Obesity and its comorbidities, including type 2 diabetes mellitus, cardiovascular disease, heart failure and non-alcoholic liver disease are a major health and economic burden with steadily increasing numbers worldwide. The need for effective pharmacological treatment options is strong, but, until recently, only few drugs have proven sufficient efficacy and safety. This article provides a comprehensive overview of obesity and its comorbidities, with a special focus on organ-specific pathomechanisms. Bariatric surgery as the so far most-effective therapeutic strategy, current pharmacological treatment options and future treatment strategies will be discussed. An increasing knowledge about the gut-brain axis and especially the identification and physiology of incretins unfolds a high number of potential drug candidates with impressive weight-reducing potential. Future multi-modal therapeutic concepts in obesity treatment may surpass the effectivity of bariatric surgery not only with regard to weight loss, but also to associated comorbidities.

Endocrine-disrupting chemicals (EDCs) are exogenous substances known to interfere with endocrine homeostasis and promote adverse health outcomes. Their impact on the adrenal cortex, corticosteroids and their physiological role in the organism has not yet been sufficiently elucidated. In this review, we collect experimental and epidemiological evidence on adrenal disruption by relevant endocrine disruptors. In vitro data suggest significant alterations of gene expression, cell signalling, steroid production, steroid distribution, and action. Additionally, morphological studies revealed disturbances in tissue organization and development, local inflammation, and zone-specific hyperplasia. Finally, endocrine circuits, such as the hypothalamic-pituitary-adrenal axis, might be affected by EDCs. Many questions regarding the detection of steroidogenesis disruption and the effects of combined toxicity remain unanswered. Not only due to the diverse mode of action of adrenal steroids and their implication in many common diseases, there is no doubt that further research on endocrine disruption of the adrenocortical system is needed.

A relevant issue on the treatment of adrenocortical carcinoma (ACC) concerns the optimal duration of adjuvant mitotane treatment. We tried to address this question, assessing whether a correlation exists between the duration of adjuvant mitotane treatment and recurrence-free survival (RFS) of patients with ACC. We conducted a multicenter retrospective analysis on 154 ACC patients treated for ≥12 months with adjuvant mitotane after radical surgery and who were free of disease at the mitotane stop. During a median follow-up of 38 months, 19 patients (12.3%) experienced recurrence. We calculated the RFS after mitotane (RFSAM), from the landmark time-point of mitotane discontinuation, to overcome immortal time bias. We found a wide variability in the duration of adjuvant mitotane treatment among different centers and also among patients cared for at the same center, reflecting heterogeneous practice. We did not find any survival advantage in patients treated for longer than 24 months. Moreover, the relationship between treatment duration and the frequency of ACC recurrence was not linear after stratifying our patients in tertiles of length of adjuvant treatment. In conclusion, the present findings do not support the concept that extending adjuvant mitotane treatment over two years is beneficial for ACC patients with low to moderate risk of recurrence.

The hypothalamus is the main integrator of peripheral and central signals in the control of energy homeostasis. Its functional relevance for the effectivity of bariatric surgery is not entirely elucidated. Studying the effects of bariatric surgery in patients with hypothalamic damage might provide insight. Prospective study to analyze the effects of bariatric surgery in patients with hypothalamic obesity (HO) vs. matched patients with common obesity (CO) with and without bariatric surgery. 65 participants were included (HO-surgery: n = 8, HO-control: n = 10, CO-surgery: n = 12, CO-control: n = 12, Lean-control: n = 23). Body weight, levels of anorexic hormones, gut microbiota, as well as subjective well-being/health status, eating behavior, and brain activity (via functional MRI) were evaluated. Patients with HO lost significantly less weight after bariatric surgery than CO-participants (total body weight loss %: 5.5 % vs. 26.2 %, p = 0.0004). After a mixed meal, satiety and abdominal fullness tended to be lowest in HO-surgery and did not correlate with levels of GLP-1 or PYY. Levels of PYY (11,151 ± 1667 pmol/l/h vs. 8099 ± 1235 pmol/l/h, p = 0.028) and GLP-1 (20,975 ± 2893 pmol/l/h vs. 13,060 ± 2357 pmol/l/h, p = 0.009) were significantly higher in the HO-surgery vs. CO-surgery group. Abundance of Enterobacteriaceae and Streptococcus was increased in feces of HO and CO after bariatric surgery. Comparing HO patients with lean-controls revealed an increased activation in insula and cerebellum to viewing high-caloric foods in left insula and cerebellum in fMRI. Hypothalamic integrity is necessary for the effectiveness of bariatric surgery in humans. Peripheral changes after bariatric surgery are not sufficient to induce satiety and long-term weight loss in patients with hypothalamic damage.

Background: Eosinophils appear to contribute to the efficacy of immunotherapy and their frequency was suggested as a predictive biomarker. Whether this observation could be transferred to patients treated with targeted therapy remains unknown. Methods: Blood and serum samples of healthy controls and 216 patients with advanced melanoma were prospectively and retrospectively collected. Freshly isolated eosinophils were phenotypically characterized by flow cytometry and co-cultured in vitro with melanoma cells to assess cytotoxicity. Soluble serum markers and peripheral blood counts were used for correlative studies. Results: Eosinophil-mediated cytotoxicity towards melanoma cells, as well as phenotypic characteristics, were similar when comparing healthy donors and patients. However, high relative pre-treatment eosinophil counts were significantly associated with response to MAPKi (p = 0.013). Eosinophil-mediated cytotoxicity towards melanoma cells is dose-dependent and requires proximity of eosinophils and their target in vitro. Treatment with targeted therapy in the presence of eosinophils results in an additive tumoricidal effect. Additionally, melanoma cells affected eosinophil phenotype upon co-culture. Conclusion: High pre-treatment eosinophil counts in advanced melanoma patients were associated with a significantly improved response to MAPKi. Functionally, eosinophils show potent cytotoxicity towards melanoma cells, which can be reinforced by MAPKi. Further studies are needed to unravel the molecular mechanisms of our observations.

International guidelines recommend local therapies (LTs) such as local thermal ablation (LTA; radiofrequency, microwave, cryoablation), transarterial (chemo)embolisation (TA(C)E), and transarterial radioembolisation (TARE) as therapeutic options for advanced adrenocortical carcinoma (ACC). However, the evidence for these recommendations is scarce. We retrospectively analysed patients receiving LTs for advanced ACC. Time to progression of the treated lesion (tTTP) was the primary endpoint. The secondary endpoints were best objective response, overall progression-free survival, overall survival, adverse events, and the establishment of predictive factors by multivariate Cox analyses. A total of 132 tumoural lesions in 66 patients were treated with LTA (n = 84), TA(C)E (n = 40), and TARE (n = 8). Complete response was achieved in 27 lesions (20.5%; all of them achieved by LTA), partial response in 27 (20.5%), and stable disease in 38 (28.8%). For the LTA group, the median tTTP was not reached, whereas it was reached 8.3 months after TA(C)E and 8.2 months after TARE (p < 0.001). The median time interval from primary diagnosis to LT was >47 months. Fewer than four prior therapies and mitotane plasma levels of >14 mg/L positively influenced the tTTP. In summary, this is one of the largest studies on LTs in advanced ACC, and it demonstrates a very high local disease control rate. Thus, it clearly supports the guideline recommendations for LTs in these patients.