SAP deletion promotes malignant insulinoma progression by inducing CXCL12 secretion from CAFs via the CXCR4/p38/ERK signalling pathway.

Malignant insulinoma is an extremely rare type of functioning pancreatic neuroendocrine tumour with a high degree of malignancy and a high incidence of metastasis. However, it is still unclear how malignant insulinomas develop and metastasize. Serum amyloid P component (SAP), a member of the pentraxin protein family, is an acute-phase protein secreted by liver cells. The role of SAP in insulinoma and the related mechanism are still unknown. To determine the effect of SAP on insulinoma, we crossed Rip1-Tag2 mice, which spontaneously develop insulinoma, and SAP knockout (KO) mice to generate Rip1-Tag2;SAP-/- mice. We found that SAP deletion significantly promoted the growth, invasion and metastasis of malignant insulinoma through C-X-C motif chemokine ligand 12 (CXCL12) secreted by cancer-associated fibroblasts (CAFs). Further study showed that SAP deletion promoted CXCL12 secretion by CAFs through the CXCR4/p38/ERK signalling pathway. These findings reveal a novel role and mechanism of SAP in malignant insulinoma and provide direct evidence that SAP may be a therapeutic agent for this disease.

Clinical Management of Malignant Insulinoma: a single Institution's experience over three decades.

BACKGROUND: Malignant insulinoma is extremely rare and accounts for only 10% of total insulinoma cases. The goal of this study is to retrospectively analyze clinical data from 15 patients with malignant insulinoma treated at Peking Union Medical College Hospital (PUMCH) from 1984 to April 2017. METHODS: "Malignant insulinoma" was used as the keywords in the PUMCH medical record retrieval system to search and obtain patients' clinical information. We identified subjects diagnosed with malignant insulinoma based on clinical or surgical pathological signs and subsequently analyzed their clinical data. RESULTS: Eight males and seven females with a median age at diagnosis of 40 years (38-54 years) were included. Eight patients (53%) had developed metastases at diagnosis, while the others (46.67%) developed metastases during the follow-up visits. The major sites of metastasis were the liver (86.7%), local tissues and blood vessels (33%) and abdominal lymph nodes (13%). All patients displayed neuroglycopenic (100%) and/or autonomic (60%) symptoms, mostly during fasting periods (73.3%), with an average blood glucose level of 1.66 ± 0.51 mmol/L. A total of 93% of the patients had one primary pancreatic lesion, 53% had a lesion in the head of the pancreas, and 47% had a lesion in the tail of the pancreas, with diameters ranging between 0.9 and 6.0 cm. Most liver metastases were multiple lesions. Selective celiac arteriography yielded 100% sensitivity for both primary pancreatic lesions and liver metastases. Most patients received synthetical treatments, including surgery, chemoembolization, and octreotide. CONCLUSIONS: Malignant insulinomas have a similar diagnostic process to that of benign insulinomas but require far more comprehensive therapies to alleviate hypoglycemic symptoms and extend patients' survival.

Management of a metastasized high grade insulinoma (G3) with refractory hypoglycemia: case report and review of the literature.

Insulinomas represent the most common functional neuroendocrine tumor of the pancreas. They are usually solitary, benign, well differentiated (G1/G2) and curable by surgery. We describe the case of a 45 year old male Caucasian with a unique malignant, metastasized pancreatic insulinoma (Ki 67 of 70%, G3). To control excessive insulin production emanating in refractory hypoglycemia and growth of the highly proliferating tumor a multimodal therapeutic approach including the consecutive use of tumor debulking surgery, chemotherapy, TACE, SIRT, PRRT as well as a drug therapy with diazoxide, somatostatin analogs and everolimus was employed. Chemotherapy with carboplatin/etoposide plus everolimus provided the longest normoglycemic period. After progress chemotherapy with dacarbazine had the most positive effect, while debulking approaches such as surgery and liver directed therapies, as well as PRRT were less efficient with only transient success.

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.

Aggressive versus indolent insulinomas: new clinicopathological insights.

Insulinomas are rare functional pancreatic neuroendocrine tumors. While most insulinomas are indolent and cured after surgery, 10-15% of cases show aggressive or malignant tumor behavior and metastasize locally or to distant organs. Patients with metastatic insulinoma survive significantly shorter. Recognizing aggressive insulinomas can help to predict prognosis, guide therapy and determine follow-up intensity after surgery. This review offers a summary of the literature on the significant clinical, pathological, genetic and epigenetic differences between indolent and aggressive insulinomas. Aggressive insulinomas are characterized by rapid onset of symptoms, larger size, expression of ARX and alpha-1-antitrypsin and decreased or absent immunohistochemical expression of insulin, PDX1 and GLP-1R. Moreover, aggressive insulinomas often harbor ATRX or DAXX mutations, the alternative lengthening of telomeres phenotype and chromosomal instability. Tumor grade and MEN1 and YY1 mutations are less useful for predicting behavior. Aggressive insulinomas have similarities to normal alpha-cells and non-functional pancreatic neuroendocrine tumors, while indolent insulinomas remain closely related to normal beta-cells. In conclusion, indolent and aggressive insulinoma are different entities, and distinguishing these will have future clinical value in determining prognosis and treatment.

Insulinoma in childhood: a retrospective review of 22 patients from one referral centre.

Background: Insulinomas are very rare in childhood with sparse knowledge on the clinical aspects and the presence of Multiple Endocrine Neoplasia type 1 (MEN1). Methods: We conducted a retrospective review of patients diagnosed with insulinoma between 1995 and 2021, presenting to one referral centre in Russia. Clinical, biochemical, genetic, imaging and histological data were collected. In addition, follow-up and family data were obtained. Results: A total of twenty-two children aged 5 to 16 years were identified. The median (range) gap between the first hypoglycaemia symptoms and diagnosis was 10 (1-46) months. Twelve children (55%) were misdiagnosed to have epilepsy and were treated with anticonvulsants before hypoglycemia was revealed. Contrast enhanced MRI and/or CT were accurate to localize the lesion in 82% (n=18). Five patients (23%) had multiple pancreatic lesions. All children underwent surgical treatment. The median (range) diameter of removed tumors was 1.5 (0.3-6) cm. Histopathological studies confirmed the presence of insulinoma in all cases. Immunohistochemical studies revealed G2 differentiation grade in 10 out of 17 cases. Two patients were diagnosed with metastatic insulinoma. One of them had metastases at the time of insulinoma diagnosis, while the other was diagnosed with liver metastases eight years after the surgery. Eight children (36%) were found to carry MEN1 mutations, inherited n=5, de novo n=1, no data, n=2. Children with MEN1 had significantly higher number of pancreatic tumors compared to sporadic cases. All of them developed additional MEN1 symptoms during the following 2-13 years. In the five patients with inherited MEN1, seven family members had hitherto undiscovered MEN1 manifestations. Conclusions: In this large cohort of children with rare pediatric insulinomas, MEN1 syndrome and G2 tumors were frequent, as well as hitherto undiscovered MEN1 manifestations in family members. Our data emphasize the need of genetic testing in all children with insulinoma and their relatives, even in the absence of any other features, as well as the importance of a prolonged follow-up observation.

Emerging therapies for advanced insulinomas and glucagonomas.

Pancreatic neuroendocrine neoplasms (panNENs) are rare relatively malignancies that, despite their frequently slow-growing pattern, have the ability to metastasize. Metastatic and/or advanced insulinomas and glucagonomas are functioning panNENs emerging from the pancreas displaying unique peculiarities, depending on their hormonal syndromes and increased malignant potential. Advanced insulinomas management follows usually the panNENs therapeutic algorithm, but some distinctions are well advised together with aiming to control hypoglycemias that occasionally can be severe and refractory to treatment. When first-generation somatostatin analogues (SSAs) fail to control hypoglycemia syndrome, second-generation SSAs and everolimus have to be considered for exploiting their hyperglycemic effect. There is evidence that everolimus is still effective after rechallenge retaining its hypoglycemic effect independently of its antitumor effect that seems to be mediated by different molecular pathways. Peptide receptor radionuclide therapy (PRRT) constitutes a promising therapeutic option for both its antisecretory and antitumoral action. Similarly, advanced and/or metastatic glucagonomas management also follows the panNENs therapeutic algorithm, but the clinical syndrome has to be addressed by aminoacid infusion and by first-generation SSAs to improve the patient performance status. PRRT seems to be an effective treatment when surgery and SSAs fail. The application of these therapeutic modalities has been shown to be efficacious in controlling the manifestations of the secretory syndrome and prolonging the overall survival of patients suffering from these malignancies.

Report of a Novel Molecular Profile in Malignant Insulinoma.

Pancreatic neuroendocrine tumors, or pNETs, represent a rare and clinically heterogenous subset of pancreatic neoplasms. One such pNET, the insulinoma, is found to be malignant in just 4% of all insulinomas. Due to the exceedingly uncommon occurrence of these tumors, there is controversy regarding the optimal evidence-based management for these patients. We therefore report on a 70-year-old male patient admitted with 3 months of episodic confusion with concurrent hypoglycemia. The patient was found to have inappropriately elevated endogenous insulin levels during these episodes, and somatostatin-receptor subtype 2 selective imaging revealed a pancreatic mass metastatic to local lymph nodes, spleen, and the liver. Fine needle aspiration of pancreatic and liver lesions confirmed the diagnosis of a low grade pancreatic neuroendocrine tumor. Molecular analysis of tumor tissue revealed a novel mutational profile consistent with pNET. The patient was initiated on octreotide therapy. However, treatment with octreotide alone demonstrated limited efficacy in controlling the patient's symptoms, prompting consideration of other therapies.

Malignant insulinoma: Can we predict the long-term outcomes?

Insulinomas are the most frequent type of functional pancreatic neuroendocrine tumors with a variety of neuroglycopenic and autonomic symptoms and well-defined diagnostic criteria; however, prediction of their clinical behavior and early differentiation between benign and malignant lesions remain a challenge. The comparative studies between benign and malignant cases are limited, suggesting that short clinical history, early hypoglycemia during fasting, high proinsulin, insulin, and C-peptide concentrations raise suspicion of malignancy. Indeed, malignant tumors are larger with higher mitotic count and Ki-67 proliferative activity, but there are no accurate histological criteria to distinguish benign from malignant forms. Several signaling pathways have been suggested to affect the pathophysiology and behavior of insulinomas; however, our knowledge is limited, urging a further understanding of molecular genetics. Therefore, there is a need for the identification of reliable markers of metastatic disease that could also serve as therapeutic targets in patients with malignant insulinoma. This opinion review reflects on current gaps in diagnostic and clinical aspects related to the malignant behavior of insulinoma.

Pasireotide for Refractory Hypoglycemia in Malignant Insulinoma- Case Report and Review of the Literature.

Malignant insulinomas are functional neuroendocrine tumors of the pancreas and the primary cause of tumor-related hypoglycemia. Malignant insulinoma is rare and has a poor prognosis. We report a case of metastatic malignant insulinoma in a 64-year-old female patient with severe and refractory hypoglycemia. After several ineffective locoregional and systemic therapeutic lines for the secretory disease, the introduction of pasireotide, a second-generation somatostatin analog, provided an improved clinical and secretory evolution both quickly and sustainably, with an excellent safety profile. Pasireotide is an effective and well-tolerated therapy in the treatment of refractory hypoglycemia in metastatic insulinoma.

Canine insulinoma as a model for human malignant insulinoma research: Novel perspectives for translational clinical studies.

Insulinomas are considered rare indolent neuroendocrine neoplasms in human medicine, however when metastases occur no curative treatment is available thus, novel therapies are needed. Recently advances have been made in unraveling the pathophysiology of malignant insulinoma still major challenges hinder the development of a functional model to study them. Canine malignant insulinoma have similar recurrence and a poor prognosis as human malignant insulinoma. Additionally, both human and canine patients share extensively the same environment, tend to develop insulinoma seemingly spontaneously with an etiological role for hormones, at a similar incidence and stage of lifespan, with metastasis commonly to liver and regional lymph nodes, which are unresponsive to current therapies. However, the occurrence of metastases in dogs is as high as 95% compared with only 5-16% in human studies. From a comparative oncology perspective, the shared features with human insulinoma but higher incidence of metastasis in canine insulinoma suggests the latter as a model for human malignant insulinomas. With the common purpose of increasing survival rates of human and veterinary patients, in this review we are going to compare and analyze clinical, pathological and molecular aspects of canine and human insulinomas to evaluate the suitability of the canine model for future translational clinical studies.

Alternative Lengthening of Telomeres and Differential Expression of Endocrine Transcription Factors Distinguish Metastatic and Non-metastatic Insulinomas.

Insulin-producing pancreatic neuroendocrine tumors (PanNETs)/insulinomas are generally considered to be indolent tumors with an excellent prognosis after complete resection. However, some insulinomas have a poor prognosis due to relapses and metastatic disease. Recently, studies in non-functional PanNETs indicated that behavior can be stratified according to alpha- and beta-cell differentiation, as defined by expression of the transcription factors ARX and PDX1, respectively. It is unknown whether similar mechanisms play a role in insulinomas. Therefore, we determined ARX and PDX1 expression in a cohort of 35 sporadic primary insulinomas and two liver metastases of inoperable primary insulinomas. In addition, WHO grade and loss of ATRX or DAXX were determined by immunohistochemistry, and alternative lengthening of telomeres (ALT) and CDKN2A status by fluorescence in situ hybridization. These findings were correlated with tumor characteristics and clinical follow-up data. In total, five out of 37 insulinoma patients developed metastatic disease. Metastatic insulinomas were all larger than 3 cm, whereas the indolent insulinomas were smaller (p value < 0.05). All three primary insulinomas that metastasized showed ARX expression, 2/3 showed ALT, and 1/3 had a homozygous deletion of CDKN2A as opposed to absence of ARX expression, ALT, or CDKN2A deletions in the 32 non-metastatic cases. The two liver metastases also showed ARX expression and ALT (2/2). The presence of ARX expression, which is usually absent in beta-cells, and genetic alterations not seen in indolent insulinomas strongly suggest a distinct tumorigenic mechanism in malignant insulinomas, with similarities to non-functional PanNETs. These observations may inform future follow-up strategies after insulinoma surgery.

Clinical remission of an inoperable malignant insulinoma by the combination treatment with octreotide and everolimus.

We report a 52-year-old woman with inoperable malignant insulinoma with multiple liver metastases. Histological examination of biopsy specimens from the pancreatic and hepatic lesions revealed pancreatic neuroendocrine tumor (pNET), G2. The tumor cells were positive for somatostatin receptor (SSTR) 2, 5, and the mammalian target of rapamycin (mTOR). Monthly intramuscular administration of octreotide LAR and once-daily oral administration of everolimus combination treatment markedly reduced the sizes of liver metastases, and hypoglycemia was well controlled. Combination treatment with somatostatin analog and mTOR inhibitor may be another effective approach in inoperable metastatic malignant insulinoma.

Rare malignant insulinoma with multiple liver metastases derived from ectopic pancreas: 3-year follow-up and literature review.

Here, we report the diagnosis and treatment of a very rare case of malignant insulinoma derived from ectopic pancreas. A middle-aged woman presented with a 6-year history of recurrent hypoglycemia with multiple lesions in liver. Admission workup revealed elevated serum insulin and C-peptide, as well as multiple lesions in the liver (largest being 4.3 cm), enlarged lymph nodes around the pancreas, and a lesion (of 3.5 cm) at the proximal jejunum, as shown by contrast computed tomography (CT). Liver biopsy showed the lesions to be well-differentiated neuroendocrine tumors, grade G1. 68Gallium-exendin-4 positron emission tomography/CT confirmed the origin as the lesion located at the jejunum. The combination treatment of everolimus plus long-acting octreotide relieved symptoms and achieved a partial tumor response. Maintenance treatment of the somatostatin analog (ie, octreotide) alone was administered. Three years of follow-up, up to the writing of this report, showed good survival, with the patient remaining asymptomatic and euglycemic without disease progression. This case shows that 68Gallium-exendin-4 positron emission tomography/CT is useful for locating insulinoma, especially for insulinoma derived from ectopic pancreas, and that everolimus plus octreotide with maintenance somatostatin analog alone is an effective drug strategy for treating inoperable malignant insulinoma.

Giant insulinoma: report of a case and review of published reports.

BACKGROUND: Larger insulinomas are reportedly more likely to be malignant; however, their biological behavior has not been clearly elucidated. We here report the characteristics and treatment of a giant insulinoma with local invasion and lymph node metastasis. We also review published reports concerning the clinical features of giant insulinomas and comparing their grading with that of pancreatic neuroendocrine tumors. CASE PRESENTATION: A 71-year-old man was referred to our hospital for investigation of persistent hypoglycemia. On the current presentation, laboratory tests showed serum glucose, immunoreactive insulin, and C peptide concentrations of 45 mg/dL, 17.2 µIU/mL and 4.1 ng/mL, respectively. Dynamic magnetic resonance imaging showed a hypervascular tumor measuring 13.5 cm in the head of the pancreas. Computed tomography scanning demonstrated local invasion and lymph node involvement. He thus had Whipple's triad, which is associated with malignant insulinoma. No distant metastases having been identified, pancreaticoduodenectomy was performed. Intraoperatively, three separate tumors were identified in the pancreatic head. Pathological examination showed all three tumors were pancreatic neuroendocrine tumors; the tumor cells in the largest mass were strongly immunoreactive for insulin. The Ki-67 index was 2-5% in most parts of the largest tumor and over 20% in the poorly differentiated areas. This tumor was classified as neuroendocrine carcinoma in accordance with the 2010 World Health Organization classification of pancreatic endocrine neoplasms. He remains free of evidence of recurrence 2 years postsurgery. A review of published reports indicated that giant insulinomas are more malignant than smaller ones, and metastatic disease is found on presentation in 56% of patients with giant insulinomas; however, we were unable to identify any correlation between grade of pancreatic neuroendocrine tumor and biological behavior of giant insulinomas. CONCLUSIONS: Giant insulinomas more frequently exhibit malignant behavior, such as local invasion, lymph node involvement, and liver metastasis, than smaller ones. However, there was no relationship between grade and rate of metastases or survival in this small case series. Identification of useful biological markers is necessary.

Embolización de metástasis hepáticas en insulinoma maligno: de la hipoglicemia a la hiperglicemia / Embolisation of liver metastasis in malignant insulinoma: from hyperglycaemia to hypoglycaemia

Resumen Se describe el caso de un paciente de 75 años sin antecedentes de relevancia, que fue diagnosticado con insulinoma maligno en estado avanzado, con metástasis hepáticas, con síntomas por hipoglucemia hiperinsulinémica refractaria al tratamiento, y con diazóxido y octreotide de acción corta. El paciente presentó una respuesta clínica poco esperada a la embolización transarterial de metástasis hepáticas, pues a pesar de que persisten las lesiones tumorales, desarrolló hiperglucemia persistente y requirió manejo con insulina. Adicionalmente, se hace una breve revisión de la literatura sobre las opciones terapéuticas disponibles para el tratamiento sintomático de la hipoglucemia hiperinsulinémica.

Abstract The case is presented of a 75 year-old man who was diagnosed with malignant insulinoma in an advanced stage with diffuse liver metastases and symptoms due to hyperinsulinaemic hypoglycaemia refractory to treatment with diazoxide and short-acting octreotide. The patient had an unexpected clinical response to trans-arterial embolisation of liver metastases, since, despite still having the tumour, he developed persistent hyperglycaemia that required insulin treatment. A brief review of the literature is also presented on the treatment options for hyperinsulinaemic hypoglycaemia.

Tumor neuroendócrino pancreático metastásico, caso clínico / Metastatic pancreatic neuroendocrine tumor: clinical case

Introducción: los insulinomas son tumores neuroendocrinos pancreáticos secretores de insulina, la incidencia en la población en general estimada es de 1 a 4 casos en un millón de habitantes por año. Los insulinomas constituyen el 60% de los tumores de páncreas, de los cuales el 90% son benignos y únicos; el 10% son múltiples, la mayoría asociados a MEN 1 (Neoplasia Endocrina Múltiple) y del 5 al 10% son malignas. La posibilidad de recidiva obliga a un diagnóstico y seguimiento a largo plazo. La característica clínica del insulinoma es la hipoglucemia en ayunas, con signos y síntomas de neuroglucopenia, que pueden estar precedidos o no por manifestaciones adrenérgicas. El tratamiento de elección es el quirúrgico; en etapas irresecables o avanzadas se proponen tratamientos paliativos o sintomáticos con quimioterapia o procedimientos mediante radiología intervencionista con pobres respuestas. Se ha demostrado que con nuevos tratamientos con inhibidores de la tirosina kinasa e inhibidores de la vía de la rapamicina en tumores neuroendocrinos pancráticos bien diferenciados las respuestas tanto en sobrevida libre de progresión así como sobrevida global mejoran importantemente. Caso: presentamos el caso de un hombre de 44 años, con diagnóstico de insulinoma y MEN 1, debutó con convulsiones tónico clónicas generalizadas tratado con pancreatectomia parcial, siete años más tarde, tras haber permanecido asintomático nuevo episodio de convulsiones, documentándose hipoglicemias severas y múltiples metástasis hepáticas, sometido a una pancreatoduodenectomia y como tratamiento sintomático recibió corticoides en altas dosis, diazóxido, octreotide mensual y dos líneas de quimioterapia, además de embolización de las metástasis hepáticas de mayor tamaño y por progresión de enfermedad se inició inhibidores de tirosin-kinasa por un período de tres meses y el paciente fallece.

Introduction: the Insulinomas are pancreatic neuroendocrine tumors secreting insulin. The incidence in the general population is estimated 1-4 per 1 000 000 yearly Insulinoma accounts for 60% of pancreatic tumors, of which 90% are benign and unique, 10% are multiple, mostly associated with MEN 1 (Multiple Endocrine Neoplasia), and 5-10% is malignant. The possibility of recurrence requires diagnosis and long-term monitoring. The clinical characteristic of insulinoma is fasting hypoglycemia, with signs and symptoms of neuroglucopenia, which may be preceded or not by adrenergic manifestations. Surgery is the treatment of choice, in irrsecable; and in advanced stages the proposed palliatives or symptomatic treatments are with chemotherapy or procedures through interventional radiologist with poor responses. It has been shown that new treatments with inhibitors of tyrosine kinase inhibitors and rapamycin pathway for pancreatic neuroendocrine well differentiated tumors, the response in both progression-free survival and overall survival signifcantly improved. Case study: we report the case of a 44 year old male of, diagnosed with insulinoma and MEN 1, debuted with tonic clonic seizures treated with partial pancreatectomy, 7 years later after a new episode of seizures documented severe hypoglycemia and multiple liver metastases, underwent a pancreatoduodenectomy and as symptomatic treatment received high-dose corticosteroids, diaxozido, octreotide monthly and 2 lines of chemotherapy, in addition to embolization of the larger liver metastases masses, and due to disease progression tyrosine kinase inhibitors was initiated for a period of 3 months and the patient dies.

[Malignant insulinoma].

According to official statistics, malignant insulinomas account for a small fraction of gastroenteropathic endocrine neoplasms, the majority of insulinomas being essentially benign tumours. This paper reports a clinical case of malignant insulin-producing neuroendocrine tumour of the pancreas tail in a 28 year-old woman. She had multiple liver metastases and organic hyperinsulinism. Results of comprehensive examination of the patient at the Endocrinological Research Centre including laboratory diagnostic data and their evaluation are presented. Her surgical treatment was accomplished in N.N. Burdenko Facultative Surgery Clinic, I.M. Sechenov Moscow Medical Academy. Treatment strategy in the post-operative period and follow-up observations are described.

Management challenges in a child with hyperinsulinemic hypoglycemia.

Malignant insulinoma is very rare in children. Herein, we present a case of a child with malignant insulinoma along with islet cell hyperplasia. She initially presented with features of hyperinsulinemic hypoglycemia at 18 mo of age. Magnetic resonance imaging (MRI) of the abdomen showed a mass at the junction of the head and body of the pancreas. The tumor was enucleated. Five months later symptoms of hypoglycemia recurred. A subtotal pancreatectomy was performed. She continued to have hypoglycemia, although less frequently. She was put on increasing doses of diazoxide. Seven months later, MRI of the abdomen and a PET scan revealed metastatic deposits in the liver, which were confirmed by histopathology and immunostaining. To the best of our knowledge, this is the youngest child with metastatic insulinoma reported so far.