Familial and sporadic human renal cell carcinoma: evidence against a double-loss mechanism of carcinogenesis

It has been speculated that renal cell carcinoma (RCC) is an example of a double-loss mutation. We analyzed the age distribution of 71 cases of familial RCC and of 11 population-based cancer registries [German Democratic Republic, Denmark, Finland, Norway, Sweden, U.S.A. Whites, U.S.A. Blacks, Miyagi and Osaka Prefectures (Japan), Hong Kong, and Israeli Jews] according to the multi-hit and clonal growth models of carcinogenesis. The analysis rules out a double-loss mechanism for RCC. On both of the two models analyzed, carcinogenesis in the familial cases of RCC arises as a result of a three- to ten-fold increase in the average rate of mutation at the susceptible loci, as compared with the sporadic cases. In general, the clonal growth model provides a somewhat better fit to the age-distribution of RCC incidence than does the multi-hit model.     

Large granular lymphocyte leukemia associated with hepatocellular carcinoma: a case report

Both primary and metastatic malignancies of the masseter muscle are rare. We report a case of metastatic renal cell carcinoma to the masseter muscle. It was incidentally found as a hypervascular mass in carotid angiography for delineating a recurrent metastatic brain tumour. Prior to surgical removal, intravascular embolization via the left facial artery was performed in order to decrease intra-operative bleeding. The tumour was removed with minimum damage to the muscle fibres by the extraoral method, followed by a transient lower lip palsy. Metastatic intramuscular tumours, which are assumed to be due to haematogenous spread, are generally a sign of poor prognosis.     

Dopamine quinone formation and protein modification associated with the striatal neurotoxicity of methamphetamine: evidence against a role for extracellular dopamine

Methamphetamine-induced toxicity has been shown to require striatal dopamine and to involve mechanisms associated with oxidative stress. Dopamine is a reactive molecule that can oxidize to form free radicals and reactive quinones. Although this has been suggested to contribute to the mechanism of toxicity, the oxidation of dopamine has never been directly measured after methamphetamine exposure. In this study we sought to determine whether methamphetamine-induced toxicity is associated with the oxidation of dopamine by measuring the binding of dopamine quinones to cysteinyl residues on protein. We observed that administration of neurotoxic doses of methamphetamine to rats resulted in a two- to threefold increase in protein cysteinyl-dopamine in the striatum 2, 4, and 8 hr after treatment. When methamphetamine was administered at an ambient temperature of 5 degreesC, no increase in dopamine oxidation products was observed, and toxicity was prevented. Furthermore, as shown by striatal microdialysis, animals treated with methamphetamine at 5 degreesC showed DA release identical to that of animals treated at room temperature. These data suggest that the toxicity of methamphetamine and the associated increase in dopamine oxidation are not exclusively the result of increases in extracellular dopamine. Because dopamine-induced modifications of protein structure and function may result in cellular toxicity, it is likely that dopamine oxidation contributes to methamphetamine-induced toxicity to dopamine terminals, adding support to the role of dopamine and the evidence of oxidative stress in this lesion model.     

Treatment of hepatocellular carcinoma associated with cirrhosis in the era of liver transplantation

PURPOSE: To review the treatment of cirrhotic patients with hepatocellular carcinoma in the era of liver transplantation and to determine the most appropriate approach to the treatment of patients at different stages of disease. DATA SOURCES: A MEDLINE search of English-language articles published between 1981 and 1997 and the clinical experience of the Mount Sinai Liver Transplant Program. STUDY SELECTION: Selected studies were 1) original articles reporting results of resection and transplantation in the treatment of hepatocellular carcinoma in cirrhotic patients and 2) initial reports from major transplantation centers of multimethod therapies combining chemotherapy with transplantation. DATA EXTRACTION: Study designs were assessed with careful attention to methods and aims. Relevant data on patient population, tumor stage distribution, treatment, survival, and rate of recurrent disease were extracted and analyzed. DATA SYNTHESIS: Options for the treatment of hepatocellular carcinoma in cirrhotic patients vary according to tumor stage and severity of underlying liver disease. Resection remains an important method primarily in eastern countries, where the screening of high-risk populations has been associated with early detection of small asymptomatic lesions. Long-term survival after resection, however, is low. In western countries, liver transplantation is becoming the treatment of choice in patients with advanced cirrhosis and small, unresectable lesions; resection is reserved for cirrhotic patients with small, peripheral lesions and preserved hepatic function. Minimally invasive procedures (such as percutaneous ethanol injection and transarterial chemoembolization) have been developed to treat unresectable tumors. Transarterial chemoembolization may also be effective in patients with advanced cirrhosis and unresectable lesions who are awaiting transplantation. CONCLUSIONS: The efficacy of liver transplantation for hepatocellular carcinoma has been proven mainly in patients with advanced cirrhosis and small lesions. Future studies may clarify the role of approaches combining neoadjuvant chemotherapy with transplantation for large (stage III) tumors.     

Fibrolamellar carcinoma of the liver with a mixture of ordinary hepatocellular carcinoma: a case report

Fibrolamellar carcinoma (FLC) of the liver is a rare variant of hepatocellular carcinoma (HCC), and only 13 cases have been reported in Japan up to 1997. We described a histologically unusual case of FLC. A 52-yr-old man was admitted to our hospital for work-up of hepatic mass. Laboratory examinations revealed no abnormalities except elevated serum alpha-fetoprotein (AFP) (2098 ng/ml). A diagnosis of HCC was made by imaging findings, and left lobectomy of the liver was performed. Histologically, the tumor was composed of areas of FLC mixed with ordinary HCC and those of pure ordinary HCC. Staining for AFP was positive in the HCC component and negative in the FLC component. Some cases of such mixed tumors have been reported in Europe and the United States, but not in Japan. We regarded our case as the first of the mixed tumor in Japan.     

Disease progression and hepatocellular carcinogenesis in patients with chronic viral hepatitis: a prospective observation of 2215 patients

BACKGROUND/AIMS/METHODS: The aim of this study was to elucidate the rate of development to cirrhosis and the rate of appearance of hepatocellular carcinoma in chronic viral hepatitis and to assess the risk factors for the development of disease in 2215 consecutive patients with viral hepatitis who were prospectively studied for a median observation period of 4.1 years. RESULTS: The rates of development to cirrhosis were 7.6%, 21.7%, and 32.2%, at the 5th, 10th, and 15th year, respectively. The carcinogenesis rates were 3.4%, 10.5%, and 22.4% at the 5th, 10th, and 15th year, respectively. The appearance rates of cancer in 645 patients with only hepatitis B surface antigen and in 1500 patients with only anti-hepatitis C virus antibodies were 2.1% and 4.8% at the 5th year, 4.9% and 13.6% at the 10th year, and 18.8% and 26.0% at the 15th year, respectively. The proportional hazard model identified that the amount of alcohol intake (p= 0.0002) and the indocyanine green retention rate (p= 0.022) were independently associated with carcinogenesis in hepatitis type B; and stage of hepatitis (p<0.0001), gamma-glutamyl transpeptidase (p= 0.0046), history of blood transfusion (p=0.0093), albumin (p=0.012), and amount of alcohol intake (p= 0.031) were independently associated with the carcinogenesis rate in hepatitis type C. Although the severity of portal fibrosis was closely correlated with the future disease development and carcinogenesis in chronic hepatitis C, it was not a good predictor in chronic hepatitis B. CONCLUSION: These epidemiological results suggest that there are some differences in the activity and modes of disease progression and cancer promotion between hepatitis B virus infection and hepatitis C virus infection.     

A case of hepatocellular carcinoma associated with troublesome hypoglycemia: management by cytoreduction using percutaneous ethanol injection

Hypoglycemia is a well-known paraneoplastic manifestation of hepatocellular carcinoma. However, hypoglycemia as the first presentation is extremely uncommon. We herein report a case of HCC presenting with severe, uncontrollable hypoglycemia that was managed with percutaneous ethanol injection therapy.     

Onset of hepatocellular carcinoma in a non-cirrhotic patient affected with haemochromatosis

Forensic pathologists are frequently asked to describe the interval between injury and the onset of symptoms in child abuse head injury deaths. A prospective, postmortem study examined the interval between injury and onset of symptoms in 76 head injury deaths in which this information was available. The head injury deaths were divided by mechanism of injury. The mechanisms were shake (no impact), combined shake and blunt impact, and blunt impact (no history of shaking). The interval was less than 24 hours in 80% of shakes, 71.9% of combined, and 69.2% of blunt injuries. The interval was greater than 24 hours in more than 25% of each of these latter groups and was more than 72 hours in four children. The variable intervals between injury and severe symptoms warrant circumspection in describing the interval for investigators or triers of fact. It should be noted that in all of the cases where information was supplied by someone other than the perpetrator, the child was not normal during the interval.     

Metallothionein expression and concentrations of copper and zinc are associated with tumor differentiation in hepatocellular carcinoma

Metallothionein is the carrier protein of heavy metal ions, such as copper (Cu) and zinc (Zn). In this study, the relationships among immunohistochemical expression of metallothionein, concentrations of Cu and Zn, histological differentiation and proliferative activity of hepatocellular carcinoma were investigated in 51 cases. The concentrations of Cu and Zn in both tumor and non-tumor tissues were determined using electron probe microanalysis. Immunohistochemical expression of metallothionein in tumor tissues decreased with the degree of differentiation, whereas the number of hepatocytes positive for Ki-67 increased. Furthermore, the concentrations of Cu and Zn in tumor tissues decreased with the degree of histological differentiation in human hepatocellular carcinoma.     

Carbon monoxide-induced relaxation of the ductus arteriosus in the lamb: evidence against the prime role of guanylyl cyclase

1. We have previously found that carbon monoxide (CO) potently relaxes the lamb ductus arteriosus and have ascribed this response to inhibition of a cytochrome P450-based mono-oxygenase reaction which sustains contractile tone. Our proposal, however, has been questioned on the evidence of findings in other blood vessels implicating the guanylyl cyclase-based relaxing mechanism as the target for CO. To investigate this issue further, we have carried out experiments in the isolated ductus from near-term foetal lambs and have examined the effect of CO concomitantly on muscle tone and cyclic GMP content, both in the absence and presence of guanylyl inhibitors, or during exposure to monochromatic light at 450 nm. 2. CO (65 microM) reversed completely, or nearly completely, the tone developed by the vessel in the presence of oxygen (30%) and indomethacin (2.8 microM). Cyclic GMP content tended to increase with the relaxation, but the change did not reach significance. Sodium nitroprusside (SNP), a NO donor, mimicked CO in relaxing the ductus. Contrary to CO, however, SNP caused a marked accumulation of cyclic GMP with levels being positively correlated with the relaxation. 3. Methylene blue (10 microM) reduced marginally the CO relaxation, whilst LY-83583 (10 microM) had an obvious, albeit variable, inhibitory effect. Basal cyclic GMP content was lower in tissues treated with either compound and rose upon exposure to CO. However, the levels attained were still within the range of values for tissues prior to any treatment. Furthermore, the elevation in cyclic GMP was not related to the magnitude of the CO relaxation. 4. Illumination of the ductus with monochromatic light at 450 nm reversed the CO relaxation and any concomitant increase in cyclic GMP. In the absence of CO, light by itself had no effect. 5. Ductal preparation with only muscle behaved as the intact preparations in reacting to CO, both in the absence and presence of guanylyl cyclase inhibitors, or during illumination. 6. We conclude that the primary action of CO in the ductus arteriosus is not exerted on the guanylyl cyclase heme and that cyclic GMP may only have an accessory role in the relaxation to this agent. This finding reasserts the importance of a cytochrom P450-based mono-oxygenase reaction for generation of tone and as a target for CO in the ductus.     

The postnatal emergence of dehydration anorexia in rats is temporally associated with the emergence of dehydration-induced inhibition of gastric emptying

Osmotic dehydration produced by systemic hypertonic NaCl (HS) inhibits gastric motility and emptying and also inhibits feeding in adult rats. Conversely, in neonatal rats, dehydration does not inhibit feeding. The present study examined whether the postnatal emergence of dehydration anorexia is temporally associated with the emergence of dehydration-induced inhibition of gastric emptying. Rat pups 4 to 19 days old were injected subcutaneously with HS (0.75 M NaCl; 200 microL/10 g body weight). Control rats were injected with isotonic saline (0.15 M NaCl). Thirty minutes later, rats were given access to milk that could be lapped from paper towels on the floor of a warm testing chamber. Other HS-treated and control rats were given an intragastric load of 0.15 M NaCl (2% body weight) and then killed after 30 min to determine how much of the load had emptied from the stomach. Consistent with previous reports, HS-treated rats consumed significantly more milk than control rats from postnatal Day 4 (P4) through P11 but consumed significantly less milk than controls at P19. HS treatment did not affect gastric emptying of 0.15 M NaCl at P4 or P11. Conversely, HS treatment significantly inhibited gastric emptying at P19. These findings suggest that the hypophagic effects of dehydration develop in tandem with inhibitory effects on gastric motility and are consistent with the view that the full complement of mature homeostatic responses to plasma hyperosmolality requires coordinated activation of forebrain and hindbrain neural circuits that are only partially formed in neonatal rats.     

Macrophage migration inhibitory factor production by Leydig cells: evidence for a role in the regulation of testicular function

Macrophage migration inhibitory factor (MIF), described originally as a product of activated T lymphocytes, recently has been found to be released by monocytes/macrophages and the anterior pituitary gland. Immunohistochemical studies of the adult rat testis using an affinity-purified polyclonal antimurine MIF antibody demonstrated strong staining for MIF in Leydig cells and their putative precursors. Peritubular myoid cells and the seminiferous epithelium were negative for MIF staining; however, a weak reaction around the heads of elongated spermatids also was observed. The expression of MIF messenger RNA and protein in whole rat testis was demonstrated by Northern blot and Western blot analyses, respectively. Both MIF messenger RNA and protein immunoreactivity in Leydig cells was observed in testes obtained from long term hypophysectomized rats. Significant concentrations of intracellular MIF were detected in lysates of the TM3 Leydig cell line (7.23 +/- 2.6 pg/microgram protein), and testicular interstitial fluid contained 14.7 +/- 1.6 ng/ml MIF protein, as measured by MIF-specific enzyme-linked immunosorbent assay. To gain insight into the possible biological role of MIF in the testis, cultures of adult rat seminiferous tubules and purified Leydig cells were incubated together with recombinant murine MIF (rMIF). Neither rMIF (50 ng/ml) nor a neutralizing anti-MIF antiserum was found to affect basal or LH-stimulated Leydig cell steroidogenesis in vitro. However, a dose-dependent decrease in the secretion of inhibin by the seminiferous tubules was observed at rMIF concentrations ranging from 10-100 ng/ml. Taken together, these data indicate that Leydig cells produce MIF in vivo and suggest an important regulatory role for this newly discovered mediator of testicular function.     

Altered Gq/G11 guanine nucleotide regulatory protein expression in a rat model of hepatocellular carcinoma: role in mitogenesis

Guanine nucleotide regulatory proteins (G-proteins) represent an important transmembrane pathway whereby extra-cellular signals are transduced to intracellular signaling pathways. The mitogen-activated protein kinase (MAPK) cascade has been identified as a key factor in transducing numerous mitogenic stimuli. MAPK activity is regulated via numerous receptor types, including those linked to Gq/G11-proteins, which regulate phospholipase-C activity. We hypothesized that alterations in a Gq/G11-PLC pathway may contribute to the enhanced cellular mitogenesis characteristic of hepatocellular carcinoma (HCC), possibly via a MAPK-dependent pathway. By using an in vivo model of HCC we investigated changes in Gq/G11-protein expression in tumorigenic tissue versus adjacent, non-neoplastic liver. In addition we addressed the role of Gq/G11-proteins in the regulation of MAPK-linked mitogenesis by using rat hepatic tumorigenic cells (H4IIE) and isolated hepatocytes in culture. Western blot analysis showed significant increases in Gqalpha and G11alpha expression in tumorigenic liver versus normal liver specimens, an effect that was augmented in cultured H4IIE cells versus isolated cultured hepatocytes. Furthermore, phosphoinositol specific phospholipase-C (PLC) activity was significantly increased in HCC versus normal liver. A specific PLC inhibitor (Et-18-OCH3) caused a dose-dependent decrease in serum stimulated DNA synthesis in both cultured H4IIE cells and isolated rat hepatocytes, the H4IIE cell line showing greater sensitivity to Et-18-OCH3. In addition, serum-stimulated MAPK activity was significantly enhanced in H4IIE versus cultured hepatocytes. Moreover, treatment with Et-18-OCH3 significantly attenuated serum stimulated MAPK activity in both cultured hepatocytes and H4IIE cells. Furthermore, U73122 (Gqalpha-PLC specific uncoupler) and GP2A (Gqalpha specific inhibitor) mirrored the effects of those observed for Et-18-OCH3 whereas PD98059 (specific MEK inhibitor) completely abolished serum-stimulated DNA synthesis in tumorigenic H4IIE cells. We conclude that HCC is associated with enhanced Gq/G11-PLC expression/activity as compared with normal liver. Furthermore, a PLC-linked MAPK cascade plays a significant role in the progression of the enhanced mitogenesis characteristic of HCC.     

Long-term follow-up of a patient with hepatocellular carcinoma associated with triple hepatitis virus (HBV, HDV, HCV) infection

OBJECTIVE: To determine the serum levels of soluble vascular cell adhesion molecule-1 (sVCAM-1) and soluble E-selectin (sE-selectin) in patients with systemic sclerosis (SSc). METHOD: Serum samples from 80 patients with SSc and 20 healthy control subjects were examined by a sensitive enzyme-linked immunosorbent assay. RESULTS: The serum levels of sVCAM-1 and sE-selectin were significantly higher in the patients with SSc than in the healthy controls. The serum levels of sVCAM-1 were correlated with the presence of pulmonary fibrosis, joint involvement and elevated erythrocyte sedimentation rate levels. The serum levels of sE-selectin were correlated with the presence of pulmonary fibrosis. CONCLUSION: These results suggest that endothelial activation is involved in the development of this disease.     

Expression of human aldehyde dehydrogenase-3 associated with hepatocellular carcinoma: promoter regions and nuclear protein factors related to the expression

Studies in our laboratory have shown that as early as day 8.5 of development, mouse yolk sac cells can generate T cells when placed in a thymic microenvironment. At this stage, yolk sac cells can also differentiate into myeloid cells in vitro. B cell differentiation in vitro was achieved with day 9 yolk sac by providing a bone marrow stromal feeder layer. We have now established endothelial cell lines and clones from yolk sacs of day 8-12 mouse embryos. These vary in their ability to support stem cell maintenance and differentiation. Our principal work has been carried out with day 12 cloned endothelial cell lines. One clone supported the > 100 fold expansion of yolk sac hematopoietic stem cells that subsequently could generate B cells, T cells and myeloid cells both in vitro and in vivo. Preliminary experiments with endothelial cells from younger embryos are also described.     

The role of MMP-2 in the invasion and metastasis of hepatocellular carcinoma (HCC)

OBJECTIVES: To get insights into the role of MMP-2 in the invasion and metastasis of hepatocellular carcinoma (HCC), and to find a method to judge the invasion and metastasis of HCC through MMP-2. METHODS: Zymograph and immunohistochemistry were used to study the content and types of positive cells of MMP-2 in the HCC, and statistical methods were used to analyse the association between the content of MMP-2 and the pathological indexes of HCC. RESULTS: MMP-2 was expressed by all the normal liver, HCC and surrounding liver parenchyma. The increase of MMP-2 and the presence of the active type of MMP-2 were related to the invasion and metastasis of HCC. The content of MMP-2 in HCC being higher than that in surrounding liver parenchyma was an important index to judge the invasion and metastasis of the HCC. The positive cells of MMP-2 found in immunohistochemistry were normal hepatocytes, cholangioepithelial cells, Ito cells, regenerated hepatocytes, new generated cholangioepithelial cells, and HCC cells. CONCLUSION: MMP-2 was related to the invasion and me astasis of HCC. The content of MMP-2 in HCC being higher than that in surrounding liver parenchyma could be bused as an important index to judge the invasion and metastasis of HCC.     

Gastrointestinal disorders: the role of diet in cause and management

Diet has a definite role in certain gastrointestinal disorders, and dietary manipulation often is beneficial. In other cases, such as peptic ulcer, traditional dietary therapy cannot be justified by available evidence.