Use Of Somatostatin Analogues Research Articles

Gastroenteropancreatic Neuroendocrine Tumor with Peritoneal Metastasis: A Review of Current Management.

Peritoneal metastasis in gastroenteropancreatic neuroendocrine tumors poses a significant clinical challenge, with limited data guiding management strategies. We review the existing literature on surgical and systemic treatment modalities for peritoneal metastasis from gastroenteropancreatic neuroendocrine tumors. Surgical interventions, including cytoreductive surgery, have shown promise in improving symptom control and overall survival-particularly in cases in which 70% cytoreduction can be achieved. Hyperthermic intraperitoneal chemotherapy remains controversial due to a paucity of high-level evidence and a lack of consensus for routine use. The use of systemic therapy in the setting of peritoneal metastasis from gastroenteropancreatic neuroendocrine tumors is extrapolated from high-quality evidence for its use in the setting of the solid organ metastasis of this disease. The use of somatostatin analogs for symptom control and some antiproliferative effects is supported by large clinical trials. Additional strong evidence exists for the use of interferon-alpha, everolimus, and sunitinib, particularly in pancreatic neuroendocrine tumors. Cytotoxic chemotherapy and peptide receptor radionuclide therapy may be used in select cases, though as an emerging treatment modality, the optimal sequence of peptide receptor radionuclide therapy within the existing algorithms is unknown. Significant gaps in understanding and standardized management exist, particularly for those patients presenting with peritoneal metastasis, and targeted research to optimize outcomes in this population is needed.

Clinical trial: The effectiveness of long-acting somatostatin analogue for output reduction of high-output intestinal fistula or small bowel enterostomy. A randomised controlled trial.

High-output intestinal fistulas and small bowel enterostomies are associated with morbidity and mortality. Current standard treatment for output reduction consists of fluid and dietary restrictions and medical therapy. There is conflicting evidence regarding the use of somatostatin analogues for output reduction. The aim of this study is to investigate whether lanreotide, added to current standard treatment, further reduces intestinal output in patients with high-output fistulas and enterostomies. This was an open-label, multicentre, randomised controlled trial. Adult patients with a high-output intestinal fistula (>500 mL/24 h) or small bowel enterostomy (>1500 mL/24 h) more than 4 weeks post-surgery and receiving standard medical treatment (dietary- and fluid restriction, PPI, loperamide and codeine) for at least 2 weeks were eligible for inclusion. We randomised patients 1:1 between continuing standard treatment (control), and subcutaneous lanreotide 120 mg every 4 weeks with standard treatment. The primary outcome was the number of responders, with response defined as an output reduction of ≥25%, 8 weeks after randomisation. We also investigated the proportional change in output. We randomised 40 patients; 17 had a fistula and 23 a small bowel enterostomy. There were 9/20 responders in the intervention group and 2/20 in the control group (p = 0.013). The proportional output reduction was -26% (IQR -4 to -38) in the intervention group, compared to an increase of 4% (IQR 20 to -13) in the control group (p = 0.004). In patients with a high-output fistula or small bowel enterostomy, addition of lanreotide to current standard treatment can provide a clinically relevant output reduction. EudraCT: 2013-003998-10.

An Uncommon Culprit: Pancreatic Neuroendocrine Tumor in a Patient with Uncontrolled Diabetes

Pancreatic Neuro Endocrine Tumors (NETs) are rare neoplasms that originate from the endocrine tissues of the pancreas, accounting for only 1-2% of pancreatic tumors. Despite their low incidence, these tumors present with a wide range of symptoms and have the ability to secrete hormones, posing significant challenges for their diagnosis and treatment. There are two distinct types of pancreatic NETs: functioning and nonfunctioning. Functioning tumors are characterized by hormone-related clinical syndromes, while nonfunctioning tumors are often found incidentally. The pathogenesis of pancreatic NETs involves both sporadic and hereditary factors, including syndromes such as MEN1, VHL, and NF1. Typically, these tumors are diagnosed in individuals between the ages of 40 and 60, and their effective management requires a multidisciplinary approach. Diagnostic imaging techniques, such as CT and EUS, play a crucial role in accurate diagnosis, while PET scans aid in staging and treatment planning. Histological analysis is essential for determining the tumor grade and predicting prognosis. Treatment strategies are tailored to the tumor's characteristics and the patient's overall health. These may include the use of somatostatin analogs, such as Lanreotide and Octreotide, to control hormone secretion and inhibit tumor growth, as well as systemic therapies like everolimus, sunitinib, and PRRT for metastatic disease. This case report describes the clinical course of a 66-year-old male with a well-differentiated pancreatic NET who initially presented with persistent hyperglycemia. Further investigations revealed a sizable pancreatic mass and liver metastases. Diagnostic evaluation confirmed a grade 1 Neuro Endocrine Tumor, and the patient was started on treatment with Lanreotide. However, his management was complicated by the development of hepatic encephalopathy, which necessitated treatment with lactulose and rifaximin. This case highlights the importance of considering pancreatic NETs in cases of atypical diabetes presentations and emphasizes the need for a multidisciplinary team to provide optimal care. Given the complex nature of pancreatic NETs, a comprehensive diagnostic workup and personalized treatment approach are essential for improving patient outcomes.

Efficacy of a somatostatin analogue in a case of obscure gastrointestinal bleeding

Gastrointestinal bleeding can have many reasons and therapy becomes tricky when the diagnostic workout is not conclusive. We describe the case of an 89 y.o. woman with severe anemia and gastrointestinal bleeding of an unknown origin after conventional imaging and endoscopic procedures, thus averting endoscopic, angiographic or surgical approach. This condition required 39 blood transfusions in 2 months. Subcutaneous Octreotide, reducing gastrointestinal mucosal perfusion, achieved hemodynamic stability, improved blood cell count, and ended the blood transfusions. The use of somatostatin analogues can be considered in refractory patients with digestive bleedings of an unknown origin not susceptible of first line therapy.

Use of perioperative telotristat in a patient with carcinoid heart disease.

Carcinoid heart disease is a rare complication of carcinoid syndrome, resulting in right-sided valvular heart disease and subsequent heart failure due to long-term exposure to vasoactive substances. The management of this condition is complex, often requiring surgical intervention. Current perioperative regimens entail the use of prophylactic somatostatin analogs to prevent carcinoid crisis; however, regimens vary widely among practitioners and evidence supporting their efficacy in this clinical setting is mixed. This case report describes the perioperative management of a 65-year-old man with carcinoid heart disease requiring tricuspid and pulmonary valve replacement surgery. As an adjunct to somatostatin analog therapy, the novel tyrosine hydroxylase inhibitor, telotristat, was initiated preoperatively. This combination resulted in normalization of preoperative urinary 5-HIAA levels. The patient successfully underwent tricuspid and pulmonic valve replacement without evidence of carcinoid crisis. This clinical case is the first published documenting the use of telotristat in the perioperative period in a patient with carcinoid syndrome and carcinoid heart disease and was associated with a good long-term outcome despite the high-risk nature of the case. Carcinoid crisis is a life-threatening complication of carcinoid syndrome, resulting in hemodynamic instability, bronchospasm, and arrhythmia. Cardiac surgical patients with carcinoid syndrome present a unique challenge as they are subject to physiologic conditions and medications which can potentiate intraoperative carcinoid crisis. Perioperative management of patients with carcinoid syndrome currently entails the use of prophylactic somatostatin analogs; however, these agents do not prevent carcinoid crisis in all cases. Telotristat, a tryptophan hydroxylase inhibitor, shows promise as an adjunctive therapy to somatostatin analogs to reduce the risk of intraoperative carcinoid crisis.

Cytotoxicity on low-grade canine meningioma with the use of somatostatin analog (octreotide): An in vitro study.

Meningioma is the most common tumor of the central nervous system of dogs. For this tumor, surgery remains the treatment of choice, either alone or in combination with radiotherapy. Unfortunately, chemotherapeutic strategies are practically absent in dogs and palliative therapies are the only option to surgery. Somatostatin receptor subtype 2 (SSTR2) is expressed in canine meningioma. Since the potent cell-proliferation inhibiting effect of somatostatin (SST), the aim of this study was to investigate in vitro the effects of octreotide, as SST analog, in the viability of canine meningioma. Four surgical canine meningiomas were used in this study to establish cell cultures. Expression of SSTR2 was verified with immunolabelling in FFPE samplesand cell cultures. The effects of octreotide on cell viability were assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT). After 24 hours they were exposed to different concentrations of octreotide (0.1nM, 1nM, 10nM, 100nM) for 24 and 48 hours. All meningiomas consisted of grade I tumors. The cultured neoplastic cells expressed SSTR2 from 80% to 100%. Octreotide significantly increased cell death after 48 hours of continuous exposure, with 10 and 100nM octreotide doses. The percentage of cell viability was 80.92 ± 4.9 and 80.49 ± 3.61, compared to the control, respectively, consistent with decreased cell viability of about 20% for both doses. Octreotide reduced the alive neoplastic cultured cells of low-grade canine meningioma in a dose-dependent pattern with continuous exposition for 48 hours. These results support an alternative systemic treatment of meningioma with octreotide in the dog.

Use of long-acting somatostatin analogue in a paediatric patient with MEN1 - a case report

Use of long-acting somatostatin analogue in a paediatric patient with MEN1 - a case report

The cycle effect quantified: reduced tumour uptake in subsequent cycles of [177Lu]Lu-HA-DOTATATE during peptide receptor radionuclide therapy.

Clear evidence regarding the effect of reduced tumour accumulation in later peptide receptor radionuclide therapy (PRRT) cycles is lacking. Therefore, we aimed to quantify potential cycle effects for patients treated with [177Lu]Lu-HA-DOTATATE using a population pharmacokinetic (PK) modelling approach. A population PK model was developed using imaging data from 48 patients who received multiple cycles of [177Lu]Lu-HA-DOTATATE. The five-compartment model included a central, kidney, spleen, tumour and lumped rest compartment. Tumour volume and continued use of long-acting somatostatin analogues (SSAs) were tested as covariates in the model. In addition, the presence of a cycle effect was evaluated by relating the uptake rate in a specific cycle as a fraction of the (tumour or organ) uptake rate in the first cycle. The final PK model adequately captured observed radioactivity accumulation in kidney, spleen and tumour. A higher tumour volume was identified to increase the tumour uptake rate, where a twofold increase in tumour volume resulted in a 2.3-fold higher uptake rate. Also, continued use of long-acting SSAs significantly reduced the spleen uptake rate (68.4% uptake compared to SSA withdrawal (10.5% RSE)). Lastly, a cycle effect was significantly identified, where tumour uptake rate decreased to 86.9% (5.3% RSE) in the second cycle and even further to 79.7% (5.6% RSE) and 77.6% (6.2% RSE) in the third and fourth cycle, respectively, compared to cycle one. Using a population PK modelling approach, the cycle effect of reduced tumour uptake in subsequent PRRT cycles was quantified. Our findings implied that downregulation of target receptors is probably not the major cause of the cycle effect, due to a plateau in the decrease of tumour uptake in the fourth cycle.

Abstract #1411806: A Case of Thyrotropin Secreting Adenoma and Review of Literature

Elevations of TSH, FT4, and FT3 are a feature of secondary hyperthyroidism which could occur in the setting of resistance of thyroid hormone at the pituitary gland, alteration of certain deiodinase enzymes causing lower T3 at the pituitary or a TSH secreting tumor in the pituitary. Other conditions include pregnancy and the use of drugs (amiodarone, heparin). We present a case of secondary hyperthyroidism that was diagnosed with a TSH-secreting adenoma (TSHoma). A 72-year-old male presented with complaints of chest pain. He had a past medical history of primary hyperaldosteronism, occipital lobe ischemic infarct, osteoporosis with low-intensity rib, wrist, and vertebral fractures, coronary artery disease, and had undergone CABG. He was diagnosed with paroxysmal atrial fibrillation and had thyroid function testing which showed a TSH of 7.72μIU/mL (0.42-4.50), FT3 6.2pg/mL (2.0-4.4) and FT4 1.74ng/dL (0.70-1.48). A subsequent CT Head revealed a sellar mass measuring 1.4 cm craniocaudally with abutment of the optic chiasm. Repeat thyroid testing continued to show an elevated TSH, FT3, and FT4. αsubunit glycoprotein was 4.1ng/mL (< 0.5), IGF-1 by LC/MS was 31ng/mL (32-200), prolactin was 46.5ng/mL (4.0-15.2) and SHBG 131.6nmol/L (13.3-89.5). He was managed with methimazole and underwent trans-sphenoidal resection of the tumor. Pathology showed a 3.5 x 1.8 x 0.3 cm mass that on immunoperoxidase stains demonstrated expression of synaptophysin by many of the neoplastic cells. Some expressed GH, few expressed prolactin while rare neoplastic cells expressed TSH. TSHomas are rare pituitary adenomas with a prevalence of 1-2 cases/million. Up to 30% can be associated with hypersecretion of GH, prolactin, LH and FSH. The cells express TRH, somatostatin, and dopamine receptors. Clinical features include headaches, visual field defects, goiter, signs/symptoms of hyperthyroidism, pressure effects of the adenoma, cardiac manifestations (atrial fibrillation, heart failure, pericardial effusion) and vertebral fractures. αsubunit glycoprotein is elevated and an αsubunit to TSH molar ratio >1 can be used with 90% sensitivity to differentiate it from other causes of elevated TSH, FT3 and FT4. Elevations in SHBG are also found in patients. Resistance to the thyroid hormone at the pituitary level can give rise to a similar presentation. Elevated levels of SHBG and αsubunit glycoprotein seen in TSHoma can aid in differentiation. Dynamic testing such as a T3 suppression test with LT3 fails to suppress TSH production in cases of TSHoma. In addition, a TRH stimulation test fails to increase levels of TSH or αsubunit in TSHomas. Due to the presence of somatostatin receptors, TSH reduction starts to occur within hours after the use of somatostatin analogs. Surgical removal is the cornerstone of management and helps achieve normal TSH levels in more than 75% of patients. Pre-operative treatment with octreotide is shown to reduce TSH levels by up to 50% and cause a reduction in size by 20-50%. Undetectable TSH 1-week post-op has good prognostic value and a reduction in TSH on a T3 suppression test has optimal sensitivity and specificity to demonstrate cure.

Akromegali hastalarında üst gastrointestinal system endoskopi taramasının değerlendirilmesi: tek merkez deneyimi

Purpose: The prevalence of precancerous or cancerous lesions in the upper gastrointestinal tract in acromegalic patients is not well known. The aim of this study is to evaluate the endoscopic findings of the upper gastrointestinal system (GIS) of patients with acromegaly and to assess whether the pathological findings are related to the disease and the use of somatostatin analogs.&#x0D; Materials and Methods: Between January 2010 and October 2021, patients diagnosed with acromegaly were identified by retrospective medical record scanning. This study included 49 patients with acromegaly who underwent upper GIS endoscopy. The acromegaly patients were divided into two groups: those who were taking somatostatin analogs at the time of endoscopy and those who were not. It was investigated whether there was a difference between these two groups in terms of lesion development. The patients with acromegaly and the control group were compared in terms of endoscopic findings and biopsy results.&#x0D; Results: Of these patients, 53% (n=26) were male and 46.9% (n=23) were female. The incidence of Helicobacter pylori (HP) was significantly higher in the acromegaly patients than in the control subjects. In the acromegaly group, 62.5% (n=15) of the 24 patients with antral and pangastritis were taking somatostatin analogs. There was no significant difference between the use of somatostatin analogs and the development of gastritis. The development of esophagitis was statistically higher in patients with acromegaly taking somatostatin analogs.&#x0D; Conclusion: The incidence of HP was higher in patients with acromegaly than in the normal population. No clear results were found regarding the development of gastritis. The incidence of esophagitis was high in acromegalic patients taking somatostatin analogs. Large-scale studies are needed to uncover the relationship between the etiology of the disease and the drugs taken.

High-quality phase 3 studies do not support the use of somatostatin analogues to reduce vomiting in malignant bowel obstruction

High-quality phase 3 studies do not support the use of somatostatin analogues to reduce vomiting in malignant bowel obstruction

Pulmonary neuroendocrine tumours and somatostatin receptor status: an assessment of unlicensed use of somatostatin analogues in the clinical practice

BackgroundThe use of somatostatin analogues (SSAs) has not been formally approved in pulmonary neuroendocrine tumours (NETs) in the absence of positive controlled trials, even though it is recommended as a potential therapeutic option in recent guidelines.Patients and methodsWe have assessed the use of SSA in the general practice in Austria by retrospectively analysing patients with pulmonary NETs referred to our European Neuroendocrine Tumor Society centre in Vienna for second opinion or further therapy. In addition, we have analysed the somatostatin receptor (SSTR) expression of those patients by immunohistochemistry (IHC) and SSTR imaging, e.g. 68Ga-DOTANOC-positron emission tomography/computed tomography, and whether such analyses had been carried out before referral at our centre.ResultsOut of 34 patients (19 atypical and 15 typical carcinoids) with metastatic or advanced disease, 10/34 (29%) had been prescribed SSA before referral. No IHC for SSTR had been carried out, and only 9/34 (27%) had undergone SSTR imaging by nuclear medicine. Sufficient material for IHC was available in 29/34 (85%) patients and SSTR-IHC was rated negative in 13/29 (45%), weakly positive in 4/29 (14%), moderately positive in 5/29 (17%) and strongly positive in 7/29 (24%) patients. On SSTR imaging, 8/34 patients (24%) were positive, 13/34 (38%) negative and 13/34 patients (38%) showed a mix of positive and negative NET lesions. In 11/29 (38%) patients with both IHC and imaging available, discordance of SSTR expression on imaging and histological assessment was detected.ConclusionsThese data show that uncritical use of SSA should be discouraged, and assessment of SSTR, preferably by imaging, is mandatory before prescription of SSA in pulmonary NETs.

A New Medical Therapy for Multiple Endocrine Neoplasia Type 1?

Pancreatic neuroendocrine tumours (pNETs) are a major manifestation of multiple endocrine neoplasia type 1 (MEN1), and the most significant cause of morbidity and mortality in this disorder. There is some evidence that the early use of somatostatin analogues can retard progression, especially of small non-functioning tumours, but there are no other prophylactic therapies for patients, and the treatment of metastatic disease is similar to that for sporadic pNETs. A recent study has shown that in cell line and animal models, MEN1 mutations lead to an upregulation of the enzyme dihydroorotate dehydrogenase (DHODH), which is involved in increasing precursor metabolites for the synthesis of pyrimidines. In these studies, blockade of this pathway by various means, including the DHODH inhibitor leflunomide, attenuates cell growth and tumour progression, suggesting a critical dependence on DHODH specifically in MEN1-mutated tissue. Preliminary clinical studies in three patients with MEN1 and pNETs have indicated some therapeutic potential of this drug, which has previously been used for some years in patients with rheumatoid arthritis. It is suggested that further clinical trials of this re-purposed drug are indicated to evaluate its potential for the treatment of patients with MEN1 and pNETS. This article describes the clinical problem of MEN1 and pNETs, and reviews the recent publication reporting on these initial results.

Modern principles of diagnosis and treatment of patients with neuroendocrine carcinoma of the prostate

Background. Prostate cancer (PCa) is well-known as the 2nd leading cause of death from malignant neoplasms among the males from developed countries. One of the variants of the disease - neuroendocrine carcinoma of the prostate (NECP) -manifests itself as the form of castration-resistant PCa. Distinctive manifestations of NECP include a low level of serum prostate specific antigen (PSA), a high potential rate of metastasis, and resistance to hormone replacement therapy. There are very few medical publications on the possibilities of diagnosis and therapy of this type of tumor.The objective of the study is to review the current foundations of pathogenesis, methods of diagnosis and treatment of patients with NECP.Materials and methods. The data of modern medical literature from the PubMed/Crossref archives, from the Elsevier and Scopus databases for 1991-2020 were studied. The materials on the epidemiology and pathogenesis of NECP, as well as the methods of diagnosis and treatment of patients with this pathology are summarized. A comparative analysis of the levels of neuroendocrine markers in castration-resistant and localized forms of PCa was carried out. The schemes of combination therapy of NECP with the use of somatostatin analogs are considered.Results. The detection rate of NECP is reduced due to the blurred clinical picture and morphological characteristics similar to poorly differentiated carcinoma. The basis for the diagnosis of NECP is the determination of the levels of neuronal markers - chromogranin A, neuron-specific enolase, and a number of potentially mitogenic hormones, including PTHrP, NT, serotonin, bombesin, calcitonin, and thyroid-stimulating hormone. The worst prognosis was observed in patients with initially high levels of chromogranin A, which emphasizes the high significance of this indicator for monitoring NECP. The drug of choice in the treatment of patients with this pathology is the somatostatin analogue octreotide-depot, the use of which in combination with hormone replacement therapy leads to stabilization of PCa in 50 % of cases. During therapy with an analogue of somatostatin alone or in cases of tumor progression against the background of chemotherapy, a decrease in PSA level is noted in 50-60 % of cases, and PSA level stabilization - in 41.7-53.3 %.Conclusion. We founded an insufficient number of randomized clinical trials of NECP, therefore, the prognosis of the development of this pathology remains completely unclear. The use of somatostatin analogues, along with targeted therapy, is the main choice of therapy for NECP, but requires further study in the program of randomized trials. If a positive result is obtained, it will be possible to use somatostatin analogs more widely to improve the quality and increase the life expectancy of patients with NECP.

Neuroendocrine neoplasia and bone (Review).

This is a narrative review focusing on neuroendocrine neoplasia (NEN) and bone status, in terms of metastases and osteoporosis/fractures. One fifth of NEN have skeletal dissemination, this affinity being regulated by intrinsic tumor factors such as the C-X-C chemokine receptor 4 (CXCR4). Bone colonization impairs the patient quality of life, representing a surrogate of reduced survival. Patients with NEN without bone metastases may exhibit low bone mineral density, perhaps carcinoid-related osteoporosis, yet not a standardized cause of osteoporosis. Case-finding strategies to address bone health in NEN with a good prognosis are lacking. Contributors to fractures in NEN subjects may include: menopausal status and advanced age, different drugs, induced hypogonadism, malnutrition, malabsorption (due to intestinal resection, carcinoid syndrome), hypovitaminosis D, impaired glucose profile (due to excessive hormones such as glucagon, somatostatinoma or use of somatostatin analogues), various corticoid regimes, and high risk of fall due to sarcopenia. Pheocromocytoma/paraganglioma involve bone through malignant forms (bone is an elective site) and potential secondary osteoporosis due to excessive hormonal content and increased sympathetic activity which is a key player of bone microarchitecture/quality as reflected by low Trabecular Bone Score. Glucocorticoid osteoporosis is related to NEN-associated ectopic Cushing syndrome. Currently, there are a lack of studies to emphasis that excessive gut-derivate serotonin in NENs with carcinoid syndrome is a specific activator of bone loss thus a contributor to carcinoid-related osteoporosis.

A rare case of a metastatic neuroendocrine tumor of the pancreas

Aim. To study a rare sporadic case of metastatic gastrinoma associated with mutations in the MEN1 and TSC2 genes in a 25-year-old male. Materials and methods . A retrospective analysis of the history of a 25-year-old patient with sporadic gastrinoma with a highly aggressive clinical course and high metastatic potential was performed. Sequencing of the DNA extracted from the surgical tumor biopsy was performed on the Illumina NextSeq 550 sequencer (Illumina Inc., USA) with the mean coverage of at least 100× using the AmpliSeq target panel for Illumina Comprehensive Cancer Panel for studying exons of 409 genes, mutations in which are associated with oncopathology. Results. The article presents the results of complex diagnosis and treatment of metastatic gastrinoma using modern locoregional therapy and drugs from the group of somatostatin analogues. Using next generation sequencing and Sanger sequencing, sporadic mutations in the MEN1 and TSC2 genes with pronounced clinical significance were identified in the extracted DNA. Conclusion. The identified mutations, being the drivers of the tumor process, apparently determined the atypical development of the presented clinical case – the sporadic Zollinger – Ellison syndrome. Complete morphological and immunohistochemical validation of the neuroendocrine tumor before treatment determined a successful treatment strategy, including the use of somatostatin analogues in adjuvant and neoadjuvant therapies in combination with chemoembolization of hepatic metastases.

A Rare Case of Thyrotropin Secreting Pituitary Macroadenoma Primarily Treated With Somatostatin Analogue

Introduction/Background: Thyrotropin secreting pituitary adenomas (TSH-oma) are a rare cause of hyperthyroidism. They account for <1% of the cases of hyperthyroidism with a reported incidence of 2.8 per 1 million in Sweden. Diagnosis is suspected by the presence of elevated T4 and T3 in the setting of an unsuppressed TSH level. The presence of large pituitary adenoma is highly suggestive of the diagnosis and can be differentiated from thyroid hormone resistance by elevated alpha subunit and SHBG levels. Trans-sphenoidal surgery is the definitive treatment. Peri-operative medical treatment with somatostatin analogues is indicated to achieve euthyroidism and prevent surgical risks and thyroid storm. The use of somatostatin analogues as a primary treatment for TSH-oma is still under investigation. We hereby report a rare case of TSH-oma where somatostatin analogues successfully resulted in normalization of thyroid function and tumor size reduction. Clinical Case: A 61 years old gentleman with a history of hypothyroidism diagnosed three years before presentation to the Pituitary clinic. He was treated with Levothyroxine. On clinical examination, he had mild tremor and warm sweaty palms with no stigmata of Grave’s disease. The thyroid function test showed elevated free T4 of 3.6 ng/dl (0.9-1.7), elevated free T3 of 8.6 pg/ml (2.0-4.4), and a high TSH level of 9.10 μIU/ml (0.27-4.20). His prolactin level was mildly elevated at 24.8 ng/ml(4.0-15.2). Testosterone, IGF-1, and cortisol levels were normal. An MRI of his pituitary gland showed large pituitary macroadenoma with supra-sellar extension and mild compression of the optic nerve. He had an elevated alpha subunit of 5.6 ng/ml (<1.37) and a high SHBG level of 198 nmol/l(10-80). TSH adenoma was diagnosed and he was planned for trans-sphenoidal surgery. Pre-operative treatment with somatostatin analogue Lanerotide 90 mg monthly injection was initiated. Interestingly normal thyroid function was observed approximately 1 month after his first injection. Repeat MRI showed a considerable decrease in the size of the pituitary macroadenoma. The patient opted to hold on to surgery and to continue on medical treatment. His thyroid function remains normal 15 months after initiation of treatment and his MRI continues to show stable pituitary adenoma. Conclusion: Somatostatin analogues can be used as a primary treatment for thyrotropin secreting pituitary adenomas when the patient is unable or unwilling to undergo surgery. It is use is associated with normalization of thyroid function and in some cases with a reduction in the adenoma size.

Medication for Acromegaly Reduces Expression of MUC16, MACC1 and GRHL2 in Pituitary Neuroendocrine Tumour Tissue.

Acromegaly is a disease mainly caused by pituitary neuroendocrine tumor (PitNET) overproducing growth hormone. First-line medication for this condition is the use of somatostatin analogs (SSAs), that decrease tumor mass and induce antiproliferative effects on PitNET cells. Dopamine agonists (DAs) can also be used if SSA treatment is not effective. This study aimed to determine differences in transcriptome signatures induced by SSA/DA therapy in PitNET tissue. We selected tumor tissue from twelve patients with somatotropinomas, with half of the patients receiving SSA/DA treatment before surgery and the other half treatment naive. Transcriptome sequencing was then carried out to identify differentially expressed genes (DEGs) and their protein–protein interactions, using pathway analyses. We found 34 upregulated and six downregulated DEGs in patients with SSA/DA treatment. Three tumor development promoting factors MUC16, MACC1, and GRHL2, were significantly downregulated in therapy administered PitNET tissue; this finding was supported by functional studies in GH3 cells. Protein–protein interactions and pathway analyses revealed extracellular matrix involvement in the antiproliferative effects of this type of the drug treatment, with pronounced alterations in collagen regulation. Here, we have demonstrated that somatotropinomas can be distinguished based on their transcriptional profiles following SSA/DA therapy, and SSA/DA treatment does indeed cause changes in gene expression. Treatment with SSA/DA significantly downregulated several factors involved in tumorigenesis, including MUC16, MACC1, and GRHL2. Genes that were upregulated, however, did not have a direct influence on antiproliferative function in the PitNET cells. These findings suggested that SSA/DA treatment acted in a tumor suppressive manner and furthermore, collagen related interactions and pathways were enriched, implicating extracellular matrix involvement in this anti-tumor effect of drug treatment.

Doubling Time of Residual Tumor Volume for Metastatic Neuroendocrine Tumors Determines Survival Outcomes after Hepatic Resection

Introduction: Estimates of the percentage of resectable tumor to guide debulking surgery for metastatic gastro-entero-pancreatic neuroendocrine tumors (GEP-NET) does not account for tumor biology and absolute hepatic tumor burden. Thus, we studied the growth kinetics of residual metastatic disease after debulking surgery for GEP-NET to determine whether these tumor-specific factors correlated with survival. Methods: Patients with measurable residual metastatic disease by imaging after debulking surgery for GEP-NET with or without resection of primary tumors between 2000-2017 were studied. Residual tumor volumes were measured over time to determine tumor growth kinetics. The primary outcome of interest was time from debulking surgery to adjuvant therapy or death. Results: Twenty-eight patients had residual metastatic GEP-NET and half had an estimated ≥90% debulking resection. Median residual tumor volume (Y0) after debulking surgery was 3.0 (IQR 0.45-20.8) ml. Median tumor volume doubling time was 53.9 (IQR 29-159.2) weeks. Grade of tumor differentiation, Ki-67 index, and estimated percentage of debulking were not associated with outcomes. Multi-variate analysis showed that, after adjusting for Y0 and the use of somatostatin-analogues post-operatively, only tumor volume doubling time ≥52 weeks was associated with the time to adjuvant therapy or death (HR 0.17 95%CI 0.04-0.82). Patients with a tumor doubling time ≥52 weeks had improved overall survival at 1, 3, and 5 years when compared to a doubling time < 52 weeks (100.0%, 90.9%, 90.9% vs 92.3%, 68.4%, 68.4%; p=0.034). Conclusions: Tumor volume doubling time, not the proportion of debulking performed, determines outcomes after debulking surgery for residual metastatic GEP-NET.

Chronic Use of Long-Acting Somatostatin Analogues (SSAs) and Exocrine Pancreatic Insufficiency (EPI) in Patients with Gastroenteropancreatic Neuroendocrine Tumors (GEP-NETs): An Under-recognized Adverse Effect

Somatostatin Analogues (SSAs) are used to treat Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) and acromegaly. Side effects of SAAs usually include biliary disorders, gastrointestinal disorders, injection-site pain and hyperglycemia. Exocrine Pancreatic Insufficiency (EPI) is often misdiagnosed as disease progression or failure to SAAs or diagnosed after a delay in patients receiving SAAs. We present our experience with EPI developing in patients following use of SAAs. We reviewed chart and pharmacy records of 110 GEP-NETs patients who received SSAs. Data was collected including demographics, pathology, stage, dose/duration of long and short-acting SA, use of antidiarrheal, pancreatic enzyme replacement (PER), proton pump inhibitors (PPI) or H2 blockers). Laboratory data include chromogranin-A (CgA), urine 5-HIAA and quantitative fecal fat test (QFFT) or fecal elastase test (FE). EPI was defined by a FE below normal level OR by a reduction of ≥ 21.2% or steatorrhea on QFFT. Patients who were identified to develop EPI were treated with pancreatic exocrine replacement therapy (PERT). Among, 110 GEP-NETs patients, 104 received LA Octreotide and 6 Somatuline Depot Injection. Of these, 23 received short-acting SSA for worsening diarrhea, 96 had intensification of antidiarrheal and 1 got telotristat ethyl. QFFT confirmed EPI in 19, 11 based on clinical symptoms, and 16 had sample error or refusal to collect specimen. CTCAE 4.0 grades of EPI were: grade 2(69%), grade 3(22%) and grade 4(9%). Median time to development of EPI was 12 months (95%CI 3 - 23). Except 1, all patients received PERT either with concomitant PPI (13) or later if no improvement with PERT (6) and 2 on H2 blockers. 37% of the patients had improvement in EPI within 4-8 weeks. Deficiency of vitamins and trace elements was found in 11 of 19 patients, who received supplementation. Our experience constitutes the first and the largest study addressing EPI as a rare but serious complication of chronic use of SAAs. Although SAAs are used to treat diarrhea, paradoxically they can worsen diarrhea secondary to EPI. Early recognition and diagnosis of this under-diagnosed and under-reported side effect of SAAs, such as EPI, can improve not only diarrhea and weight loss in these patients but also can reduce cost of using short-acting SAAs and antidiarrheal.