Hepatic Steatosis in Lean Patients: Risk Factors and Impact on Mortality.

BACKGROUND: The prognostic impact of liver steatosis in obese patients is well established. Limited data on the risk factors for and impact of hepatic steatosis in lean patients are available. AIMS: Assess risk factors for liver steatosis in lean patients and investigate its impact on survival. METHODS: Patients without viral hepatitis and with a BMI ≤ 25 kg/m2 undergoing liver stiffness measurement (LSM) and controlled attenuation parameter (CAP) by transient elastography were retrospectively identified. Clinical characteristics and laboratory test results were obtained at the time of LSM/CAP measurement. National death registry data were obtained in order to assess survival. RESULTS: Among n = 218 lean patients, n = 97 (34.5%) showed significant liver steatosis (CAP ≥ 268 dB/m), while n = 184 (65.5%) had no or just mild steatosis (CAP < 268 dB/m). Patients with steatosis had higher GGT (238.0(± 450.3) vs. 112.1(± 180.0) IU/mL; p = 0.013), AST (63(± 67.4) vs. 38.5(± 32.9) IU/mL; p = 0.001), ALT (59.1(± 58.8) vs. 44.3(± 52.7) IU/mL; p = 0.048) and triglyceride levels (120.1(± 80.3) vs. 96.1(± 58.2) mg/dL; p = 0.014), and showed a trend toward more severe fibrosis (LSM 15.6(± 19.5) vs. 12.0(± 15.7) kPa; p = 0.115). In multivariate binary logistic regression analysis, only serum uric acid levels were independently associated with liver steatosis (odds ratio 1.43 per unit mg/dL; 95% CI 1.001-2.054; p = 0.049). During a mean follow-up of 38.9(± 10.6) months, n = 14 patients (5.0%) died. In the absence of advanced fibrosis, survival after 1 year was similar in patients without (98.7%) and with (98.6%) significant steatosis. Patients with advanced fibrosis had worse 1-year survival without concomitant significant steatosis (84.8%) than patients with steatosis (95.8%; log-rank p < 0.001). CONCLUSIONS: High serum uric acid levels increase the risk of liver steatosis in lean patients. Liver fibrosis but not hepatic steatosis is a risk factor for impaired survival in lean patients.

Experimental nerve transfer model in the neonatal rat.

Clinically, peripheral nerve reconstructions in neonates are most frequently applied in brachial plexus birth injuries. Most surgical concepts, however, have investigated nerve reconstructions in adult animal models. The immature neuromuscular system reacts differently to the effects of nerve lesion and surgery and is poorly investigated due to the lack of reliable experimental models. Here, we describe an experimental forelimb model in the neonatal rat, to study these effects on both the peripheral and central nervous systems. Within 24 hours after birth, three groups were prepared: In the nerve transfer group, a lesion of the musculocutaneous nerve was reconstructed by selectively transferring the ulnar nerve. In the negative control group, the musculocutaneous nerve was divided and not reconstructed and in the positive control group, a sham surgery was performed. The animal´s ability to adapt to nerve lesions and progressive improvement over time were depict by the Bertelli test, which observes the development of grooming. Twelve weeks postoperatively, animals were fully matured and the nerve transfer successfully reinnervated their target muscles, which was indicated by muscle force, muscle weight, and cross sectional area evaluation. On the contrary, no spontaneous regeneration was found in the negative control group. In the positive control group, reference values were established. Retrograde labeling indicated that the motoneuron pool of the ulnar nerve was reduced following nerve transfer. Due to this post-axotomy motoneuron death, a diminished amount of motoneurons reinnervated the biceps muscle in the nerve transfer group, when compared to the native motoneuron pool of the musculocutaneous nerve. These findings indicate that the immature neuromuscular system behaves profoundly different than similar lesions in adult rats and explains reduced muscle force. Ultimately, pathophysiologic adaptations are inevitable. The maturing neuromuscular system, however, utilizes neonatal capacity of regeneration and seizes a variety of compensation mechanism to restore a functional extremity. The above described neonatal rat model demonstrates a constant anatomy, suitable for nerve transfers and allows all standard neuromuscular analyses. Hence, detailed investigations on the pathophysiological changes and subsequent effects of trauma on the various levels within the neuromuscular system as well as neural reorganization of the neonatal rat may be elucidated. This study was approved by the Ethics Committee of the Medical University of Vienna and the Austrian Ministry for Research and Science (BMWF-66.009/0187-WF/V/3b/2015) on March 20, 2015.

[Endocrine and neuroendocrine tumors]. / Endokrine und neuroendokrine Tumoren.

Endocrine tumors and here in particular gastrointestinal neuroendocrine neoplasms (GEP-NET), pheochromocytomas (PC), paragangliomas (PGL) and thyroid tumors are prime examples of the importance of molecular pathology and molecular biology for the diagnostics, classification and ultimately also the (surgical) treatment of these diseases. The GEP-NETs are graded using the Ki-67 index. This determines the type of molecular imaging (DOTA/DOPA/FDG-PET/CT), the possible treatment (surgical and/or radiopeptide therapy), antiproliferative and symptom-controlling treatment with somatostatin analogues and ultimately also the prognosis. The PC/PGLs can be hereditary (MEN2A, VHL, NF1, SDH mutations), which significantly influences the surgical treatment and preoperative medication. Molecular imaging is very important and can lead the way in cases of borderline biochemistry. Adrenal carcinomas can also be genetically determined. In the case of thyroid tumors, the pathology of the C­cell (C-cell hyperplasia, medullary thyroid carcinoma) should be emphasized. In the case of hereditary diseases (FMTC, MEN2), early prophylactic surgery is often necessary and prevents the occurrence of advanced carcinomas; however, the determination of the extent of resection in follicular lesions or the distinction between noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) and follicular variants of papillary thyroid carcinoma can also be determined with the help of specific markers. Overall, molecular pathology has an increasingly more important role in these entities and is also the topic of ongoing research projects.

A retrospective analysis of venous thromboembolism trends in chemotherapy-induced anemia: Red blood cell transfusion versus erythrocyte stimulating agent administration.

Background: Patients receiving a variety of chemotherapy regimens often develop chemotherapy-induced anemia (CIA), which contributes to poor outcomes including increased mortality. Prompt and effective treatment of CIA is essential to prevent fewer chemotherapy dose delays and reductions. Optimal therapy of CIA is controversial and involves the solitary and combined use of intravenous iron, red blood cell (RBC) transfusions, and erythropoietin stimulating agents (ESAs). Despite the baseline coagulopathies present in patients with malignancy, administration of both RBC transfusions and ESAs is associated with venous thromboembolism (VTE). It remains unknown whether the risk of VTE in patients with CIA is greater among patients who receive RBC transfusions or ESAs. Methods: A retrospective study analyzed 10,269 University of Pennsylvania Health System patients with malignancies of various type, stage, and histopathology who developed CIA between 2008 and 2017. Using multivariate Cox regression, we determined adjusted hazard ratios (and corresponding 95% confidence intervals) of VTE development after adjusting for RBC and ESA intervention (all during the 90 days following CIA diagnosis). Results: Among the 10,269 patients with CIA, 2,642 (25.7%) developed a VTE within the 90-day period. VTE risk following RBC transfusion (HR = 1.37, 95% CI 1.24-1.50, P < .001) was more than twice as common as VTE risk following ESA administration (HR = 0.53, 95% CI 0.40-0.69, P < .001). Conclusion: While both RBC transfusion and ESA are independently associated with VTE, our data suggest a greater risk of VTE development with RBC transfusion as compared with ESA.

Medical, Technical and Audiological Outcomes of Hearing Rehabilitation with the Bonebridge Transcutaneous Bone-Conduction Implant: A Single-Center Experience.

Bone-conduction implants are a standard therapeutic option for patients with conductive, unilateral, or mixed hearing loss who either do not tolerate conventional hearing aids or can benefit from surgery. The aim of this study was to evaluate long-term medical and technical outcomes, and audiological results with the Bonebridge transcutaneous bone-conduction implant. This retrospective study included all patients implanted with a bone-conduction hearing implant at a tertiary medical referral center between March 2012 and October 2018. Medical and technical outcomes included the mean length of implant usage, medical and technical complications (skin and wound infection, lack of benefit, technical failure), explantations and revisions, coupling approaches, implant failure rate, implant survival and the implant loss for added follow-up years. Auditory results were measured by functional hearing gain and the Freiburger monosyllabic test at 65 dB sound pressure level. Sixty-four patients were included in the study; five of these were implanted bilaterally (69 devices). Five unilaterally implanted patients were lost to follow-up. The mean follow-up was 27.1 months (range: 0.2 months-6.3 years). The mean implant usage was 25.9 months (range: 0.2 months-6.3 years). Fifty-seven implants (89.1%) were in use at the end of the follow-up period. Complications occurred in six ears (9.4%). Five implants (7.8%) were explanted without reimplantation. Device failure occurred in one implant (1.6%), which was possibly caused by recurrent head trauma. The rate of implant loss due to technical device failure (damage to device) was 1 per 72 follow-up years. The mean improvement on the Freiburger monosyllabic test (52.1%, p = 0.0001), and in functional hearing gain across frequencies (26.5 dB, p = 0.0001) was significant. This single-center follow-up reveals the medical and technical reliability of a transcutaneous bone-conduction implant for hearing rehabilitation because complication and revision rates were low. The majority of patients still used the device at the end of the observation period. Implantation resulted in favorable hearing outcomes in comparison to that of unaided conditions. Cautious patient selection mainly regarding co-morbidities, the history of chronic otologic diseases and proper surgical technique seems to be crucial in reducing complications.

Inhibition of the transcriptional repressor complex Bcl-6/BCoR induces endothelial sprouting but does not promote tumor growth.

The oncogenic potential of the transcriptional repressor Bcl-6 (B-cell lymphoma 6) was originally discovered in non-Hodgkin patients and the soluble Bcl-6 inhibitor 79-6 was developed to treat diffuse large B-cell lymphomas with aberrant Bcl-6 expression. Since we found Bcl-6 and its co-repressor BCoR (Bcl-6 interacting co-repressor) to be regulated in human microvascular endothelium by colorectal cancer cells, we investigated their function in sprouting angiogenesis which is central to tumor growth. Based on Bcl-6/BCoR gene silencing we found that the transcriptional repressor complex in fact constitutes an endogenous inhibitor of vascular sprouting by supporting the stalk cell phenotype: control of Notch target genes (HES1, HEY1, DLL4) and cell cycle regulators (cyclin A and B1). Thus, when endothelial cells were transiently transfected with Bcl-6 and/or BCoR siRNA, vascular sprouting was prominently induced. Comparably, when the soluble Bcl-6 inhibitor 79-6 was applied in the mouse retina model of physiological angiogenesis, endothelial sprouting and branching were significantly enhanced. To address the question whether clinical treatment with 79-6 might therefore have detrimental therapeutic effects by promoting tumor angiogenesis, mouse xenograft models of colorectal cancer and diffuse large B-cell lymphoma were tested. Despite a tendency to increased tumor vessel density, 79-6 therapy did not enhance tumor expansion. In contrast, growth of colorectal carcinomas was significantly reduced which is likely due to a combined 79-6 effect on cancer cells and tumor stroma. These findings may provide valuable information regarding the future clinical development of Bcl-6 inhibitors.