A Patient-Reported Outcomes Analysis Of Lanreotide In The Treatment Of NETs Patients With Carcinoid Syndrome: Evidence From The ELECT Trial.

PURPOSE: The purpose of this analysis of patient-reported outcomes from the ELECT (Evaluation of Lanreotide Depot/Autogel Efficacy and Safety as a Carcinoid Syndrome Treatment) trial (NCT00774930) was to explore the effect of lanreotide on symptoms of carcinoid syndrome. Specifically, this post hoc analysis was designed to identify the most important patient-reported outcomes for patients in ELECT. METHODS: The post hoc analysis of ELECT, a placebo-controlled study of lanreotide in patients with neuroendocrine tumors, evaluated patient-reported outcomes during the double-blind phase of the trial, specifically daily diarrhea and flushing symptoms, octreotide rescue use, and the EORTC QLQ-C30 and QLQ-GINET21 questionnaires at baseline and week 12. Principal component (PC) analysis was applied on baseline data to identify independent variable clusters and clinically meaningful summary measures that highly correlated to these PCs. From those, the minimum clinical important differences were derived so to perform a responder analysis. RESULTS: The three largest PCs captured 42.9% of the variation among baseline variables. The C30 summary score (C30-SS), diarrhea burden, and flushing burden were highly correlated with PC1, PC2, and PC3, respectively. Lanreotide patients were more likely to experience an improvement on the C30-SS (risk ratio [RR] 2.42; P=0.023), diarrhea burden (RR 2.85; P=0.005), and flushing burden (RR 1.39; P=0.31) compared to placebo patients. Lanreotide-treated patients have a higher probability of being a responder on at least one of the three domains of C30-SS, diarrhea burden, or flushing burden compared to placebo patients (RR 1.48; P=0.06). CONCLUSION: The higher response rates in the diarrhea burden are consistent with the previously reported effects of lanreotide on octreotide rescue medication use, while the findings of a greater efficacy of lanreotide vs placebo in the quality-of-life domains represent a novel aspect in the benefits of lanreotide. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00774930.

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.

Low blood pressure levels for fall injuries in older adults: the Health, Aging and Body Composition Study.

Fall injuries cause morbidity and mortality in older adults. We assessed if low blood pressure (BP) is associated with fall injuries, including sensitivity analyses stratified by antihypertensive medications, in community-dwelling adults from the Health, Aging and Body Composition Study (N = 1819; age 76.6 ± 2.9 years; 53% women; 37% black). Incident fall injuries (N = 570 in 3.8 ± 2.4 years) were the first Medicare claims event from clinic visit (7/00-6/01) to 12/31/08 with an ICD-9 fall code and non-fracture injury code, or fracture code with/without a fall code. Participants without fall injuries (N = 1249) were censored over 6.9 ± 2.1 years. Cox regression models for fall injuries with clinically relevant systolic BP (SBP; ≤ 120, ≤ 130, ≤ 140, > 150 mmHg) and diastolic BP (DBP; ≤ 60, ≤ 70, ≤ 80, > 90 mmHg) were adjusted for demographics, body mass index, lifestyle factors, comorbidity, and number and type of medications. Participants with versus without fall injuries had lower DBP (70.5 ± 11.2 vs. 71.8 ± 10.7 mmHg) and used more medications (3.8 ± 2.9 vs. 3.3 ± 2.7); all P < 0.01. In adjusted Cox regression, fall injury risk was increased for DBP ≤ 60 mmHg (HR = 1.25; 95% CI 1.02-1.53) and borderline for DBP ≤ 70 mmHg (HR = 1.16; 95% CI 0.98-1.37), but was attenuated by adjustment for number of medications (HR = 1.22; 95% CI 0.99-1.49 and HR = 1.12; 95% CI 0.95-1.32, respectively). Stratifying by antihypertensive medication, DBP ≤ 60 mmHg increased fall injury risk only among those without use (HR = 1.39; 95% CI 1.02-1.90). SBP was not associated with fall injury risk. Number of medications or underlying poor health may account for associations of low DBP and fall injuries.

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.

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.

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.

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.

Bariatric Surgery Restores Cardiac and Sudomotor Autonomic C-Fiber Dysfunction towards Normal in Obese Subjects with Type 2 Diabetes.

OBJECTIVE: The aim was to evaluate the impact of bariatric surgery on cardiac and sudomotor autonomic C-fiber function in obese subjects with and without Type 2 diabetes mellitus (T2DM), using sudorimetry and heart rate variability (HRV) analysis. METHOD: Patients were evaluated at baseline, 4, 12 and 24 weeks after vertical sleeve gastrectomy or Roux-en-Y gastric bypass. All subjects were assessed using SudoscanTM to measure electrochemical skin conductance (ESC) of hands and feet, time and frequency domain analysis of HRV, Neurologic Impairment Scores of lower legs (NIS-LL), quantitative sensory tests (QST) and sural nerve conduction studies. RESULTS: Seventy subjects completed up to 24-weeks of follow-up (24 non-T2DM, 29 pre-DM and 17 T2DM). ESC of feet improved significantly towards normal in T2DM subjects (Baseline = 56.71±3.98 vs 12-weeks = 62.69±3.71 vs 24-weeks = 70.13±2.88, p<0.005). HRV improved significantly in T2DM subjects (Baseline sdNN (sample difference of the beat to beat (NN) variability) = 32.53±4.28 vs 12-weeks = 44.94±4.18 vs 24-weeks = 49.71±5.19, p<0,001 and baseline rmsSD (root mean square of the difference of successive R-R intervals) = 23.88±4.67 vs 12-weeks = 38.06±5.39 vs 24-weeks = 43.0±6.25, p<0.0005). Basal heart rate (HR) improved significantly in all groups, as did weight, body mass index (BMI), percent body fat, waist circumference and high-density lipoprotein (HDL). Glycated hemoglobin (HbA1C), insulin and HOMA2-IR (homeostatic model assessment) levels improved significantly in pre-DM and T2DM subjects. On multiple linear regression analysis, feet ESC improvement was independently associated with A1C, insulin and HOMA2-IR levels at baseline, and improvement in A1C at 24 weeks, after adjusting for age, gender and ethnicity. Sudomotor function improvement was not associated with baseline weight, BMI, % body fat or lipid levels. Improvement in basal HR was also independently associated with A1C, insulin and HOMA2-IR levels at baseline. CONCLUSION: This study shows that bariatric surgery can restore both cardiac and sudomotor autonomic C-fiber dysfunction in subjects with diabetes, potentially impacting morbidity and mortality.

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.

Clinical Presentation and Diagnosis of Neuroendocrine Tumors.

Neuroendocrine tumors (NETs) are slow-growing neoplasms capable of storing and secreting different peptides and neuroamines. Some of these substances cause specific symptom complexes, whereas others are silent. They usually have episodic expression, and the diagnosis is often made at a late stage. Although considered rare, the incidence of NETs is increasing. For these reasons, a high index of suspicion is needed. In this article, the different clinical syndromes and the pathophysiology of each tumor as well as the new and emerging biochemical markers and imaging techniques that should be used to facilitate an early diagnosis, follow-up, and prognosis are reviewed.

The New Age of Sudomotor Function Testing: A Sensitive and Specific Biomarker for Diagnosis, Estimation of Severity, Monitoring Progression, and Regression in Response to Intervention.

Sudorimetry technology has evolved dramatically, as a rapid, non-invasive, robust, and accurate biomarker for small fibers that can easily be integrated into clinical practice. Though skin biopsy with quantitation of intraepidermal nerve fiber density is still currently recognized as the gold standard, sudorimetry may yield diagnostic information not only on autonomic dysfunction but also enhance the assessment of the small somatosensory nerves, disease detection, progression, and response to therapy. Sudorimetry can be assessed using Sudoscan™, which measures electrochemical skin conductance (ESC) of hands and feet. It is based on different electrochemical principles (reverse iontophoresis and chronoamperometry) to measure sudomotor function than prior technologies, affording it a much more practical and precise performance profile for routine clinical use with potential as a research tool. Small nerve fiber dysfunction has been found to occur early in metabolic syndrome and diabetes and may also be the only neurological manifestation in small fiber neuropathies, beneath the detection limits of traditional nerve function tests. Test results are robust, accomplished within minutes, require little technical training and no calculations, since established norms have been provided for the effects of age, gender, and ethnicity. Sudomotor testing has been greatly under-utilized in the past, restricted to specialized centers capable of handling the technically demanding and expensive technology. Yet, evaluation of autonomic and somatic nerve function has been shown to be one of the best estimates of cardiovascular risk. Evaluation of sweating has the appeal of quantifiable non-invasive determination of the integrity of the peripheral autonomic nervous system, and can now be accomplished rapidly at point of care clinics with the determination of ESC, allowing intervention for morbid complications prior to permanent structural nerve damage. We review here sudomotor function testing technology, the research evidence accumulated supporting the clinical utility of measuring ESC, the medical applications of sudorimetry now available to physicians with this device, and clinical vignettes illustrating its use in the clinical decision-making process.

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.

Early detection of sporadic pancreatic cancer: summative review.

Pancreatic cancer (PC) is estimated to become the second leading cause of cancer death in the United States by 2020. Early detection is the key to improving survival in PC. Addressing this urgent need, the Kenner Family Research Fund conducted the inaugural Early Detection of Sporadic Pancreatic Cancer Summit Conference in 2014 in conjunction with the 45th Anniversary Meeting of the American Pancreatic Association and Japan Pancreas Society. This seminal convening of international representatives from science, practice, and clinical research was designed to facilitate challenging interdisciplinary conversations to generate innovative ideas leading to the creation of a defined collaborative strategic pathway for the future of the field. An in-depth summary of current efforts in the field, analysis of gaps in specific areas of expertise, and challenges that exist in early detection is presented within distinct areas of inquiry: Case for Early Detection: Definitions, Detection, Survival, and Challenges; Biomarkers for Early Detection; Imaging; and Collaborative Studies. In addition, an overview of efforts in familial PC is presented in an addendum to this article. It is clear from the summit deliberations that only strategically designed collaboration among investigators, institutions, and funders will lead to significant progress in early detection of sporadic PC.

Detection of undisclosed neuropathy and assessment of its impact on quality of life: a survey in 25,000 Romanian patients with diabetes.

AIMS: The objective of this cross-sectional survey was to capture undiagnosed neuropathy in Romanian patients with self-reported diabetes using Norfolk QoL-DN as a screening tool and to assess its impact on quality of life (QoL). METHODS: 25,000 Romanian-translated, validated Norfolk QoL-DN questionnaires were distributed between June and December 2012. 21,261 patients who self-reported diabetes and answered questions related to neuropathy, ulceration, gangrene and amputation were included in the analysis. RESULTS: 52% of diabetic patients (n = 6615) who answered "no" to the question "Do you have neuropathy?" had total QoL scores above the cut-off, suggesting the presence of diabetic neuropathy. 13,854 (65.2%) patients answered "yes" to the question "Do you have neuropathy?" and 3,150 (14.8%) reported at least one episode of ulceration, gangrene or amputation. Total QoL score was 3-fold higher (worse) for patients who answered "yes" to the question "Do you have neuropathy?" than for those who answered "no" (38.39 vs. 13.71; p < 0.001) and 1.4-fold worse for patients who reported ulceration, gangrene or amputation than for those who did not report any of these (50.38 vs. 34.87; p < 0.001). CONCLUSIONS: We found a high prevalence of undisclosed diabetic neuropathy in this population and showed that neuropathy severity has an increasing impact on total QoL and its domains.

Falls risk in older adults with type 2 diabetes.

Falls are a major health issue for older adults, especially for those who develop type 2 diabetes who must contend with age-related declines in balance, muscle strength, and walking ability. They must also contend with health-related issues specific to the disease process. Given the general association between these variables and falls, being able to identify which measures negatively impact on balance in older diabetic persons is a critical step. Moreover, designing specific interventions to target these physiologic functions underlying balance and gait control will produce the greatest benefit for reducing falls in older persons with diabetes.

Epidemiology of polyneuropathy in diabetes and prediabetes.

Diabetic distal symmetric sensorimotor polyneuropathy (DSPN) represents a major health problem, associated with excruciating neuropathic pain, increased morbidity and impaired quality of life. The understanding of its epidemiology is difficult due to methodological issues. Inconsistency in the selection of diagnostic procedures renders comparison between studies problematic. Further problems arise from selection bias due to the inclusion of hospital-based populations. DSPN affects approximately 30% of hospital-based populations, 20% of community-based samples, and 10% of the diabetic population identified by screening. Chronic painful DSPN is present in 13-26% of diabetic patients. Between 25% and 62% of patients with idiopathic peripheral neuropathy have prediabetes. Among pre-diabetic subjects, 11-25% exhibit peripheral neuropathy and 13-26% neuropathic pain. Evidence from population-based studies indicates that there is a gradient in the prevalence of neuropathy. Indeed, the highest frequency is found in patients with manifest diabetes mellitus, followed by individuals with impaired glucose tolerance, then impaired fasting glucose and, finally, those with normoglycemia. The most important etiologic factors are poor glycemic control, age, diabetes duration, visceral obesity, height, hypertension, age, smoking, hypoinsulinemia, and dyslipidemia. Clinic-based data suggest that DSPN is associated with increased mortality in diabetes, but confirmatory prospective population-based studies are required.

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.

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.

Diabetic autonomic neuropathy.

Autonomic neuropathy, once considered to be the Cinderella of diabetes complications, has come of age. The autonomic nervous system innervates the entire human body, and is involved in the regulation of every single organ in the body. Thus, perturbations in autonomic function account for everything from abnormalities in pupillary function to gastroparesis, intestinal dysmotility, diabetic diarrhea, genitourinary dysfunction, amongst others. "Know autonomic function and one knows the whole of medicine!" It is now becoming apparent that before the advent of severe pathological damage to the autonomic nervous system there may be an imbalance between the two major arms, namely the sympathetic and parasympathetic nerve fibers that innervate the heart and blood vessels, resulting in abnormalities in heart rate control and vascular dynamics. Cardiac autonomic neuropathy (CAN) has been linked to resting tachycardia, postural hypotension, orthostatic bradycardia and orthostatic tachycardia (POTTS), exercise intolerance, decreased hypoxia-induced respiratory drive, loss of baroreceptor sensitivity, enhanced intraoperative or perioperative cardiovascular lability, increased incidence of asymptomatic ischemia, myocardial infarction, and decreased rate of survival after myocardial infarction and congestive heart failure. Autonomic dysfunction can affect daily activities of individuals with diabetes and may invoke potentially life-threatening outcomes. Intensification of glycemic control in the presence of autonomic dysfunction (more so if combined with peripheral neuropathy) increases the likelihood of sudden death and is a caveat for aggressive glycemic control. Advances in technology, built on decades of research and clinical testing, now make it possible to objectively identify early stages of CAN with the use of careful measurement of time and frequency domain analyses of autonomic function. Fifteen studies using different end points report prevalence rates of 1% to 90%. CAN may be present at diagnosis, and prevalence increases with age, duration of diabetes, obesity, smoking, and poor glycemic control. CAN also cosegregates with distal symmetric polyneuropathy, microangiopathy, and macroangiopathy. It now appears that autonomic imbalance may precede the development of the inflammatory cascade in type 2 diabetes and there is a role for central loss of dopaminergic restraint on sympathetic overactivity. Restoration of dopaminergic tone suppresses the sympathetic dominance and reduces cardiovascular events and mortality by close to 50%. Cinderella's slipper can now be worn!