These guidelines update previous guidance published in 2005. They have been revised by a group who are members of the UK and Ireland Neuroendocrine Tumour Society with endorsement from the clinical committees of the British Society of Gastroenterology, the Society for Endocrinology, the Association of Surgeons of Great Britain and Ireland (and its Surgical Specialty Associations), the British Society of Gastrointestinal and Abdominal Radiology and others. The authorship represents leaders of the various groups in the UK and Ireland Neuroendocrine Tumour Society, but a large amount of work has been carried out by other specialists, many of whom attended a guidelines conference in May 2009. We have attempted to represent this work in the acknowledgements section. Over the past few years, there have been advances in the management of neuroendocrine tumours, which have included clearer characterisation, more specific and therapeutically relevant diagnosis, and improved treatments. However, there remain few randomised trials in the field and the disease is uncommon, hence all evidence must be considered weak in comparison with other more common cancers.

https://gut.bmj.com/content/gutjnl/61/1/6.full.pdf

Guidelines for the management of gastroenteropancreatic neuroendocrine (including carcinoid) tumours (NETs)

Diabetic autonomic neuropathy

http://pic1.cmt.com.cn/newspic/files/dm-guidelines-ccp.pdf

American association of clinical endocrinologists and american college of endocrinology - clinical practice guidelines for developing a diabetes mellitus comprehensive care plan - 2015.

Neuroendocrine tumors (NETs) are heterogeneous malignancies arising from the diffuse neuroendocrine system. They frequently originate in the gastroenteropancreatic (GEP) tract and the bronchopulmonary tree, and their incidence has steadily increased in the last 3 decades. Fundamental biologic and genomic differences underlie the clinical heterogeneity of NETs, and distinct molecular features characterize NETs of different grades and different primary sites. Although surgery remains the cornerstone of treatment for localized tumors, systemic treatment options for patients with metastatic NETs have expanded considerably. Somatostatin analogs have demonstrated both antisecretory and antitumor efficacy. Peptide receptor radionuclide therapy with lutetium-177 dotatate (177 Lu-DOTATATE) has been approved for advanced GEP-NETs. The antitumor activity of everolimus has been demonstrated across a wide spectrum of NETs, and the antiangiogenic agent sunitinib has been approved for pancreatic NETs (pNETs). Chemotherapy with temozolomide and capecitabine has recently demonstrated an unprecedented prolongation of progression-free survival in a randomized trial of pNETs. Multiple retrospective series have reported the efficacy of liver-directed therapies both for palliating symptoms of hormone excess and for controlling tumor growth. Telotristat, an oral inhibitor of tryptophan hydroxylase, has been shown to reduce diarrhea in patients with carcinoid syndrome. Defining the therapeutic algorithm and identifying biomarkers predictive of response to treatments are among the main priorities for the next decade of research in the NET field.

https://acsjournals.onlinelibrary.wiley.com/doi/pdf/10.3322/caac.21493

Gastroenteropancreatic Neuroendocrine Tumors.

Neuroendocrine tumors (NETs) are a form of cancer that differ from other neoplasia in that they synthesize, store, and secrete peptides, e.g., chromogranin A (CgA) and amines. A critical issue is late diagnosis due to failure to identify symptoms or to establish the biochemical diagnosis. We review here the utility of CgA measurement in NETs and describe its biological role and the clinical value of its measurement. Literature review and analysis of the utility of plasma/serum CgA measurements in NETs and other diseases. CgA is a member of the chromogranin family; its transcription and peptide processing are well characterized, but its precise function remains unknown. Levels are detectable in the circulation but vary substantially (~25%) depending on which assay is used. Serum and plasma measurements are concordant. CgA is elevated in ~90% of gut NETs and correlates with tumor burden and recurrence. Highest values are noted in ileal NETs and gastrointestinal NETs associated with multiple endocrine neoplasia type 1. Both functioning and nonfunctioning pancreatic NETs have elevated values. CgA is more frequently elevated in well-differentiated tumors compared to poorly differentiated NETs. Effective treatment is often associated with decrease in CgA levels. Proton pump inhibitors falsely increase CgA, but levels normalize with therapy cessation. CgA is currently the best available biomarker for the diagnosis of NETs. It is critical to establish diagnosis and has some utility in predicting disease recurrence, outcome, and efficacy of therapy. Measurement of plasma CgA is mandatory for the effective diagnosis and management of NET disease.

Chromogranin A—Biological Function and Clinical Utility in Neuro Endocrine Tumor Disease

Introduction. Diabetics die from cardiovascular disease at a much greater rate than nondiabetics. Cardiac autonomic imbalance predicts increased cardiovascular risk and mortality. We studied the relationship between cardiac autonomic imbalance and adipose tissue-derived inflammation in newly diagnosed and established type 2 diabetes. Materials and Methods. Non-diabetics, newly diagnosed diabetics, and established diabetics were included. Anthropomorphic and biochemical measurements were obtained, and insulin resistance was approximated. Cardiac autonomic function was assessed using conventional measures and with power spectral analysis of heart rate. Results and Discussion. Heart rate variability was reduced in all diabetics. Interleukin-6 was higher in diabetics, as was the high molecular weight adiponectin-to-leptin ratio. Interleukin-6 correlated negatively with measures of autonomic balance. Ratios of adiponectin to leptin correlated positively with measures of autonomic balance. Cardiac autonomic imbalance and inflammation occur early in diabetes and are interrelated. Conclusions. Cardiac autonomic imbalance correlates with the adipose tissue-derived inflammation seen early in type 2 diabetes.

/pdf/cardiac-autonomic-imbalance-in-newly-diagnosed-and-v986r6iaxz.pdf

Cardiac Autonomic Imbalance in Newly Diagnosed and Established Diabetes Is Associated with Markers of Adipose Tissue Inflammation

ObjectiveProton pump inhibitors (PPIs) are used primarily to treat gastroesophageal reflux disease. Proton pump inhibitor–induced achlorhydria increases circulating gastrin and chromogranin A (CGA). Chromogranin is a widely used biomarker for the diagnosis and follow-up for gut-based neuroendocrine

A prospective evaluation of the effect of chronic proton pump inhibitor use on plasma biomarker levels in humans.

Objectives5-Hydroxyindoleacetic acid (5-HIAA) is used for the evaluation of neuroendocrine tumors (NETs) but currently requires a 24-hour urine collection.MethodsWe developed a gas chromatography mass spectroscopy–based plasma 5-HIAA assay. We compared 24-hour urine 5-HIAA values against plasma 5-HI

/pdf/a-single-fasting-plasma-5-hiaa-value-correlates-with-24-hour-2ypgwqv961.pdf

A Single Fasting Plasma 5-HIAA Value Correlates With 24-Hour Urinary 5-HIAA Values and Other Biomarkers in Midgut Neuroendocrine Tumors (NETs)

Development of effective prophylaxis against intraoperative carcinoid crisis

Objectives: Octreotide long acting repeatable (LAR) is widely used for the control of symptoms of functional neuroendocrine tumors. At doses of 30 mg/mo, up to 40% of patients require subcutaneous octreotide ‘‘rescue’’ and up to 40% of patients are given more than 30 mg of LAR/mo. Octreotide acetate binds to the sst2 receptor with an affinity (Kd) of approximately 1 3 10 29 mol/L (@1000 pg/mL), but higher (@10,000 pg/mL) concentrations of octreotide are required to completely saturate this receptor. Octreotide blood level measurement may be useful to guide LAR therapy in symptomatic patients or in patients who have tumor growth on traditional LAR doses. We hypothesize that LAR doses of 60 mg/mo will produce blood levels of 10,000 pg/mL or greater. At identical monthly LAR doses, patients with higher weights will require more medication to achieve similar plasma octreotide levels than individuals with lower body weights. Methods: Trough plasma, serum, urine, and saliva octreotide levels were obtained from 52 patients with carcinoid syndrome receiving 20 (n = 8), 30 (n = 19), or 60 mg LAR/mo (n = 10). Octreotide levels were determined by radioimmunoassay. Results: The mean 6 SD plasma octreotide levels for patients receiving 20, 30, or 60 mg LAR/mo were 2518 6 1020, 5241 6 3004, and 10,925 6 5330 pg/mL, respectively. Patient weight (kilograms) was inversely related to plasma octreotide levels. There was a significant correlation between plasma octreotide levels and octreotide levels measured in urine, saliva, and serum. Conclusions: Frequent measurement of octreotide levels may be useful to guide octreotide therapy in patients with poorly controlled symptoms or those patients experiencing tumor growth.

/pdf/effect-of-octreotide-lar-dose-and-weight-on-octreotide-blood-3nuyy9n6kx.pdf

Gregg Mamikunian

Papers

Cardiac Autonomic Imbalance in Newly Diagnosed and Established Diabetes Is Associated with Markers of Adipose Tissue Inflammation

A prospective evaluation of the effect of chronic proton pump inhibitor use on plasma biomarker levels in humans.

A Single Fasting Plasma 5-HIAA Value Correlates With 24-Hour Urinary 5-HIAA Values and Other Biomarkers in Midgut Neuroendocrine Tumors (NETs)

Development of effective prophylaxis against intraoperative carcinoid crisis

Effect of octreotide LAR dose and weight on octreotide blood levels in patients with neuroendocrine tumors.