Targeted therapy of advanced parathyroid carcinoma guided by genomic and transcriptomic profiling.

Parathyroid carcinoma (PC) is an ultra-rare malignancy with a high risk of recurrence after surgery. Tumour-directed systemic treatments for PC are not established. We used whole-genome and RNA sequencing in four patients with advanced PC to identify molecular alterations that could guide clinical management. In two cases, the genomic and transcriptomic profiles provided targets for experimental therapies that resulted in biochemical response and prolonged disease stabilization: (a) immune checkpoint inhibition with pembrolizumab based on high tumour mutational burden and a single-base substitution signature associated with APOBEC (apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like) overactivation; (b) multi-receptor tyrosine kinase inhibition with lenvatinib due to overexpression of FGFR1 (Fibroblast Growth Factor Receptor 1) and RET (Ret Proto-Oncogene) and, (c) later in the course of the disease, PARP (Poly(ADP-Ribose) Polymerase) inhibition with olaparib prompted by signs of defective homologous recombination DNA repair. In addition, our data provided new insights into the molecular landscape of PC with respect to the genome-wide footprints of specific mutational processes and pathogenic germline alterations. These data underscore the potential of comprehensive molecular analyses to improve care for patients with ultra-rare cancers based on insight into disease biology.

[New therapeutic developments in the treatment of type 2 diabetes mellitus]. / Neue Entwicklungen in der Therapie des Diabetes mellitus Typ 2.

Diabetes mellitus has become a widespread disease worldwide. In recent years, there has been a rapid development of therapeutic options in the field of diabetology. Many new drugs and therapeutic strategies are now available or will be available in the near future, which have the potential to significantly improve the care of patients even if they do not have diabetes. In this article, we would like to present the latest therapeutic options and possible further applications. The article focuses, among other things, on the new findings of SGLT-2-inhibitors in cardiac and chronic renal failure and the further development of incretin-based drugs toward dual GIP/GLP-1-receptor agonists. Once-weekly insulin and the selective mineralocorticoid receptor antagonist finerenone will also be presented.

Effectiveness of wearable devices as a support strategy for maintaining physical activity after a structured exercise intervention for employees with metabolic syndrome: a randomized controlled trial.

BACKGROUND: Metabolic syndrome (MetS) is associated with an increased risk for cardiovascular events and high socioeconomic costs. Despite lifestyle interventions focusing on exercise are effective strategies to improve parameters of the above aspects, many programs fail to show sustained effects in the long-term. METHODS: At visit 2 (V2) 129 company employees with diagnosed MetS, who previously participated in a 6-month telemonitoring-supported exercise intervention, were randomized into three subgroups for a 6-month maintenance treatment phase. A wearable activity device was provided to subgroup A and B to assess and to track physical activity. Further subgroup A attended personal consultations with individual instructions for exercise activities. Subgroup C received neither technical nor personal support. 6 months later at visit (V3), changes in exercise capacity, MetS severity, work ability, health-related quality of life and anxiety and depression were compared between the subgroups with an analysis of variance with repeated measurements. RESULTS: The total physical activity (in MET*h/week) declined between visit 2 and visit 3 (subgroup A: V2: 48.0 ± 33.6, V3: 37.1 ± 23.0; subgroup B: V2: 52.6 ± 35.7, V3: 43.8 ± 40.7, subgroup C: V2: 51.5 ± 29.7, V3: 36.9 ± 22.8, for all p = 0.00) with no between-subgroup differences over time (p = 0.68). In all three subgroups the initial improvements in relative exercise capacity and MetS severity were maintained. Work ability declined significantly in subgroup C (V2: 40.3 ± 5.0, V3: 39.1 ± 5.7; p < 0.05), but remained stable in the other subgroups with no between-subgroup differences over time (p = 0.38). Health-related quality of life and anxiety and depression severity also showed no significant differences over time. CONCLUSIONS: Despite the maintenance of physical activity could not be achieved, most of the health related outcomes remained stable and above baseline value, with no difference regarding the support strategy during the maintenance treatment phase. Trial registration The study was completed as a cooperation project between the Volkswagen AG and the Hannover Medical School (ClinicalTrials.gov Identifier: NCT02029131).

[Insulin autoimmune syndrome : A rare, but important differential diagnosis of hypoglycemia]. / Insulinautoimmunsyndrom : Eine seltene, aber wichtige Differentialdiagnose der Hypoglykämie.

A 69-year-old female patient was referred to the Medical University of Hanover for further diagnostic evaluation of recurrent severe hypoglycemia. The patient had previously been started on clopidogrel after arterial stenting for peripheral arterial obstructive disease (PAOD). The presence of an insulinoma and paraneoplastic syndrome was excluded. Increased serum insulin and insulin autoantibodies levels were confirmed, despite normal to low blood sugar levels. An insulin autoimmune syndrome was diagnosed, most likely induced by the prior intake of clopidogrel. Treatment with immunoadsorption was initiated, achieving a significant reduction in hypoglycemic events and a lasting response to treatment over 3 months.

Telemonitoring-Supported Exercise Training in Employees With Metabolic Syndrome Improves Liver Inflammation and Fibrosis.

INTRODUCTION: Metabolic syndrome (MetS) is a major health problem worldwide and the main risk factor for metabolic-associated fatty liver disease (MAFLD). Established treatment options are lifestyle interventions facilitating dietary change and increased physical activity. Here, we tested the effect of a telemonitoring-supported intervention on liver parameter of inflammation and fibrosis in individuals with MetS. METHODS: This was a prospective, randomized, parallel-group, and assessor-blind study performed in workers of the main Volkswagen factory (Wolfsburg, Germany). Volunteers with diagnosed MetS were randomly assigned (1:1) to a 6-month lifestyle intervention focusing on supervised, activity-tracker-guided exercise or to a waiting-list control group. This secondary analysis assessed the effect of the intervention on liver enzymes and MAFLD-related parameters. RESULTS: We screened 543 individuals between October 10, 2017, and February 27, 2018, of whom 314 were randomly assigned to the intervention group (n = 160) or control group (n = 154). Liver transaminases, alkaline phosphatase, and gamma-glutamyl transferase significantly decreased after 6 months in the intervention group compared with the CG. Furthermore, an aspartate aminotransferase-to-platelet ratio index score as a marker for liver fibrosis significantly decreased in the intervention group. These improvements were associated with changes in obesity and exercise capacity. DISCUSSION: A 6-month lifestyle intervention based on exercise training with individualized telemonitoring-based supervision led to improvements of liver inflammation and fibrosis in employees with MetS. Therefore, this intervention shows therapeutic potential for individuals at high risk of MAFLD (ClinicalTrials.gov Identifier: NCT03293264).

Multicenter, Observational Study of Lanreotide Autogel for the Treatment of Patients with Acromegaly in Routine Clinical Practice in Germany, Austria and Switzerland.

BACKGROUND: Evidence from controlled trials has shown that lanreotide autogel is effective in achieving biochemical and symptom control in patients with acromegaly. However, it is important to better understand the real-world patient population receiving lanreotide autogel treatment. METHODS: In this non-interventional study the long-term treatment response to lanreotide autogel in adult patients with acromegaly from office-based centers or clinics in Germany, Austria and Switzerland was studied. Assessments included growth hormone and insulin-like growth factor-I levels, symptoms, quality of life, lanreotide plasma levels and tumor somatostatin receptor subtype expression. The primary endpoint was achievement of full biochemical control, defined as growth hormone ≤2.5 µg/L and insulin-like growth factor I normalization at month 12. RESULTS: 76 patients were enrolled from 21 sites. 7/51 (13.7%) patients of the efficacy population had full biochemical control at baseline, 15/33 (45.5%) at month 12 and 10/26 (38.5%) at month 24 of treatment. At 12 months of treatment higher rates of biochemical control were observed in the following subgroups: older patients (>53 years [median]), females, treatment-naïve patients, and patients with a time since diagnosis of longer than 1.4 years (median). No clinically relevant differences in acromegaly symptoms or quality of life scores were observed. Median fasting blood glucose and glycated hemoglobin levels remained unchanged throughout the study. No new safety signals were observed. Overall tolerability of treatment with lanreotide autogel was judged by 80.8% of the enrolled patients at month 12 as 'very good' or 'good'. CONCLUSION: Treatment with lanreotide autogel in a real-world setting showed long-term effectiveness and good tolerability in patients with acromegaly.

Dapagliflozin effects on haematocrit, red blood cell count and reticulocytes in insulin-treated patients with type 2 diabetes.

Recent studies have shown that high-risk patients with type 2 diabetes mellitus (T2DM) treated with sodium glucose cotransporter 2 (SGLT2) inhibitors have improved cardiovascular (CV) outcomes. In an exploratory analysis of data from the EMPA-REG study, elevations in haematocrit were shown to be strongly associated with beneficial CV effects. As insulin treatment has been shown to be antinatriuretic, with an associated increase in extracellular fluid volume, it is important to confirm whether haematocrit increase is maintained with concomitant insulin therapy. Here, we investigate the effect of the SGLT2 inhibitor dapagliflozin on haematocrit, red blood cell (RBC) counts and reticulocyte levels in high-risk patients with T2DM receiving insulin. A 24-week, double-blinded, randomised, placebo-controlled trial (ClinicalTrials.gov: NCT00673231) was reported previously with extension periods of 24 and 56 weeks (total of 104 weeks). Patients receiving insulin were randomised 1:1:1:1 to placebo or dapagliflozin at 2.5, 5 or 10 mg. Haematocrit, RBC and reticulocyte measurements were conducted during this study, and a longitudinal repeated-measures analysis was performed here to examine change from baseline during treatment. Dapagliflozin treatment in combination with insulin resulted in a dose-dependent increase in haematocrit levels and RBCs over a 104 week period. There was a short-term increase in reticulocyte levels at the start of treatment, which dropped to below baseline after 8 weeks. SGLT2 inhibition with dapagliflozin leads to a sustained increase in haematocrit in patients receiving chronic insulin treatment.

Employers With Metabolic Syndrome and Increased Depression/Anxiety Severity Profit Most From Structured Exercise Intervention for Work Ability and Quality of Life.

BACKGROUND: Major depressive disorder and anxiety disorders are associated with less productivity, earlier retirement, and more sick-days at the workplace. These associations also exist for patients with metabolic syndrome. For both, exercise is a generally recommended part of multimodal treatments. However, for individuals with metabolic syndrome, in which depression and anxiety is more prevalent and severe, evidence for the efficacy of exercise interventions is limited. METHODS: Company employees with diagnosed metabolic syndrome (n=314, age: 48 ± 8 yrs) were randomized to a 6-month exercise intervention (150 min per week) or wait-list control. Participants received individual recommendations for exercise activities by personal meetings, telephone, or via a smartphone app. Physical activities were supervised and adapted using activity monitor data transferred to a central database. Work ability (work ability index), depression severity and anxiety severity [hospital anxiety and depression scale (HADS)], and health-related quality of live [short form 36 (SF-36)] were assessed. RESULTS: We included 314 subjects from which 287 finished the intervention. Total work ability, depression- and anxiety severity, and the mental component score of the SF-36 improved after 6 months exercise compared to controls. After baseline stratification for normal (HADS scores 0-7) and increased depression- and anxiety scores (HADS scores 8-21) individuals with increased severity scores had similar age, body composition, blood lipids, and cardiorespiratory fitness compared to those with normal scores, but lower total work ability and component sum scores of health-related quality of life. After 6 months total work ability increased in the exercise group compared to controls with the magnitude of the observed increase being significantly greater for subjects with increased depression- and anxiety severity at baseline compared to those with normal severity scores. CONCLUSIONS: A 6-month exercise intervention for company employees with metabolic syndrome showed strongest effects on self-perceived work ability in individuals with mild to severe depression- and anxiety severity. This suggests exercise programs offered to workers with metabolic syndrome not only reduces individual disease risk but may also reduce healthcare and employers costs arising from metabolic syndrome and mental disease conditions. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, identifier NCT03293264.

Telemonitoring-supported exercise training, metabolic syndrome severity, and work ability in company employees: a randomised controlled trial.

BACKGROUND: Metabolic syndrome is a predisposing factor for cardiovascular and metabolic disease, but also has socioeconomic relevance by affecting the health and productivity of workers. We tested the effect of regular telemonitoring-supported physical activity on metabolic syndrome severity and work ability in company employees. METHODS: This was a prospective, randomised, parallel-group, and assessor-blind study done in workers in the main Volkswagen factory (Wolfsburg, Germany). Volunteers with diagnosed metabolic syndrome according to American Heart Association/National Heart, Lung, and Blood Institute criteria were randomly assigned (1:1) to a 6-month lifestyle intervention focusing on regular exercise (exercise group), or to a waiting-list control group, using a computer-based assignment list with variable block length. Participants in the exercise group received individual recommendations for exercise at face-to-face meetings and via a smartphone application, with the aim of doing 150 min physical activity per week. Activities were supervised and adapted using activity-monitor data, which were transferred to a central database. Participants in the control group continued their current lifestyle and were informed about the possibility to receive the supervised intervention after study completion. The primary outcome was the change in metabolic syndrome severity (metabolic syndrome Z score) after 6 months in the intention-to treat population. This trial is registered with ClinicalTrials.gov, number NCT03293264, and is closed to new participants. FINDINGS: 543 individuals were screened between Oct 10, 2017, and Feb 27, 2018, of whom 314 (mean age 48 years [SD 8]) were randomly assigned to receive the intervention (n=160; exercise group) or to a waiting list (n=154; control group). The mean metabolic syndrome Z score for the exercise group was significantly reduced after the 6-month intervention period (0·93 [SD 0·63] before and 0·63 [0·64] after the intervention) compared with the control group (0·95 [0·55] and 0·90 [0·61]; difference between groups -0·26 [95% CI -0·35 to -0·16], p<0·0001). We documented 11 adverse events in the exercise group, with only one event (a twisted ankle) regarded as directly caused by the intervention. INTERPRETATION: A 6-month exercise-focused intervention using telemonitoring systems reduced metabolic syndrome severity. This form of intervention shows significant potential to reduce disease risk, while also improving mental health, work ability, and productivity-related outcomes for employees at high risk for cardiovascular and metabolic disease. FUNDING: Audi BKK health insurance and the German Research Foundation through the Cluster of Excellence REBIRTH.

Vitamin D deficiency in community-acquired pneumonia: low levels of 1,25(OH)2 D are associated with disease severity.

OBJECTIVES: We aimed to explore the association between vitamin D levels and the severity, mortality and microbiological etiology of community-acquired pneumonia. METHODS: Vitamin D levels (both, the reservoir form 25-OH and the activated form 1,25-OH2) of 300 randomly selected patients with community-acquired pneumonia due to pre-specified pathogens included in the German competence network (CAPNETZ) study were measured. Prior to statistical analysis, values of 25-OH and 1,25-OH2 were power-transformed to achieve parametric distribution. All further analyses were performed with seasonally and age adjusted values. RESULTS: There was only a modest (Spearman Coefficient 0.38) positive correlation between 25-OH and 1,25-OH2. For 1,25-OH2 but not 25-OH, the general linear model revealed a significant inverse correlation between serum concentration and CURB score (p = 0.011). Liver and respiratory co-morbidity were associated with significantly lower 25-OH values and renal co-morbidity with significantly lower 1,25-OH2 values. No significant differences of 1,25-OH2 or 25-OH between different pathogens (influenza virus, Legionella spp., Streptococcus pneumoniae) were detected. CONCLUSION: For 1,25-OH2, we found a significant and independent (controlled for age, season and pathogen) negative correlation to pneumonia severity. Therefore, supplementation of non-activated vitamin D to protect from pneumonia may be non-sufficient in patients that have a decreased capacity to hydroxylate 25-OH to 1,25-OH2.

Hypercortisolaemia due to ectopic adrenocorticotropic hormone secretion by a nasal paraganglioma: a case report and review of the literature.

BACKGROUND: Adrenocorticotropic hormone-producing extraadrenal paragangliomas are extremely rare. We present a case of severe hypercortisolemia due to ectopic adrenocorticotropic hormone secretion by a nasal paraganglioma. CASE PRESENTATION: A 70-year-old Caucasian woman, was emergently admitted to our department with supraventricular tachycardia, oedema of face and extremities and hypertensive crisis. Initial laboratory evaluation revealed severe hypokalemia and hyperglycemia without ketoacidosis, although no diabetes mellitus was previously known. Computed tomography revealed a large tumor obliterating the left paranasal sinus and a left-sided adrenal mass. After cardiovascular stabilisation, a thorough hormonal assessment was performed revealing marked adrenocorticotropic hormone-dependent hypercortisolism. Due to the presence of a cardiac pacemaker magnetic resonance imaging of the hypophysis was not possible. [68Ga-DOTA]-TATE-Positron-Emission-Tomography was performed, showing somatostatin-receptor expression of the paranasal lesion but not of the adrenal lesion or the hypophysis. The paranasal tumor was resected and found to be an adrenocorticotropic hormone-producing paraganglioma of low-proliferative rate. Postoperatively the patient became normokaliaemic, normoglycemic and normotensive without further need for medication. Genetic testing showed no mutation of the succinatdehydrogenase subunit B- and D genes, thus excluding hereditary paragangliosis. CONCLUSION: Detection of the adrenocorticotropic hormone source in Cushing's syndrome can prove extremely challenging, especially when commonly used imaging modalities are unavailable or inconclusive. The present case was further complicated by the simultaneous detection of two tumorous lesions of initially unclear biochemical behaviour. In such cases, novel diagnostic tools - such as somatostatin-receptor imaging - can prove useful in localising hormonally active neuroendocrine tissue. The clinical aspects of the case are discussed and relevant literature is reviewed.

Procedure-related pulmonary hypertension in patients with hepatocellular carcinoma undergoing percutaneous ethanol injection--role of ethanol, hemolysis, asymmetric dimethylarginine, and the nitric oxide system.

OBJECTIVE: Local percutaneous tumor ablation with ethanol injection (PEI) under general anesthesia is an established therapy for patients with nonresectable hepatocellular carcinoma (HCC). There are reports of sudden hypotension immediately after PEI therapy, which was attributed to an acute increase in pulmonary vascular resistance. The aim of our study was to objectively confirm pulmonary hypertension by right heart catheterization and to evaluate biochemical markers with relevance to the pulmonary circulation. DESIGN: Cross-sectional clinical study. SETTING: Interventional Gastroenterology in a tertiary care center. PATIENTS: We studied 40 patients with HCC who underwent percutaneous ethanol injection under general anesthesia for the treatment of nonresectable HCC. RESULTS: In patients with HCC, PEI leads to a significant increase in pulmonary arterial pressure. Concomitantly, free hemoglobin and blood ethanol level significantly increased, whereas the l-arginine/asymmetric dimethylarginine ratio, a parameter of nitric oxide (NO) production capacity, and nitrite, a marker of NO synthesis, significantly decreased. CONCLUSION: Procedure-related pulmonary hypertension in patients undergoing PEI is multifactorial. Plasma concentrations of the NO precursor l-arginine are reduced by arginase released from lysed erythrocytes, a condition further exacerbated by the increased concentrations of symmetric dimethylarginine, which may compete with the cellular uptake of l-arginine. The result would be reduced synthesis of NO, the concentration of which would be further decreased extracellularly through free hemoglobin. Predictably, the result would be severe endothelial dysfunction and pulmonary hypertension in patients undergoing PEI. These mechanisms might also be relevant in other states of (sudden) hemolysis.

Outcome and quality of life in patients with polycystic liver disease after liver or combined liver-kidney transplantation.

In advanced stages of polycystic liver disease, often associated with polycystic kidney disease, a curative therapy is liver or combined liver-kidney transplantation. However, little is known about long-term outcome and quality of life. Between 1990 and 2003, 36 patients (32 female, 4 male) with polycystic liver or combined liver-kidney disease underwent liver (n = 21) or liver-kidney (n = 15) transplantation at our center. Main indications for liver transplantation were cachexia, muscle atrophy, loss of weight, recurrent cyst infections, portal hypertension, and ascites. Apart from clinical parameters, 2 anonymous questionnaires (standard short form 36 and self-designed) addressing quality of life and social status were evaluated. Five patients (14 %) died due to sepsis or myocardial infarction with pneumonia, all within 61 days after transplantation. The follow-up time of the remaining 31 patients ranged from 5 to 156 months, with a mean of 62 months. Of the 23 (74%) answered the questionnaires, 91% of patients felt "much better" or "better," only 9% felt "worse" than before, and 52% of patients participated in sports regularly. Fatigue, physical fitness, loss of appetite, and vomiting improved significantly after transplantation. Physical attractiveness and interest in sex increased as well. Professional occupation did not change for 71% of patients. Family situation before and after transplantation changed in 1 case only. Finally, 78% of patients said they would opt for transplantation again, while 17% were undecided; 1 patient would not repeat transplantation. In conclusion, patients with advanced polycystic liver or polycystic liver-kidney disease have an excellent survival rate and an improved quality of life after liver or combined liver-kidney transplantation.

Sympathoadrenal counterregulation in patients with hypothalamic craniopharyngioma.

In humans, the role of hypothalamic centers for activation of counterregulatory release of catecholamines and glucagon during hypoglycemia is unclear. To address this question, we investigated the counterregulatory response to acute insulin-induced hypoglycemia of glucagon, epinephrine, and norepinephrine in eight patients who had undergone transcranial surgery for a craniopharyngioma extending to the hypothalamic region. We compared the patients' responses with those of four patients suffering from hypopituitarism and of six healthy subjects. After the i.v. injection of 0.1 U of human insulin per kg of body weight in the patients or 0.15 U in healthy subjects, the plasma glucose concentrations decreased to similar minimum levels within 30 min in all three groups. All subjects recovered spontaneously from hypoglycemia within 2 h. In five of eight craniopharyngioma patients, only a small counterregulatory rise in plasma epinephrine (< or =2-fold) and norepinephrine could be observed (P < 0.05 for epinephrine and P = 0.22 for norepinephrine vs. healthy controls). During hypoglycemia, virtually no adrenergic symptoms (tremor, heart pounding, and anxiety) were reported by these five patients, and changes in the heart rate were diminished. In three craniopharyngioma patients, the counterregulatory increase in catecholamines was unimpaired, adrenergic symptoms were reported and a rise in heart rate was observed during hypoglycemia. In all craniopharyngioma patients, the counterregulatory glucagon response to hypoglycemia was preserved and orthostasis increased both catecholamines and the heart rate similar to in the patients with hypopituitarism as well as in the healthy controls. Our results demonstrate selective impairment of counterregulatory sympathoadrenal activation in patients who had undergone surgery for a craniopharyngioma extending to the hypothalamic region. This strongly suggests the involvement of hypothalamic centers in hypoglycemia-induced activation of the sympathoadrenal axis in humans. It remains unclear as to whether hypoglycemia-induced glucagon secretion is also controlled by the hypothalamus. However, a common hypothalamic center controlling both counterregulatory catecholamine and glucagon release is unlikely, and sympathoadrenal activation is not required for hypoglycemia-induced glucagon secretion in humans.