Context Germline mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene are responsible for a subset of familial isolated pituitary adenoma (FIPA) cases and sporadic pituitary neuroendocrine tumors (PitNETs). Objective To compare prospectively diagnosed AIP mutation-positive (AIPmut) PitNET patients with clinically presenting patients and to compare the clinical characteristics of AIPmut and AIPneg PitNET patients. Design 12-year prospective, observational study. Participants & Setting We studied probands and family members of FIPA kindreds and sporadic patients with disease onset ≤18 years or macroadenomas with onset ≤30 years (n = 1477). This was a collaborative study conducted at referral centers for pituitary diseases. Interventions & Outcome AIP testing and clinical screening for pituitary disease. Comparison of characteristics of prospectively diagnosed (n = 22) vs clinically presenting AIPmut PitNET patients (n = 145), and AIPmut (n = 167) vs AIPneg PitNET patients (n = 1310). Results Prospectively diagnosed AIPmut PitNET patients had smaller lesions with less suprasellar extension or cavernous sinus invasion and required fewer treatments with fewer operations and no radiotherapy compared with clinically presenting cases; there were fewer cases with active disease and hypopituitarism at last follow-up. When comparing AIPmut and AIPneg cases, AIPmut patients were more often males, younger, more often had GH excess, pituitary apoplexy, suprasellar extension, and more patients required multimodal therapy, including radiotherapy. AIPmut patients (n = 136) with GH excess were taller than AIPneg counterparts (n = 650). Conclusions Prospectively diagnosed AIPmut patients show better outcomes than clinically presenting cases, demonstrating the benefits of genetic and clinical screening. AIP-related pituitary disease has a wide spectrum ranging from aggressively growing lesions to stable or indolent disease course.

ObjectiveGrowth hormone (GH) replacement therapy currently requires daily injections, which may cause distress and low compliance. C-terminal peptide (CTP)-modified growth hormone (MOD-4023) is being developed as a once-weekly dosing regimen in patients with GH deficiency (GHD). This study’s objective is to evaluate the safety, pharmacokinetics (PK), pharmacodynamics (PD) and efficacy of MOD-4023 administered once-weekly in GHD adults.Design54 adults with GHD currently treated with daily GH were normalized and randomized into 4 weekly dosing cohorts of MOD-4023 at 18.5%, 37%, 55.5% or 123.4% of individual cumulative weekly molar hGH dose. The study included 2 stages: Stage A assessed the effectiveness and PK/PD profiles of the 4 dosing regimens of MOD-4023. Stage B was an extension period of once-weekly MOD-4023 administration (61.7% molar hGH content) to collect further safety data and confirm the results from Stage A.ResultsDose-dependent response was observed for both PK and PD data of weekly MOD-4023 treatment. Insulin-like growth factor I (IGF-I) SDS levels were maintained within normal range. The 18.5% cohort was discontinued due to low efficacy. MOD-4023 was well tolerated and exhibited favorable safety profile in all dose cohorts. The reported adverse events were consistent with known GH-related side effects.ConclusionsOnce-weekly MOD-4023 administration in GHD adults was found to be clinically effective while maintaining a favorable safety profile and may obviate the need for daily injections. Weekly GH injections may improve compliance and overall outcome. The promising results achieved in this Phase 2 study led to a pivotal Phase 3 trial, which is currently ongoing.

We investigated whether the blood spot thyrotropin (TSH) method was adequate for screening elderly subjects with abundant iodine intake (median excretion 330 microg/g creatinine) for hypothyroidism. In 97 healthy adults (group A), 210 nursing home residents (group B) and 265 elderly subjects living at home (group C) serum (sensitivity < 0.02 mU/L, cost 1.2 U.S. dollars [USD]) and blood spot TSH (sensitivity < 1.0 mU/L, cost 0.4 USD) were measured, and the sensitivity and specificity of different blood spot TSH cutoff points to detect cases with elevated serum TSH were calculated. Elevated (> 3.5 mU/L) serum TSH levels (group A, 6.2%; group B, 16.2%; group C, 22.3%; B > A, p = 0.025; C > A, p < 0.001) were detected with the required sensitivity of greater than 0.9 only if the cutoff point of the blood spot TSH was set as low as 2.5 mU/L, but this led to a considerable loss of specificity. At cutoff point 2.5 mU/L, the rate of positivity was 39.3% and the cost of blood spot screening/person increased to 0.88 USD, considering that positive cases have to be rechecked by serum TSH to exclude false positivity. Cases with significantly elevated (> 10.0 mU/L) serum TSH (group A, 1.03%; group B, 2.85%; group C, 2.20%) were detected at blood spot cutoff points 10.0-4.0 mU/L with a sensitivity of 1.0 and without considerable loss of specificity. We conclude that while screening for hypothyroidism in the elderly population with abundant iodine intake is justified by the high prevalence of elevated ultrasensitive serum TSH values, the sensitivity of the blood spot method is insufficient to detect the subclinical hypothyroidism accurately and would, therefore, fail to detect most affected subjects.

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A szerzők egy 82 éves férfi kórtörténetét ismertetik, akit gyakori hypoglykaemia miatt vizsgáltak. Betegüknél 4 évvel korábban prosztatacarcinomát diagnosztizáltak, de a műtéttől elzárkózott. Vizsgálataik organikus hypoglykaemia mellett szóltak, alacsony széruminzulin-értékek mellett. Az insulinoma irányába végzett vizsgálatok negatív eredménnyel zárultak. Csökkent széruminzulinszerű növekedési faktor-1-és normális szérum-chromogranin-A-érték mellett élettani tartományban lévő hypophysis-és perifériáshormon-szinteket találtak. Mindezek alapján inzulinszerű növekedési faktor-2 prohormont, illetve inzulinszerű növekedési faktor-2-t szintetizáló és szekretáló prosztatatumor jelenlétére gondoltak. Az inzulinszerű növekedési faktor-2 prohormon és az inzulinszerű növekedési faktor-2 közvet-lenül serkenti a daganat, az izom-és a zsírszövet glükózfelvételét, csökkenti a májból a glükóz kiáramlását, továbbá csökkenti az inzulinszintézist a pancreas béta-sejtjeire kifejtett gátlóhatása miatt. Terápiaként 5%-os, majd 20%-os glükózinfúzió folyamatos adására szorultak, más készítmények csak átmeneti javulást eredményeztek. A tartós hypoglykaemia miatt prosztataműtét lett volna szükséges, de az ismétlődő hypoglykaemiák és a beteg rossz általános álla-pota miatt az nem volt kivihető. Később diazoxid-és glükózinfúzió hatására a hypoglykaemiák uralhatók voltak, azonban a beteg hamarosan elhunyt. A prosztata szövettani feldolgozása során immunhisztokémiai vizsgálattal a daganatsejtek igen erőteljes IGF-2-pozitivitást mutattak, ami megerősíti, hogy esetükben inzulinszerű növekedési faktor-2-t szekretáló prosztatatumor állt a súlyos hypoglykaemiák hátterében. Orv. Hetil., 2014, 155(33), 1319-1324.Kulcsszavak: nem szigetsejttumor okozta hypoglykaemia, prosztatacarcinoma, inzulinszerű növekedési faktor-2 (IGF-2) Insulin-like growth factor-II secreting prostate tumour causing severe hypoglycaemiaThe authors present a case of an 82-year-old male patient who presented with frequent hypoglycaemia. Four years prior to the current evaluation the patient had been diagnosed with prostate carcinoma; however, he refused surgical treatment. Initial diagnostic tests indicated organic hypoglycaemia with low serum insulin levels. Insulinoma was excluded and further laboratory tests showed reduced serum insulin-like growth factor-II and normal serum chromogranin A levels as well as normal hypophysis and peripheral hormone values. The authors hypothesised that the severe hypoglycaemia might be the consequence of synthesis and secretion of insulin-like growth factor-II (or its prohormone) by the previously diagnosed prostate tumour. Insulin-like growth factor-II and its prohormone directly increases glucose uptake of the tumour, muscle and adipose tissue, decreases glucose release from the liver and downregulates insulin synthesis due to inhibition of the pancreatic beta cells. The patient required continuous intravenous glucose substitution initially with 5%, subsequently with 20% glucose infusion. Administration of other agents resulted only in tem...