A muscarinic receptor antagonist reverses multiple indices of diabetic peripheral neuropathy: preclinical and clinical studies using oxybutynin.

Preclinical studies indicate that diverse muscarinic receptor antagonists, acting via the M1 sub-type, promote neuritogenesis from sensory neurons in vitro and prevent and/or reverse both structural and functional indices of neuropathy in rodent models of diabetes. We sought to translate this as a potential therapeutic approach against structural and functional indices of diabetic neuropathy using oxybutynin, a muscarinic antagonist approved for clinical use against overactive bladder. Studies were performed using sensory neurons maintained in vitro, rodent models of type 1 or type 2 diabetes and human subjects with type 2 diabetes and confirmed neuropathy. Oxybutynin promoted significant neurite outgrowth in sensory neuron cultures derived from adult normal rats and STZ-diabetic mice, with maximal efficacy in the 1-100 nmol/l range. This was accompanied by a significantly enhanced mitochondrial energetic profile as reflected by increased basal and maximal respiration and spare respiratory capacity. Systemic (3-10 mg/kg/day s.c.) and topical (3% gel daily) oxybutynin reversed paw heat hypoalgesia in the STZ and db/db mouse models of diabetes and reversed paw tactile allodynia in STZ-diabetic rats. Loss of nerve profiles in the skin and cornea of db/db mice was also prevented by daily topical delivery of 3% oxybutynin for 8 weeks. A randomized, double-blind, placebo-controlled interventional trial was performed in subjects with type 2 diabetes and established peripheral neuropathy. Subjects received daily topical treatment with 3% oxybutynin gel or placebo for 6 months. The a priori designated primary endpoint, significant change in intra-epidermal nerve fibre density (IENFD) in skin biopsies taken before and after 20 weeks of treatments, was met by oxybutynin but not placebo. Secondary endpoints showing significant improvement with oxybutynin treatment included scores on clinical neuropathy, pain and quality of life scales. This proof-of-concept study indicates that muscarinic antagonists suitable for long-term use may offer a novel therapeutic opportunity for treatment of diabetic neuropathy. Trial registry number: NCT03050827.

Effect of Lanreotide Depot/Autogel on Urinary 5-Hydroxyindoleacetic Acid and Plasma Chromogranin A Biomarkers in Nonfunctional Metastatic Enteropancreatic Neuroendocrine Tumors.

BACKGROUND: Urinary 5-hydroxyindoleacetic acid (5-HIAA) is an established biomarker in neuroendocrine tumors and carcinoid syndrome; however, its role in nonfunctional neuroendocrine tumors is not defined. We present post hoc data on urinary 5-HIAA and plasma chromogranin A (CgA) from the CLARINET study. METHODS: Patients with well- or moderately differentiated, nonfunctioning, locally advanced or metastatic enteropancreatic neuroendocrine tumors were randomized to deep subcutaneous lanreotide depot/autogel 120 mg or placebo once every 28 days for 96 weeks. Tumor response, evaluated centrally (RECIST 1.0), and progression-free survival (PFS) were assessed by treatment and biochemical response, defined as (a) baseline >upper limit of normal (ULN, 41.6 µmol per day 5-HIAA; 98.1 µg/L CgA) and (b) ≥50% decrease from baseline and to ≤ULN value on study. RESULTS: Forty-eight percent (82 of 171; lanreotide, n = 45; placebo, n = 37) and 66% (129 of 195; lanreotide, n = 65; placebo, n = 64) of randomized patients had 5-HIAA and CgA > ULN at baseline. Among patients with >ULN baseline values who did not progress after 96 weeks of treatment, significantly greater reductions in 5-HIAA and CgA were observed in lanreotide-treated versus placebo-treated patients throughout the study (all p < .05). PFS was significantly prolonged among 5-HIAA responders versus nonresponders (median not reached vs. 16.2 months, p < .0001; hazard ratio [HR] = 0.21, 95% confidence interval [CI], 0.09-0.48) and CgA responders versus nonresponders (median not reached vs. 16.2 months, p = .0070; HR = 0.30, 95% CI, 0.12-0.76), regardless of treatment arm. PFS was also significantly prolonged among lanreotide-treated 5-HIAA responders versus nonresponders (p = .0071) but was not significantly different among placebo-treated 5-HIAA responders versus nonresponders. There were no significant differences in PFS between lanreotide-treated CgA responders versus nonresponders or between placebo-treated CgA responders versus nonresponders. CONCLUSIONS: The 5-HIAA findings are noteworthy because they occurred in patients with nonfunctioning enteropancreatic neuroendocrine tumors. Monitoring 5-HIAA and CgA may be useful when treating patients with nonfunctional neuroendocrine tumors. IMPLICATIONS FOR PRACTICE: Current guidelines focus only on the monitoring of 5-hydroxyindoleacetic acid (5-HIAA) in the diagnosis and management of functional neuroendocrine tumors with carcinoid syndrome. The current post hoc analysis of patients with nonfunctional enteropancreatic neuroendocrine tumors in the CLARINET study demonstrated that measuring and following both 5-HIAA and chromogranin A as biomarkers of disease progression may be useful in the management of patients with nonfunctional neuroendocrine tumors.

LANREOTIDE THERAPY IN CARCINOID SYNDROME: PROSPECTIVE ANALYSIS OF PATIENT-REPORTED SYMPTOMS IN PATIENTS RESPONSIVE TO PRIOR OCTREOTIDE THERAPY AND PATIENTS NAÏVE TO SOMATOSTATIN ANALOGUE THERAPY IN THE ELECT PHASE 3 STUDY.

OBJECTIVE: This ELECT prospective analysis examined lanreotide depot/autogel for carcinoid syndrome (CS) symptom control in patients with neuroendocrine tumors (NETs) who were responsive to prior octreotide (prior octreotide group) compared with patients who were naïve to prior somatostatin analogue treatment (de novo group). METHODS: Adults with histopathologically confirmed NET and stable CS (diarrhea and/or flushing) were randomized to subcutaneous (SC) lanreotide 120 mg or placebo every 4 weeks for 16 weeks. Patients reported diarrhea and/or flushing symptom severity and frequency and short-acting SC octreotide rescue therapy daily using an Interactive Voice/Web Response System. To evaluate the efficacy of lanreotide compared with placebo, the novel primary endpoint of patient-determined use of SC octreotide rescue therapy for breakthrough symptoms was used as a surrogate for symptom control. Clinically meaningful patient-reported treatment benefit was examined using daily patient-reported symptoms of diarrhea and flushing. RESULTS: Of the 115 randomized patients, 51 (n = 26 lanreotide, n = 25 placebo) were octreotide-naïve (de novo) and 64 (n = 33 lanreotide; n = 31 placebo) received prior octreotide. Lanreotide versus placebo patients had a lower mean percentage of days of SC octreotide rescue therapy in de novo and prior octreotide groups (least squares [LS] mean difference -19.1, P = .0477 and -6.9, P = .4332, respectively). The mean percentage of days with moderate/severe diarrhea and/or flushing was lower in lanreotide versus placebo patients in de novo and prior octreotide groups (LS mean difference -14.6, P = .0140 and -10.9, P = .0746, respectively). The transition from octreotide to lanreotide was generally well-tolerated. CONCLUSION: Improvement in CS symptoms occurred with lanreotide treatment, regardless of prior octreotide use. ABBREVIATIONS: CI = confidence interval CS = carcinoid syndrome DB = double blind ELECT = Evaluation of Lanreotide depot/autogel Efficacy and safety as a Carcinoid-syndrome Treatment IOL = initial open-label IVRS/IWRS = interactive voice/web response system LS = least square NET = neuroendocrine tumor OR = odds ratio SC = subcutaneous SSA = somatostatin analogue SSTR = somatostatin receptor TEAE = treatment-emergent adverse event.

BIOCHEMICAL RESPONSES IN SYMPTOMATIC AND ASYMPTOMATIC PATIENTS WITH NEUROENDOCRINE TUMORS: POOLED ANALYSIS OF 2 PHASE 3 TRIALS.

OBJECTIVE: Neuroendocrine tumors (NETs) are associated with elevated 5-hydroxyindoleacetic acid (5-HIAA) and chromogranin A (CgA) levels. This study aimed to analyze relationships between urinary 5-HIAA and plasma CgA levels and clinical outcomes. METHODS: Centrally assessed biomarker levels and correlations with progression-free survival (PFS) and carcinoid syndrome (CS) symptom control were evaluated in a pooled analysis of CLARINET (96-week randomized, double-blind, placebo-controlled) and ELECT (16-week randomized, double-blind, placebo-controlled, 32-week initial open label and ≥2 year long-term extension open label) studies of adults with NETs, with (ELECT) or without (CLARINET) CS at 97 institutions. Patients were treated with subcutaneous lanreotide depot 120 mg monthly. RESULTS: Of 319 pooled patients, 86% and 95% had baseline 5-HIAA and CgA data, respectively, with 47% and 74% having levels greater than the upper limit of normal (ULN). PFS was longer among patients who experienced a decrease in biomarker levels at week 12, with statistical significance reached in the CgA cohort (not reached vs. 14.4 months; P<.0001). A large proportion (87%) of patients without symptoms of CS in the CLARINET study had detectable levels of 5-HIAA (48% >ULN). In ELECT, patients with CS who received lanreotide and experienced a biochemical response (≥50% decrease from baseline) achieved greater symptom control. CONCLUSION: This pooled analysis of two randomized, placebo-controlled trials demonstrated that 5-HIAA and CgA are secreted as biochemical biomarkers in many patients with NETs, regardless of clinical syndromes. Significant biochemical response was associated with improved clinical outcomes, as measured by improved PFS or improved CS symptom control. ABBREVIATIONS: 5-HIAA = 5-hydroxyindoleacetic acid; CgA = chromogranin A; CI = confidence interval; CLARINET = Controlled Study of Lanreotide Antiproliferative Response in Neuroendocrine Tumors; CS = carcinoid syndrome; ELECT = Evaluation of Lanreotide Depot/Autogel Efficacy and Safety as a Carcinoid Syndrome Treatment; HR = hazard ratio; ITT = intention-to-treat; NET = neuroendocrine tumor; PanNET = pancreatic NET; PFS = progression-free survival; PPI = proton pump inhibitor; SSA = somatostatin analogue; ULN = upper limit of normal.

Content validity of symptom-based measures for diabetic, chemotherapy, and HIV peripheral neuropathy.

INTRODUCTION: No treatments for axonal peripheral neuropathy are approved by the United States Food and Drug Administration (FDA). Although patient- and clinician-reported outcomes are central to evaluating neuropathy symptoms, they can be difficult to assess accurately. The inability to identify efficacious treatments for peripheral neuropathies could be due to invalid or inadequate outcome measures. METHODS: This systematic review examined the content validity of symptom-based measures of diabetic peripheral neuropathy, HIV neuropathy, and chemotherapy-induced peripheral neuropathy. RESULTS: Use of all FDA-recommended methods to establish content validity was only reported for 2 of 18 measures. Multiple sensory and motor symptoms were included in measures for all 3 conditions; these included numbness, tingling, pain, allodynia, difficulty walking, and cramping. Autonomic symptoms were less frequently included. CONCLUSIONS: Given significant overlap in symptoms between neuropathy etiologies, a measure with content validity for multiple neuropathies with supplemental disease-specific modules could be of great value in the development of disease-modifying treatments for peripheral neuropathies. Muscle Nerve 55: 366-372, 2017.

PRECISION MEDICINE IN ADRENAL DISORDERS: THE NEXT GENERATION.

OBJECTIVE: Discuss exciting new research in the area of adrenal disorders that has emerged in the last few years. Advances in genetics, biochemical diagnosis, and imaging modalities that have set new standards for diagnosis and treatment are described. METHODS: A literature review was conducted on adrenal disorders using PubMed. RESULTS: We highlight new developments in adrenal diseases from new genes discovered in aldosterone-producing adenomas, cortisol-producing tumors to pheochromocytomas/paragangliomas. In addition, we discuss new information regarding the question of whether nonfunctional adrenal adenomas are really functional or not. In congenital adrenal hyperplasia, emerging steroids that might be helpful in the near future for diagnostic purposes are discussed. New types of imaging are now available to identify endocrine neoplasms to help clinicians find lesions after biochemical confirmation. CONCLUSION: The tremendous knowledge gained thus far in adrenal diseases sets the stage for not only new precision treatment modalities for individualized care but also for prevention. ABBREVIATIONS: ACC = adrenal cortical carcinoma; APA = aldosterone-producing adenoma; APCC = aldosterone-producing cell cluster; CAH = congenital adrenal hyperplasia; CT = computed tomography; DOTATATE = [68Ga]-DOTA(0)-Tyr(3)-octreotate; FDG = fluorodeoxyglucose; FH = fumarate hydratase; MR = miner-alocorticoid; MDH2 = malate dehydrogenase 2; PCC = pheochromocytoma; PET = positron emission tomography; PGL = paraganglioma; SCS = subclinical cortisol-secreting; SDHB = succinate dehydrogenase subunit B; TCGA = The Cancer Genome Atlas.

AGING, DIABETES, AND FALLS.

KEY POINTS Falls are a major health issue for older adults, leading to adverse events and even death. Older persons with type 2 diabetes are at increased risk of falling compared to healthy adults of a similar age. Over 400 factors are associated with falls risk, making identification and targeting of key factors to prevent falls problematic. However, the major risk factors include hypertension, diabetes, pain, and polypharmacy. In addition to age and polypharmacy, diabetes-related loss of strength, sensory perception, and balance secondary to peripheral neuropathy along with decline in cognitive function lead to increased risk of falling. Designing specific interventions to target strength and balance training, reducing polypharmacy to improve cognitive function, relaxation of diabetes management to avoid hypoglycemia and hypotension, and relief of pain will produce the greatest benefit for reducing falls in older persons with diabetes. Abbreviation: DPN = diabetic polyneuropathy.

AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS AND AMERICAN COLLEGE OF ENDOCRINOLOGY POSITION STATEMENT ON TESTING FOR AUTONOMIC AND SOMATIC NERVE DYSFUNCTION.

This document represents the official position of the American Association of Clinical Endocrinologists and the American College of Endocrinology. Where there were no randomized controlled trials or specific U.S. FDA labeling for issues in clinical practice, the participating clinical experts utilized their judgment and experience. Every effort was made to achieve consensus among the committee members. Position statements are meant to provide guidance, but they are not to be considered prescriptive for any individual patient and cannot replace the judgment of a clinician.

Capsaicin 8% patch repeat treatment plus standard of care (SOC) versus SOC alone in painful diabetic peripheral neuropathy: a randomised, 52-week, open-label, safety study.

BACKGROUND: This 52-week study evaluated the long-term safety and tolerability of capsaicin 8% w/w (179 mg) patch repeat treatment plus standard of care (SOC) versus SOC alone in painful diabetic peripheral neuropathy (PDPN). METHODS: Phase 3, multinational, open-label, randomised, controlled, 52-week safety study, conducted in Europe. Patients were randomised to capsaicin 8% patch repeat treatment (30 or 60 min; 1-7 treatments with ≥ 8-week intervals) to painful areas of the feet plus SOC, or SOC alone. The primary objective was the safety of capsaicin 8% patch repeat treatment (30 min and 60 min applications) plus SOC versus SOC alone over 52 weeks, assessed by changes in Norfolk Quality of Life-Diabetic Neuropathy (QOL-DN) total score from baseline to end of study (EOS). Secondary safety endpoints included Utah Early Neuropathy Scale (UENS) assessments and standardised testing of sensory perception and reflex function. RESULTS: Overall, 468 patients were randomised (30 min plus SOC, n = 156; 60 min plus SOC, n = 157; SOC alone, n = 155). By EoS, mean changes in Norfolk QOL-DN total score from baseline [estimated mean difference versus SOC alone; 90% CI for difference] were: 30 min plus SOC, -27.6% [-20.9; -31.7, -10.1]; 60 min plus SOC, -32.8% [-26.1; -36.8, -15.4]; SOC alone, -6.7%. Mean changes [difference versus SOC alone] in UENS total score by EoS versus baseline were: 30 min plus SOC, -2.1 [-0.9; -1.8, 0.1]; 60 min plus SOC, -3.0 [-1.7; -2.7, -0.8]; SOC alone, -1.2. No detrimental deterioration was observed in any of the Norfolk or UENS subscales by EoS with capsaicin. Also, no worsening in sensory perception testing of sharp, warm, cold and vibration stimuli was found with capsaicin by EoS. Capsaicin treatment was well tolerated and the most frequent treatment-emergent adverse events were application site pain (30 min, 28.2%; 60 min, 29.3%), burning sensation (30 min, 9.0%; 60 min, 9.6%) and application site erythema (30 min, 7.7%; 60 min, 8.9%). CONCLUSION: In patients with PDPN, capsaicin 8% patch repeat treatment plus SOC over 52 weeks was well tolerated with no negative functional or neurological effects compared with SOC alone. TRIAL REGISTRATION: ClinicalTrials.gov registration: NCT01478607 . Date of registration November 21, 2011; retrospectively registered.

EVALUATION OF LANREOTIDE DEPOT/AUTOGEL EFFICACY AND SAFETY AS A CARCINOID SYNDROME TREATMENT (ELECT): A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED TRIAL.

OBJECTIVE: To evaluate the efficacy and safety of lanreotide depot/autogel 120 mg for the control of carcinoid syndrome (CS) symptoms in patients with neuroendocrine tumors (NETs). METHODS: This was a 16-week, randomized, double-blind, phase 3 trial (Clinicaltrials.gov: NCT00774930). Patients with/without prior somatostatin analog (SSA) use were randomized to lanreotide depot/autogel 120 mg or placebo every 4 weeks, with access to short-acting octreotide as rescue medication. The primary endpoint was the percentage of days in which short-acting octreotide was used, which was assessed from daily diaries using an analysis of covariance including the stratification variables baseline short-acting octreotide use and frequency of diarrhea/flushing. The proportions of patients experiencing treatment success was a supportive analysis. Adverse events were recorded at all visits. RESULTS: A total of 115 patients were enrolled (lanreotide, n = 59; placebo, n = 56). The adjusted mean (95% confidence interval [CI]) percentage of days with rescue octreotide use (primary endpoint) was significantly lower in the lanreotide (33.7%; 95% CI, 25.0%-42.4%) versus the placebo group (48.5%; 95% CI, 39.6%-57.4%), representing an absolute difference of -14.8% (95% CI, -26.8% to -2.8%; P = .017). The odds ratio of full/partial treatment success (≤3 days short-acting octreotide use weeks 12 to 15) was significantly greater with lanreotide than placebo (2.4; 95% CI, 1.1-5.3; P = .036). No new safety concerns were identified, and lanreotide was well tolerated. CONCLUSION: Lanreotide depot/autogel is effective for the control of CS symptoms in patients (SSA-naïve or experienced) with NETs. ABBREVIATIONS: AE = adverse event BMI = body mass index CS = carcinoid syndrome ELECT = Evaluating Lanreotide Efficacy and safety as a Carcinoid-syndrome Treatment HRQoL = health-related quality of life LTOLE = long-term open-label extension NET = neuroendocrine tumor OL = open label SSA = somatostatin analog.

Sensorimotor Peripheral Nerve Function and the Longitudinal Relationship With Endurance Walking in the Health, Aging and Body Composition Study.

OBJECTIVES: To determine whether lower extremity sensorimotor peripheral nerve deficits are associated with reduced walking endurance in older adults. DESIGN: Prospective cohort study with 6 years of follow-up. SETTING: Two university research clinics. PARTICIPANTS: Community-dwelling older adults enrolled in the Health, Aging and Body Composition Study from the 2000-2001 annual clinical examination (N=2393; mean age ± SD, 76.5±2.9y; 48.2% men; 38.2% black) and a subset with longitudinal data (n=1178). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Participants underwent peripheral nerve function examination in 2000-2001, including peroneal motor nerve conduction amplitude and velocity, vibration perception threshold, and monofilament testing. Symptoms of lower extremity peripheral neuropathy included numbness or tingling and sudden stabbing, burning, pain, or aches in the feet or legs. The Long Distance Corridor Walk (LDCW) (400 m) was administered in 2000-2001 and every 2 years afterward for 6 years to assess endurance walking performance over time. RESULTS: In separate, fully adjusted linear mixed models, poor vibration threshold (>130 µm), 10-g and 1.4-g monofilament insensitivity were each associated with a slower 400-m walk completion time (16.0 s, 14.4s, and 6.9 s slower, respectively; P<.05 for each). Poor motor amplitude (<1 mV), poor vibration perception threshold, and 10-g monofilament insensitivity were related to greater slowing per year (4.7, 4.2, and 3.8 additional seconds per year, respectively; P<.05), although poor motor amplitude was not associated with initial completion time. CONCLUSIONS: Poorer sensorimotor peripheral nerve function is related to slower endurance walking and greater slowing longitudinally. Interventions to reduce the burden of sensorimotor peripheral nerve function impairments should be considered to help older adults maintain walking endurance-a critical component for remaining independent in the community.

AACE/ACE disease state clinical review: diagnosis and management of midgut carcinoids.

OBJECTIVE: Neuroendocrine tumors (NETs) are a collection of complex tumors that arise from the diffuse endocrine system, primarily from the digestive tract. Carcinoid tumors most commonly originate from the small intestine. These tumors are either referred to as small intestinal neuroendocrine tumors or midgut carcinoids (MGCs). The purpose of this review article is to survey the diagnostic and therapeutic pathways for patients with MGC and provide an overview of the complex multidisciplinary care involved in improving their quality of life, treatment outcomes, and survival. METHODS: The current literature regarding the diagnosis and management of MGCs was reviewed. RESULTS: Dry flushing and secretory diarrhea are the hallmarks of the clinical syndrome of MGC. Managing MGC requires attention to the overall symptom complex, including the physical effects of the tumor and biomarker levels. The somatostatin analogs (SAs) octreotide and lanreotide are highly efficacious for symptomatic improvement. MGCs require resection to encompass the primary tumor and mesenteric lymph node metastases and should include cholecystectomy if the patient is likely to receive SA therapy. Debulking of liver metastasis by resection in combination with ablative therapies and other liver-directed modalities may help palliate symptoms and hormonal overproduction in carefully selected patients. Quality of life is an important measure of patients' perception of the burden of their disease and impact of treatment modalities and may be a useful guide in deciding changes in therapy to alter apparent health status. CONCLUSION: MGC is a challenging malignancy that requires the input of a multidisciplinary team to develop the best treatment plan. Consultation with expert centers that specialize in NETs may also be indicated for complex cases. With expert care, patients can be cured or live with the disease and enjoy good quality of life.

Norfolk QOL-DN: validation of a patient reported outcome measure in transthyretin familial amyloid polyneuropathy.

The Norfolk Quality of Life-Diabetic Neuropathy (QOL-DN) questionnaire is an instrument to assess QOL in diabetic polyneuropathy. The objective of this observational, cross-sectional study in 61 patients with V30M transthyretin familial amyloid polyneuropathy (TTR-FAP) and 16 healthy volunteers was to validate the Norfolk QOL-DN for assessment of QOL in TTR-FAP. Comparisons were conducted to identify the best items to discriminate disease stages and assess which individual Norfolk domains (symptoms, large fiber, small fiber, autonomic, and activities of daily living) would be most affected by disease stage. Analysis of individual items revealed a significant pattern of discrimination among disease stages (p < 0.001). Total QOL scores increased (indicating worsening) with duration of symptoms, with a steeper increase observed earlier in the course of disease. Significant correlations were observed between each Norfolk domain and other measures of neurological function. Limitations include cross-sectional study design, low patient numbers in this rare disease, and the ordinal-based character of the metric used; future areas to explore include item response theory approaches such as Rasch analysis. These results suggest the Norfolk QOL-DN is a reliable indicator of the impact of disease severity on QOL in patients with TTR-FAP.

Advances in diagnosis and treatment of pancreatic neuroendocrine tumors.

OBJECTIVE: To review the current state of pancreatic neuroendocrine tumors (PNETS)Methods: The literature published between 2005 and 2014 in PUBMED, Medline, Google Scholar, Cochrane reports, and ClinicalTrials.gov was examined for relevance to the topic. RESULTS: PNETS have an incidence <1 per 100,000 individuals and may functionally secrete biologically active substances or be nonfunctional (NF-PNETs). PNETs occur both sporadically and in patients with various inherited disorders. Pathology and staging range from benign, well-differentiated to metastatic and dedifferentiated and are dependent on the mitotic and Ki67 indices of cell proliferation. Bone alkaline phosphatase and N-terminal telopeptide (N-telopeptide) are markers of osteoblasts and osteoclast activation, and pancreastatin, neurokinin A (NKA), chromogranin A (CgA) and neuron-specific enolase are used to determine response to therapy and prognosis. Surgical resection of the primary tumor is recommended, even when there are metastases. New techniques are being developed for tumor localization (68Ga-tetra-azacyclododecane tetra-acetic acid-octreotate [DOTATATE] positron emission tomography [PET] scans). Somatostatin (SST) that binds to SST receptors (SSTRs) 2 and 5 partially controls symptoms and tumor growth. Two new agents have been approved for treating PNETs: a tyrosine kinase inhibitor and a mammalian target of rapamycin (mTOR) inhibitor that increases progression-free survival (PFS). An exciting addition is the use of peptide receptor radiotherapy (PRRT) using SST as the peptide with a carrier such as 68Gallium (68Ga) for localization or 177Lutetium (177Lu) or 99Yttrium (99Y) for therapy. CONCLUSION: There have been advances in PNET diagnosis, tumor localization, and therapies in the last decade, and increased understanding of their pathophysiology is likely to be rewarded with new and emerging treatments for PNETs in the not too distant future.

Exercising with peripheral or autonomic neuropathy: what health care providers and diabetic patients need to know.

Both peripheral and autonomic neuropathies are characterized by a progressive loss of nerve fiber function. Most peripheral neuropathy affects the extremities, particularly the lower legs and the feet, but also the hands, whereas damage to the autonomic nervous system may lead to imbalances between the sympathetic and parasympathetic nerve fibers that innervate the heart and blood vessels, as well as abnormalities in heart rate control and vascular dynamics. To prescribe or engage in exercise that is both safe and effective, health care providers and patients with diabetes mellitus need to increase their understanding of the pathophysiological nature of neuropathies and the physical activity hurdles that may arise from the presence of a neuropathy. With proper care and preventative measures, patients with diabetes mellitus that experience either type of neuropathy can benefit from regular participation in mild to moderate aerobic, resistance, and balance activities, assuming they take any potential alterations into account to ensure that exercise is safe and effective.

Neurovascular function and sudorimetry in health and disease.

In this review of thermoregulatory function in health and disease, we review the basic mechanisms controlling skin blood flow of the hairy and glabrous skin and illustrate the major differences in blood flow to glabrous skin, which is, in essence, sympathetically mediated, while hairy skin is dependent upon neuropeptidergic signals, nitric oxide, and prostaglandin, among others. Laser Doppler methods of quantification of blood flow--in response to iontophoresis of acetylcholine or heat--and nociceptor-mediated blood flow have relatively uniformly demonstrated an impaired capacity to increase blood flow to the skin in diabetes and in its forerunners, prediabetes and the metabolic syndrome. This reduced capacity is likely to be a significant contributor to the development of foot ulcerations and amputations in diabetes, and means of increasing blood flow are clearly needed. Understanding the pathogenic mechanisms is likely to provide a means of identifying a valuable therapeutic target. Thermoregulatory control of sweating is intimately linked to the autonomic nervous system via sympathetic C fibers, and sweat glands are richly endowed with a neuropeptidergic innervation. Sweating disturbances are prevalent in diabetes and its precursors, and quantification of sweating may be useful as an index of diagnosis of somatic and, probably, autonomic dysfunction. Moreover, quantifying this disturbance in sweating by various methods may be useful in identifying the risk of progression from prediabetes to diabetes, as well as responses to therapeutic intervention. We now have the technological power to take advantage of this physiological arrangement to better understand, monitor, and treat disorders of small nerve fibers and the somatic and autonomic nervous system (ANS). Newer methods of sudomotor function testing are rapid, noninvasive, not technically demanding, and accessible to the outpatient clinic. Whether the potential applications are screening for diabetes, following poorly controlled diabetes subjects during alteration of their treatment regimen, or simply monitoring somatic and autonomic function throughout the course of treatment, sudorimetry can be an invaluable tool for today's clinicians.

Cardiac and Sudomotor Autonomic Function in Subjects with Psoriasis With and Without Metabolic Syndrome.

Purpose: Studies have shown that subjects with psoriasis (PsO) are associated with an increased risk of developing metabolic syndrome (MetS), diabetes, and cardiovascular disease. In addition, MetS and diabetes are associated with autonomic dysfunction (AD). The aim of this study was to investigate cardiac and sudomotor autonomic function in subjects with PsO and without diabetes. Methods: A cross-sectional study was performed in 20 subjects with PsO, compared with age- and sex-matched 21 healthy controls, and 20 subjects with MetS. Subjects underwent skin evaluation by dermatologist, glycated hemoglobin (HbA1c), insulin, glucose, and lipid levels, sudomotor function testing with Sudoscan™ device (Impeto Medical, Paris, France), and cardiac autonomic function testing with ANSAR device (ANX 3.0; ANSAR Group, Inc., Philadelphia, PA). Quality of Life (QOL) and peripheral neurologic function were also assessed. Results: Participants with PsO were significantly more obese, had higher levels of fasting insulin and triglycerides, and were more insulin resistant when compared to controls. Subjects with PsO showed significantly worse cardiac autonomic function when compared to control and MetS groups. Sudomotor function and QOL scores were similar between the groups. Subgroup analysis of PsO subjects without MetS criteria (n = 15) showed persistent significantly deteriorated cardiac autonomic function when compared to the other two groups. Conclusion: This study suggests an association between PsO and cardiac AD, independent of the presence of overt dysglycemia and MetS. Additional larger studies are needed to clarify the significance of these findings and the relationship between PsO, AD, and metabolic disease.

The endocrine tumor summit 2008: appraising therapeutic approaches for acromegaly and carcinoid syndrome.

The Endocrine Tumor Summit convened in December 2008 to address 6 statements prepared by panel members that reflect important questions in the treatment of acromegaly and carcinoid syndrome. Data pertinent to each of the statements were identified through review of pertinent literature by one of the 9-member panel, enabling a critical evaluation of the statements and the evidence supporting or refuting them. Three statements addressed the validity of serum growth hormone (GH) and insulin-like growth factor-I (IGF-I) concentrations as indicators or predictors of disease in acromegaly. Statements regarding the effects of preoperative somatostatin analog use on pituitary surgical outcomes, their effects on hormone and symptom control in carcinoid syndrome, and the efficacy of extended dosing intervals were reviewed. Panel opinions, based on the level of available scientific evidence, were polled. Finally, their views were compared with those of surveyed community-based endocrinologists and neurosurgeons.