Loss of sphingosine kinase-1 in carcinoma cells increases formation of reactive oxygen species and sensitivity to doxorubicin-induced DNA damage

Sphingosine kinases (SK) catalyse the formation of sphingosine 1-phosphate, which is a key lipid mediator regulating cell responses such as proliferation, survival and migration. Here we have investigated the effect of targeted inhibition of SK-1 on cell damage and elucidated the mechanisms involved.

The essential role of radiotherapy in the treatment of Merkel cell carcinoma: a study from the Rare Cancer Network

To evaluate the role of postoperative radiotherapy (RT) in Merkel cell carcinoma (MCC).

Feasibility of image-guided radiotherapy based on tomotherapy for the treatment of locally advanced anal carcinoma

The standard of care for locally advanced anal cancer has been concurrent chemoradiation. However, conventional treatment with 3-dimensional radiotherapy is associated with significant toxicity. The feasibility of new radiotherapy techniques such as image-guided radiotherapy (IGRT) in combination with chemotherapy for the treatment of this malignancy was assessed.

Inhibition of SIRT1 Impairs the Accumulation and Transcriptional Activity of HIF-1α Protein under Hypoxic Conditions

Sirtuins and hypoxia-inducible transcription factors (HIF) have well-established roles in regulating cellular responses to metabolic and oxidative stress. Recent reports have linked these two protein families by demonstrating that sirtuins can regulate the activity of HIF-1 and HIF-2. Here we investigated the role of SIRT1, a NAD+-dependent deacetylase, in the regulation of HIF-1 activity in hypoxic conditions. Our results show that in hepatocellular carcinoma (HCC) cell lines, hypoxia did not alter SIRT1 mRNA or protein expression, whereas it predictably led to the accumulation of HIF-1α and the up-regulation of its target genes. In hypoxic models in vitro and in in vivo models of systemic hypoxia and xenograft tumor growth, knockdown of SIRT1 protein with shRNA or inhibition of its activity with small molecule inhibitors impaired the accumulation of HIF-1α protein and the transcriptional increase of its target genes. In addition, endogenous SIRT1 and HIF-1α proteins co-immunoprecipitated and loss of SIRT1 activity led to a hyperacetylation of HIF-1α. Taken together, our data suggest that HIF-1α and SIRT1 proteins interact in HCC cells and that HIF-1α is a target of SIRT1 deacetylase activity. Moreover, SIRT1 is necessary for HIF-1α protein accumulation and activation of HIF-1 target genes under hypoxic conditions.

The impact of frozen sections on final surgical margins in squamous cell carcinoma of the oral cavity and lips: a retrospective analysis over an 11 years period

Taking intraoperative frozen sections (FS) is a widely used procedure in oncologic surgery. However so far no evidence of an association of FS analysis and premalignant changes in the surgical margin exists. Therefore, the aim of this study was to evaluate the impact of FS on different categories of the final margins of squamous cell carcinoma (SCC) of the oral cavity and lips.

Antegrade perfusion with bacillus Calmette-Guérin in patients with non-muscle-invasive urothelial carcinoma of the upper urinary tract: who may benefit?

There is paucity of data on bacillus Calmette-Guérin (BCG) perfusion in patients with non-muscle-invasive urothelial carcinoma (NMIUC) of the upper urinary tract (UUT).

Prognostic value of microvascular invasion in predicting the cancer specific survival and risk of metastatic disease in renal cell carcinoma: a multicenter investigation

While microvascular invasion is an accepted risk factor in various cancers, its prognostic role in renal cell carcinoma is still unclear. Therefore, a large multicenter study examining the experience of 5 international institutions was performed to evaluate the prognostic value of microvascular invasion in the occurrence of metastases and cancer specific survival.

Smoking negatively impacts renal cell carcinoma overall and cancer-specific survival

Tobacco use is a leading cause of premature death, yet few studies have investigated the effect of tobacco exposure on the outcome of patients with renal cell carcinoma (RCC). The authors of this report retrospectively studied the impact of smoking on clinicopathologic factors, survival outcomes, and p53 expression status in a large cohort of patients with RCC.

Comparative effectiveness of cisplatin-based and carboplatin-based chemotherapy for treatment of advanced urothelial carcinoma

Cisplatin-based chemotherapy is a standard treatment of metastatic urothelial carcinoma (UC), though carboplatin-based chemotherapy is frequently substituted due to improved tolerability. Because comparative effectiveness in clinical outcomes of cisplatin- versus carboplatin-based chemotherapy is lacking, a meta-analysis was carried out.

Lymph node dissection in renal cell carcinoma

Although lymphadenectomy (lymph node dissection [LND]) is currently accepted as the most accurate and reliable staging procedure for the detection of lymph node invasion (LNI), its therapeutic benefit in renal cell carcinoma (RCC) still remains controversial.

Expression patterns of Bmi-1 and p16 significantly correlate with overall, disease-specific, and recurrence-free survival in oropharyngeal squamous cell carcinoma

BACKGROUND: The objective of this study was to link expression patterns of B-cell-specific Moloney murine leukemia virus integration site 1 (Bmi-1) and p16 to patient outcome (recurrence and survival) in a cohort of 252 patients with oral and oropharyngeal squamous cell cancer (OSCC). METHODS: Expression levels of Bmi-1 and p16 in samples from 252 patients with OSCC were evaluated immunohistochemically using the tissue microarray method. Staining intensity was determined by calculating an intensity reactivity score (IRS). Staining intensity and the localization of expression within tumor cells (nuclear or cytoplasmic) were correlated with overall, disease-specific, and recurrence-free survival. RESULTS: The majority of cancers were localized in the oropharynx (61.1%). In univariate analysis, patients who had OSCC and strong Bmi-1 expression (IRS >10) had worse outcomes compared with patients who had low and moderate Bmi-1 expression (P = .008; hazard ratio [HR], 1.82; 95% confidence interval [CI], 1.167-2.838); this correlation was also observed for atypical cytoplasmic Bmi-1 expression (P = .001; HR, 2.164; 95% CI, 1.389-3.371) and for negative p16 expression (P < .001; HR, 0.292; 95% CI, 0.178-0.477). The combination of both markers, as anticipated, had an even stronger correlation with overall survival (P < .001; HR, 8.485; 95% CI, 4.237-16.994). Multivariate analysis demonstrated significant results for patients with oropharyngeal cancers, but not for patients with oral cavity tumors: Tumor classification (P = .011; HR, 1.838; 95%CI, 1.146-2.947) and the combined marker expression patterns (P < .001; HR, 6.254; 95% CI, 2.869-13.635) were correlated with overall survival, disease-specific survival (tumor classification: P = .002; HR, 2.807; 95% CI, 1.477-5.334; combined markers: P = .002; HR, 5.386; 95% CI, 1.850-15.679), and the combined markers also were correlated with recurrence-free survival (P = .001; HR, 8.943; 95% CI, 2.562-31.220). CONCLUSIONS: Cytoplasmic Bmi-1 expression, an absence of p16 expression, and especially the combination of those 2 predictive markers were correlated negatively with disease-specific and recurrence-free survival in patients with oropharyngeal cancer. Therefore, the current results indicate that these may be applicable as predictive markers in combination with other factors to select patients for more aggressive treatment and follow-up. Cancer 2011;. © 2011 American Cancer Society.

IL28B alleles associated with poor hepatitis C virus (HCV) clearance protect against inflammation and fibrosis in patients infected with non-1 HCV genotypes

Genetic polymorphisms near IL28B are associated with spontaneous and treatment-induced clearance of hepatitis C virus (HCV), two processes that require the appropriate activation of the host immune responses. Intrahepatic inflammation is believed to mirror such activation, but its relationship with IL28B polymorphisms has yet to be fully appreciated. We analyzed the association of IL28B polymorphisms with histological and follow-up features in 2335 chronically HCV-infected Caucasian patients. Assessable phenotypes before any antiviral treatment included necroinflammatory activity (n = 1,098), fibrosis (n = 1,527), fibrosis progression rate (n = 1,312), and hepatocellular carcinoma development (n = 1,915). Associations of alleles with the phenotypes were evaluated by univariate analysis and multivariate logistic regression, accounting for all relevant covariates. The rare G allele at IL28B marker rs8099917-previously shown to be at risk of treatment failure-was associated with lower activity (P = 0.04), lower fibrosis (P = 0.02) with a trend toward lower fibrosis progression rate (P = 0.06). When stratified according to HCV genotype, most significant associations were observed in patients infected with non-1 genotypes (P = 0.003 for activity, P = 0.001 for fibrosis, and P = 0.02 for fibrosis progression rate), where the odds ratio of having necroinflammation or rapid fibrosis progression for patients with IL28B genotypes TG or GG versus TT were 0.48 (95% confidence intervals 0.30-0.78) and 0.56 (0.35-0.92), respectively. IL28B polymorphisms were not predictive of the development of hepatocellular carcinoma.

[Liver transplantation - when and for whom it should be performed]

During the past two decades, orthotopic liver transplantation (OLT) emerged to the treatment of choice for patients with end-stage liver disease. In Switzerland, about 100 liver transplantations are performed every year, while the shortage of cadaveric organs considerably outmatches the demand. Common indications for OLT include cirrhosis due to alcoholic liver disease or chronic viral hepatitis related to hepatitis B or C, and hepatocellular carcinoma. With the advent of the new allocation policy in Switzerland in 2007, patients listed for OLT are mainly stratified based on the Model of End-stage Liver Disease (MELD) score. Using a patient's laboratory values for serum bilirubin, serum creatinin, and the international normalized ratio for prothrombin time (INR), the MELD score accurately predicts three-month mortality among patients on the waiting list. Compared to the pre-MELD era, patients with significantly higher MELD scores undergo transplantation which leads in turn to more complications and higher costs yet with a comparable outcome. Timely referral of potential candidates to a transplant center is crucial since thorough evaluation to rule out contraindications such as uncontrolled infection, extrahepatic malignancy or advanced cardiopulmonary disease is essential. Taken together, every patient presenting with acute liver failure, decompensated cirrhosis or suspected hepatocellular carcinoma should be evaluated in a center with liver transplantation capability.

Biomarkers for Hepatocellular Apoptosis in the Management of Liver Diseases

Apoptosis is a rare event in normal hepatocytes. However, multiple signals can trigger apoptosis in hepatocytes and it plays a role in the pathogenesis of many liver diseases. This review summarizes the mechanisms of hepatocellular apoptosis and the importance of apoptosis in the pathological processes of liver disease. The potential for non-invasive biomarkers of apoptosis to gauge the extent and follow the evolution of clinical disease is emphasized.

[Non-alcoholic steatohepatitis - from NAFLD to MAFLD]

Non-alcoholic steatohepatitis (NASH) as one entity of non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome and accompanies the rise in the prevalence of obesity, diabetes mellitus, hypertension and hyperlipidemia in the western world. It is not known why some patients progress in the disease and develop inflammation in the liver, whereas others remain in the stage of simple steatosis, which generally has a benign course. However, NASH can progress to fibrosis and cirrhosis as well as hepatocellular carcinoma. Therefore, it is important to determine the stage of the disease in patients presenting with the metabolic syndrome and abnormal liver function tests, suggesting NAFLD. Liver biopsy is the only tool that allows for reliable detection, grading and staging of liver disease. The main strategies in the treatment of NASH are correction of risk factors (lifestyle modifications, insuline sensitizer) and anti-oxidants (ursodeoxycholic acid, vitamin E) which both have been shown to improve liver histology as well as liver enzymes. Patients wih alcoholic fatty liver disease (AFLD) present the same liver histology and often also metabolic alterations similar to metabolic syndrome. Therefore, MAFLD (metabolic syndrome-associated fatty liver disease) might describe both patient populations more accurately and also describes the pathophysiological characteristics.