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.

Everolimus dramatically improves glycemic control in unresectable metastatic insulinoma: a case report.

Hypoglycemia poses a significant management challenge in patients with unresectable metastatic insulinoma. A 57-year-old woman with pancreatic neuroendocrine tumor with multiple liver metastases was referred to our institution. During the clinical course of pancreatic neuroendocrine tumor, she had experienced palpitations, cold sweats and faintness between meals that indicated her tumors had attained the characteristics of an insulinoma, and her quality of life was impacted by frequent hypoglycemic episodes which could not be prevented by conventional therapies. Shortly after the approval of everolimus for pancreatic neuroendocrine tumor in Japan, we began oral administration at 10 mg per day, which produced a rapid and substantial improvement in glycemic control. The serum insulin level decreased dramatically despite the tumor size remaining stable on computed tomography evaluation. Despite a dose reduction of everolimus to 5 mg per day in response to the adverse reaction of interstitial pneumonitis and a subsequent moderate increase in the serum insulin level, the patient has maintained normoglycemia for a year. Everolimus might represent the treatment of choice for unresectable insulinoma in terms of not only tumor stabilization but also glycemic control.

[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.

Paralemmin-1 is expressed in lymphatic endothelial cells and modulates cell migration, cell maturation and tumor lymphangiogenesis.

The lymphatic system, the network of lymphatic vessels and lymphoid organs, maintains the body fluid balance and ensures the immunological surveillance of the body. In the adult organism, the de novo formation of lymphatic vessels is mainly observed in pathological conditions. In contrast to the molecular mechanisms governing the generation of the lymphatic vasculature during embryogenesis, the processes underlying pathological lymphangiogenesis are less well understood. A genome-wide screen comparing the transcriptome of tumor-derived lymphatic endothelial cells with that of blood vessel endothelial cells identified paralemmin-1 as a protein prominently expressed in lymphatic endothelial cells. Paralemmin-1 is a lipid-anchored membrane protein that in fibroblasts and neurons plays a role in the regulation of cell shape, plasma membrane dynamics and cell motility. Here, we show that paralemmin-1 is expressed in tumor-derived lymphatic endothelial cells as well as in lymphatic endothelial cells of normal, non-tumorigenic tissue. Paralemmin-1 represses cell migration and delays the formation of tube-like structures of lymphatic endothelial cells in vitro by modulating cell-substrate adhesion, filopodia formation and plasma membrane blebbing. While constitutive genetic ablation of paralemmin-1 expression in mice has no effect on the development and physiological function of the lymphatic system, the loss of paralemmin-1 impaired tumor-associated lymphangiogenesis. Together, these results newly identify paralemmin-1 as a protein highly expressed in lymphatic endothelial cells. Similar to its function in neurons, it may link the cytoskeleton to the plasma membrane and thereby modulate lymphatic endothelial cell adhesion, migration and lymphangiogenesis.

Surgery for metastatic neuroendocrine tumors with occult primaries.

INTRODUCTION: Neuroendocrine tumors (NETs) frequently metastasize prior to diagnosis. Although metastases are often identifiable on conventional imaging studies, primary tumors, particularly those in the midgut, are frequently difficult to localize preoperatively. MATERIALS AND METHODS: Patients with metastatic NETs with intact primaries were identified. Clinical and pathologic data were extracted from medical records. Primary tumors were classified as localized or occult based on preoperative imaging. The sensitivities and specificities of preoperative imaging modalities for identifying the primary tumors were calculated. Patient characteristics, tumor features, and survival in localized and occult cases were compared. RESULTS: Sixty-one patients with an intact primary tumor and metastatic disease were identified. In 28 of these patients (46%), the primary tumor could not be localized preoperatively. A median of three different preoperative imaging studies were utilized. Patients with occult primaries were more likely to have a delay (>6 mo) in surgical referral from time of onset of symptoms (57% versus 27%, P = 0.02). Among the 28 patients with occult primary tumors, 18 (64%) were found to have radiographic evidence of mesenteric lymphadenopathy corresponding, in all but one case, to a small bowel primary. In all but three patients (89%), the primary tumor could be identified intraoperatively. CONCLUSION: The primary tumor can be identified intraoperatively in a majority of patients with metastatic NETs, irrespective of preoperative localization status. Referral for surgical management should not, therefore, be influenced by the inability to localize the primary tumor.

Misleading features of neuroimaging and electroencephalography: insulinoma misdiagnosed as temporal lobe epilepsy.

Epilepsy is a common disorder but diagnosis remains largely clinical. Although MRI and EEG significantly aid the diagnosis of epilepsy, these techniques may also be misleading and indicate abnormalities not related to phenomenology. Consequences of erroneous diagnosis of epilepsy may lead to aggressive and escalating pharmacotherapy with potentially serious side effects. Metabolic disorders, which may mimic epilepsy, should always be considered as they are potentially curable and may be fatal if untreated. We report a case of an insulinoma, misdiagnosed as temporal lobe epilepsy. We highlight the risks associated with misinterpretation of neuroimaging and EEG and outline an approach to differentiate between symptoms of insulinoma or neuroglycopenia and temporal epileptic seizures.

Prolonged survival in an aged Labrador retriever with a metastatic insulinoma.

This case report highlights an unusually prolonged, asymptomatic, disease-free interval in an aged male Labrador retriever that underwent partial pancreatectomy for a functionally active pancreatic insulinoma with histologically confirmed hepatic metastasis. The patient developed pancreatitis and nonseptic suppurative peritonitis 24 hr after surgical resection of the insulinoma and was managed medically until discharge. Three mo after surgery, the dog was diagnosed with exocrine pancreatic insufficiency (EPI) that was effectively managed with parenteral pancreatic enzymes. Due to normal glucose levels 3 mo postsurgically, liver samples from the initial surgery were resubmitted for immunohistochemistry. Results confirmed insulinoma metastasis with insulin expression. Ten mo postsurgically, the blood glucose was normal and serum insulin levels were slightly above the upper reference limit. The first hypoglycemic episode was documented 23 mo postoperatively, which was effectively managed with prednisone. The cause for the prolonged disease remission and survival was unknown, but was possibly a result of pancreatitis and peritonitis, partial spontaneous regression of metastatic lesions, or idiopathic. Despite life-threatening postoperative complications, this patient enjoyed a profoundly longer than expected survival. This case highlights the importance of removing the primary tumor (insulinoma) despite the presence of metastatic disease.

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.

Successful control of intractable hypoglycemia using radiopharmaceutical therapy with strontium-89 in a case with malignant insulinoma and bone metastases.

This report describes the case of a 57-year-old woman with liver and bone metastases from malignant insulinoma, who was afflicted with severe hypoglycemia. Treatment of the liver metastases using octreotide, diazoxide and transarterial embolization failed to raise her blood glucose level and she required constant glucose infusion (about 1000 kcal/day) and oral feeding (about 2200 kcal/day) to avoid a hypoglycemic attack. Subsequently, 110 MBq (2.0 MBq/kg) of strontium-89 were administered by intravenous injection. Three weeks after the strontium-89 injection, we could reduce the dose of constant glucose infusion while maintaining a euglycemic status. Six weeks after the injection, the constant glucose infusion was discontinued. Although strontium-89 therapy is indicated for patients with multiple painful bone metastases, it was also useful as a means of inhibiting tumor activity and controlling hypoglycemia in this case. To our knowledge, this is the first report to provide evidence that strontium-89 can be useful in controlling intractable hypoglycemia in patients with malignant insulinoma with bone metastases.

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.

[Malignant insulinoma]. / Malignus insulinoma.

Authors present the history of a 56-year-old man who was evaluated for recurrent epigastric pain. Clinical investigation revealed a 4-cm tumor in the head of the pancreas and a solitary liver metastasis. Pathological examination of the surgically excised pancreatic tumor indicated a moderately differentiated neuroendocrine carcinoma and Ki-67 labeling index revealed moderate proliferative activity. Despite short-term chemotherapy combined with interferon and somatostatin analogue administration, the metastatic disease rapidly progressed. Octreotide scintigraphy disclosed abundant expression of somatostatin receptors both on primary tumor and hepatic metastases. 9°Yttrium-DOTATOC treatment was performed in three sessions within 9 months (3 x 200 mCi) with a mixed therapeutic response. Endocrine symptoms were not observed during the first 33 months of the disease. 34 months after the initial diagnosis of the neoplastic disease, imaging studies and chromogranin A measurement revealed rapidly progressing disease and the patient developed frequent episodes of hypoglycemic attacks. Serum insulin and C-peptide measurements confirmed insulin oversecretion. Continuous administration of somatostatin analogue was supplemented with diazoxide, but the latter therapy was not tolerated because of severe water retention. The high dose oral carbohydrate intake was supplemented with continuous glucose infusion. As a rescue procedure, repeated liver chemoembolization was performed, which resulted only in a short-term effect. The autopsy and the immunohistochemical investigations confirmed the diagnosis of insulin-producing, metastatic neuroendocrine carcinoma.

Malignant insulinoma in a child.

Insulinomas are rare tumors with an estimated incidence of one per 250,000 person-years. Most insulinomas are benign with less than 10% demonstrating malignant behavior, the vast majority of which occur in adults. A systemic review of the literature revealed only nine cases of malignant insulinomas occurring in children. Herein, we present a case of metastatic malignant insulinoma in a 12-year-old child. The occurrence of this diagnosis in a child, its unusual pattern of metastases and the challenging management of severe hypoglycemia make this case worth reporting.

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.

The CM cell line derived from liver metastasis of malignant human insulinoma is not a valid beta cell model for in vitro studies.

The CM cell line is derived from the ascitic fluid of a patient with liver metastasis of a malignant insulinoma. Insulin levels potentially derived from the insulinoma were detected only once in vivo in the subject with the malignant pancreatic tumor and hypoglycemia. After multiple unsuccessful attempts to detect insulin in the culture medium, insulin levels were again detected only once in vitro. In our repeated experiments, we extensively exposed early-passages of the CM cell line to 0.91 mM glucose and acutely to increasingly higher glucose concentrations (2.75, 5.5, 11, and 22 mM) and did not detect any insulin secretion as well as any significant insulin cell content. The electronic microscopic examinations of several vials containing early-passages of the CM cell lines showed a polyclonal nature of the cells mostly resembling fibroblasts. The karyotype detected severe and consistent chromosomal aberrations of the CM cell line, including the chromosome 11 tetraploidy and the genetic material translocation in three out of four chromosomes 11 at the insulin gene locus 11p15.1. These data, unfortunately, exclude the possibility of considering the CM cell line as a valid beta cell model in vitro.

Aggressive multimodal therapy of sporadic malignant insulinoma can improve survival: a retrospective 35-year study of 12 patients.

AIM: Sporadic malignant insulinoma (SMI) is a rare disease, and the consequent paucity of data in the literature and the development of aggressive treatments for liver metastases have led us to retrospectively analyze a series of 12 cases of SMI. METHODS: Every patient presenting with SMI, according to the WHO 2004 histopathology criteria, between 1970 and June 2005 in Marseille was included in the study. Patients with multiple endocrine neoplasia type 1 (MEN-1) and tumours of uncertain malignant potential were excluded. RESULTS: The ratio of male/female was 4/8, and mean age at diagnosis was 52.5 years. A 48-h fasting test in 10 patients was conclusive in nine, after a mean duration of 12 h 45 min. SMI size ranged from 7-120 mm (mean 30.3mm). Six patients had liver metastases and one had isolated lymph-node invasion. Surgery was performed in 12 patients. Five persisting diseases (mean follow-up of 1.8 years) required other treatments (chemoembolization, radiofrequency thermoablation [RFTA], liver transplantation); one patient relapsed 8.5 years after surgery; six were still in complete remission (mean follow-up of 5.8 years), and one patient had died by the time of the 24-month follow-up. CONCLUSION: Aggressive sequential multimodal therapy can prolong the survival of patients with SMI even in the presence of liver metastases.

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.