Coleus vettiveroides ethanolic root extract induces cytotoxicity by intrinsic apoptosis in HepG2 cells.

Hepatocellular carcinoma (HCC) contributes to more than 80% of all primary cancers globally and ranks fourth in cancer-related deaths, due to the lack of an effective, definite therapeutic drug. Coleus vettiveroides (CV) has been used in Indian traditional medicine to treat diabetes, liver ailments, skin diseases, leukoderma, and leprosy. This study investigates the anticancer effect of CV ethanolic root extract in HepG2 cells. HepG2 cells were treated with CV extract, and its cytotoxicity was analyzed by MTT assay. AO/EB staining, propidium iodide staining, DCFH-DA assay, phalloidine staining, flow cytometry, and qPCR studies were performed for ROS expression, apoptosis and cell cycle analysis. The phytochemical analysis confirmed the presence of quercetin and galangin in CV root extract. The results showed that CV inhibited the proliferation of HepG2 cells, with altered cellular and nuclear morphology. CV was also found to increase intracellular ROS levels and oxidative stress markers in HepG2 cells. CV significantly altered the actin microfilament distribution in HepG2 cells and caused cell cycle arrest at the sub G0 -G1 phase. CV also induced mitochondria-mediated apoptosis, as evidenced by increased expression of p53, Bax, cytochrome C, Apaf-1, PARP, caspase-3 and caspase-9, and downregulated Bcl-2 expression. Therefore, CV exerts its anticancer effect by inducing mitochondrial dysfunction, oxidative stress, cytoskeletal disorganization, cell cycle arrest, and mitochondria-mediated apoptosis, and it could be a potent therapeutic option for HCC.

Glucagonoma syndrome with atypical necrolytic migratory erythema.

Necrolytic migratory erythema is most commonly associated with glucagonoma syndrome. We report a rare case of glucagonoma syndrome with necrolytic migratory erythema presenting as pruritic papules and follicular pustules in a 57-year-old woman; showing eosinophilic infiltration on histology. However, the final diagnosis was confirmed by demonstrating neuroendocrine tumour on histopathological examination of the liver metastases. Nutrition therapy was administered as a palliative treatment. This case also highlights the atypical clinical features and nonspecific histology of necrolytic migratory erythema which makes the diagnosis difficult.

Identification of novel chemotherapeutic strategies for metastatic uveal melanoma.

Melanoma of the uveal tract accounts for approximately 5% of all melanomas and represents the most common primary intraocular malignancy. Despite improvements in diagnosis and more effective local therapies for primary cancer, the rate of metastatic death has not changed in the past forty years. In the present study, we made use of bioinformatics to analyze the data obtained from three public available microarray datasets on uveal melanoma in an attempt to identify novel putative chemotherapeutic options for the liver metastatic disease. We have first carried out a meta-analysis of publicly available whole-genome datasets, that included data from 132 patients, comparing metastatic vs. non metastatic uveal melanomas, in order to identify the most relevant genes characterizing the spreading of tumor to the liver. Subsequently, the L1000CDS2 web-based utility was used to predict small molecules and drugs targeting the metastatic uveal melanoma gene signature. The most promising drugs were found to be Cinnarizine, an anti-histaminic drug used for motion sickness, Digitoxigenin, a precursor of cardiac glycosides, and Clofazimine, a fat-soluble iminophenazine used in leprosy. In vitro and in vivo validation studies will be needed to confirm the efficacy of these molecules for the prevention and treatment of metastatic uveal melanoma.

PARK2 polymorphisms predict disease progression in patients infected with hepatitis C virus.

 Background. The protein encoded by PARK2 gene is a component of the ubiquitin-proteasome system that mediates targeting of proteins for the degradation pathway. Genetic variations at PARK2 gene were linked to various diseases including leprosy, typhoid and cancer. The present study investigated the association of single nucleotide polymorphisms (SNPs) in the PARK2 gene with the development of hepatitis C virus (HCV) infection and its progression to severe liver diseases. MATERIAL AND METHODS: A total of 800 subjects, including 400 normal healthy subjects and 400 HCV-infected patients, were analyzed in this study. The patients were classified as chronic HCV patients (group I), patients with cirrhosis (group II) and patients with hepatocellular carcinoma (HCC) in the context of cirrhosis (group III). DNA was extracted and was genotyped for the SNPs rs10945859, rs2803085, rs2276201 and rs1931223. RESULTS: Among these SNPs, CT genotype of rs10945859 was found to have a significant association towards the clinical progression of chronic HCV infection to cirrhosis alone (OR = 1.850; 95% C. I. 1.115-3.069; p = 0.016) or cirrhosis and HCC (OR = 1.768; 95% C. I. 1.090-2.867; p value = 0.020). CONCLUSION: SNP rs10945859 in the PARK2 gene could prove useful in predicting the clinical outcome in HCV-infected patients.

Impact of model-based risk analysis for liver surgery planning.

PURPOSE: A model-based risk analysis for oncologic liver surgery was described in previous work (Preim et al. in Proceedings of international symposium on computer assisted radiology and surgery (CARS), Elsevier, Amsterdam, pp. 353­358, 2002; Hansen et al. Int I Comput Assist Radiol Surg 4(5):469­474, 2009). In this paper, we present an evaluation of this method. METHODS: To prove whether and how the risk analysis facilitates the process of liver surgery planning, an explorative user study with 10 liver experts was conducted. The purpose was to compare and analyze their decision-making. RESULTS: The results of the study show that model-based risk analysis enhances the awareness of surgical risk in the planning stage. Participants preferred smaller resection volumes and agreed more on the safety margins' width in case the risk analysis was available. In addition, time to complete the planning task and confidence of participants were not increased when using the risk analysis. CONCLUSION: This work shows that the applied model-based risk analysis may influence important planning decisions in liver surgery. It lays a basis for further clinical evaluations and points out important fields for future research.

Primary multicentric cutaneous epithelioid angiosarcoma.

Cutaneous epithelioid angiosarcoma is a rare malignant vascular tumor, most commonly affecting elderly men, and is usually located on the extremities. We report a case of an 81-year-old lady who presented with two ulcerated plaques over the right temporal and parietal scalp of 1 year duration. The right submaxillary and submandibular lymph nodes were enlarged and tender. Computed tomography (CT) scan of the head showed soft tissue swelling over parietal and temporal areas and there was no intracranial extension. Ultrasonogram of the abdomen showed hyperechoic areas in liver suggestive of secondaries. Histopathology of the skin lesion showed the dermis and subcutis composed of clusters of atypical epithelioid cells with vesicular nuclei, prominent nucleoli and eosinophilic cytoplasm with increased mitotic figures. Immunohistochemical staining revealed CD-31, 33, 34 and vimentin positivity, while cytokeratin was negative confirming the diagnosis of epitheloid angiosarcoma. This case report highlights the unusual occurrence of multicentric epitheloid angiosarcoma on the scalp with secondaries in the liver.

Dose calculation in biological samples in a mixed neutron-gamma field at the TRIGA reactor of the University of Mainz.

To establish Boron Neutron Capture Therapy (BNCT) for non-resectable liver metastases and for in vitro experiments at the TRIGA Mark II reactor at the University of Mainz, Germany, it is necessary to have a reliable dose monitoring system. The in vitro experiments are used to determine the relative biological effectiveness (RBE) of liver and cancer cells in our mixed neutron and gamma field. We work with alanine detectors in combination with Monte Carlo simulations, where we can measure and characterize the dose. To verify our calculations we perform neutron flux measurements using gold foil activation and pin-diodes. Material and methods. When L-α-alanine is irradiated with ionizing radiation, it forms a stable radical which can be detected by electron spin resonance (ESR) spectroscopy. The value of the ESR signal correlates to the amount of absorbed dose. The dose for each pellet is calculated using FLUKA, a multipurpose Monte Carlo transport code. The pin-diode is augmented by a lithium fluoride foil. This foil converts the neutrons into alpha and tritium particles which are products of the (7)Li(n,α)(3)H-reaction. These particles are detected by the diode and their amount correlates to the neutron fluence directly. Results and discussion. Gold foil activation and the pin-diode are reliable fluence measurement systems for the TRIGA reactor, Mainz. Alanine dosimetry of the photon field and charged particle field from secondary reactions can in principle be carried out in combination with MC-calculations for mixed radiation fields and the Hansen & Olsen alanine detector response model. With the acquired data about the background dose and charged particle spectrum, and with the acquired information of the neutron flux, we are capable of calculating the dose to the tissue. Conclusion. Monte Carlo simulation of the mixed neutron and gamma field of the TRIGA Mainz is possible in order to characterize the neutron behavior in the thermal column. Currently we also speculate on sensitizing alanine to thermal neutrons by adding boron compounds.

Hepatitis C virus infection in a Japanese leprosy sanatorium for the past 67 years.

Oku-Komyo-En is one of the national leprosy sanatoria, located on a small island in Setouchi city, Okayama prefecture of Japan since 1938. Since autopsies were carried out routinely on almost all patients who had died in the sanatorium up to 1980, approximately 1,000 formalin-fixed autopsy tissue samples were available for analysis. When these samples were reviewed, the pathological data indicated a sharp rise in the death rate caused by cirrhosis of the liver and hepatocellular carcinoma (HCC) since 1960 and 1970, respectively. Hepatitis C virus (HCV) infection is a common cause of HCC in Japan. The presence of HCV RNA was demonstrated in paraffin sections prepared from the autopsied liver tissue fixed in formalin for a prolonged period of time, by employing nested RT-PCR using type-specific primers. The data showed that HCV RNA was detectable in samples of the liver archived as early as 1940, representing the liver tissues kept in formalin for up to 67 years. HCV genotypes 1b and 2a were found by RT-PCR at 85.7% and 14.3%, respectively, in patients with leprosy.

Malignant acanthosis nigricans with liver secondaries from an occult primary adenocarcinoma of gastrointestinal tract.

A 38-year-old female presented with hyperpigmented velvety plaques on the nape and the sides of the neck with diffuse pigmentation of the face and flexures suggestive of acanthosis nigricans. The dorsa of both the hands showed increased rugosity, hyperpigmentation and hyperkeratosis of the palms, suggestive of tripe palms. Investigations revealed multiple secondaries in the liver. Histopathology showed the secondaries to be from adenocarcinoma of the gastrointestinal tract.

A phase II study of oral clofazimine in unresectable and metastatic hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma is highly refractory to most chemotherapeutic agents. Clofazimine, a riminophenazine compound used to treat leprosy since 1962, inhibits various cancer cell lines, including hepatocellular carcinoma cell lines, via phospholipase A2 dependant processes. Clofazimine also inhibits p170-glycoprotein, the mdr1 gene product. PATIENTS AND METHODS: Thirty patients (26 males and four females) with unresectable (25) or metastatic (5) hepatocellular carcinoma received oral clofazimine 600 mg daily for two weeks, followed by 400 mg daily until progression or death. RESULTS: There were three responses (10%)--one of a soft tissue metastasis, and two of local disease, with 13 patients disease stabilizing for up to 20 months. The overall median survival was 13 weeks. Adverse events included hyperpigmentation, eczematous skin rashes and palpitations. CONCLUSIONS: Although only three patients had an objective response (10%), the 13 patients with stable disease for up to 20 months, and an overall median survival of 13 weeks, suggest that clofazimine, or other riminophenazine compounds may prove to be of value in hepatocellular carcinoma.

Leprosy and malignancy: autopsy findings of 252 leprosy patients.

The occurrence of malignant tumors in leprosy patients was studied in 252 autopsied cases. Malignant tumors were found in 33 out of 110 autopsy cases from 1962 to 1971, and in 51 out of 141 autopsy cases from 1977 to 1989 (until July). In 1974, a lepromatous case with Kaposi's sarcoma was autopsied. The incidence of malignant tumors in our 252 cases were 33.7% (85 out of 252). Carcinoma of the alimentary system was most common: stomach, liver and large intestine, in that order. There was an increased number of hepatocellular carcinoma closely related to liver cirrhosis. Carcinoma of the lung has increased remarkably in leprosy patients quite recently. Malignant lymphoma was the most common of the nonepithelial malignant tumors, and four of these cases were seen in lepromatous leprosy patients. Eight cases showed double or triple cancers; seven of these were autopsied during 1977 to 1989. Further studies should be done to ascertain which types of leprosy showed the highest incidence, and which sex showed more frequent malignant tumors.

[Hepatic granulomatosis]. / Granulomatosi epatiche.

Granulomatous hepatitis is not a uniform disease entity but a generic histopathologic diagnosis. The present review of aetiology and epidemiology of granulomas in the liver, shows that in the past tuberculosis and sarcoidosis were the most frequent but there remained a large percentage of "undiagnosis" cases; at the present drug-induced granulomatous hepatitis are frequently reported and "undiagnosed cases" are rare. Analysis of the hystological features of the most common granulomas is presented.

Plasma CEA levels in small cell lung cancer. Correlation with stage, distribution of metastases, and survival.

Plasma CEA levels were determined in 61 patients with small cell lung cancer entering chemotherapy protocols between 1976 and 1980. Five quantitative categories were determined: less than 2.5 ng/ml (the standard normal for Hansen assay); 2.6-5.0 ng/ml (the extended normal for smokers); 5.1-20.0 ml; (the intermediate elevation and the transition for the indirect to the direct assay); 20-100 ng/ml; and greater than 100 ng/ml. Forty-seven percent of patients had levels less than 5 ng/ml and only ten of 61 or 16% had levels greater than 20 ng/ml. There was no clearcut relationship of plasma CEA level to stage of disease, in that 40% of patients with extensive disease (32 patients) had levels less than 5 ng/ml and 45% of patients with limited disease (29 patients) had levels greater than 5 ng/ml. Similarly, there was no relationship of CEA level to site of metastases, although levels greater than 100 ng/ml were always associated with liver metastases. The median survival for each quantitative category was similar, ranging from seven to nine months. The use of sequential determinations of CEA to correlate with tumor response was studied in only eight patients with levels greater than 20 ng/ml and a measurable parameter of disease. The qualitative direction of change of CEA was appropriate in those patients responding to treatment but in three nonresponding patients the direction of CEA change paradoxically decreased. In five patients who developed progressive disease, the plasma CEA level predicted the clinical relapse. CEA as a tumor marker for oat cell carcinoma must be applied in conjunction with other tumor parameters and is meaningful in only a small proportion of the total small cell patient population.

Primary hepatocellular carcinoma in intertropical Africa: relationship between age and hepatitis B virus etiology.

Clinical observations of patients with primary hepatocellular carcinoma (PHC) at Le Dantec Hospital, Dakar, Senegal, were studied to determine a correlation with hepatitis B virus (HBV) infection. Of the 103 patients with PHC, 80 had an active HBV infection (HBsAg and/or anti-HBc); 23 showed signs of previous HBV infection (anti-HBs and anti-HBc). The two groups were similar in the detection of alpha-fetoprotein (approximately 60%) and in the major clinical findings: hepatomegaly, 76.25% and 86.96%, respectively; and ascites, 57.50% and 47.83%, respectively. Jaundice, however, was three times more frequent (P < 0.01) in the group of patients with signs of active HBV replication. Distribution of HBV markers as a function of age at onset of PHC revealed that the presence of HBsAg was primarily confined to the sera of the younger patients (< 50 yr old). When compared with leprosy patients and blood donors, the younger PHC patients differed in the frequency of detection of HBsAg and anti-HBs. The older people (> 50 yr old) in the three groups (PHC patients, leprosy patients, and blood donors) had identical HBV markers.

Chemical structure--acute toxicity relation of m-substituted derivatives N,N-dimethyl-4-aminoazobenzene with hepatocarcinogen effects.

The mol LD50 values were correlated with Hammett sigma constants in terms of the Hansen empiric equation 7 for meta substituted derivatives of N,N-dimethyl-4-aminoazobenzene. Good agreement and the line slope of the correlation was achieved. Relation acute toxicity--carcinogenity was discussed in the end.

[Distribution of HBs antigen in Tananarive (author's transl)]. / Répartition de l'antigène HBs à Tananarive.

This survey has been conducted among blood donors and patients with hepatitis, cirrhosis, liver carcinomas and various causes of liver dysfunction or enlargement. The frequency is 5,4 p. 100 among blood donors and 50 p. 100 among cases of hepatitis.

Lymphatic dynamics of liver by hepatic lymphography using lipiodol ultra fluid.

Hepatic lymphography by intra-parenchymal injection of four to ten millilitres (ml) of lipiodol ultrafluid, our modification of functional hepatography, performed on sixty one patients helped study lymphatic dynamics of liver. In conditions associated with significant hepatic venous outflow obstructions, such as hepatic cirrhosis, inflammatory diseases of liver and primary or secondary malignant lesions of the liver, this study delineated liver lymphatics and portal and para aortic lymph nodes. In one case mediastinal nodes were also delineated by flow of lipiodol from the bare area of the liver via trans-diaphragmatic and pleural lymphatic. The lymphangio-architecture of the opacified nodes depicted the nature of pathology inflicting them and the liver. Lipiodol in the lymphatic system, staying longer than the freely diffusible aqueous contrast, provided more detail and better information.