Specific Hepatic Sphingolipids Relate to Insulin Resistance, Oxidative Stress, and Inflammation in Nonalcoholic Steatohepatitis.

OBJECTIVE: Insulin resistance and nonalcoholic fatty liver disease have been linked to several lipid metabolites in animals, but their role in humans remains unclear. This study examined the relationship of sphingolipids with hepatic and peripheral metabolism in 21 insulin-resistant obese patients without (NAFL-) or with (NAFL+) nonalcoholic fatty liver and nonalcoholic steatohepatitis (NASH) and 7 healthy lean individuals undergoing tissue biopsies during bariatric or elective abdominal surgery. RESEARCH DESIGN AND METHODS: Hyperinsulinemic-euglycemic clamps with d-[6,6-2H2]glucose were performed to quantify tissue-specific insulin sensitivity. Hepatic oxidative capacity, lipid peroxidation, and the phosphorylated-to-total c-Jun N-terminal kinase (pJNK-to-tJNK) ratio were measured to assess mitochondrial function, oxidative stress, and inflammatory activity. RESULTS: Hepatic total ceramides were higher by 50% and 33% in NASH compared with NAFL+ and NAFL-, respectively. Only in NASH were hepatic dihydroceramides (16:0, 22:0, and 24:1) and lactosylceramides increased. Serum total ceramides and dihydroceramides (hepatic dihydroceramides 22:0 and 24:1) correlated negatively with whole-body but not with hepatic insulin sensitivity. Hepatic maximal respiration related positively to serum lactosylceramide subspecies, hepatic sphinganine, and lactosylceramide 14:0. Liver lipid peroxides (total ceramides, sphingomyelin 22:0) and the pJNK-to-tJNK ratio (ceramide 24:0; hexosylceramides 22:0, 24:0, and 24:1) all positively correlated with the respective hepatic sphingolipids. CONCLUSIONS: Sphingolipid species are not only increased in insulin-resistant humans with NASH but also correlate with hepatic oxidative stress and inflammation, suggesting that these lipids may play a role during progression of simple steatosis to NASH in humans.

Adaptation of hepatic mitochondrial function in humans with non-alcoholic fatty liver is lost in steatohepatitis.

The association of hepatic mitochondrial function with insulin resistance and non-alcoholic fatty liver (NAFL) or steatohepatitis (NASH) remains unclear. This study applied high-resolution respirometry to directly quantify mitochondrial respiration in liver biopsies of obese insulin-resistant humans without (n = 18) or with (n = 16) histologically proven NAFL or with NASH (n = 7) compared to lean individuals (n = 12). Despite similar mitochondrial content, obese humans with or without NAFL had 4.3- to 5.0-fold higher maximal respiration rates in isolated mitochondria than lean persons. NASH patients featured higher mitochondrial mass, but 31%-40% lower maximal respiration, which associated with greater hepatic insulin resistance, mitochondrial uncoupling, and leaking activity. In NASH, augmented hepatic oxidative stress (H2O2, lipid peroxides) and oxidative DNA damage (8-OH-deoxyguanosine) was paralleled by reduced anti-oxidant defense capacity and increased inflammatory response. These data suggest adaptation of the liver ("hepatic mitochondrial flexibility") at early stages of obesity-related insulin resistance, which is subsequently lost in NASH.

Prognostic value of a cell-cycle progression score in men with prostate cancer managed with active surveillance after MRI-guided prostate biopsy--a pilot study.

BACKGROUND/AIM: Initial inaccurate staging is a common problem associated with active surveillance (AS) for patients detected by transrectal ultrasound-guided prostate biopsy (TRUS-GB). Subsequently, repeated biopsies are necessary to monitor such patients. Thus, in addition to the already established clinicopathological criteria, there is a considerable demand for new, objective decision criteria to more accurately select AS candidates. Recently, a novel RNA expression signature derived from 31 cell-cycle progression (CCP) genes has been shown to be a strong predictor of outcome in patients after radical prostatectomy or radiotherapy. This is a qualitative pilot study to evaluate the prognostic value of the CCP-score (CCP-S) for the first time in men managed with AS after MRI-guided prostate biopsy (MRI-GB). PATIENTS AND METHODS: Nine patients previously diagnosed with prostate cancer during an ongoing, prospective trial assessing MRI-GB with additional TRUS-GB and were subsequently managed with AS. CCP-S were retrospectively derived from biopsy specimens. The CCP-S is defined as the expression level of 31 CCP genes, normalized to 15 housekeeping genes, and is clinically validated in a range between -1.3 and 4.7. To assess the estimated 10-year mortality risk (without curative treatment), the CCP-S from each patient was combined with the individual CAPRA (Cancer of the Prostate Risk Assessment) score (CAPRA-S). RESULTS: Median patient age was 72 (range=58-77) years. Mean pre-biopsy PSA level was 6.33±1.94 (range 4.23-9.97) ng/ml. Eight cases had Gleason score 6 (3+3) and one cancer had Gleason score 7 (3+4). Median CCP-S was -0.9 (range=-1.5 to 0.0). Combining CCP-S with CAPRA-S [CAPRA-S: 1 (n=4), 2 (n=4), 3 (n=1)] the estimated 10-year mortality risk was not calculable for three patients because their CCP-S [CCP-S -1.4 (n=2) and -1.5 (n=1)] was outside the validated range. For the other 6 patients the estimated 10-year mortality ranged from 1.0-3.0%. CONCLUSION: The CCP-S confirms accurate staging of AS patients detected by MRI-based biopsy strategies and may significantly reduce inaccurate staging of AS patients and subsequent unnecessary re-biopsies. The CCP score may help to more accurately select for active surveillance candidates.

Intrahepatic endometriosis as differential diagnosis: case report and literature review.

Intrahepatic endometriosis is one of the rarest forms of atypical endometriosis; only eighteen cases have been reported in the English literature. We describe the case of a 32-year-old woman, who presented with persistent, non-cyclical upper right quadrant abdominal pain, a central liver cyst, and no history of endometriosis. Three years previous, she was diagnosed with an intrahepatic cyst. The lesion progressed and two laparoscopic deroofing-operations were performed, yet the diagnosis of intrahepatic endometriosis was never reached. She presented in our clinic with further progress of the cyst as well as obstruction of the intrahepatic biliary system. The magnetic resonance imaging showed a 9.5 cm × 12 cm, lobulated intrahepatic cyst. We performed an ultrasonic pericystectomy. Immunostaining confirmed intrahepatic endometriosis. Only one of the previously described eighteen patients with intrahepatic endometriosis presented with cyclical pain in the upper right abdominal quadrant accompanying menstruation. This lack of a "typical" clinic makes it challenging to diagnose extragonadal endometriosis without histopathology. A previous history of endometriosis was described in only twelve cases, thus the diagnosis of this condition should not be limited to patients with a known history of endometriosis. Six of 18 patients were postmenopausal, demonstrating this condition is not limited to women of reproductive age. A preoperative diagnosis was only reached in seven of the previously described cases, highlighting the importance of preoperative biopsies. Yet due to the potential adverse effects, a transhepatic biopsy must be discussed individually. Although rare, intrahepatic endometriosis should always be considered as a differential diagnosis in women with recurrent hepatic cysts, regardless of age or previous medical history. In such cases, histology is essential and a pericystectomy should be performed as standard of care.

Cylindroma of head and neck: review of the literature and report of two rare cases.

Cylindromas are very rare and benign adnexal tumours of the skin. Very few reports of these benign tumours are reported in the literature. Dermal cylindromas are characterised as a benign neoplasm of the eccrine sweat glands. The most frequent location is the head and neck. Multiple occurrences are often linked to the Brooke-Spiegler syndrome. The Brooke-Spiegler syndrome is inherited as an irregular autosomal dominant trait. A malignant transformation to an adenoid cystic carcinoma is also described in the literature. The leading treatment modality described in the literature is the complete surgical removal of the lesions. Here, a systematic review of the literature is presented with two rare cases of cylindromas.

Discovery of TP53 splice variants in two novel papillary urothelial cancer cell lines.

BACKGROUND: Using a novel cell culture technique, we established two new cell lines, BC44 and BC61, from papillary urothelial carcinoma and analyzed them for genetic changes typical of this tumor type. METHODS AND RESULTS: Karyotyping revealed aneuploid karyotypes with loss of chromosome 9 and rearranged chromosome 5p. Molecular analysis showed CDKN2A deletions but wild-type PIK3CA. BC61 contained a G372C FGFR3 mutation. TP53 was not mutated in either cell line and BC61 expressed normal full-length protein. In contrast, BC44 exclusively expressed cytoplasmic and nuclear p53Δ40 and 133 isoforms from the alternative promoter P2 as revealed by Western blotting, immunocytochemistry and PCR. The only discernible difference in TP53 in BC44 was homozygosity for the deletion allele of the rs17878362 polymorphism in the P2 promoter. Expression of p53 isoforms was also detected in a few other urothelial carcinoma cell lines and tumor cultures and in 4 out of 28 carcinoma tissues. CONCLUSION: In urothelial cancers, TP53 is typically inactivated by mutations in one allele and loss of the wildtype allele and more frequently in invasive compared to papillary carcinomas. We show that some urothelial carcinomas may predominantly or exclusively express isoforms which are not detected by commonly used antibodies to epitopes located in the p53 TA amino-terminal region. Expression of these isoforms may constitute a further mode of p53 inactivation in urothelial carcinoma. Our findings raise the question to which extent this mechanism may compromise wildtype p53 function in papillary tumors in particular, where point mutations in the gene are rare.