The influence of obesity, diabetes mellitus and smoking on fuchs endothelial corneal dystrophy (FECD).

To detect environmental factors, which may be possible risk factors in the disease course of Fuchs' endothelial corneal dystrophy (FECD). Evaluation of patients with FECD registered in the FECD genetics database of the Center for Ophthalmology, University Hospital Cologne. For the evaluation, disease onset, central corneal thickness, best spectacle corrected visual acuity (BSCVA, logMAR), and modified Krachmer grading (grades 1-6) were correlated with the presence of diabetes mellitus (DM), body mass index (BMI), and smoking behavior. To put the age-related increase in Krachmer grading into perspective, a correction of grading were formed. Depending on the variables studied, differences between groups were examined by Mann-Whitney U test and chi-square test. The significance level was 5%. 403 patients with FECD were included in the analysis. The mean age of the patients was 70.0 ± 10.32 (range 28-96) years. The mean age at diagnosis of those patients was 63.1 ± 13.2 years. The female-to-male ratio was 1.46:1. Patients with a BMI > 30.0 kg/m2 developed FECD significantly earlier than patients with a BMI < 30 kg/m2, p = 0.001. Patients with DM showed significantly more often an Krachmer grade of 5, p = 0.015. Smoking had a negative effect on Krachmer grading (p = 0.024). Using the mediation analysis, the presence of DM correlated Krachmer Grade 5 (p = 0.015), and the presence of DM correlated with BMI > 30.0 kg/m2 (p = 0.012). In addition to smoking and DM our study shows for the first time that obesity may have a negative impact on the development of FECD. Whether dietary interventions and hormones can influence the development or progression of the disease needs to be investigated in future studies.

[Surgical treatment of intracaval tumor relapse after radical tumor nephrectomy in locally advanced renal cell carcinoma]. / Chirurgische Therapie des intrakavalen Tumorrezidivs nach radikaler Tumornephrektomie lokal fortgeschrittener Nierenzellkarzinome.

BACKGROUND: About 4-10% of patients with renal cell carcinoma (RCC) demonstrate intracaval tumor thrombi at the time of diagnosis. Furthermore, 2-3% of patients might develop local relapses of which intracaval recurrences represent a rare event with fewer than 15 cases reported in the literature. We report the diagnosis, surgical technique, perioperative complications, and oncological outcome in an additional 6 cases. PATIENTS AND METHODS: Between 2008 and 2019, 6 patients were treated with isolated intracaval relapse of RCC. All patients had undergone radical nephrectomy with thrombectomy in the past. The mean time between first surgery and relapse was 45.2 (6-114) months and the mean age of patients was 75 (70-80) years: 2, 3 and 1 patient demonstrated thrombus level II, III, and IV, respectively. A thoracoabdominal and a transperitoneal surgical approach was chosen in 4 and 2 patients, respectively. Perioperative complications were reported according to the Clavien-Dindo classification. Relapse-free, cancer-specific and overall survival were calculated with the Kaplan-Meier method. RESULTS: The cava thrombus could be resected completely in all cases. The mean time of surgery was 330 (260-510) min and the mean blood loss was 1500 (300-6500) ml. Clavien-Dindo grade II and IV complications developed in 2 and 1 patients, respectively. The 90-day readmission rate and mortality were 0%. After a mean follow-up of 32.3 (6-96) months, 5 patients are relapse-free and 1 patient developed pulmonary and hepatic metastases managed by immuno-oncological therapy. One patient died 27 months postoperatively due to multiple myeloma. CONCLUSION: Secondary thrombectomy for isolated intracaval tumor thrombus relapse represents a challenging surgery which is associated with a high oncological control rate and tolerable surgery-related morbidity. This type of surgery should be performed in centres with significant expertise in radical nephrectomy for locally advanced disease and thrombus surgery.

ETS-dependent p16INK4a and p21waf1/cip1 gene expression upon endothelin-1 stimulation in malignant versus and non-malignant proximal tubule cells.

AIM: Cellular senescence, leading to cell death through prevention of regular cell renewal, is associated with the upregulation of the tumor suppressor gene p16(INK4a). While this mechanism has been described as leading to progressive nephron loss, p16(INK4a) upregulation in renal cell carcinoma has been linked to a disease-specific improved patient survival rate. While in both conditions endothelin-1 is also upregulated, the signaling pathway connecting ET-1 to p16(INK4a) has not been characterized until this study. MAIN METHODS: Cell culture, qRT-PCR, Western Blot, immunoprecipitation (IP), proximity ligation assay (PLA), and non-radioactive electrophoretic mobility shift assay (EMSA). KEY FINDINGS: In malignant renal proximal tumor cells (Caki-1), an activation of p16(INK4a) and p21(waf1/cip1) was observed. An increased expression of E-26 transformation-specific (ETS) transcription factors was detectable. Using specific antibodies, a complex formation between ETS1 and extracellular signal-regulated kinase-2 (ERK2) was shown. A further complex partner was Mxi2. EMSA with supershift analysis for ETS1 and Mxi2 indicated the involvement of both factors in the protein-DNA interaction. After specifically blocking the endothelin receptors, ETS1 expression was significantly downregulated. However, the endothelin B receptor dependent downregulation was stronger than that of the A receptor. In contrast, primary proximal tubule cells showed a nuclear decrease after ET-1 stimulation. This indicates that other ETS members may be involved in the observed p16(INK4a) upregulation (as described in the literature). SIGNIFICANCE: ETS1, ERK2 and Mxi2 are important complex partners initiating increased p16(INK4a) and p21w(af1/cip1) activation in renal tumor cells.