Peptide Receptor Radionuclide Therapy Is Effective for Clinical Control of Symptomatic Metastatic Insulinoma: A Long-Term Retrospective Analysis.

Metastatic insulinoma is a rare malignant neuroendocrine tumor characterized by inappropriate insulin secretion, resulting in life-threatening hypoglycemia, which is often difficult to treat. There is currently very limited information about the efficacy of peptide receptor radionuclide therapy (PRRT) for clinical control of hypoglycemia. The aim of this long-term retrospective study was to evaluate the therapeutic efficacy of PRRT for improving hypoglycemia, to evaluate the change of medication after PRRT, and to calculate progression-free survival (PFS) and overall survival (OS). Methods: Inclusion criteria were histologically proven somatostatin receptor-positive metastatic malignant insulinoma and at least 2 cycles of [90Y]Y-DOTATOC or [177Lu]Lu-DOTATOC therapy from early 2000 to early 2022. A semiquantitative scoring system was used to quantify the severity and frequency of hypoglycemic episodes under background antihypoglycemic therapy (somatostatin analog, diazoxide, everolimus, corticosteroids): score 0, no hypoglycemic episodes; score 1, hypoglycemic events requiring additional conservative treatment with optimization of nutrition; score 2, severe hypoglycemia necessitating hospitalization and combined medication or history of hypoglycemic coma. Hypoglycemic score before and after PRRT was analyzed. Time of benefit was defined as a time range of fewer hypoglycemic episodes in the observation period than at baseline. Information on antihypoglycemic medication before and after therapy, PFS, and OS was recorded. Results: Twenty-six of 32 patients with a total of 106 [90Y]Y-DOTATOC/[177Lu]Lu-DOTATOC cycles were included. The average observation period was 21.5 mo (range, 2.3-107.4 mo). Before therapy, 81% (n = 21) of the patients had a hypoglycemia score of 2 and 19% (n = 5) had a score of 1. After PRRT, 81% of patients (n = 21) had a decreased score, and the remaining 5 patients showed a stable situation. There was temporary worsening of hypoglycemia just after injection of [90Y]Y-DOTATOC/[177Lu]Lu-DOTATOC in 19% of patients. The average time of benefit in the observation period was 17.2 mo (range, 0-70.2 mo). Antihypoglycemic medication reduction was achieved in 58% (n = 15) of patients. The median OS and PFS after the start of PRRT were 19.7 mo (95% CI, 6.5-32.9 mo) and 11.7 mo (95% CI, 4.9-18.5 mo), respectively. Conclusion: To our knowledge, our study included the largest cohort of patients with malignant insulinoma to be evaluated. Long-lasting symptom control and reduction of antihypoglycemic medications were shown in most patients after late-line PRRT.

Case report - Selective internal radiation therapy (SIRT) in a patient with hyperinsulinemic hypoglycemia due to a metastatic insulinoma with late onset of endocrine activity.

Insulinomas are the most common functioning pancreatic neuroendocrine tumors (NET), which can lead to hyperinsulinemic hypoglycemia. In advanced metastatic stages of the disease, the prognosis is poor. Patients with hormonally active insulinomas primarily present with features of neuroglycopenia. Transformation from a nonfunctional to a functional NET is rare. Here, we present a case of a 59-year-old male adult with a metastatic insulinoma and late onset of endocrine activity. Besides medical treatment with Diazoxide and small frequent feedings, continuous intravenous glucose application was eventually required to avoid hypoglycemia. Furthermore, we show that selective internal radiation therapy (SIRT) can be an effective therapeutic approach for symptom reduction in advanced metastatic disease.

Complete Resolution of Disease After Peptide Receptor Radionuclide Therapy in a Patient of Metastatic Insulinoma.

ABSTRACT: A 48-year-old man, a case of metastatic insulinoma, who failed transarterial chemoembolization of liver metastases underwent multiple cycles of peptide receptor radionuclide therapy with 177Lu-DOTATATE, following which a complete morphologic and metabolic response was demonstrated on 68Ga-DOTATATE PET/CT. Patient had a remarkable improvement in his quality of life as intractable hypoglycemic episodes resolved after treatment. Peptide receptor radionuclide therapy is a promising targeted radionuclide therapy in patients of metastatic insulinomas that can result in reduced tumor burden and improved quality of life, particularly those who fail the conventional treatment modalities as seen in the present case.

Insulinoma-associated protein 1 controls nasopharyngeal carcinoma to radiotherapy by modulating cyclin D1-dependent DNA repair machinery.

Insulinoma-associated protein 1 (INSM1), a zinc finger transcriptional factor, is proven to be deregulated in several types of cancers. However, comprehension of the molecular mechanism of INSM1-mediated tumor progression remains poor. Here, we show that the radioresistant nasopharyngeal carcinoma (NPC) patients have higher expressions of INSM1 that correlated with poor prognosis. Genetic manipulation of INSM1 expression sufficiently controls the response of NPC cells to irradiation (IR). Mechanistically, cells exposed to IR, increased intracellular INSM1 competitively disrupts the interaction of cyclin D1 and CDK4 resulting in cell survival by the cyclin D1-dependent DNA repair machinery. Moreover, knockdown of INSM1 sensitives NPC cells to IR in vivo and protects xenograft mice from mortality. Taken together, these results indicate that INSM1 modulates NPC to radiotherapy by controlling cyclin D1-dependent DNA repair machinery that could be manipulated as a novel molecular target for NPC therapy.

Preparation of [177Lu]Lu-DOTA-Ahx-Lys40-Exendin-4 for radiotherapy of insulinoma: a detailed insight into the radiochemical intricacies.

INTRODUCTION: [177Lu]Lu-DOTA-Ahx-Lys40-Exendin-4 ([177Lu]Lu-DOTA-Exendin-4) is a potential agent for radiotherapy of insulinomas owing to its specificity towards GLP-1 (Glucagon like peptide-1) receptors over-expressed on such cancers. The objective of the present study is to optimize the various radiochemistry parameters for the consistent formulation of the agent with high radiolabeling yield using carrier added [177Lu]LuCl3 and also to evaluate its biological behaviour in small animal model. METHODS: In order to optimize the radiolabeling parameters, DOTA-Exendin-4 was radiolabeled with [177Lu]LuCl3 in two different buffer systems (sodium acetate and HEPES) at three different temperatures (45, 65 and 95 °C) using three different ligand to metal ratios (3:1, 4:1 and 5:1). The radiolabeled peptide was characterized by both paper chromatography and HPLC. The effect of addition of three different radio-protectors on complexation yield was also studied. Bio-distribution studies were carried out in healthy Swiss mice to evaluate the pharmacokinetic behaviour of the radiolabeled peptide as well as to determine the in vivo specificity of the radiotracer towards GLP-1 receptors (blocking studies). Urine and kidney lysate of the animals were analyzed at various post-administration time-points in order to determine the in vivo stability of the radiolabeled peptide. RESULTS: The [177Lu]Lu-DOTA-Exendin-4 complex could be prepared consistently with >95% radiolabeling yield using the optimized reaction conditions. Bio-distribution studies revealed early accumulation of [177Lu]Lu-DOTA-Exendin-4 in pancreas along with fast clearance via renal pathway. Significantly high accumulation of the radiotracer was observed in kidneys. Analyses of urine and kidney lysate of the animals revealed in vivo stability of [177Lu]Lu-DOTA-Exendin-4. Blocking studies showed displacement of significant amount of radiotracer from GLP-1 receptor-positive organs such as, pancreas and lungs (p <0.05) in presence of unlabeled peptide, indicating the specificity of the radiolabeled preparation towards GLP-1 receptors. CONCLUSIONS: Present study shows that [177Lu]Lu-DOTA-Exendin-4 could be formulated for radiotherapeutic application with high radiochemical purity and adequate in vivo stability using [177Lu]LuCl3 produced via direct neutron irradiation. ADVANCES IN KNOWLEDGE AND IMPLICATIONS FOR PATIENT CARE: Findings of the present study will be helpful in preparing the patient dose of [177Lu]Lu-labeled Exendin for radiotherapy of insulinoma using carrier added [177Lu]LuCl3, produced in a medium flux reactor, without the requirement of post-labeling purification.

Improving the Theranostic Potential of Exendin 4 by Reducing the Renal Radioactivity through Brush Border Membrane Enzyme-Mediated Degradation.

As highly expressed in insulinomas, the glucagon-like peptide-1 receptor (GLP-1R) is believed to be an attractive target for diagnosis, localization, and treatment with radiolabeled exendin 4. However, the high and persistent radioactivity accumulation of exendin 4 in the kidneys limits accurate diagnosis and safe, as well as effective, radiotherapy in insulinomas. In this study, we intend to reduce the renal accumulation of radiolabeled exendin 4 through degradation mediated by brush border membrane enzymes. A new exendin 4 ligand NOTA-MVK-Cys40-Leu14-Exendin 4 containing Met-Val-Lys (MVK) linker between the peptide and 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA) chelator was synthesized and labeled with 68Ga. The in vitro mouse serum stability and cell binding affinity of the tracer were evaluated. Initial in vitro cleavage of the linker was determined by incubation of a model compound Boc-MVK-Dde with brush border membrane vesicles (BBMVs) with and without the inhibitor of neutral endopeptidase (NEP). Further cleavage studies were performed with the full structure of NOTA-MVK-Cys40-Leu14-Exendin 4. Kidney and urine samples were collected in the in vivo metabolism study after intravenous injection of 68Ga-NOTA-MVK-Cys40-Leu14-Exendin 4. The microPET images were acquired in INS-1 tumor model at different time points; the radioactivity uptake of 68Ga-NOTA-MVK-Cys40-Leu14-Exendin 4 in tumor and kidneys were determined and compared with the control radiotracer without MVK linker. 68Ga-NOTA-MVK-Cys40-Leu14-Exendin 4 was stable in mouse serum. The MVK modification did not affect the affinity of NOTA-MVK-Cys40-Leu14-Exendin 4 toward GLP-1R. The in vitro cleavage study and in vivo metabolism study confirmed that the MVK sequence can be recognized by BBM enzymes and cleaved at the amide bond between Met and Val, thus releasing the small fragment containing Met. MicroPET images showed that the tumor uptake of 68Ga-NOTA-MVK-Cys40-Leu14-Exendin 4 was comparable to that of the control, while the kidney uptake was significantly reduced. As a result, more favorable tumor to kidney ratios were achieved. In this study, a novel exendin 4 analogue, NOTA-MVK-Cys40-Leu14-Exendin 4, was successfully synthesized and labeled with 68Ga. With the cleavable MVK sequence, this ligand could be cleaved by the enzymes on kidneys, and releasing the fragment of 68Ga-NOTA-Met-OH, which will rapidly excrete from urine. As the high and consistent renal radioactivity accumulation could be significantly reduced, NOTA-MVK-Cys40-Leu14-Exendin 4 shows great potential in the diagnosis and radiotherapy for insulinoma.

Peptide receptor radionuclide therapy with 177Lu-DOTA-TATE as a promising treatment of malignant insulinoma: a series of case reports and literature review.

INTRODUCTION: Insulinomas are a rare type of pancreatic neuroendocrine tumours characterized by insulin hypersecretion. They are considered malignant when metastases are present. Traditional therapies often promote only temporarily symptomatic relief and may be associated with severe adverse effects. There is scarce experience in treating malignant insulinomas with peptide receptors radionuclide therapy (PRRNT). PATIENTS AND METHODS: We describe PRRNT results in four patients with inoperable malignant insulinomas with poorly controllable hypoglycaemia. All patients received therapy with 177Lu-DOTA-TATE after conventional therapies failed in controlling disease progression and symptoms. The activity administered per cycle was 4.8-7.4 GBq. The interval between cycles was 10-16 weeks. Haematology, liver and kidney function tests were performed before treatment initiation and 5 and 10 weeks after each cycle. RESULTS: Patient 1 presented significant clinical benefit for 13 months after PRRNT, with imaging improvement. Patient 2 obtained reduction of the number and severity of hypoglycaemic episodes during 15 months after therapy. Patient 3 is asymptomatic since PRRNT first cycle performed 23 months ago and revealed significant imaging improvement. Patient 4 had resolution of hypoglycaemia only 3 days after PRRNT first cycle and today, 16 months after therapy, the disease seems to be in remission and the patient maintains euglycaemic state. PRRNT was well tolerated, with only hematologic grade 2 toxicity in patient 1 and mild kidney toxicity in patient 3. CONCLUSIONS: After the start of 177Lu-DOTA-TATE all patients achieved hypoglycaemia symptomatic control and had evident improvement of their quality of life. Three patients showed imagiological improvement suggesting reduced tumour load.

Succinylated Gelatin Improves the Theranostic Potential of Radiolabeled Exendin-4 in Insulinoma Patients.

Being highly expressed in insulinomas, the glucagonlike peptide-1 receptor (GLP-1R) is a potential target for diagnosis, localization, and treatment with the radiolabeled GLP-1R agonist exendin. Tracer accumulation in the kidneys, however, hampers accurate diagnostic visualization of pancreatic tissue and prohibits the therapeutic application of radiolabeled exendin for ß-cell-derived tumors. Therefore, we evaluated the ability of succinylated gelatin (Gelofusine) to reduce the renal accumulation of radiolabeled exendin in humans, and we performed dosimetric calculations to estimate the maximum absorbed insulinoma dose that could be achieved if exendin were to be used for peptide receptor radionuclide therapy. Methods: Ten healthy volunteers received 50 MBq of 111In-exendin-4, in combination with Gelofusine or saline, in a crossover design. SPECT/CT images were obtained after 24 h. The procedure was repeated 3 wk later. Uptake of 111In-exendin was determined by drawing regions of interest around the kidneys and in the pancreas. Planar scintigraphic 111In-exendin images of 5 insulinoma patients were used for dosimetry studies estimating the maximum insulinoma absorbed dose that could be achieved without causing radiotoxicity to other organs. Results: Gelofusine reduced the renal accumulation of 111In-exendin-4 by 18.1%, whereas the pancreatic uptake remained unchanged. In 3 of 10 subjects, the kidney uptake was reduced to such an extent that the pancreatic tail could be better discriminated from the kidney signal. Dosimetric estimations suggested that the insulinoma absorbed dose ranges from 30.3 to 127.8 Gy. This dose could be further increased to maximally 156.1 Gy if Gelofusine was used. Conclusion: We have shown that Gelofusine can reduce the renal accumulation of 111In-exendin-4 in humans. This reduction not only allows more accurate qualitative and quantitative analyses of radiolabeled exendin uptake in the tail region of the pancreas but also potentiates the safe delivery of a higher radiation dose to GLP-1R-positive tumors for therapy.

Metastatic Insulinoma Pancreatic Neuroendocrine Tumor Treated With 177Lu-DOTATATE Induction and Maintenance Peptide Receptor Radionuclide Therapy: A Suggested Protocol.

A 70-year-old woman presented with frequent episodes of hypoglycemia. Imaging revealed a 6-cm pancreatic mass with several liver lesions. The pancreatic mass was resected and confirmed to be a well-differentiated insulinoma. Surgery improved but did not resolve her hypoglycemic episodes, and she was referred for peptide receptor radionuclide therapy with 177Lu-DOTATATE to treat her residual disease. A modified protocol with a continuous IV dextrose infusion was used, and the treatments were well tolerated. After 4 induction and 2 maintenance treatments, her hypoglycemic symptoms resolved completely and her disease stabilized. She has been progression free for 24 months.

Spinal cord compression after radiolabeled metaiodobenzylguanidine analogue therapy in advanced malignant insulinoma.

Malignant insulinomas are frequently diagnosed at a late stage. Medical management is necessary to slow progression of the disease and control of hypoglycemic symptoms when cure by surgical treatment is not possible. Multimodal treatment, in these cases, has been used with variable clinical response. We describe a 68-yr-old woman who presented response failure to usual treatment and was alternatively treated with radiolabeled metaiodobenzylguanidine ([131I]-MIBG) analogue therapy with development of neurologic complications. We also present a review of the current role of [131I]-MIBG treatment in insulinomas.

Spinal cord compression after radiolabeled metaiodobenzylguanidine analogue therapy in advanced malignant insulinoma

Malignant insulinomas are frequently diagnosed at a late stage. Medical management is necessary to slow progression of the disease and control of hypoglycemic symptoms when cure by surgical treatment is not possible. Multimodal treatment, in these cases, has been used with variable clinical response. We describe a 68-yr-old woman who presented response failure to usual treatment and was alternatively treated with radiolabeled metaiodobenzylguanidine ([131I]-MIBG) analogue therapy with development of neurologic complications. We also present a review of the current role of [131I]-MIBG treatment in insulinomas.

Image-based 3D modeling study of the influence of vessel density and blood hemoglobin concentration on tumor oxygenation and response to irradiation.

PURPOSE: Hypoxia is one of the most important factors influencing clinical outcome after radiotherapy. Improved knowledge of factors affecting the levels and distribution of oxygen within a tumor is needed. The authors constructed a theoretical 3D model based on histological images to analyze the influence of vessel density and hemoglobin (Hb) concentration on the response to irradiation. METHODS: The pancreases of a Rip-Tag2 mouse, a model of malignant insulinoma, were excised, cryosectioned, immunostained, and photographed. Vessels were identified by image thresholding and a 3D vessel matrix assembled. The matrix was reduced to functional vessel segments and enlarged by replication. The steady-state oxygen tension field of the tumor was calculated by iteratively employing Green's function method for diffusion and the Michaelis-Menten model for consumption. The impact of vessel density on the radiation response was studied by removing a number of randomly selected vessels. The impact of Hb concentration was studied by independently changing vessel oxygen partial pressure (pO(2)). For each oxygen distribution, the oxygen enhancement ratio (OER) was calculated and the mean absorbed dose at which the tumor control probability (TCP) was 0.99 (D(99)) was determined using the linear-quadratic cell survival model (LQ model). RESULTS: Decreased pO(2) shifted the oxygen distribution to lower values, whereas decreased vessel density caused the distribution to widen and shift to lower values. Combined scenarios caused lower-shifted distributions, emphasising log-normal characteristics. Vessel reduction combined with increased blood pO(2) caused the distribution to widen due to a lack of vessels. The most pronounced radiation effect of increased pO(2) occurred with tumor tissue with 50% of the maximum vessel density used in the simulations. A 51% decrease in D(99), from 123 to 60 Gy, was found between the lowest and highest pO(2) concentrations. CONCLUSIONS: Our results indicate that an intermediate vascular density region exists where enhanced blood oxygen concentration may be beneficial for radiation response. The results also suggest that it is possible to distinguish between diffusion-limited and anemic hypoxia from the characteristics of the pO(2) distribution.

Radiolabeled glucagon-like peptide-1 analogues: a new pancreatic ß-cell imaging agent.

Glucagon-like peptide-1 (GLP-1) is a potent antihyperglycemic hormone. It can induce glucose-dependent insulin secretion. GLP-1 has a short half-life of less than 2 min in vivo due to degradation by the dipeptidyl peptidase-IV. GLP-l analogues, such as exendin-4 and exendin-3, have similar biological activity but a longer in-vivo half-life. Pancreatic ß-cells and pancreatic islet cell tumors highly express GLP-1 receptors. Hence, radiolabeled GLP-1 analogues play a potential role in imaging and radiation therapy of pancreatic islet cell tumors as well as in the monitoring of pancreatic ß-cell transplantation.

New therapeutic options for metastatic malignant insulinomas.

Insulinomas are the most common, functioning, pancreatic neuroendocrine tumours. The great majority (>90%) of insulinomas are nonmetastatic at presentation and can be surgically cured. The <10% patients with distant (liver-bone) metastases have a median survival of < 2 years. Everolimus and sunitinib have been recently introduced as targeted therapies for metastatic pancreatic neuroendocrine tumours. An additional advantage of everolimus in the treatment of patients with metastatic insulinomas is its capability to increase blood glucose levels. Peptide receptor radiotherapy using radiolabelled somatostatin analogues has also been shown to be successful in controlling tumour growth of metastatic pancreatic neuroendocrine tumours. In patients with metastatic insulinomas, this therapeutic modality was also effective in controlling hypoglycaemia, even in the presence of tumour regrowth. With the introduction of these new therapeutic modalities, the therapeutic arsenal for the 'tailor-made' approach of patients with metastatic insulinomas is further expanded.

Insulinoma.

Insulinomas are the most common islet cell tumors and are located almost exclusively in the pancreas. Most of these tumors are sporadic, but they may also be associated with the multiple endocrine neoplasia type I syndrome. More than 90% of insulinomas are benign. Preoperative radiographic localization may prove difficult. Intraoperative palpation and ultrasound remain the gold standard for detection and appropriately planned resection. Although many options are available to treat the patient with malignant and metastatic disease, the mainstay of treatment remains surgery. Laparoscopic ultrasound and enucleation/resection may be increasingly used in the management of patients with insulinoma.