Induction of neoplasms in the Egyptian toad Bufo regularis by gibberellin A3

Force feeding the Egyptian toads (Bufo regularis) with gibberellin A3 (10 ppm) twice a week for 5 months induced neoplasms in 8 out of 50 (16%) experimental animals. Primary tumours developed in the liver (hepatocellular carcinomas). Two secondary tumours in the kidneys and another 2 in the ovaries of toads developed due to metastases from the hepatocellular carcinomas. The results show that gibberellic acid (gibberellin A3) has a carcinogenic effect in the Egyptian toads.     

Cytotoxic Potential of Indian Spices (Extracts) Against Esophageal Squamous Carcinoma Cells

Diet is one of the important factors in cancer etiology and prevention. The Indian diet is particularly interesting in its many unique dietary constituents, including spices like chili pepper, cloves, black pepper and black cumin, that have promise as chemopreventive agents. The objective of the present study was to compare the in vitro anticancer activities of aqueous and ethanolic extracts against the TE-13 (esophageal squamous cell carcinoma) cell line. All extracts showed cytotoxic activity but aqueous extracts were found to be more potent than alcoholic extracts. Morphological analysis, DAPI staining and DNA fragmentation assays showed maximum cell death and apoptotic cell demise (88% ) to occur within 24 hours with an aqueous extract of chili pepper at 300μl/ml.     

Tissue distribution of DNA adducts in CDF1 mice fed 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) and 2-amino-3,4-dimethylimidazo[4,5-f]quinoline (MeIQ)

Male and female CDF1 mice were administered a single oral dose of 3 mumol of the food mutagens 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) or 2-amino-3,4-dimethylimidazo[4,5-f]quinoline (MeIQ) and killed 24 h later. DNA was isolated from the livers, lungs, kidneys, colon and forestomach and analysed by 32P-postlabelling for the presence of IQ and MeIQ adducts. Several adduct-enrichment procedures were investigated, including ATP-deficient labelling conditions, butanol extraction and nuclease P1 digestion, and only the ATP-deficient procedure was found to produce the same adduct pattern on polyethyleneimine--cellulose TLC as the standard procedure. Up to nine adduct spots were detected in liver DNA from IQ-treated mice, two of which were not detected in other tissues. The levels of binding in both male and female mice were in the order liver greater than kidney greater than colon greater than forestomach greater than lung. Analysis of DNA from MeIQ-treated mice revealed the presence of up to seven adducts, one of which was detected in liver but not in other tissues. The relative order of DNA binding was kidney greater than liver greater than or equal to colon greater than forestomach greater than lung. As dietary feeding of IQ induces liver, lung and forestomach tumours, and MeIQ induces liver and forestomach tumours in this mouse strain, these binding levels do not correlate with the susceptibility of the organs to carcinogenesis induced by these compounds; the results may indicate the importance of additional factors in determining organ specificity of carcinogenicity.     

Carcinogenic effect of force-feeding an extract of black pepper (Piper nigrum) in Egyptian toads (Bufo regularis)

50 male and 50 female Bufo regularis were treated, by force-feeding, with an extract of black pepper, at a dose level of 2 mg, 3 times a week for 5 months. The first tumors appeared after 2 months. Liver tumors (hepatocellular carcinomas, lymphosarcomas and fibrosarcomas) were found in 12 males and 18 females. Metastatic deposits of hepatocellular carcinomas were registered in the spleen, kidney, fat body and ovary.     

Percutaneous microwave ablation for liver tumours adjacent to the marginal angle

Purpose: This study was designed to describe the technical essentials of microwave ablation (MWA) for tumours adjacent to the liver marginal angle (LMA) and to determine the feasibility, safety and efficacy of this approach. Materials and methods: A total of 22 patients with primary or metastatic liver tumours adjacent to the LMA were enrolled. There were 19 small tumours (≤3?cm) and three larger tumours (>3?cm) with maximum diameters ranging from 0.7–2.7?cm (mean 1.7?±?0.6?cm) and 4.7–6.6?cm (mean 5.4?±?1.0?cm), respectively. For small tumours the entire acute angle was segmentally blocked utilising MWA. For larger tumours, the feeding arteries were initially blocked with ethanol before conformal ablation. Artificial ascites, real-time monitoring, small ethanol doses, colour Doppler flow imaging or contrast enhanced ultrasound guidance was used as an additional technique to assist with ablation. Contrast imaging was performed to evaluate the ablative efficacy. Treatment responses, local tumour progression (LTP) and complications were recorded. Results: All patients achieved a complete response. LTP was identified in two cases (9.1%) during the 4.5 month median follow-up period (range 2–29 months). A total of five additional sessions were performed, and secondary effectiveness was achieved in patients with LTP. No major complications were observed. Conclusions: Percutaneous MWA is a new promising technique for tumours adjacent to the LMA, especially in cases with small tumours. Technical improvements to this procedure are expected to improve the results for large tumours abutting the LMA.     

Imaging of cancer invasion and metastasis using green fluorescent protein

The use of green fluorescent protein to fluorescently tag tumour cells has allowed investigators to open the “black box” of metastasis in order to visualise the behaviour of tumour cells in living tissues. Analysis of cells leaving the primary tumour indicates that highly metastatic cells are able to polarise more effectively towards blood vessels while poorly metastatic cells fragment more often when interacting with blood. In addition, there appear to be greater numbers of host immune system cells interacting with metastatic tumours. After arresting in target organs such as the lungs or liver, most tumour cells become dormant or apoptose. A small fraction of the arrested cells form metastases. In some target organs, migration of tumour cells may enhance the ability to form metastases.     

The predictive value of mouse liver tumour induction in carcinogenicity testing--a literature survey

A survey of the available data in the literature was carried out in an attempt to verify the possible correlation between the capacity of a number of chemicals to induce parenchymal liver tumours in the mouse and their capacity to induce tumours in the liver and/or other organs in the rat and hamster. Data on 58 chemicals were collected. A positive correlation appears to exist between the capacity of a chemical to induce liver tumours in the mouse and its capacity to induce tumours at any site in the rat or the hamster. The strongest correlation is found when the chemical, given to adult mice, induces tumours of the liver and other sites in both sexes. The induction of liver tumours in the mouse by a chemical does not signify that the liver would be the target organ in the rat or the hamster. Among the 58 chemicals considered, seven are recognized or suspected human carcinogens. All were hepatocarcinogenic in the mouse and six were carcinogenic in the liver and/or other organs in the rat. Four were tested in the hamster and found to be carcinogenic.     

Induction of liver cell adenomata in the rat by a single treatment with N-methyl-N-nitrosourea given at various times after partial hepatectomy

A single treatment of adult animals with the potent carcinogen NMU was known to induce tumours in a wide variety of organs, with the notable exception of liver. Administration of NMU after partial hepatectomy gave rise to the first liver cell adenomata ever observed in rats due to this carcinogen. The tumours were induced when NMU was given during the period of increased DNA synthesis but not when given early in the pre-replicative period. Although tumours were induced in other organs, the incidence of these did not correlate with the timing of NMU administration. It is suggested that replication of damaged DNA may be a relevant event in carcinogenesis.     

MR-guided laser-induced thermotherapy (LITT) of liver tumours: experimental and clinical data

MR-guided laser-induced interstitial thermotherapy (LITT) is a percutaneous, minimally invasive treatment modality for treating liver lesions/metastases, soft tissue tumours and musculoskeletal lesions. In this group, MR-guided LITT is currently performed under local anaesthesia on an out-patient basis with a specially designed saline-cooled laser application system. Nd:YAG laser (1064?nm wave length) was used for tumour ablation. Magnetic resonance imaging (MRI) using both open and closed MR units has proven clinically effective in validating the exact positioning of optical fibres. It also allows for real time-monitoring of thermal effects and the evaluation of treatment-induced coagulation necrosis. In liver tumours, percutaneous MR-guided LITT achieves a local tumour control rate of 98.7% at 3 months post-therapy and 97.3% at 6 months with metastases smaller than 5?cm in diameter. The mean survival rate for 1259 patients with 3440 metastases treated with 14 694 laser applications at the institute (calculated with the Kaplan-Meier method) was 4.4 years (95% confidence interval: 4.1–4.8?years) and median survival was 3.00 years. No statistically significant difference in survival rates was observed in patients with liver metastases from colorectal cancer vs metastases from other primary tumours. The rate of clinically relevant side effects and complications requiring secondary treatment was 2.2%. The clinical use of MR guided LITT (size<5?cm, number<5) is justified in patients with liver metastases of colorectal and/or breast cancers if the inclusion criteria are carefully observed. Further indications for MR guided LITT include recurrent cancer lesions in the head and neck, lung metastases and bone and soft tissue lesions.     

Lebertransplantation bei primären Non-HCC-Tumoren und sekundären Malignomen der Leber

Liver transplantation currently represents not only an effective but also a safe treatment for many patients with liver disease. Liver transplantation is also a crucial part of the treatment of hepatic malignancies and is the current treatment of choice in early stages of hepatocellular carcinoma (HCC) in cirrhosis. In other primary and secondary liver malignancies, liver transplantation can be a curative treatment option as well. However, these malignancies comprise a heterogeneous group of liver tumours that are considerably different in terms of tumour characteristics, treatment modalities, and prognosis. Therefore, the importance of liver transplantation in the treatment strategy varies among the different tumour entities. The current criteria for organ allocation influence and limit the use of this treatment modality in these heterogeneous settings. Supported by the advancing establishment of living donor liver transplantation, the importance of transplantation in the general oncological concept of some of these tumour entities is currently increasing again. This review gives an overview, based on the current literature, of the role of liver transplantation for treating primary non-HCC tumours and secondary malignancies of the liver.     

MR-guided laser-induced thermotherapy (LITT) of liver tumours: experimental and clinical data.

MR-guided laser-induced interstitial thermotherapy (LITT) is a percutaneous, minimally invasive treatment modality for treating liver lesions/metastases, soft tissue tumours and musculoskeletal lesions. In this group, MR-guided LITT is currently performed under local anaesthesia on an out-patient basis with a specially designed saline-cooled laser application system. Nd:YAG laser (1064 nm wave length) was used for tumour ablation. Magnetic resonance imaging (MRI) using both open and closed MR units has proven clinically effective in validating the exact positioning of optical fibres. It also allows for real time-monitoring of thermal effects and the evaluation of treatment-induced coagulation necrosis. In liver tumours, percutaneous MR-guided LITT achieves a local tumour control rate of 98.7% at 3 months post-therapy and 97.3% at 6 months with metastases smaller than 5 cm in diameter. The mean survival rate for 1259 patients with 3440 metastases treated with 14 694 laser applications at the institute (calculated with the Kaplan-Meier method) was 4.4 years (95% confidence interval: 4.1-4.8 years) and median survival was 3.00 years. No statistically significant difference in survival rates was observed in patients with liver metastases from colorectal cancer vs metastases from other primary tumours. The rate of clinically relevant side effects and complications requiring secondary treatment was 2.2%. The clinical use of MR guided LITT (size < 5 cm, number < 5) is justified in patients with liver metastases of colorectal and/or breast cancers if the inclusion criteria are carefully observed. Further indications for MR guided LITT include recurrent cancer lesions in the head and neck, lung metastases and bone and soft tissue lesions.     

Alkylation of DNA related to organ-specific carcinogenesis by N-nitroso compounds.

Alkylation of DNA by a number of methylating and ethylating carcinogens, mainly N-nitroso compounds, has been examined in target and non-target organs of rats and Syrian hamsters. Six hours after administration by gavage of small doses identical to those given twice weekly for several months to elicit tumours, animals were killed and dissected. DNA was isolated from several organs and hydrolysed, and the content of methyl- and ethylguanines was measured using high-performance liquid chromatography for separation. In most experiments, radiolabelled carcinogen was used, but in some cases measurement of alkylguanines was by fluorescence. Methylation, O6- and N7-, by methylating compounds was much more extensive than ethylation by the corresponding ethyl compounds, irrespective of their relative potencies in inducing tumours. Similar patterns of alkylation were found in target organs and in non-target organs of the carcinogens. Only marginal differences in methylation were seen with N-nitro-sobis(2-oxopropyl)amine between male and female rat livers, although liver tumours are induced only in females, in feminized males and in old males. Deuterium labelling of the methylene of N-nitrosoethylmethylamine had little effect on methylation or ethylation of DNA in rat liver, although the deuterated compound was a much more potent liver carcinogen. The conclusion is that reactions of the carcinogen other than alkylation of DNA are important in giving rise to tumours.     

The emergent role of focal liver ablation techniques in the treatment of primary and secondary liver tumours

Only 20% of patients with primary or secondary liver tumours are suitable for resection because of extrahepatic disease or the anatomical distribution of their disease. These patients could be treated by ablation of the tumour, thus preserving functioning liver. This study presents a detailed review of established and experimental ablation procedures. The relative merits of each technique will be discussed and clinical data regarding the efficacy of the techniques evaluated. A literature search from 1966 to 2003 was undertaken using Medline, Pubmed and Web of Science databases. Keywords were Hepatocellular carcinoma, liver metastases, percutaneous ethanol injection, cryotherapy, microwave coagulation therapy, radiofrequency ablation, interstitial laser photocoagulation, focused high-intensity ultrasound, hot saline injection, electrolysis and acetic acid injection. Ablative techniques offer a promising therapeutic modality to treat unresectable tumours. Large-scale randomised controlled trials are required before widespread acceptance of these techniques can occur.     

Place de la radiothérapie stéréotaxique dans la prise en charge des tumeurs hépatiques

Stereotactic radiotherapy is a high-precision technique based on the administration of high doses to a limited target volume. This treatment constitutes a therapeutic progress in the management of many tumours, especially hepatic ones. If surgery remains the standard local therapy, stereotactic radiotherapy is first dedicated to inoperable patients or unresectable tumours. Patients with moderately altered general status, preserved liver function and tumour lesions limited in number as in size are eligible to this technique. Results in terms of local control are satisfying, regarding primary tumours (notably hepatocellular carcinomas) as metastases stemming from various origins. If treatment protocols and follow-up modalities are not standardized to this day, iconographic acquisition using four-dimensional computed tomography, target volumes delineation based on morphological and/or metabolic data, and image-guided radiotherapy contribute to an oncologic efficacy and an improved sparing of the functional liver. The purpose of this literature review is to report the results of the main works having assessed stereotactic radiotherapy in the management of primary and secondary liver tumours. Technical particularities of this radiation modality will also be described.     

The role of N-(nitrosomethylamino)propionitrile in betel-quid carcinogenesis

N-(Nitrosomethylamino)propionitrile (NMAP) was isolated and identified in the saliva of betel-quid chewers in amounts ranging from 0.5 to 11.4 micrograms/l. Groups of 21 male and 21 female rats were given 60 subcutaneous injections of NMAP over a 20-week period (total doses, 0.055 and 0.23 mmol/rat). After 106 weeks, the higher dose had induced 18 (86%) malignant tumours of the nasal cavity in male and 15 (71%) in female rats. Nine (43%) liver tumours were observed among animals treated with the lower dose. Fischer 344 rats were treated with a single dose of NMAP (intravenously or subcutaneously, 0.4 mmol/kg; or by swabbing the oral cavity, 2.21 mmol/kg), and the levels of N7-methylguanine (7-meG) and O6-methylguanine (O6-meG) were measured in DNA isolated from oesophagus and nasal mucosa, which are target organs, and from liver which is not. Higher levels of O6-meG and 7-meG were detected in the nasal mucosa and lesser DNA methylation in the liver and oesophagus, independent of the mode of administration. This correlates with the results of the study of the tumorigenic properties of NMAP in rats.     

Evaluation of dimethylhydrazine induced tumours in mice as a model system for colorectal cancer

The evolution and structure of adenomatous polyps and adenocarcinomata of the colon in NMRI mice induced by dimethylhydrazine are described. Severe toxic reactions in the liver and other organs are produced by dimethylhydrazine (DMH), but tumours are induced only in the colon and around the anus. The 100% incidence and growth characteristics of the tumours make it potentially a good model system, but investigators should take into account the widespread nonspecific cellular injury induced by this carcinogen.     

Genomic alterations (LOH, MI) on chromosome 17q21-23 and prognosis of sporadic colorectal cancer

Genomic alterations at the long arm of chromosome 17, and in particular at the nm23 locus, are still controversial in colorectal cancer (CRC). Our aim was to investigate the possible relationship of loss of heterozygosity (LOH) and microsatellite instability (MI), at 4 microsatellite loci spanning the 17q21-23 region, to the risk of liver metastasis and nm23 protein expression. Genomic DNA extracted from 58 primary and 54 liver secondary formalin-fixed and paraffin-embedded CRCs was obtained from 82 patients. A fluorescent PCR coupled with an automated DNA sequencer was applied. Increasing fraction of loci showing LOH was positively associated with risk of liver metastases (logrank test for trend, p = 0.005); this remained independent after adjusting to T-stage (Cox regression, p = 0.022), N-stage (p = 0.007), or Dukes' stage (p = 0.012). Conversely, increasing frequency of MI was associated with a reduced risk of liver metastases in Dukes' B tumours (logrank test for trend, p = 0.032). When comparing 30 primary and matched liver secondary lesions, we found concordant genomic alteration in 72% (NME1) to 43% (D17S579). Finally, we observed a trend in association between the proportion of loci with LOH and nm23 positivity (chi2 test for trend, p = 0.024). Our findings suggest that genomic alterations in the 17q21-23 region may affect prognosis of CRC as well as regulation of the nm23 protein expression via an unknown underlying mechanism.     

Therapy for hepatocellular-carcinoma (review)

Hepatocellular carcinoma remains one of the commonest malignant tumours in the world. It usually arises on a background of hepatic cirrhosis which limits the possibility of resection or transplantation. The literature contains few good randomised trials of therapy for this common tumour. This review discusses the role of surgery and liver transplantation together with recent developments in medical therapy, namely chemoembolisation, percutaneous ethanol injection and hormonal treatment, and arrives at a consensus as to the place of these treatments in the current management of hepatoma.     

Effects of black tea, green tea and wine extracts on intestinal carcinogenesis induced by azoxymethane in F344 rats

We investigated whether polyphenolic extracts from black tea, green tea or red wine affect azoxymethane (AOM)-induced intestinal carcinogenesis. Male F344 rats were treated 10 times (1 week apart) with AOM (7.4 mg/kg, s.c.) and then allocated into groups receiving black tea, green tea or red wine extracts mixed in the diet at a dose of 50 mg/kg body weight for 16 weeks. In the rats treated with black tea or wine extracts, there were significantly fewer colorectal tumours than in controls (the mean +/- SE number of tumours/rat was 2.54 +/- 1.6 in controls, 1.54 +/- 1.4 in the black tea group, 3.2 +/- 1.9 in the green tea group and 1.63 +/- 1.6 in the wine extract group). Significantly fewer rats in the black tea and wine extract groups had adenomas than in controls (86%, 59%, 90% and 50% of rats in the control, black tea, green tea and wine extract groups, respectively, had adenomas). The tumours from the black tea group and, to a lesser extent, those from the wine group, had a significantly greater apoptotic index than tumours in controls (mean +/- SE apoptotic index: 2.92 +/- 0.25, 4.13 +/- 0.46, 2.88 +/- 0.30 and 3.72 +/- 0.46 in controls, black tea, green tea or wine extract groups, respectively). In contrast, the apoptotic index of the normal mucosa did not vary among groups. These data indicate that black tea and wine extracts, but not green tea extracts, can protect against AOM-induced colon carcinogenesis by a mechanism probably involving increased apoptosis in tumours.     

Results of 27 cases with hepatic metastases treated by combination chemotherapy

The results of using a standard combination of cytotoxic agents in 27 cases of secondary liver cancer are reported. A brief review of the methods available for treating hepatic metastases from solid tumours, as opposed to lymphomata, is included. The response rate depends on the site of the primary lesion. It is suggested that in patients with mammary or colorectal primary tumours, combination chemotherapy represents an advance in treatment with an objective response rate of 73% and 66% respectively in the 2 groups. The method requires no specialized equipment as neither grossly deranged liver enzymes nor jaundice are contra-indications to treatment, and toxicity is easily monitored and readily controlled.