OBJECTIVE:Daily growth hormone (GH) therapy for growth disorders requires long-term adherence. The aim of this study was to investigate the association of adherence with 2-year growth outcomes in paediatric patients receiving daily GH therapy in a clinical registry. DESIGN:Retrospective cohort study. PATIENTS:Patients with growth disorder were categorized after 2 years of treatment into low adherence (< 85%), high adherence (85%-110%) and adherence > 110% groups. Only patients with consistent adherence classification across both years were included in the 2-year outcome analysis. MEASUREMENTS:Growth outcomes were compared the change in height standard deviation score (ΔHSDS) over 2 years. Statistical tests were performed using the nonparametric Spearman's rank correlation coefficient and a general linear regression model. RESULTS:Seventy-four patients were analysed after 2 years of treatment. Mean ΔHSDS was 0.87 in the high adherence group and 0.33 in the low adherence group (absolute difference 0.54). Using the Spearman's correlation coefficient, ΔHSDS was statistically significantly positively correlated with high adherence compared to low adherence (rs = 0.33; p < 0.01). The linear regression results support these findings and estimate an improved ΔHSDS of 0.44 for patients in the high adherence group compared to the low adherence group (p = 0.03). Mean ΔHSDS in the adherence > 110% group was 0.79. CONCLUSION:Sustained high adherence (≥ 85%) to daily GH therapy was associated with clinically meaningful improvement in growth over 2 years.

In (pre)historic human bones, analysis of bone density and microstructure may be useful for anthropological research to assess skeletal health as well as physical fitness and handedness. Physical strain between arms and legs can be compared. HR-pQCT may provide information on such parameters, but has not yet been used in (pre)historic bones without soft tissue and bone marrow. Three macroscopically intact skeletons of young persons who died ca. 120-200 years ago at an age of approximately 20 years could be identified in the medico-historical anatomical collection in Marburg/Germany. Distal radii und tibiae were measured using HR-pQCT (XtremeCT, Scanco Medical) and analyzed with the standard evaluation script used for patients in clinical routine. We analyzed the quality of the images of the bones in comparison to two healthy living person of the same age group and investigated for which quantitative parameters plausible results could be calculated. The quality of the images was completely comparable between the historical bones and those of young living persons. Calculation of trabecular number, cortical thickness and cortical bone density revealed plausible results comparable to young living persons (77.5 +/- 26.9% vs. 84.4 +/- 28.3% of sex-related mean for persons 20-29 years old; n.s. [pooled data]). Calculation of trabecular bone volume / tissue volume and trabecular thickness, however, revealed unplausible results (-29.1 +/- 24.1% vs. 104.9 +/- 11.7; p<0.001). In conclusion, HR-pQCT generates images of historical bones in good quality. Calculation of trabecular number, cortical thickness, and cortical bone density reveals plausible results, whereas this is not the case for trabecular bone volume/tissue volume and trabecular thickness. This can be explained by the calculation method for these bone parameters, which is affected by the absence of soft tissue and bone marrow.

CONTEXT:Patients discharged as "healthy" with the symptoms of spontaneous hypoglycemia, commonly known as Whipple's triad, need more attention. OBJECTIVE:Characterization and long-term follow-up of symptom development in patients with spontaneous hypoglycemia discharged as "healthy". The objective was to ascertain whether any conditions related to the symptoms were diagnosed during the follow-up period. METHODS:Retrospective analysis of patient data and evaluation of a specific questionnaire on the development of symptoms of spontaneous hypoglycemia. In addition, patient questionnaires were evaluated and primary care physicians were asked about possible diseases not recorded at baseline that occurred during the follow-up period. SETTING:Center for Endocrinology, Diabetology, and Osteology at the University Hospital Marburg, Inpatient Department, Germany. PATIENTS:All patients who presented to our center for the 72-hour fast between 2005 and 2018 and were discharged without an internal medicine diagnosis were included. INTERVENTIONS:Survey by questionnaire, via telephone interview. MAIN OUTCOME MEASURES:Patient-reported information on current symptoms compared to original symptoms, diagnosis of insulinoma or diabetes mellitus during follow-up, matched with primary care physician data, and metabolic and biometric data such as body mass index (BMI), homeostasis model assessment for insulin resistance (HOMA IR), insulin sensitivity Matsuda Index (ISI-M), and area under the curve. RESULTS:A total of 41 datasets were evaluated at baseline and 38 patients were followed for an average of approximately 10 years. In total, 61% of respondents still reported the same symptoms as at baseline. No insulinoma was missed in these patients. Only two of the 38 patients developed diabetes mellitus. CONCLUSION:The high percentage of patients who are discharged as "healthy" and still have symptoms after many years is disturbing. It is possible that the symptoms are not due to low blood glucose. We urge caution with use of the term "healthy". We advocate a multidisciplinary therapeutic approach after an organic cause of hypoglycemia has been ruled out. Psychosomatic treatment seems to be useful. In addition, more research should be conducted on this topic.

Zusammenfassung Abaloparatid ist ein synthetisches Strukturanalogon des Parathormon-verwandten Peptids (PTHrP). Durch Bindung an Parathormon-1-Rezeptor stimuliert es Osteoblasten zum Knochenaufbau, dies bei einer geringeren begleitenden Osteoklastenstimulation, so dass in der Summe ein größerer osteoanaboler Nettoeffekt im Vergleich zu Teriparatid resultiert. Auch klinisch ist es mindestens so stark wirksam wie Teriparatid, möglicherweise diesem sogar überlegen, wobei hier unmittelbare head-to-head Studien derzeit nicht vorliegen. Abaloparatid reduziert effektiv das Auftreten vertebraler und peripherer osteoporotischer Frakturen mit auch entsprechenden günstigen Effekten auf die Knochendichte und die Knochenumbaumarker. Zu beachten ist, dass nach der subcutanen Injektion ein moderater Anstieg der Herzfrequenz beobachtet werden kann, wobei es aber keine Anhaltspunkte dafür gibt, dass dies mit schwerwiegenderen kardiovaskulären Komplikationen zu assoziieren wäre. Abaloparatid (Eladynos) wurde in Europa zur Behandlung der Osteoporose bei postmenopausalen Frauen mit erhöhtem Frakturrisiko für eine Therapiedauer von 18 Monaten zugelassen. Nachfolgend ist die Durchführung einer osteoklasteninhibierenden Bisphosphonattherapie als Sequenz zu empfehlen.

In endocrinology, endoscopic ultrasound (EUS) may be used to image the adrenals, the endocrine pancreas, and other organs where endocrine neoplasms may occur. During the recent decades, EUS has been established predominantly to assess multiple endocrine neoplasia type 1, to localize insulinomas, and to identify aldosterone-producing adenomas. EUS in endocrinology requires special skills and individual experience in order to provide reliable diagnostic information.

Purpose Most insulinomas are small solitary, benign neoplasms. Imaging and surgical techniques improved over the last 20 years. Thus, the aim of the present study was to analyze changes in diagnosis and surgery of insulinoma patients in a referral center over two decades. Methods Operated patients with a histologically proven insulinoma were retrieved from a prospective database. Clinico-pathological characteristics and outcomes were retrospectively analyzed with regard to the time periods 2000–2010 (group 1) and 2011–2020 (group 2). Results Sixty-one of 202 operated patients with pNEN had an insulinoma, 37 (61%) in group 1 and 24 (39%) in group 2. Of those 61 insulinomas, 49 (80%) were sporadic benign, 8 (13%) benign MEN1-associated insulinomas, and 4 (7%) sporadic malignant insulinomas. In 35 of 37 (95%) patients of group 1 and all patients of group 2, the insulinoma was preoperatively identified by imaging. The most sensitive imaging modality was endoscopic ultrasound (EUS) with correctly diagnosed and localized insulinomas in 89% of patients in group 1 and 100% in group 2. In group 1, significantly less patients were operated via minimally invasive approach compared to group 2 (19% (7/37) vs. 50% (12/24), p = 0.022). Enucleation was the most frequently performed operation (31 of 61, 51%), followed by distal resection (15 of 61, 25%) without significant differences between groups 1 and 2. The rate of relevant postoperative complications was not different between groups 1 and 2 (24% vs. 21%, p = 0.99). Two patients with benign insulinoma (1 out of each group) experienced disease recurrence and underwent a second resection. After a median follow-up of 134 (1–249) months, however, all 57 (100%) patients with benign insulinoma and 3 out of 4 patients with malignant insulinoma had no evidence of disease. Conclusion Insulinoma can be preoperatively localized in almost all patients, allowing for a minimally invasive, parenchyma-sparing resection in selected patients. The long-term cure rate is excellent.

Aim: The aim of this research was to evaluate the long-term outcome of pancreaticoduodenectomy (PD) versus other duodenopancreatic resections (non-PD) for the surgical treatment of the Zollinger–Ellison syndrome (ZES) in patients with multiple endocrine neoplasia type 1 (MEN1). Methods: Prospectively recorded patients with biochemically confirmed MEN1-ZES who underwent duodenopancreatic surgery were retrospectively analyzed in terms of clinical characteristics, complications, cure rate, and long-term morbidity, including quality of life assessment (EORTC QLQ-C30). Results: 35 patients (16 female, 19 male) with MEN1-ZES due to duodenopancreatic gastrinomas with a median age of 42 (range 30–74) years were included. At the time of diagnosis, 28 (80%) gastrinomas were malignant, but distant metastases were only present in one (3%) patient. Eleven patients (31.4%) underwent pancreatoduodenectomy (PD) as the initial procedure, whereas 24 patients underwent non-PD resections involving duodenotomy with gastrinoma excision, enucleation of the pNEN from the head of the pancreas, and peripancreatic lymphadenectomy, either with or without distal pancreatectomy (i.e., either Thompson procedure, n = 12, or DUODX, n = 12). There was no significant difference in perioperative morbidity and mortality between the two groups (p ≥ 0.05). One (9%) patient of the PD group required reoperation for recurrent or metastatic ZES compared to eight (22.8%) patients of the non-PD resection groups. After a median follow-up time of 134 months (range 6–480) nine of 11 (82%) patients in the PD group, two of 12 (16%) patients in the Thompson procedure group, and three of 12 (25%) patients in the DUODX group had normal serum gastrin levels. In addition, the global health QoLScore was better in the PD group (76.9) compared to the Thompson procedure (57.4) and DUODX (59.5) groups. Conclusions: Initial PD seems to be the superior surgical procedure for MEN1-ZES, resulting in a long-term cure rate of about 80%, fewer duodenopancreatic reoperations, and an acceptable quality of life.

The ongoing COVID-19 pandemic, caused by a coronavirus named SARS-CoV-2, has struck the planet with great force. As of December 2019, the virus has made its devasting route across all continents . In January 2022, the World Health Organization (WHO) registered over 5.5 million COVID-19 related deaths. Most of these people had suffered from pneumonia and acute respiratory distress syndrome , and in some cases, extensive damage to all organ systems. To get hold of this pandemic, it was vital to find effective vaccines against it. The two vaccine candidates BNT162b2 (BioNTech/Pfizer) and ChAdOx1 (University of Oxford and AstraZeneca) offer a high level of protection against COVID-19 by providing immunity due to antibody production against the spike protein of SARS-CoV-2. In addition to general side effects, immunological side effects such as subacute thyroiditis can follow the vaccination. This transient inflammatory condition of the thyroid gland is characterized with hyperthyroxinemia, inflammation, pain, and tenderness in the thyroid region, as well as an elevation of serum thyroglobulin concentration. There are only a few reports on the occurrence of this disease after receiving a COVID-19 vaccine. We present two cases of subacute thyroiditis after vaccination with the vaccines BNT162b2 and ChAdOx1 and try to enlighten the problem of immunological phenomena after vaccination. It must be discussed whether cross-reactivity of the spike protein and tissue proteins such as thyroid peroxidase (TPO), an “autoimmune/inflammatory syndrome by adjuvants” (ASIA), or the circulating spike protein itself after vaccination are responsible for the SAT.

Objective Insulinoma is a rare tumor of the pancreas that can lead to spontaneous hypoglycemia due to excessive insulin secretion. Seventy-two-hour fast is the gold standard for finding the correct diagnosis. Endoscopic ultrasound (EUS) is an established examination method to identify the suspicious lesion. Previous studies correlate the measured size of insulinoma and their endocrine behavior. This study was designed to find a relation between these variables. Methods We took the data of patients who had a histologically confirmed insulinoma after receiving an endoscopic ultrasound in our department. Size and echogenicity were correlated with the endpoint of the 72-hour fast and hormone levels. Results A total of 45 patients were identified. Most insulinomas were small with a volume of<2 cm3 (median 1.15 cm3). There was no correlation between the duration of fasting, hormone levels, and the size of the insulinoma. In addition, in a subgroup analysis, no connection could be established between the size of the insulinoma and the amount of insulin released after oral glucose exposure. We found that homogeneous tumors were significantly smaller and had a lower Ki-67 index. Furthermore, there was a tendency towards a shorter duration for the 72-hour fast for the small tumors. Discussion This data suggests that the measured size of insulinoma by EUS is not related to the time until termination of the 72-hour fast and measured hormone levels. The echogenicity seems more important, showing that homogenous tumors are an indicator of a higher differentiation, which can result in a shorter duration of the fasting period. The differences in the secretion behavior of the insulinomas could complicate the correlation of size and the 72-hour fast period.

ObjectivesPancreatic neuroendocrine neoplasias (pNENs) in multiple endocrine neoplasia type 1 are predominantly found in the dorsal anlage. Whether their growth velocity and incidence might be related to their location in the pancreas has not been investigated yet.MethodsWe studied 117 patients using endoscopic ultrasound.ResultsGrowth velocity could be calculated for 389 pNENs. Increase of largest tumor diameter (% per month) was 0.67 (standard deviation [SD], 2.04) in the pancreatic tail (n = 138), 1.12 (SD, 3.00) in the pancreatic body (n = 100), 0.58 (SD, 1.19) in the pancreatic head/uncinate process-dorsal anlage (n = 130), and 0.68 (SD, 0.77) in the pancreatic head/uncinate process-ventral anlage (n = 12). Comparing growth velocity of all pNENs in the dorsal (n = 368, 0.76 [SD, 2.13]) versus ventral anlage, no significant difference was detected. Annual tumor incidence rate was 0.21 in the pancreatic tail, 0.13 in the pancreatic body, 0.17 in the pancreatic head/uncinate process-dorsal anlage, 0.51 dorsal anlage together, and 0.02 in the pancreatic head/uncinate process-ventral anlage.ConclusionsMultiple endocrine neoplasia type 1 pNENs are unequally distributed between ventral (low prevalence and incidence) and dorsal anlage. However, there are no regional differences in growth behavior.

Purpose Pheochromocytoma (PCC) and adrenocortical carcinoma (ACC) are two rare endocrine diseases. Early diagnosis is crucial to significantly reduce morbidity and mortality. In this study, we used endoscopic ultrasound (EUS) for high-resolution imaging to investigate the endosonographic morphology pattern of PCC and ACC. Materials and Methods This retrospective cohort study included 58 PCC/ACC lesions diagnosed by EUS imaging at two tertiary care centers between 1997 and 2015. The following groups were defined by histology or by the presence of a pheochromocytoma-associated syndrome without histological proof: bPCC (benign PCC), mPCC (malignant PCC), and ACC. Results In our cohort, mPCC tended to be larger at the time of diagnosis (n=5; 39.9±41.9 mm) than bPCC (n=46; 27.3 ±20.8 mm, P=0.548). ACC lesions were significantly larger (n=7; 50.6±14.8 mm) than bPCC and mPCC (n=51; 28.5±23.3 mm, P=0.002). In EUS, bPCC and ACC lesions frequently appeared to have a round shape and nodular structure. bPCC and ACC tended to be more hyperechoic (P=0.112 and P=0.558, respectively) and heterogeneous (P=0.501 and P=0.098, respectively) than mPCC. Compared to PCC, ACC did not show high hyperperfusion (P=0.022). In contrast to adenoma, all tumor entities showed hypo-/anechoic areas within the tumor (P<0.05). Conclusion No significant differences in EUS morphology were found to reliably distinguish benign from malignant PCC and ACC lesions. However, EUS may be a reasonable alternative or complementary method to conventional imaging techniques for the early detection of these tumor entities.

ABSTRACT:Sporadic adult insulinomatosis is an extremely rare clinical condition. Adult proinsulinomatosis has not yet been described. We report the case of a 48-year-old female patient with recurrent hypoglycemia caused by benign proinsulin-secreting pancreatic neuroendocrine neoplasias (pNENs) with no history of multiple endocrine neoplasia type 1. Initial workup revealed elevated serum proinsulin levels and a positive fasting test. Magnetic resonance imaging and endosonography visualized 2 pNENs in the pancreatic body and tail that were treated by robotic-assisted enucleation. After initial biochemical cure, the patient's hypoglycemia recurred 3 months after surgery. Imaging showed a new lesion in the pancreatic body, so that now a spleen-preserving subtotal distal pancreatectomy was performed. The pathological examination revealed 17 neuroendocrine microadenomas and 1 well-differentiated pNEN (Ki-67% 1%-2%) of 22-mm size as well as more than 200 (pro)insulin-producing β-cell precursor lesions, confirming the diagnosis of adult proinsulinomatosis. Mutation analysis of the germline DNA identified the in-frame deletion mutation (p.His207del) in the MAFA gene on chromosome 8. The patient was biochemically cured 16 months after the last surgical resection. Similarly to adult insulinomatosis, the presence of proinsulin-secreting tumors causes recurrent hypoglycemia and might be associated with germline mutations in the MAFA gene.

OBJECTIVES:Pancreatic neuroendocrine neoplasias (pNENs) frequently occur in multiple endocrine neoplasia type 1 (MEN1). Their distribution referring to embryology, that is, the pancreatic anlagen, has not been investigated yet.METHODS:In the time between 1998 and 2019, we studied the distribution of pNENs in MEN1 concerning the embryologic origin of the pancreas, that is, the dorsal versus ventral anlage using endoscopic ultrasound in 117 MEN1 patients: 56 women, 61 men; aged 40 years (standard deviation, 14 years) at first endoscopic ultrasound.RESULTS:In 105 patients, a total of 628 pNENs were detected. They were located in the pancreatic tail: 231; pancreatic body: 177; pancreatic head/uncinate process: 220. Of the latter, 22 were located in the ventral anlage, 176 in the dorsal anlage, and 22 remained undefined. In summary, just 3.5% of all detected pNENs were located in the ventral anlage, 93.0% in the dorsal anlage, and 3.5% could not be assigned.CONCLUSIONS:Our study indicates that the vast majority of pNENs in MEN1 is located in the dorsal anlage, whereas the ventral anlage of the pancreas seems to be to a large extend spared from pNENs. Implications for new surgical strategies might be considered.

Background/Aim: It is a major challenge in the diagnosis of primary aldosteronism to identify patients with aldosterone producing adrenal adenoma which may benefit from surgical treatment (adrenalectomy/adenomectomy). Adrenal adenomas may be visualized by endoscopic ultrasound. However, a possible role and relevance of endoscopic ultrasound in the diagnostic process of primary aldosteronism has not been investigated systematically yet. Methods: We included 112 patients (48 females, 64 males, 54 ± 12 years) between 1997 to 2019 with positive screening test (aldosterone/renin-ratio) and arterial hypertension undergoing endoscopic ultrasound imaging of the adrenals into this study. Final diagnosis of aldosterone producing adenoma based on confirmation tests, imaging, selective blood sampling, histopathology and postsurgical improvement. Results: In 44 patients, diagnosis of aldosterone producing adrenal adenoma could finally be defined. Endoscopic ultrasound detected and localized 39/44 (89%) correctly (tumor diameter 15.6 ± 5.4 (5.7 to 26.0) mm). Computed tomography (n=26) localized correctly in 81%, magnetic resonance imaging (n=25) in 76%, and conventional sonography (n=19) in 32%. Endoscopic ultrasound was the only method localizing correctly in 8 cases (18%). Conclusion: Endoscopic ultrasound is a reliable and highly sensitive diagnostic tool in suspected aldosterone producing adrenal adenoma with a high negative predictive value. It can be useful to define patients which benefit from surgical treatment.

Background: Some gender-related differences have been reported in multiple endocrine neoplasia type 1 (MEN1), although not all reports are conclusive. This systematic review with analysis of the own MEN1 cohort evaluates gender differences and potential consequences for screening. Methods: A systematic review of the literature between 1990 and 2019 with the search terms “MEN1” or “multiple endocrine neoplasia type 1” and “gender” or “sex” was performed. In addition, the prospectively collected data of a genetically confirmed MEN1 cohort of the Philipps University Marburg were retrospectively analyzed. Results: Review of the literature identified five retrospective case series with original data of 1,057 MEN1 patients. One series suggested a higher frequency of pancreatic neuroendocrine neoplasms (NEN), especially gastrinomas, in men (61 vs. 54%) and a higher frequency of pituitary tumors in women (47 vs. 30%), but others did not. Only thymic NEN occurred predominantly in men throughout all studies. Women with MEN1 were found to have an increased risk of breast cancer. In the own series consisting of 116 MEN1 patients (male = 58, female = 58), thymic lesions were also more frequently detected in male patients (male = 5, female = 1). No gender difference was found with regard to the other manifestations. Conclusion: Regarding the typical MEN1 tumor manifestations, gender-adapted diagnostic and therapeutic approaches cannot be recommended. Female MEN1 patients should be encouraged to participate in breast cancer screening programs.

Purpose It is assumed that primary hyperparathyroidism (pHPT) in Multiple Endocrine Neoplasia (MEN) and lithium-associated pHPT (LIHPT) are associated with multiple gland disease (MGD), persistence and recurrence. The studies purpose was to determine frequencies, clinical presentation and outcome of sporadic pHPT (spHPT), LIHPT and pHPT in MEN. Additional main outcome measures were the rates of MGD and persistence/recurrence. Methods Retrospective analysis of medical records of 682 patients with pHPT who had attended the University Hospital of Marburg between 01-01-2004 and 30-06-2013. All patients were sent a questionnaire asking about their history of lithium medication. Results Out of 682 patients, 557 underwent primary surgery (532 spHPT, 5 LIHPT, 20 MEN), 38 redo-surgery (31 spHPT, 7 MEN), 55 were in follow-up due to previous surgery (16 spHPT, 1 LIHPT, 38 MEN) and 37 were not operated (33 spHPT, 1 LIHPT, 3 MEN). Primary surgeries were successful in 97.4%, revealed singular adenomas in 92.4 %, double adenomas in 2.9 % and MGD in 3.4% of the cases. Rates of MGD in MEN1 (82.35 %) were significantly higher than in spHPT (3.8 %), while there was no significant difference between LIHPT (20 %) and spHPT. Rates of persistence/recurrence did not significantly differ due to type of surgery (bilateral/unilateral) or type of HPT (spHPT/LIHPT/MEN). Conclusions History of lithium medication is rare among pHPT patients. While MGD is common in MEN1, rates of MGD, persistence or recurrence in LIHPT were not significantly higher than in spHPT.

Use of electronic media is widespread among adolescents. Many male adolescents spend a major part of their evenings playing video games. The increased exposure to artificial light as well as the exciting nature of this pastime is under suspicion to impair sleep. Sleep is considered to be important for memory consolidation, so there is also a potential risk for memory impairment due to video gaming. As learning and gaining knowledge is a very important part of adolescence, we decided to study the effects of prolonged video gaming on sleep and memory. The study was structured in a repeated measures design. Eighteen male participants played either the violent video game "Counter Strike: Global Offensive" or the board game "Monopoly" for five hours each on two Saturday nights. The game evenings were followed by sleep studies. Memory testing and vigilance evaluation was performed the next morning. During the course of the study, saliva samples were taken to determine melatonin and cortisol levels. The results of this crossover study showed slightly reduced sleep efficiency after "Counter Strike: Global Offensive" (-3.5%, p = .017) and impaired declarative memory recall (p = .005) compared to "Monopoly". Melatonin levels at bedtime were lower after "Counter Strike: Global Offensive" (p = .005), cortisol levels were elevated while playing the video game (p = .031). Negative effects on sleep were not strong but consistent with more wake after sleep onset (+12 min) and a higher arousal index after "Counter Strike: Global Offensive". We conclude that excessive video gaming in the evening can contribute to worsened sleep and impaired memory in male adolescents.