapeutic treatment groups reported no adverse advents or signs of toxicity. The image analysis using Re188 P2045 was compared to CT images and demonstrated accurate detection of lung tumor lesions. The images obtained using Re188 P2045 were of sufficiently high quality to enable identification of receptor expression at the tumor site as shown in Figures 1&2. Conclusions: Rhenium Re 188 P2045, a radiolabeled somatostatin analog, may be used to both identify and treat lung cancer tumors. The ability to image and dose patients with the same targeted molecule enables a personalized medicine approach and this highly targeted patient therapy may significantly improve treatment of tumors that over express somatostatin receptor.

Surgery in combination with peptide receptor radionuclide therapy is effective in metastatic neuroendocrine tumors and is definable by blood gene transcript analysis.

e15697 Background: Neuroendocrine tumours (NET) of the pancreas (PNET) or small bowel (SBNET) frequently present with metastases at initial diagnosis, undermining the efficacy of surgical treatment. Peptide receptor radionuclide therapy (PRRT) with radiolabelled somatostatin analogues, 90Y-DOTATOC and 177Lu-DOTATATE, has been shown to achieve prolonged progression-free survival (PFS) in a substantial number of non-surgical patients with advanced NET. Our aim was to prospectively determine the efficacy of a combination of radical loco-regional surgery and PRRT in patients with metastasised NET. Methods: A set of inclusion criteria was defined (e.g. G1/G2 NET, initial tumour diagnosis, treatment naïve patient, stage IV NET, positivity on 68Ga DOTA- PET/CT, eligibility for surgery and PRRT). Patients underwent PRRT within 3 months following surgery. Follow-up included biochemistry and imaging. In a sub-cohort, blood-based neuroendocrine gene transcript analysis of 51 genes (NETest) was used to define the effectiveness of treatment. Outcome measures included 5-year overall survival (OS) and PFS from initial diagnosis. Results: Twenty-five patients (5 PNET, 20 SBNET) met eligibility criteria and were included. There were 13 men (52%) and mean age was 57.1 years. All patients with SB NET underwent right hemicolectomy, terminal ileal resection and mesenteric lympadenectomy. In all PNET patients only limited pancreatic resection was required. The median number of PRRT cycles was 4 (range 2-6). Post-treatment mortality was 0%. Surgical morbidity was 12% (all Clavien-Dindo grade 1). Transient grade 1 toxicity occurred post-PRRT in 40%. NETest scores were increased in 8 patients (100%) pre-operatively and decreased in all following treatment. NETest decreases correlated with diminished tumour volume (R2=0.37, p=0.02). Median follow-up was 48 months (range 12-72months). Five-year OS was 90% and 5-year PFS was 84.3%. Conclusions: Radical loco-regional surgery for primary tumours combined with PRRT provides a novel, highly efficacious approach in metastasised NET. The NETest accurately measures the effectiveness of treatment.

Effect of hormone secretory syndromes on neuroendocrine tumor prognosis.

The treatment of hormone hypersecretory syndromes caused by neuroendocrine tumors (NETs) can be a major challenge. NETs originating from the small intestine often secrete serotonin causing flushing, diarrhea and valve fibrosis, leading to dehydration or heart failure in severe cases. NETs from the pancreas can secrete a wider variety of hormones, like insulin, glucagon and gastrin leading to distinct clinical syndromes. Historically mortality in patients with functioning NETs was high due to the complications caused by the hypersecretion of hormones. This has been reduced with several drugs: proton-pump inhibitors decrease acid secretion caused by gastrinomas. Somatostatin analogs can inhibit the secretion of multiple hormones and these are now the cornerstone for treating patients with a gastroenteropancreatic NET. However, peptide receptor radionuclide therapy (PRRT) with radiolabeled somatostatin analogs and everolimus can also decrease symptoms of hypersecretion and increase progression-free survival. Several factors affect the survival in patients with a functioning NET. Complications of hypersecretion negatively impact survival; however, secretion of hormones is also often a sign of a well-differentiated NET and due to the symptoms, functioning NETs can be detected in an earlier stage suggesting a positive effect on prognosis. The effect on survival is also dependent on the type of hormone being secreted. This review aims to study the effect of hormone secretion on the prognosis of NETs with the contemporary treatments options available today.

Effectiveness of radiolabelled somatostatin analogues (90Y-DOTATOC and 177Lu-DOTATATE) in patients with metastatic neuroendocrine tumours: a single centre experience in Mexico.

To determine the effectiveness of therapy with the radiolabelled somatostatin analogues, 90Y-DOTATOC and 177Lu-DOTATATE, in the treatment of metastatic neuroendocrine tumours with progression to first-line treatment. A study was conducted on 30 patients diagnosed with neuroendocrine tumours (gastroenteropancreatic, bronchopulmonary, MEN2A, MEN2B, phaeochromocytoma, and paraganglioma) with metastatic disease diagnosed by the pathology department, with progression to first-line treatment, and recruited from December 2014 to February 2016. Efficacy was analysed using computed tomography (CT) according RECIST 1.1 criteria, and the molecular changes using the SUVmax of PET/CT with 68Ga-DOTATOC. Safety was carried out with a renal scan with 99mTc-MAG3. The 30 patients received a total of 49 cycles 90Y-DOTATOC (21 doses) and 177 Lu-DOTATATE (28 doses), with a mean of 1.5 cycles per patient. Of these, 17 (56.7%) showed a partial morphological response, 22 (73.3%) molecular and biochemical response, and 23 (76.6%) clinical response. One patient died during the median follow-up of 13 months. The median overall survival from diagnosis was 54 months (95% CI; 31.18-76.81), and median progression-free survival was 32 months (95% CI; 15.00-48.99). Therapy with 90Y-DOTATOC and 177Lu-DOTATATE is a promising therapy for patients with well and moderately differentiated neuroendocrine tumours. The efficacy is better the larger the number of cycles administered, inversely proportional to the number of metastases (<10), and is associated with the level of uptake according to the SUVmax by the metastases, regardless of metabolically active tumour volume.

Effectiveness of radiolabelled somatostatin analogs (90Y-DOTATOC and 177Lu-DOTATATE) in patients with metastatic neuroendocrine tumors: A single center experience in Mexico

ObjectiveTo determine the effectiveness of therapy with the radiolabelled somatostatin analogs, 90Y-DOTATOC and 177Lu-DOTATATE, in the treatment of metastatic neuroendocrine tumors with progression to first-line treatment. Material and methodsA study was conducted on 30 patients diagnosed with neuroendocrine tumors (gastroenteropancreatic, bronchopulmonary, MEN2A, MEN2B, phaeochromocytoma, and paraganglioma) with metastatic disease diagnosed by the pathology department, with progression to first-line treatment, and recruited from December 2014 to February 2016. Efficacy was analyzed using computed tomography (CT) according RECIST 1.1 criteria, and the molecular changes using the SUVmax of PET/CT with 68Ga-DOTATOC. Safety was carried out with a renal scan with 99mTc-MAG3. ResultsThe 30 patients received a total of 49 cycles 90Y-DOTATOC (21 doses) and 177Lu-DOTATATE (28 doses), with a mean of 1.5 cycles per patient. Of these, 17 (56.7%) showed a partial morphological response, 22 (73.3%) molecular and biochemical response, and 23 (76.6%) clinical response. One patient died during the median follow-up of 13 months. The median overall survival from diagnosis was 54 months (95% CI; 31.18–76.81), and median progression-free survival was 32 months (95% CI; 15.00–48.99). ConclusionTherapy with 90Y-DOTATOC and 177Lu-DOTATATE is a promising therapy for patients with well and moderately differentiated neuroendocrine tumors. The efficacy is better the larger the number of cycles administered, inversely proportional to the number of metastases (<10), and is associated with the level of uptake according to the SUVmax by the metastases, regardless of metabolically active tumor volume.

Treatment Strategies for Metastatic Neuroendocrine Tumors of the Gastrointestinal Tract.

The therapeutic landscape of gastroenteropancreatic-neuroendocrine tumors (GEP-NETs) has evolved significantly in recent years. Current and emerging treatment options include somatostatin analogs, radiolabeled somatostatin analogs, the mTOR inhibitor everolimus, and the tyrosine kinase inhibitor sunitinib. Although high-quality data from phase III trials are lacking, cytotoxic agents are commonly used for the treatment of poorly differentiated neuroendocrine carcinomas and well-differentiated NETs originating in the pancreas. Hepatic-directed therapies are recommended for patients with slow-growing, liver-predominant disease but have never been compared to systemic agents. Telotristat ethyl, a novel serotonin synthesis inhibitor, has recently demonstrated efficacy in palliating diarrhea in patients with poorly controlled carcinoid syndrome. In the absence of definite predictive biomarkers, therapeutic decisions in most cases rely on clinical and pathological criteria. However, navigating the current therapeutic algorithm may be challenging, and future trials need to address several important questions: what is the best sequence of treatment? Is there a role for combination therapies in GEP-NETs? Are neoadjuvant, adjuvant, or maintenance strategies safe and effective? Do all NET patients require active treatment? What new molecular targets can be clinically exploited? A tight integration between basic and clinical research is needed to further advance the field of NETs.

Radioguided surgery with radiolabeled somatostatin analogs: not only in GEP-NETs.

Radioguided surgery (RGS) is a surgical technique that, using intra-operative probes, enables the surgeon to identify tissues preoperatively "marked" by a radiopharmaceutical. Somatostatin receptors (SSTRs) are present in the majority of neuroendocrine cells and may be over-expressed not only by tumor cells, but also by endothelial cells of peritumoral vessels, inflammatory cells and cells of the immune system, such as activated lymphocytes, monocytes and epithelioid cells. This extra neoplastic uptake is the rationale for the use of radiolabeled somatostatin analogs (SSAs) either in some tumors not expressing SSTRs or in various non-oncological diseases. The crucial point of RGS technique lays in the establishment of a favorable tumor-to-background ratio (TBR). A wide range of probe systems are available with different detectors and many radiopharmaceuticals have been experimented and utilized, mainly using g-detection probes; in order to widen RGS application field, newer approaches with b- or b+ emitting radioisotopes have also been proposed. Together with the consolidated clinical use, a promising and effective employment of RGS may be found in neuroendocrine tumors (NETs) using 111In-pentetreotide (OCT). RGS with OCT has been demonstrated useful in the management of patients with gastroenteropancreatic (GEP) tumors, lung, brain and breast cancer. Preoperative scintigraphy or PET with DOTA-peptides combined with RGS increases the rate of successful surgery. Preliminary studies with b- probes using 90Y-SSA suggest the possible interest of this approach in patients undergoing peptide receptor radiotherapy.

SPECT/CT with radiolabeled somatostatin analogues in the evaluation of systemic granulomatous infections.

ObjectiveTo evaluate SPECT/CT with radiolabeled somatostatin analogues (RSAs) in systemic granulomatous infections in comparison with gallium-67 (67Ga) citrate scintigraphy.Materials and MethodsWe studied 28 patients with active systemic granulomatous infections, including tuberculosis, paracoccidioidomycosis, pneumocystosis, cryptococcosis, aspergillosis, leishmaniasis, infectious vasculitis, and an unspecified opportunistic infection. Of the 28 patients, 23 had started specific treatment before the study outset. All patients underwent whole-body SPECT/CT imaging: 7 after injection of 99mTc-EDDA-HYNIC-TOC, and 21 after injection of 111In-DTPA-octreotide. All patients also underwent 67Ga citrate imaging, except for one patient who died before the 67Ga was available.ResultsIn 20 of the 27 patients who underwent imaging with both tracers, 27 sites of active disease were detected by 67Ga citrate imaging and by SPECT/CT with an RSA. Both tracers had negative results in the other 7 patients. RSA uptake was visually lower than 67Ga uptake in 11 of the 20 patients with positive images and similar to 67Ga uptake in the other 9 patients. The only patient who did not undergo 67Ga scintigraphy underwent 99mTc-EDDA-HYNIC-TOC SPECT/CT-guided biopsy of a lung cavity with focal RSA uptake, which turned to be positive for aspergillosis.ConclusionSPECT/CT with 99mTc-EDDA-HYNIC-TOC or 111In-DTPA-octreotide seems to be a good alternative to 67Ga citrate imaging for the evaluation of patients with systemic granulomatous disease.

Correlation of Somatostatin Receptor-2 Expression with Gallium-68-DOTA-TATE Uptake in Neuroblastoma Xenograft Models.

Peptide-receptor imaging and therapy with radiolabeled somatostatin analogs such as 68Ga-DOTA-TATE and 177Lu-DOTA-TATE have become an effective treatment option for SSTR-positive neuroendocrine tumors. The purpose of this study was to evaluate the correlation of somatostatin receptor-2 (SSTR2) expression with 68Ga-DOTA-TATE uptake and 177Lu-DOTA-TATE therapy in neuroblastoma (NB) xenograft models. We demonstrated variable SSTR2 expression profiles in eight NB cell lines. From micro-PET imaging and autoradiography, a higher uptake of 68Ga-DOTA-TATE was observed in SSTR2 high-expressing NB xenografts (CHLA-15) compared to SSTR2 low-expressing NB xenografts (SK-N-BE(2)). Combined autoradiography-immunohistochemistry revealed histological colocalization of SSTR2 and 68Ga-DOTA-TATE uptake in CHLA-15 tumors. With a low dose of 177Lu-DOTA-TATE (20 MBq/animal), tumor growth inhibition was achieved in the CHLA-15 high SSTR2 expressing xenograft model. Although, in vitro, NB cells showed variable expression levels of norepinephrine transporter (NET), a molecular target for 131I-MIBG therapy, low 123I-MIBG uptake was observed in all selected NB xenografts. In conclusion, SSTR2 expression levels are associated with 68Ga-DOTA-TATE uptake and antitumor efficacy of 177Lu-DOTA-TATE. 68Ga-DOTA-TATE PET is superior to 123I-MIBG SPECT imaging in detecting NB tumors in our model. Radiolabeled DOTA-TATE can be used as an agent for NB tumor imaging to potentially discriminate tumors eligible for 177Lu-DOTA-TATE therapy.

SPECT-CT Modality for Imaging of Medullary Thyroid Cancer (MTC)

Medullary thyroid cancer (MTC) is a neuroendocrine tumor that arises from the parafollicular Calcitonin-producing C-cells of the thyroid. Typically the MTC is an extremely slow-growing cancer; however, it has a tendency of spreading distant metastases fairly early. Systemic chemotherapy and external been radiotherapy have not shown to give a good MTC response. As of date radical thyroidectomy is the main method of choice for therapy. New compounds like tyrosine kinase inhibitors (TKIs) targeting signaling pathways may have a positive outcome and be of great clinical benefits in patients with advanced and metastatic MTC. Somatostatin receptor are over expressed in MTC and thus allows the use of radiolabeled somatostatin analogues for scintigraphic imaging before and after treatment for proper staging and follow-up of these patients. SPECT-CT is used to optimize somatostatin-receptor scintigraphic protocols for MTC imaging. We have presented a case report of a patient who underwent total thyroidectomy with bilateral lymphadenectomy in August 2006 due to the diagnosed MTC. This patient was treated by chemotherapy and surgery during the period between January/2007- December/2014 because of the recurrent disease. In December 2014 the calcitonin level reached 56 000 pg/ml; whole body scan with 740 MBq 99mTc-EDDA/HYNIC-TOC, followed by target SPECT-CT showed a total disease progression with advanced metastatic dissemination into the body. The assigned therapy was with Caprelsa®(Vandetanib) 300 mg/d orally which was initialized from March 2015 until present. In June 2016 a control SPECT-CT somatostatinreceptor scintigraphy with 740 MBq 99mTc-Tektrotyd was performed from which was reported a partial disease response with a reduction of about 60% in size and a decrease in the number of metastatic lesions shown to correlated with the decreased calcitonin level up to 1560 pg/ml. It can be concluded that SPECT-CT with 99mTc- Tektrotyd has important clinical role for re-staging and follow-up of patients with recurrent and metastatic MTC after target therapy.

177Lu-DOTATATE treatment in neuroendocrine tumours. A preliminary study.

Therapy with radiolabelled somatostatin analogue peptides is a promising new therapy to treat neuroendocrine tumours. The aim of this preliminary study is to present our experience with 177Lu-DOTATATE therapy, and evaluate tolerability and short-term efficacy in patients with tumours expressing somatostatin receptors. A total of 7 patients with metastatic neuroendocrine tumours were treated, each with 4 doses of 177Lu-DOTATATE. The treatment response was evaluated in the form of biochemical response (tumour markers), imaging methods (somatostatin receptor scintigraphy, computed tomography, and magnetic resonance), and functional and quality of life responses using the Karnofsky performance status scale. Treatment toxicity was also evaluated. The results obtained were as follows: Biochemical response: 60% of patients showed tumour marker levels returning to normal, while they decreased significantly in the remaining 40%. Imaging response: 85.7% had a partial response, while 14.3% showed stable disease. All (100%) patients showed a significant improvement in quality of life, with increased Karnofsky scale scores. No patient had acute or chronic toxicity, and subacute transient haematological toxicity was observed in 42.8% of patients. Despite being a preliminary study, it was found that treatment with 177Lu-DOTATATE is a safe treatment with few side effects, and an objective response was achieved in most patients.

NAMPT Inhibitor GMX1778 Enhances the Efficacy of 177Lu-DOTATATE Treatment of Neuroendocrine Tumors.

Nude mice xenografted with the human NET cell line GOT1 were treated with semiefficient doses of 177Lu-DOTATATE (7.5 MBq, intravenously) or the nicotineamide phosphoribosyltransferase inhibitor GMX1778 (100 mg/kg/wk, orally). Median time to tumor progression (tumor volume larger than at day 0) was 3 d for controls, 7 d for single-dose GMX1778, 28 d for single-dose 177Lu-DOTATATE, 35 d for 3 weekly doses of GMX1778, and 98 d for combined treatment with 177Lu-DOTATATE and GMX1778 × 1. After 177Lu-DOTATATE and 3 weekly doses of GMX1778, none of the tumors progressed within 120 d. GMX1778 enhances the efficacy of 177Lu-DOTATATE treatment and induces a prolonged antitumor response.

Lutetium 177-DOTA-TATE therapy for esthesioneuroblastoma: A case report.

Esthesioneuroblastoma (ENB), also known as olfactory neuroblastoma, is a rare malignant tumor that accounts for 3% of all tumors of the nasal cavity. The incidence of ENB is 0.4 cases per million in the general population, and the most common symptoms are nasal obstruction and epistaxis. Previous studies have indicated the presence of somatostatin receptors in this tumor type. Common treatment strategies for ENB include resection and adjuvant radiotherapy and/or chemotherapy (combined treatment); however, the rate of recurrence is high. Treatment of neuroendocrine tumors using radionuclides bound to somatostatin analogues is well established in clinical practice. However, a standard and effective therapeutic approach has not been reported for ENB. The current study described the case of a 74-year-old female with numerous recurrences of ENB following multiple treatments and without possibility of resection. The patient was treated with the radiolabeled-somatostatin analogue, 177Lutetium-DOTA-octreotate (177Lu-DOTA-TATE), which successfully controlled the disease. This suggests that 177Lu-DOTA-TATE is a potential treatment for ENB and may represent an effective alternative and novel therapeutic strategy for this disease.

99mTc-EDDA/HYNIC-TOC in the diagnosis of differentiated thyroid carcinoma refractory to radioiodine treatment.

In majority of cases of differentiated thyroid carcinoma (DTC), the ablative radioiodine treatment shows high efficacy. In a small number of patients, mechanism of selective iodine uptake by the DTC cells is insufficient and alternative methods of diagnosis and treatment are needed. As demonstrated in vitro, DTC cells show expression of somatostatin recep-tors. Radiolabeled somatostatin analogs are widely used in the diagnosis of neuroendocrine tumors. The aim of the study was to evaluate the utility of peptide receptor scintigraphy with the use of 99mTc-EDDA/HYNIC-TOC in the diagnosis of DTC in patients with elevated thyroglobulin concentrations (Tg), negative WBS and no effect of the consecutive radioiodine therapies. Whole body scintigraphy as well as SPECT of neck and chest were performed 3 and 24 h after i.v. administration of 740 MBq 99mTc-EDDA/HYNIC-TOC. The obtained images were compared with other radionuclide and ra-diological imaging methods. Forty-three patients with DTC after surgery and ablative radioiodine treatment with negative WBS and elevated Tg were qualified. Patients' age: 18-83 years (mean 58.0). SRS showed foci of tracer accumulation in 29 cases (67.4%). Sensitivity was 69.0% specificity 78.6%. SRS correctly identified local recurrence in 8 pts., metastatic lymph nodes in 19 pts., lung metastases in 12 pts. and bone metastases in 5 pts. SRS showed high sensitivity in the detection of metastatic lymph nodes (100%) and bone metastases (83.3%) and lung metastases (63.2%). Positive SRS was found in pts. with higher Tg concentrations (130 ± 144 vs. 30 ± 54 ng/ml). Scintigraphy with the use of the studied technetium-99m-labeled somatostatin analog is useful in the evaluation of patients with advanced DTC. It shows relatively good sensitivity and specificity but not high enough to be recommended as a routine imaging method. The role of somatostatin receptor scintigraphy in DTC is complementary to other imaging modalities.

Somatostatin receptor scintigraphy in patients with rheumatoid arthritis and secondary Sjögren's syndrome treated with Infliximab: a pilot study.

BackgroundHuman T lymphocytes infiltrating tissues in autoimmune diseases are known to express somatostatin receptors amongst other activation markers. In this study, we evaluated whether somatostatin receptor scintigraphy (SRS) using a radiolabelled somatostatin analogue (99mTc-EDDA/tricine-HYNIC-tyr(3)-octreotide (99mTc-EDDA/HYNIC-TOC)) is able to detect the presence of immune-mediated processes in patients with rheumatoid arthritis and secondary Sjögren’s syndrome. We also aimed to evaluate whether positivity to SRS was predictive of therapeutic response and if SRS could be used for monitoring the efficacy of immunomodulatory treatment.MethodsEighteen patients with rheumatoid arthritis and secondary Sjögren’s syndrome not responding to conventional treatment were recruited for treatment with infliximab, a monoclonal antibody against TNF-α. All patients had complete blood cell count, renal and liver function tests, measurements of ESR, CRP, ANA, ENA, and anti-dsDNA antibodies, functional salivary gland scintigraphy, labial biopsy, and ophthalmologic assessment with Schirmer’s test and tear film break-up time (BUT). Diagnosis was made according to the revised criteria of the American-European Consensus Group. All patients underwent SRS at baseline and after 3–6 months of therapy with infliximab. Eleven out of 18 had repeat SRS images. Images of the salivary glands and major joints were acquired 3 h after injection of 370 MBq of 99mTc-EDDA/HYNIC-TOC. Image analysis was performed semi-quantitatively.ResultsAll patients showed uptake of 99mTc-EDDA/HYNIC-TOC in the joints. Salivary glands also showed variable radiopharmaceutical uptake in 12 out of 18 patients, but all patients showed presence of lymphocytic infiltration at labial salivary gland biopsy. All patients, who repeated the study after treatment, showed significant reduction of somatostatin uptake in the joints but not in the salivary glands.ConclusionsSRS using 99mTc-EDDA/HYNIC-TOC may be a useful imaging tool to assess disease activity and extent in patients with rheumatoid arthritis and may help to detect secondary Sjögren’s syndrome. It may also aid therapy decision-making with anti-TNFα antibodies in the joints but not in salivary glands.

Evaluation of a Fluorescent and Radiolabeled Hybrid Somatostatin Analog In Vitro and in Mice Bearing H69 Neuroendocrine Xenografts.

In the treatment of neuroendocrine tumors (NETs), complete surgical removal of malignancy is generally desirable, because it offers curative results. Preoperative guidance with radiolabeled somatostatin analogs, commonly used for NET diagnosis and preoperative planning, is limited by its low resolution, with the risk that tumor margins and small metastases will be incompletely resected with subsequent recurrence. A single hybrid probe combining radiotracer and optical dye would enable high-resolution optical guidance, also during surgery. In the current study, the hybrid labeled somatostatin analog Cy5-DTPA-Tyr(3)-octreotate (DTPA is diethylene triamine pentaacetic acid) was synthesized and evaluated for its ability to specifically trace NET cells in vitro and in an animal model. The performance of the hybrid tracer was compared with that of octreotate with only radiolabel or only optical label. The binding affinity and internalization capacity of Cy5-DTPA-Tyr(3)-octreotate were assessed in vitro. Biodistribution profiles and both nuclear and optical in vivo imaging of Cy5-(111)In -DTPA-Tyr(3)-octreotate were performed in NET-bearing mice and compared with the performance of (111)In-DTPA-Tyr(3)-octreotate. In vitro studies showed a low receptor affinity and internalization rate for Cy5-DTPA-Tyr(3)-octreotate. The dissociation constant value was 387.7 ± 97.9 nM for Cy5-DTPA-Tyr(3)-octreotate, whereas it was 120.5 ± 18.1 nM for DTPA-Tyr(3)-octreotate. Similarly, receptor-mediated internalization reduced from 33.76% ± 1.22% applied dose for DTPA-Tyr(3)-octreotate to 1.32% ± 0.02% applied dose for Cy5-DTPA-Tyr(3)-octreotate. In contrast, in vivo and ex vivo studies revealed similar tumor uptake values of Cy5-(111)In-DTPA-Tyr(3)-octreotate and (111)In -DTPA-Tyr(3)-octreotate (6.93 ± 2.08 and 5.16 ± 1.27, respectively). All organs except the kidneys showed low background radioactivity, with especially low activities in the liver, and high tumor-to-tissue ratios were achieved-both favorable for the tracer's toxicity profile. Hybrid imaging in mice confirmed that the nuclear and fluorescence signals colocalized. The correlation between findings with the optical and the nuclear probes underlines the potential of combining SPECT imaging with fluorescence guidance and shows the promise of this novel hybrid peptide for preoperative and intraoperative imaging of NET.

Potentiation of Peptide Receptor Radionuclide Therapy by the PARP Inhibitor Olaparib.

Metastases expressing tumor-specific receptors can be targeted and treated by binding of radiolabeled peptides (peptide receptor radionuclide therapy or PRRT). For example, patients with metastasized somatostatin receptor-positive neuroendocrine tumors (NETs) can be treated with radiolabeled somatostatin analogues, resulting in strongly increased progression-free survival and quality of life. There is nevertheless still room for improvement, as very few patients can be cured at this stage of disease. We aimed to specifically sensitize replicating tumor cells without further damage to healthy tissues. Thereto we investigated the DNA damaging effects of PRRT with the purpose to enhance these effects through modulation of the DNA damage response. Although PRRT induces DNA double strand breaks (DSBs), a larger fraction of the induced lesions are single strand breaks (expected to be similar to those induced by external beam radiotherapy) that require poly-[ADP-ribose]-polymerase 1 (PARP-1) activity for repair. If these breaks cannot be repaired, they will cause replication fork arrest and DSB formation during replication. Therefore, we used the PARP-1 inhibitor Olaparib to increase the number of cytotoxic DSBs. Here we show that this new combination strategy synergistically sensitized somatostatin receptor expressing cells to PRRT. We observed increased cell death and reduced cellular proliferation compared to the PRRT alone. The enhanced cell death was caused by increased numbers of DSBs that are repaired with remarkably slow kinetics, leading to genome instability. Furthermore, we validated the increased DSB induction after PARP inhibitor addition in the clinically relevant model of living human NET slices. We expect that this combined regimen can thus augment current PRRT outcomes.

Gastro-entero-pancreatic neuroendocrine tumors: Is now time for a new approach?

Gastro-entero-pancreatic tumors (GEP-NETs) are rare neoplasms often characterized by an overexpression of somatostatin receptors. Thus, radiolabeled somatostatin analogues have showed an increasing relevance both in diagnosis and treatment, especially in low- and intermediate-differentiated GEP-NETs. These evidences have led to a growing development of new functional imaging techniques as 68Ga-DOTATATE positron emission tomography/computed tomography (PET/CT) proved useful in the management of these neoplasms. However these tumors have a heterogeneous behavior also modifying their aggressiveness through time. Therefore sometimes 18F-fluorodeoxyglucose PET/CT appears to be more appropriate to obtain a better assessment of the disease. According to these considerations, the combination of different functional imaging techniques should be considered in the management of GEP-NETs patients allowing clinicians to choose the tailored therapeutic approach among available options.

Human Anti-Oxidation Protein A1M--A Potential Kidney Protection Agent in Peptide Receptor Radionuclide Therapy.

Peptide receptor radionuclide therapy (PRRT) has been in clinical use for 15 years to treat metastatic neuroendocrine tumors. PRRT is limited by reabsorption and retention of the administered radiolabeled somatostatin analogues in the proximal tubule. Consequently, it is essential to develop and employ methods to protect the kidneys during PRRT. Today, infusion of positively charged amino acids is the standard method of kidney protection. Other methods, such as administration of amifostine, are still under evaluation and show promising results. α1-microglobulin (A1M) is a reductase and radical scavenging protein ubiquitously present in plasma and extravascular tissue. Human A1M has antioxidation properties and has been shown to prevent radiation-induced in vitro cell damage and protect non-irradiated surrounding cells. It has recently been shown in mice that exogenously infused A1M and the somatostatin analogue octreotide are co-localized in proximal tubules of the kidney after intravenous infusion. In this review we describe the current situation of kidney protection during PRRT, discuss the necessity and implications of more precise dosimetry and present A1M as a new, potential candidate for renal protection during PRRT and related targeted radionuclide therapies.