Pancreatic Atrophy in Hepatocellular Carcinoma Patients Receiving Long-Term Treatment with Sorafenib

Objective: To date, sorafenib is the only approved systemic therapy for advanced hepatocellular carcinoma (HCC). Pancreatic atrophy has recently been reported in 2 patients as a novel side effect after long-term sorafenib treatment. Methods: We retrospectively analyzed clinical and radiological data of patients with advanced HCC with long-term treatment of sorafenib (median 279 days, range 153–826 days). Pancreata were semi-manually segmented section by section to calculate the pancreas volumes before and under sorafenib treatment. Results: Sorafenib reduced pancreatic volume in 18/19 (95%) HCC patients with a mean pancreatic volume loss of 25% (p = 0.002). Pancreatic volume loss depended on the dose (r = 0.36) and exposure time of sorafenib (r = 0.35) and was detectable as early as after 3 months of sorafenib treatment and already after a cumulative sorafenib dose of <100 g. Median overall survival was 13.2 months (range 7.8–31.3 months) but did not correlate with sorafenibinduced pancreatic volume reduction (hazard ratio 1.002, 95% confidence interval 0.981–1.060, p = 0.24). Conclusion: We could confirm pancreatic atrophy as a novel adverse event of sorafenib therapy in HCC patients, correlating with sorafenib dose and exposure time

Orthotopic liver transplantation in human-immunodeficiency-virus-positive patients in Germany

Objectives: This summary evaluates the outcomes of orthotopic liver transplantation (OLT) of HIV-positive patients in Germany. Methods: Retrospective chart analysis of HIV-positive patients, who had been liver-transplanted in Germany between July 1997 and July 2011. Results: 38 transplantations were performed in 32 patients at 9 German transplant centres. The reasons for OLT were end-stage liver disease (ESLD) and/or liver failure due to hepatitis C (HCV) (n = 19), hepatitis B (HBV) (n = 10), multiple viral infections of the liver (n = 2) and Budd-Chiari-Syndrome. In July 2011 19/32 (60%) of the transplanted patients were still alive with a median survival of 61 months (IQR (interquartile range): 41-86 months). 6 patients had died in the early post-transplantation period from septicaemia (n = 4), primary graft dysfunction (n = 1), and intrathoracal hemorrhage (n = 1). Later on 7 patients had died from septicaemia (n = 2), delayed graft failure (n = 2), recurrent HCC (n = 2), and renal failure (n = 1). Recurrent HBV infection was efficiently prevented in 11/12 patients; HCV reinfection occurred in all patients and contributed considerably to the overall mortality. Conclusions: Overall OLT is a feasible approach in HIV-infected patients with acceptable survival rates in Germany. Reinfection with HCV still remains a major clinical challenge in HIV/HCV coinfection after OLT

Impact of neo-adjuvant Sorafenib treatment on liver transplantation in HCC patients - a prospective, randomized, double-blind, phase III trial

Background: Liver Transplantation (LT) is treatment of choice for patients with hepatocellular carcinoma (HCC) within MILAN Criteria. Tumour progression and subsequent dropout from waiting list have significant impact on the survival. Transarterial chemoembolization (TACE) controls tumour growth in the treated HCC nodule, however, the risk of tumour development in the untreated liver is increased by simultaneous release of neo-angiogenic factors. Due to its anti-angiogenic effects, Sorafenib delays the progression of HCC. Aim of this study was to determine whether combination of TACE and Sorafenib improves tumour control in HCC patients on waiting list for LT. Methods: Fifty patients were randomly assigned on a 1:1 ratio in double-blinded fashion at four centers in Germany and treated with TACE plus either Sorafenib (n = 24) or placebo (n = 26). The end of treatment was development of progressive disease according to mRECIST criteria or LT. The primary endpoint of the trial was the Time-to-Progression (TTP). Other efficacy endpoints were Tumour Response, Progression-free Survival (PFS), and Time-to-LT (TTLT). Results: The median time of treatment was 125 days with Sorafenib and 171 days with the placebo. Fourteen patients (seven from each group) developed tumour progression during the course of the study period. The Hazard Ratio of TTP was 1.106 (95% CI: 0.387, 3.162). The results of the Objective Response Rate, Disease Control Rate, PFS, and TTLT were comparable in both groups. The incidence of AEs was comparable in the placebo group (n = 23, 92%) and in the Sorafenib group (n = 23, 96%). Twelve patients (50%) on Sorafenib and four patients (16%) on placebo experienced severe treatment-related AEs. Conclusion: The TTP is similar after neo-adjuvant treatment with TACE and Sorafenib before LT compared to TACE and placebo. The Tumour Response, PFS, and TTLT were comparable. The safety profile of the Sorafenib group was similar to that of the placebo group. Trial registration: ISRCTN2408179

Модернизация автоматизированной системы блока стабилизации давления магистрального насосного агрегата на нефтеперекачивающей станции

Объектом исследования является блок стабилизации давления магистрального насосного агрегата. Цель работы – модернизация автоматизированной системы блока стабилизации давления магистрального трубопровода нефтеперекачивающей станции с использованием ПЛК, на основе выбранной SCADA-системы. В данном проекте была разработана система контроля и управления технологическим процессом на базе промышленных контроллеров Modicon M340 BMXP34 2020, с применением SCADA-системы.The object of investigation is the pressure stabilization unit of the main pump unit. The purpose of the work is the modernization of the automated system for stabilizing the pressure of the main pipeline of the oil pumping station using PLCs, based on the SCADA system chosen. In this project, a system for monitoring and controlling the process was developed on the basis of industrial controllers Modicon M340 BMXP34 2020, using a SCADA system

Sirolimus Use in Liver Transplant Recipients With Hepatocellular Carcinoma : A Randomized, Multicenter, Open-Label Phase 3 Trial

Background We investigated whether sirolimus-based immunosuppression improves outcomes in liver transplantation (LTx) candidates with hepatocellular carcinoma (HCC). Methods In a prospective-randomized open-label international trial, 525 LTx recipients with HCC initially receiving mammalian target of rapamycin inhibitor-free immunosuppression were randomized 4 to 6 weeks after transplantation into a group on mammalian target of rapamycin inhibitor-free immunosuppression (group A: 264 patients) or a group incorporating sirolimus (group B: 261). The primary endpoint was recurrence-free survival (RFS); intention-to-treat (ITT) analysis was conducted after 8 years. Overall survival (OS) was a secondary endpoint. Results Recurrence-free survival was 64.5% in group A and 70.2% in group B at study end, this difference was not significant (P = 0.28; hazard ratio [HR], 0.84; 95% confidence interval [95% CI], 0.62; 1.15). In a planned analysis of RFS rates at yearly intervals, group B showed better outcomes 3 years after transplantation (HR, 0.7; 95% CI, 0.48-1.00). Similarly, OS (P = 0.21; HR, 0.81; 95% CI, 0.58-1.13) was not statistically better in group B at study end, but yearly analyses showed improvement out to 5 years (HR, 0.7; 95% CI, 0.49-1.00). Interestingly, subgroup (Milan Criteria-based) analyses revealed that low-risk, rather than high-risk, patients benefited most from sirolimus; furthermore, younger recipients (age 60) also benefited, as well sirolimus monotherapy patients. Serious adverse event numbers were alike in groups A (860) and B (874). Conclusions Sirolimus in LTx recipients with HCC does not improve long-term RFS beyond 5 years. However, a RFS and OS benefit is evident in the first 3 to 5 years, especially in low-risk patients. This trial provides the first high-level evidence base for selecting immunosuppression in LTx recipients with HCC.Peer reviewe

Phase i study evaluating the treatment of patients with hepatocellular carcinoma (HCC) with carbon ion radiotherapy: The PROMETHEUS-01 trial

Abstract Background Treatment options for patients with advanced hepatocellular carcinoma (HCC) are often limited. In most cases, they are not amenable to local therapies including surgery or radiofrequency ablation. The multi-kinase inhibitor sorafenib has shown to increase overall survival in this patient group for about 3 months. Radiation therapy is a treatment alternative, however, high local doses are required for long-term local control. However, due to the relatively low radiation tolerance of liver normal tissue, even using stereotactic techniques, delivery of sufficient doses for successful local tumor control has not be achieved to date. Carbon ions offer physical and biological characteristics. Due to their inverted dose profile and the high local dose deposition within the Bragg peak precise dose application and sparing of normal tissue is possible. Moreover, in comparison to photons, carbon ions offer an increased relative biological effectiveness (RBE), which can be calculated between 2 and 3 depending on the HCC cell line as well as the endpoint analyzed. Japanese Data on the evaluation of carbon ion radiation therapy showed promising results for patients with HCC. Methods/Design In the current Phase I-PROMETHEUS-01-Study, carbon ion radiotherapy will be evaluated for patients with advanced HCC. The study will be performed as a dose-escalation study evaluating the optimal carbon ion dose with respect to toxicity and tumor control. Primary endpoint is toxicity, secondary endpoint is progression-free survival and response. Discussion The Prometheus-01 trial ist the first trial evaluating carbon ion radiotherapy delivered by intensity-modulated rasterscanning for the treatment of HCC. Within this Phase I dose escalation study, the optimal dose of carbon ion radiotherapy will be determined. Trial registration NCT 01167374</p