Balancing efficacy and adverse reactions using everolimus in a patient with metastatic malignant insulinoma: Case report.

INTRODUCTION: Malignant insulinoma is a rare neuroendocrine tumor responsible for excessive insulin secretion and life-threatening hypoglycemia episodes. Computed tomography (CT) of the abdomen can identify a pancreatic tumor corresponding to insulinoma. Loco-regional metastases define the metastatic cases. The first-line therapeutic approach is surgery, while other medical treatments like diazoxide and everolimus play also a role. These treatments have shown efficacy in regulating blood glucose and, to some extent, controlling tumor progression. CASE PRESENTATION: We present the case of a 48-year-old female who was admitted for severe hypoglycemia episodes. She presented neuroglycopenic symptoms without any other clinical features. High levels of C-peptide and insulin during severe hypoglycemia confirmed the presence of endogenous hyperinsulinism. The CT scan of the abdomen confirmed the existence of an insulinoma along with several hepatic metastases. Surgery was proposed as a first-line approach. However, due to the persistent occurrence of severe hypoglycemia episodes, other treatment options were necessary such as diazoxide and everolimus. Diazoxide caused a significant improvement in the patient's blood glucose levels. Nonetheless, glycemic control was unsustainable, obligating the switch to everolimus, which showed better control of blood glucose levels with challenging management due to the appearance of grade 3 stomatitis as a side effect. The patient died 1 year after the diagnosis due to tumor progression. CONCLUSION: Balancing the benefits of enhanced glycemic control with the difficulties posed by side effect management of everolimus underscores the need to carefully consider both efficacy and potential adverse events.

Right-Side Acquired Diaphragmatic Hernia in an Adult 15 Years After Living Donor Liver Transplant.

Cases of adult liver transplant recipients with a postoperative right-side acquired diaphragmatic hernia are extremely rare. In this report, we describe an adult case of right-side acquired diaphragmatic hernia 15 years after living donor liver transplant. A 27-year-old woman was diagnosed with pancreatic insulinoma with multiple metastases in the liver. To treat the liver failure, she underwent left lobe living donor liver transplant and distal pancreatectomy with splenectomy 3 years after the transcatheter arterial chemoembolization. As a result of the liver abscesses that reached the diaphragm, the delicate diaphragm was injured, which required repair during the transplant surgery. At the age of 46 years, she developed a cough and intermittent abdominal pain. One month later, she went to another hospital's emergency room with complaints of epigastric pain. The computed tomography scan revealed colon and small intestine prolapse into the right thoracic cavity. She was referred to our hospital and underwent surgery the next day. Two adjacent right diaphragm defects were successfully sutured with nonabsorbable sutures. The patient was discharged on postoperative day 11.

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.

Metastatic Insulinoma Controlled by Targeted Radionuclide Therapy With 177Lu-DOTATATE in a Patient With Solitary Kidney and MEN-1 Syndrome.

A 54-year-old man with multiple endocrine neoplasia type 1 had previous history of parathyroid surgery and left thyroid lobectomy 5 years earlier, and was referred for recurrent hypoglycemic episodes. Ga-DOTATATE PET/CT had showed multiple lesions in the right lung, liver, and pancreas. Biopsy from pancreas revealed low-grade neuroendocrine neoplasia. After 2 fractions of Lu-DOTATATE therapy, the size of lesions and its activity reduced on the Ga-DOTATATE scan and the hypoglycemic episodes manifested every day have scaled down to 1 time over 1-year follow-up. Herein, we report a case of malignant insulinoma successfully treated with radiolabeled somatostatin receptor therapy using Lu-DOTATATE.

Ectopic insulinomas in the pelvis secondary to rectum neuroendocrine tumour.

We describe a middle-aged woman with recurrent hypoglycaemia, who confirmed with rectum G1 neuroendocrine tumour (NET) 6 years ago. Biochemical assay showed high concentration of serum insulin and C-peptide associated with hypoglycaemia. Because of recurrent hypoglycaemia in June 2015, she underwent a resection of the tail of the pancreas. However, hypoglycaemia attack happened more frequently and severely. 68Ga-DOTA-NOC positron emission tomography/CT revealed five foci in the pelvis with intense uptake. Immediately after excision of the pelvic lesions, insulin and C-peptide decreased to normal levels promptly, and therefore, serum glucose increased significantly. Hypoglycaemia was disappeared, and insulin and C-peptide were normal at 2 years follow-up after surgery. Immunohistochemistry validated the primary rectum NET and pelvic tumours expressed with higher insulin, somatostatin receptor and glucagon-like peptide-1. This is the first reported ectopic pelvic insulinomas secondary to rectum NET, which may originate both from neuroendocrine cells in the rectum and pelvic tissues.

1α,25(OH)2D3 Analog, MART-10, Inhibits Neuroendocrine Tumor Cell Metastasis After VEGF-A Stimulation.

AIMS: Pancreatic neuroendocrine tumors (PanNETs) are usually diagnosed in an advanced stage. Most patients with PanNETs die of metastasis. Vascular endothelial growth factor-A (VEGF-A) is a strong stimulator of angiogenesis and tumor metastasis. We aimed to investigate the effect of MART-10 [19-nor-2α-(3-hydroxypropyl)-1α,25(OH)2D3], a 1α,25-dihydroxy-vitamin D3 (1α,25(OH)2D3) analog, on PanNET cell metastasis after VEGF-A stimulation. MATERIALS AND METHODS: Migration and invasion assays, western blot, and immunofluorescent staining were applied in this study. RESULTS: VEGF-A increased PanNET cell migration and invasion, which was attenuated by 1α,25(OH)2D3 and MART-10. VEGF-A treatment stimulated epithelial-mesenchymal transition (EMT) of PanNET cells. During this process, expression of snail family transcriptional repressor 1 and 2, and fibronectin was up-regulated. 1α,25(OH)2D3 and MART-10 counteracted VEGF-A-induced EMT. In addition, expression of neuropilin 1, a key protein in VEGF-A signaling, was down-regulated by 1α,25(OH)2D3 and MART-10. Furthermore, synthesis of F-actin was increased by VEGF-A and reduced by 1α,25(OH)2D3 and MART-10. CONCLUSION: Our data indicate that MART-10 could be deemed a promising drug for PanNET treatment.

Pasireotide for malignant insulinoma.

UNLABELLED: Malignant insulinoma usually has a poor prognosis, as no efficient medical treatment is available. The somatostatin analogs octreotide and lanreotide have limited ability to control the hypoglycemic events. Pasireotide is a multi-receptor targeted somatostatin-analog with improved affinity for SSTR5. There is to date no reported treatment experience with this drug in such tumors. CASE DESCRIPTION: A 72-year-old patient with a G2 stage IV insulinoma, who underwent excision of the primary pancreatic tumor and multiple hepatic metastases, required further treatment for recurrent hypoglycemic events. The glycemic control achieved with pasireotide LAR was better compared with lanreotide and everolimus. However, none of these treatments showed tumor anti-proliferative effects. CONCLUSIONS: Pasireotide monthly injections achieved improved glycemic control in a patient with malignant insulinoma and recurrent hypoglycemic events compared with other medical treatments.

Insulinoma with focal hepatic lesions: malignant insulinoma?

Insulinoma is a rare tumour that is malignant in only 10% of cases. We report a case of insulinoma in a 59-year-old woman, associated with focal liver lesions, which raised the suspicion of malignancy of a pancreatic tumour. Enucleation of the insulinoma was performed with wedge resection of one hepatic nodule. Pathological examination indicated that the pancreatic tumour was compatible with insulinoma whereas the hepatic lesion was related to focal nodular hyperplasia. This clinical case highlights the need for histopathological proof of malignancy before selecting therapeutic strategies for insulinomas.

Transformation of nonfunctioning pancreatic tumor into malignant insulinoma after 3 years: an uncommon clinical course of insulinoma.

A 62-year-old man admitted to our outpatient clinic with two months of recurrent life threatening hypoglycemia episodes. He was diagnosed as malignant insulinoma with multiple metastases of liver and peripancreatic lymph nodes. Liver biopsy specimen was demonstrated grade 2 neuroendocrine tumor compatible with clinical and radiological results. He was followed under the treatment of continuous intravenous glucose infusion during the diagnostic procedures. He had a pancreatic lesion history measured 20 x 12 mm in diameter via the abdominal tomography examination approximately two years before the diagnosis. Unusual course of this case suggests the transformation of nonfunctioning pancreatic neuroendocrine tumor into functional insulin secreting tumor with metastases. The patient was found inoperable and started on chemotherapy.

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.

[A rare case of hypoglycemia in an elderly patient with type 2 diabetes mellitus: malignant metastasizing insulinoma].

The incidence of insulinoma, an insulin-producing tumour arising from pancreatic beta-cells and responsible for the development of fasting hypoglycemia, in the general population is 1-4 per 1,000,000 yearly, mostly at the age of 25-55 yr. Malignization of this neoplasm occurs in 10-15% of the cases. One third of the tumours produce metastases. The most characteristic clinical manifestation of insulinoma is the Whipple's triad, with episodes of fasting hypoglycemia (below 2.8 mmol/l) correctable by intravenous glucose injection or intake of sugar. The authors report a case of intravital diagnosis of malignant metastasizing insulinoma in a 82 year old woman with type 2 diabetes mellitus. A review of relevant literature is presented.

[Malignant hypoglycaemia]. / Maligne Hypoglykämie.

We describe the case of a 19-years old patient with seizure due to severe hypoglycaemia during general practitioner consultation. Because of hyperinsulinaemic hypoglycaemia and suspected liver metastasis a neuroendocrine hormone active tumor was suspected. After liver biopsy and CT scan a neuroendocrine pancreatic tumor could be diagnosed. Afterwards oncological therapy was induced.

Detection of metastatic insulinoma by positron emission tomography with [(68)ga]exendin-4-a case report.

CONTEXT: Insulinomas are the most common cause of endogenous hyperinsulinemic hypoglycemia in nondiabetic adult patients. They are usually benign, and curative surgery is the "gold standard" treatment if they can be localized. Malignant insulinomas are seen in less than 10% of patients, and their prognosis is poor. The glucagon like peptide-1 receptor (GLP-1R) is markedly up-regulated in insulinomas-especially benign lesions, which are difficult to localize with current imaging techniques. OBJECTIVE: The aim of the study was to assess the possibility of the detection of primary and metastatic insulinoma by positron emission tomography (PET) using [(68)Ga]Ga-DO3A-VS-Cys(40)-Exendin-4 ([(68)Ga]Exendin-4) in a patient with severe hypoglycemia. DESIGN AND SETTING: Dynamic and static PET/computed tomography (CT) examination of a patient was performed using [(68)Ga]Exendin-4 at Uppsala University Hospital, Uppsala, Sweden. PATIENTS: A patient presented with hypoglycemia requiring continuous iv glucose infusions. A pancreatic insulinoma was suspected, and an exploratory laparotomy was urgently performed. At surgery, a tumor in the pancreatic tail with an adjacent metastasis was found, and a distal pancreatic resection (plus splenectomy) and removal of lymph node were performed. Histopathology showed a World Health Organization classification grade II insulinoma. Postoperatively, hypoglycemia persisted, but a PET/CT examination using the neuroendocrine marker [(11)C]-5-hydroxy-L-tryptophan was negative. INTERVENTIONS: The patient was administered [(68)Ga]Exendin-4 and was examined by dynamic PET over the liver and pancreas. RESULTS: The stable GLP-1 analog Exendin-4 was labeled with (68)Ga for PET imaging of GLP-1R-expressing tumors. The patient was examined by [(68)Ga]Exendin-4-PET/CT, which confirmed several small GLP-1R-positive lesions in the liver and a lymph node that could not be conclusively identified by other imaging techniques. The results obtained from the [(68)Ga]Exendin-4-PET/CT examination provided the basis for continued systemic treatment. CONCLUSION: The results of the [(68)Ga]Exendin-4-PET/CT examination governed the treatment strategy of this particular patient and demonstrated the potential of this technique for future management of patients with this rare but potentially fatal disease.