Histopathology of Hepatic Sinusoidal Obstruction Syndrome After Neoadjuvant Oxaliplatin-Based Chemotherapy

Sinusoidal obstruction syndrome („blue liver syndrome“) has been frequently associated with oxaliplatin-based neoadjuvant chemotherapy in patients with colorectal liver metastasis. Hepatotoxic vascular lesions in the nontumourous liver parenchyma result in hypoperfusion and tissue hypoxia leading to lower tumour response to oncologic treatment and to increase the risk of liver metastasectomies. Furthermore, hepatic parenchyma injuries could be aggravated by hepatic resection itself. Contrary to standard surgical techniques, radiofrequency assisted liver resection significantly reduce harmful intraoperative blood loss and perfusion-reperfusion effects. We compared histological alterations in 59 specimens of bloodless radiofrequency-assisted liver recetions made for colorectal metastases to those in 38 specimens of standard liver resections. In general, the main histologic alterations in both examined groups related to oxaliplatin include SOS lesions (69.35%), fibrosis (50.95%) and steatosis (38%). After scoring of histopathological parameters based on modified criteria according to Rubbia-Brandt et al., they were statistically insignificant between both groups for portal and/or porto-portal fibrosis (59.3% vs 47.4%, respectively) and moderate/severe macrovacuolar steatosis (10.2% vs 26.3%). Similar distribution between groups was shown for surgical hepatitis with „borderline“ statistical significance (23,7% vs 42,1%, p= 0.05). However, there were significant differencies in vascular lesions, particularly for hemorrhagic centrilobular necrosis (10,2% vs 31,5%, p= 0.01) and peliosis (15,2% vs 36,8%, p= 0.04), but were not significant for sinusoidal dilatation and congestion as well as surgical necrosis. Highgrade vascular lesions such as hemorrhagic centrilobular necrosis and peliosis are less frequent in cases of radiofrequency-assisted liver recetions and might be associated with better clinical outcome in these patients.

Zederone, a Sesquiterpene from Curcuma elata Roxb, is Hepatotoxic in Mice

The present study aimed to investigate the hepatotoxicity of zederone isolated from Curcuma elata in mice. Adult male mice were intraperitoneally injected with a single dose of zederone (50-300 mg/kg body weight [BW]). Twenty-four hours after the injection, zederone induced liver enlargement with scattered white foci over the organ. The medium lethal dose (LD50) value at 24 hours of zederone was approximately 223 mg/kg BW. Hepatic centrilobular necrosis with marked increases in plasma alanine transaminase activity and total bilirubin levels was observed. Zederone at a dose of 200 mg/kg BW markedly decreased the activity of superoxide dismutase and the hepatic glutathione content, whereas the activity of catalase was not altered. The compound at this dose also increased the messenger RNA (mRNA) expression of Cyp2b10 and Cyp3a11, which are the main drug-metabolizing enzymes in the liver. The mRNA expression of proinflammatory cytokine tumor necrosis factor α was increased. The nuclear factor-E2-related factor 2 protein, which is the transcription factor regulating the antioxidant gene expression, was decreased. The histopathology of massive hepatic centrilobular necrosis with an increase in the expression of cytochrome P450 (Cyp) suggests that the possible potentiation of zederone-induced hepatotoxicity implicated the induction of Cyps, which leads to the formation of biological reactive metabolites and that cause the oxidative stress and liver cell injuries.

CLUSTERING OF GENE EXPRESSION DATA AND END-POINT MEASUREMENTS BY SIMULATED ANNEALING

Most clustering techniques do not incorporate phenotypic data. Limited biological interpretation is garnered from the informal process of clustering biological samples and then labeling groups with the phenotypes of the samples. A more formal approach of clustering samples is presented. The method utilizes simulated annealing of the Modk-prototypes objective function. Separate weighting terms are used for microarray, clinical chemistry, and histopathology measurements to control the influence of each data domain on the clustering of the samples. The weights are adapted during the clustering process. A cluster's prototype is representative of the phenotype of the cluster members. Genes are extracted from phenotypic prototypes obtained from the livers of rats exposed to acetaminophen (an analgesic and antipyretic agent) that differed in the extent of centrilobular necrosis. Map kinase signaling and linoleic acid metabolism were significant biological processes influenced by the exposures of acetaminophen that manifested centrilobular necrosis.