Endocrine immune-related adverse events in patients with metastatic renal and urothelial cancer treated with immune checkpoint-inhibitors.

PURPOSE: To evaluate the incidence, diagnosis and treatment of immune-related adverse events (e-irAE) of checkpoint inhibition (ICI) in metastatic urothelial carcinoma (mUC) and metastatic renal cell carcinoma (mRCC). METHODS: A retrospective, single-center study was conducted to identify a cohort that received ICI for mUC or mRCC. e-irAE were classified according to the CTCAE V.5.0. Patients received ICI for mUC or mCC between 01/2017 and 03/2021. A retrospective chart review was performed. T-Test, the chi-squared test, and Fisher's exact test were performed. RESULTS: 102 Patients received ICI [mUC: 40 (39%), mRCC: 62 (61%)]. 64 (63%) received an ICI monotherapy, 27 (27%) a dual ICI therapy, 11 (11%) a combination with VEGFi. e-irAE occurred in 19 (19%) patients [grade 1-2: 17 (84%), grade 3: 3 (16%)]. The median time until e-irAE was 42 days (range 11-211 days). 14 Patients developed thyroidism (14%), 4 (4%) a hypophysitis, 1 (1%) an adrenal insufficiency (AI). 7 patients (7%) had to discontinue ICI therapy [hypophysitis (100%), AI (100%), thyroidism (14%)]. 6 (86%) received cortisone. After a median range of 34 days 5 patients (71%) restarted ICI therapy. All patients (n = 4) with hypophysitis continued ICI [4 (100%) prednisone, 3 (75%) levothyroxine]. 11 (79%) presented with hyperthyroidism. 4 (37%) needed therapy (1 (7%) prednisone, 3 (21%) thiamazole, 2 (14%) beta blocker). The 9 (64%) patients with hypothyroidism received levothyroxine. Hypophysitis appears only on dual ICI (CTLA-4/PD-1) inhibition (p 0.007). CONCLUSION: This study shows the importance of adequate diagnosis and therapy of e-irAEs.

[New aspects in prevention and therapy of diabetic nephropathy]. / Neues zu Prävention und Therapie der diabetischen Nephropathie.

The reduction of micro- and macrovascular end points in patients with diabetes mellitus type 2 is achieved by control of traditional risk factors such as hyperglycemia, hyperlipidemia, obesity and hypertension. However, most of the glucose lowering medication available is excreted by the kidney. Thus, in patients with diabetes-associated chronic kidney disease, the glucose lowering therapy has to account for renal function to avoid hypoglycemic episodes and other side effects such as lactic acidosis due to metformin.

Diet-induced and age-related changes in the quadriceps muscle: MRI and MRS in a rat model of sarcopenia.

BACKGROUND: Knowledge about the molecular pathomechanisms of sarcopenia is still sparse, especially with regard to nutritional risk factors and the subtype of sarcopenic obesity. OBJECTIVE: The aim of this study was to characterize diet-induced and age-related changes on the quality and quantity of the quadriceps muscle in a rat model of sarcopenia by different magnetic resonance (MR) techniques. METHODS: A total of 36 6-month-old male Sprague-Dawley rats were randomly subdivided into 2 groups and received either a high-fat diet (HFD) or a control diet (CD). At the age of 16 months, 15 HFD and 18 CD rats underwent MR at 1.5 T. T1-weighted images as well as T2 relaxation time maps were acquired perpendicular to the long axis of the quadriceps muscles. Maximum cross-sectional area (CSA) of the quadriceps muscle was measured on T1-weighted images, and T2 relaxation times of muscle were assessed in a region without visible intramuscular fat (T2lean muscle) and across the complete CSA (T2muscle). Furthermore, (1)H-MR spectroscopy was performed to evaluate the relative lipid content of the quadriceps muscles. These measurements were repeated 5 months later in the surviving 8 HFD and 14 CD rats. RESULTS: HFD rats revealed significantly decreased CSA and CSA per body weight (BW) as well as prolonged T2 relaxation times of muscle. A higher weight gain (upper tertile during the first 6 months of diet in CD rats) resulted in a significant change of T2muscle, but had no relevant impact on CSA. Advancing age up to 21 months led to significantly decreased BW, CSA and CSA/BW, significantly prolonged T2muscle and T2lean muscle and enlarged lipid content in the quadriceps muscle. CONCLUSIONS: In an experimental setting a chronically fat-enriched diet was shown to have a relevant and age-associated influence on both muscle quantity and quality. By translational means the employed MR techniques give rise to the possibility of an early detection and noninvasive quantification of sarcopenia in humans, which is highly relevant for the field of geriatrics.

Smoldering myeloma presenting as progressive multifocal leukoencephalopathy: a case report.

INTRODUCTION: Progressive multifocal leukoencephalopathy is an opportunistic infection occurring in patients with severe cellular immunodeficiency. This case highlights the role of cellular immunodeficiency in the reactivation of John Cunningham virus in a case of an early stage plasmacytoma. CASE PRESENTATION: A 76-year-old Caucasian woman presented with progressive left-sided hemiparesis, accompanied by hypoesthesia, hypoalgesia and neuropsychological symptoms. Magnetic resonance imaging demonstrated new hyperattenuating lesions in the right thalamus and left-sided subcortically. A polymerase chain reaction test revealed 4500 copies of John Cunningham virus-deoxyribonucleic acid/ml in cerebrospinal fluid. Human immunodeficiency virus infection was ruled out. A bone marrow biopsy showed an early stage immunoglobulin G-kappa plasmacytoma. Cidofovir (5mg/kg) weekly for three weeks was started. A significant improvement of her neuropsychological symptoms was achieved, but motor system and sensory symptoms did not change. CONCLUSIONS: This case shows a rapid course of progressive multifocal leukoencephalopathy with severe residual deficits. In the diagnostic workup of all patients with atypical neurologic symptoms or immunodeficiency, progressive multifocal leukoencephalopathy should be included as a differential diagnosis.

Lipid accumulation in hepatocytes induces fibrogenic activation of hepatic stellate cells.

Despite the initial belief that non-alcoholic fatty liver disease is a benign disorder, it is now recognized that fibrosis progression occurs in a significant number of patients. Furthermore, hepatic steatosis has been identified as a risk factor for the progression of hepatic fibrosis in a wide range of other liver diseases. Here, we established an in vitro model to study the effect of hepatic lipid accumulation on hepatic stellate cells (HSCs), the central mediators of liver fibrogenesis. Primary human hepatocytes were incubated with the saturated fatty acid palmitate to induce intracellular lipid accumulation. Subsequently, human HSCs were incubated with conditioned media (CM) from steatotic or control hepatocytes. Lipid accumulation in hepatocytes induced the release of factors that accelerated the activation and proliferation of HSC, and enhanced their resistance to apoptosis, largely mediated via activation of the PI-3-kinase pathway. Furthermore, CM from steatotic hepatocytes induced the expression of the profibrogenic genes TGF-beta, tissue inhibitor of metallo-proteinase-1 (TIMP-1), TIMP-2 and matrix-metallo-proteinase-2, as well as nuclear-factor kappaB-dependent MCP-1 expression in HSC. In summary, our in vitro data indicate a potential mechanism for the pathophysiological link between hepatic steatosis and fibrogenesis in vivo. Herewith, this study provides an attractive in vitro model to study the molecular mechanisms of steatosis-induced fibrogenesis, and to identify and test novel targets for antifibrotic therapies in fatty liver disease.

Sirolimus-induced drug fever and ciclosporin-induced leukencephalopathia with seizures in one liver transplant recipient.

We describe the first case of sirolimus-induced drug fever in a female liver transplant recipient, with a history of hepatitis C-induced end-stage liver cirrhosis in 1999. In 2005, six years after transplantation, she developed calcineurin inhibitor-induced renal function impairment. Immunosuppression was switched from tacrolimus to sirolimus. Two days after the intake of sirolimus, she developed daily fever spikes, but no infectious focus was found. Antibiotic therapy had no influence on the fever. After fourteen days, sirolimus was switched back to tacrolimus and the fever disappeared. In history, the patient developed ciclosporin-induced generalized seizures eleven days after liver transplantation, followed by the development of a motoric speech disorder. Magnetic resonance imaging (MRI) findings were consistent with leucoencephalopathy, therefore immunosuppressive therapy was changed from ciclosporin to tacrolimus and the neurologic symptoms improved significantly. Our case is the first reported case of sirolimus-induced drug fever. In addition, the patient showed the rare occurrence of ciclosporin-induced leukencephalopathy with seizures.

Vasopeptidase inhibition attenuates proteinuria and podocyte injury in Zucker diabetic fatty rats.

Inhibition of the renin angiotensin aldosterone system (RAAS) produces protective effects on cardio-renal injury in type 2 diabetes. Vasopeptidase inhibitors (VPI) represent a new pharmacological tool, acting by simultaneous inhibition of the RAAS and neutral endopeptidase. We examined the effects of chronic VPI on renal function and morphology in experimental type 2 diabetes as compared to angiotensin converting enzyme inhibition (ACE-I). Zucker diabetic fatty rats aged 13 weeks were treated with either VPI (AVE7688, ZDF-VPI, n = 8) or ACE-I (Ramipril, ZDF-ACE-I, n = 7) or placebo (ZDF, n = 8). Heterozygous rats served as non-diabetic controls (Ctr, n = 8). Both treatments led to a similar decrease in blood pressure. After 10 weeks of treatment, ZDF developed marked albuminuria. The latter was significantly attenuated in ZDF-VPI as compared to ZDF and ZDF-ACE-I. Renal histology revealed a significant expansion in the glomerular tuft area in all ZDF groups. However, expression of glomerular desmin, which has been recognized as a sensitive marker of early podocyte damage, was significantly increased in ZDF as compared to Ctr. Desmin was reduced in ZDF-VPI but not in animals treated with ACE-I. There was a correlation between albumin excretion and desmin-positive glomerular area. In experimental type 2 diabetes, albuminuria correlates to podocyte damage. These hallmarks of diabetic nephropathy are attenuated by VPI to a greater extent than by ACE-I alone. These findings suggest that podocyte damage is an early critical step in the progression of diabetic nephropathy, and that VPI is a promising pharmacological tool in the treatment of diabetic renal disease.

Aldehyde oxidase 1 is highly abundant in hepatic steatosis and is downregulated by adiponectin and fenofibric acid in hepatocytes in vitro.

Adiponectin protects the liver from steatosis caused by obesity or alcohol and therefore the influence of adiponectin on human hepatocytes was analyzed. GeneChip experiments indicated that recombinant adiponectin downregulates aldehyde oxidase 1 (AOX1) expression and this was confirmed by real-time RT-PCR and immunoblot. AOX1 is a xenobiotic metabolizing protein and produces reactive oxygen species (ROS), that promote cell damage and fibrogenesis. Adiponectin and fenofibric acid activate peroxisome proliferator-activated receptor-alpha (PPAR-alpha) and both suppress AOX1 protein and this is blocked by the PPAR-alpha antagonist RU486. Obesity is associated with low adiponectin, reduced hepatic PPAR-alpha activity and fatty liver, and AOX1 was found induced in the liver of rats on a high-fat diet when compared to controls. Free fatty acids and leptin, that are elevated in obesity, failed to upregulate AOX1 in vitro. The current data indicate that adiponectin reduces AOX1 by activating PPAR-alpha whereas fatty liver disease is associated with elevated hepatic AOX1. High AOX1 may be associated with higher ROS well described to induce fibrogenesis in liver tissue but may also influence drug metabolism and activity.

The effect of chromoendoscopy on the diagnostic improvement of gastric ulcers by endoscopists with different levels of experience.

BACKGROUND: In recent years chromoendoscopy has become popular as a diagnostic enhancement tool in endoscopy. Using the macroscopic description of gastric ulcers, experienced endoscopists may be able to differentiate malignant and benign lesions. The aim of our study was to determine whether indigo carmine staining improves the ulcer differentiation by experienced and inexperienced endoscopists. METHODS: 50 patients were enrolled, 7 with malignant gastric ulcers and 43 with benign gastric ulcers. Gastroscopy was initially videotaped native, then on a second tape after staining with 0.2% indigo carmine. Later on biopsies were taken for histology. Subsequently the tapes were randomly evaluated by three experienced (>2000 gastroscopies; group A) and by three inexperienced (<100 gastroscopies; group B) investigators blinded from any personal data of the patients. The investigators had to classify the ulcers, using published criteria, native as well as stained. The results were compared within each group and with the histology. RESULTS: The endoscopic native diagnosis showed a sensitivity of 66.3%, a specificity of 86.3%, a positive predictive value of 48.1% and a negative predictive value of 94% for group A, respectively 66%, 62.5%, 22.7% and 92% for group B. After staining, the values of these parameters were reduced insignificantly to a sensitivity of 60.2%, a specificity of 78.5%, a positive predictive value of 36.1% and a negative predictive value of 92.8% for group A. Group B, on account of one investigator who demonstrated excellent skills, showed a significant better sensitivity (79.9%) and a slight improvement of the positive and negative predictive values to 25.7% respectively 94.8%, whereas the specificity very slightly decreased to 61.3%. The diagnostic accuracy before and after staining was 83.6%, respectively 76.5%, in group A and 63.2%, respectively 63.9% in group B. The correlation with the histology, determined by Cohen's kappa coefficient (median value), decreased from 0.46 for the native to 0.30 for the chromoendoscopic diagnosis in group A and remained unchanged (0.17) in group B. CONCLUSION: We concluded that chromoendoscopy does not improve the classification of gastric ulcers with respect to malignant or benign origin. The role of endoscopic experience could only be proved in the native macroscopic diagnosis of the investigators. After staining, with the exception of one investigator, experienced as well as inexperienced endoscopists lost their diagnostic accuracy.

Contrast-detail phantom study for x-ray spectrum optimization regarding chest radiography using a cesium iodide-amorphous silicon flat-panel detector.

RATIONALE AND OBJECTIVES: The purpose of this study evaluating a cesium iodide-amorphous silicon-based flat-panel detector was to optimize the x-ray spectrum for chest radiography combining excellent contrast-detail visibility with reduced patient exposure. MATERIALS AND METHODS: A Lucite plate with 36 drilled holes of varying diameter and depth was used as contrast-detail phantom. For 3 scatter body thicknesses (7.5 cm, 12.5 cm, 21.5 cm Lucite) images were obtained at 113 kVp, 117 kVp, and 125 kVp with additional copper filter of 0.2 and 0.3 mm, respectively. For each setting, radiographs acquired with 125 kVp and no copper filter were taken as standard of reference. On soft-copy displays, 3 observers blinded to the exposure technique evaluated the detectability of each aperture in each image according to a 5-point scale. The number of points given to all 36 holes per image was added. The scores of images acquired with filtration were compared with the standard images by means of a multivariate analysis of variance. Radiation burden was approximated by referring to the entrance dose and calculated using Monte Carlo method. RESULTS: All 6 evaluated x-ray spectra resulted in a statistically equivalent contrast-detail performance when compared with the standard of reference. The combination 125 kVp with 0.3 mm copper was most favorable in terms of dose reduction (approximately 33%). CONCLUSION: Within the constraints of the presented contrast-detail phantom study simulating chest radiography, the CsI/a-Si system enables an addition of up to 0.3 mm copper filtration without the need for compensatory reduction of the tube voltage for providing constant image quality. Beam filtration reduces radiation burden by about 33%.