Improved survival prediction and comparison of prognostic models for patients with hepatocellular carcinoma treated with sorafenib.

BACKGROUND: The 'Prediction Of Survival in Advanced Sorafenib-treated HCC' (PROSASH) model addressed the heterogeneous survival of patients with hepatocellular carcinoma (HCC) treated with sorafenib in clinical trials but requires validation in daily clinical practice. This study aimed to validate, compare and optimize this model for survival prediction. METHODS: Patients treated with sorafenib for HCC at five tertiary European centres were retrospectively staged according to the PROSASH model. In addition, the optimized PROSASH-II model was developed using the data of four centres (training set) and tested in an independent dataset. These models for overall survival (OS) were then compared with existing prognostic models. RESULTS: The PROSASH model was validated in 445 patients, showing clear differences between the four risk groups (OS 16.9-4.6 months). A total of 920 patients (n = 615 in training set, n = 305 in validation set) were available to develop PROSASH-II. This optimized model incorporated fewer and less subjective parameters: the serum albumin, bilirubin and alpha-foetoprotein, and macrovascular invasion, extrahepatic spread and largest tumour size on imaging. Both PROSASH and PROSASH-II showed improved discrimination (C-index 0.62 and 0.63, respectively) compared with existing prognostic scores (C-index ≤0.59). CONCLUSIONS: In HCC patients treated with sorafenib, individualized prediction of survival and risk group stratification using baseline prognostic and predictive parameters with the PROSASH model was validated. The refined PROSASH-II model performed at least as good with fewer and more objective parameters. PROSASH-II can be used as a tool for tailored treatment of HCC in daily practice and to define pre-planned subgroups for future studies.

Seasonal variability of vitamin D status in patients with inflammatory bowel disease - A retrospective cohort study.

OBJECTIVES: Vitamin D deficiency predicts unfavorable disease outcomes in inflammatory bowel disease. Endogenous vitamin D synthesis is affected by seasonal factors including sunlight exposure, raising the question whether seasonality determines the risk of vitamin D deficiency and may mask other clinical risk factors. METHODS: Univariable and multiple regression analyses were performed in a retrospective cohort of 384 patients to determine risk factors for vitamin D deficiency. Since the observed 25-hydroxyvitamin D [25(OH)D] concentrations followed a sinusoidal pattern over the year, all 25(OH)D concentrations were normalized for the predicted variability of the respective day of analysis based on a sinusoidal regression analysis of 25(OH)D test results obtained in more than 86,000 control serum samples. RESULTS: Vitamin D deficiency was highly prevalent in patients with Crohn's disease or ulcerative colitis (63% and 55%, respectively) and associated with winter/spring seasons. After normalization of 25(OH)D concentrations for the day of analysis, vitamin D deficiency was associated with histories of complications related to inflammatory bowel disease, surgery, smoking and ongoing diarrhea while initial disease manifestation during adulthood, ongoing vitamin D supplementation and diagnosis of ulcerative colitis vs. Crohn's disease appeared to be protective. Multiple regression analyses revealed that vitamin D deficiency was associated with disease activity in Crohn's disease and anemia in ulcerative colitis patients. Only few deficient patients achieved sufficient 25(OH)D concentrations over time. However, increasing 25(OH)D concentrations correlated with improved Crohn's disease activity. CONCLUSIONS: Vitamin D deficiency was highly prevalent in patients with Crohn's disease and ulcerative colitis and dependent on the season of the year. Following normalization for seasonality by sinusoidal regression analysis, vitamin D deficiency was found to be associated with parameters of complicated disease course while increasing 25(OH)D concentrations over time correlated with reduced activity of Crohn's disease.

[Hepatocellular Carcinoma: New multimodal therapy concepts]. / Hepatozelluläres Karzinom: neue multimodale Therapiekonzepte.

STATUS QUO: Hepatocellular carcinoma guidelines are currently under revision. A new edition is expected in 2018. Patients with chronic liver diseases or cirrhosis require HCC screening by ultrasound every 6 months. Surgical resection or liver transplantation are curative treatment options for early stage HCC. LOCOREGIONAL THERAPY APPROACHES: A more and more common and well tolerated locoregional therapy approach based on study data is selective internal radio therapy (SIRT), although studies did not show an improvement in outcome comparing SIRT to transarterial chemotherapy (TACE) in BCLC B or sorafenib in BCLC C. SYSTEMIC THERAPY APPROACHES: Looking at targeted therapies regorafenib is approved for patients under treatment with sorafenib and disease progression as a second line therapy. Positive phase III-study data have been published for lenvatinib as first-line and cabozantinib as second-line therapy. Nivolumab was approved by the FDA as second-line therapy after positive phase I/II-study outcomes. A study on nivolumab versus sorafenib as first-line therapy will be published in 2018.

The lack of the organic cation transporter OCT1 at the plasma membrane of tumor cells precludes a positive response to sorafenib in patients with hepatocellular carcinoma.

BACKGROUND: Sorafenib is the drug of choice in the treatment of advanced hepatocellular carcinoma (HCC). Beneficial effects are limited by mechanisms of chemoresistance, which include downregulation and/or impaired function of plasma membrane transporters accounting for drug uptake. The organic cation transporter 1 (OCT1) plays a major role in sorafenib uptake and decreased expression in HCC has been associated with poorer response. METHODS: The multicenter retrospective TRANSFER study involved tumor biopsies from 39 patients with advanced HCC and sorafenib therapy for ≥4 wk. Endpoint was the relationship between clinicopathological features and immunohistological result. Immunostaining was performed using specific primary anti-OCT1-head and anti-OCT1-tail antibodies. Tumors were classified according to a simplified staining score as absent, weak, moderate or strong, taking into account the localization of the staining at the plasma membrane as positive or negative. RESULTS: Results confirmed OCT1 downregulation in half of the cases investigated (10% absent, 38% weak). However, only one third of tumors expressing OCT1 displayed plasma membrane location (15% vs. 36% cytosolic expression). When comparing HCC with and without OCT1 expression, no different sorafenib response was found. When tumors expressing OCT1 at the plasma membrane were considered separately, a marked longer survival was found (Log Rank p<0.001). No association between OCT1 expression at the plasma membrane with tumor stage, previous treatment with TACE or radiological response was seen.In conclusion, these results indicate that the presence of OCT1 at the plasma membrane, rather than its expression levels, is related to better outcome of HCC patients treated with sorafenib.

[Hepatocellular Carcinoma: therapeutic options 2015]. / Das hepatozelluläre Karzinom--Therapieoptionen 2015.

The incidence of hepatocellular carcinoma (HCC), a common neoplasm, is rising and the prognosis is poor. Many factors have to be taken into account when deciding on the best mode of therapy, like tumor size and number, liver function, sequelae of portal hypertension or other comorbidities. These factors are reflected in the Barcelona Clinic Liver Cancer (BCLC) classification. Resection, radiofrequency ablation (RFA) and liver transplantation can be seen as curative therapies for the early and localized HCC. For the intermediate state of the HCC, there are other therapeutic modalities in therapy available: transarterial chemoembolization (TACE), selective internal radiation therapy (SIRT, rarer occasions), off label: stereotactic body radiation therapy (SBRT). At the moment, Sorafenib is the only option in treating advanced stages of HCC. Alternative treatment strategies, like e.g. immunological therapies, are being investigated.