Management of adrenal metastasis from hepatocellular carcinoma

Purpose: Although the adrenal gland is a common site of extrahepatic metastasis from hepatocellular carcinoma (HCC), there are no definitive guidelines for the treatment of adrenal metastasis. This study examines the effectiveness of various treatments for this disease. Methods: We retrospectively analyzed 20 patients treated for adrenal metastasis of HCC by adrenalectomy (n = 13), transarterial chemoembolization (TACE), or percutaneous ethanol injection therapy (PEIT) (n = 7). Results: There were no significant differences in cumulative survival rates between patients given adrenalectomy and those given TACE or PEIT, either after completing treatment for primary HCC or after the first treatment for adrenal metastasis. Six of seven patients with tumor thrombi in the inferior vena cava (IVC) from adrenal metastasis underwent adrenalectomy combined with intracaval thrombectomy, five of whom survived for more than 1 year after surgery, and two of whom are still alive without any recurrence more than 3 years after surgery. PEIT showed good results for small adrenal metastasis. Conclusion: These findings suggest that therapeutic modalities should be chosen according to the clinical features of each individual, including the size of the metastatic tumor, whether there is invasion into the IVC, the function of the remaining liver, and the existence of intra- and/or nonadrenal extrahepatic lesions. Furthermore, intracaval tumor thrombectomy could be indicated for patients with IVC thrombus if they are suitable candidates for surgery. Received: July 9, 2001 / Accepted: July 2, 2002 Reprint requests to: Y. Shimahara     

Calcium regulation by troponin and its genetic disorder in striated muscle contraction

Contraction of skeletal and cardiac muscles is regulated by Ca2+ through specific Ca(2+)-regulatory proteins, troponin and tropomyosin, located in the thin filament. Troponin is a Ca2+ receptive protein consisting of three differet components, troponins C, I, and T. The essential mechanisms of Ca(2+)-regulation are the inhibition of contractile interaction between myosin and actin by the inhibitory action of troponin I and the reversal of the inhibition by troponin I through the Ca(2+)-binding to troponin C. All three components of troponin are required for the Ca(2+)-regulation of contraction. This article reviews following aspects of troponin researches: 1) early studies on the structure and function of troponin, 2) molecular mechanisms of Ca(2+)-regulation, 3) principles of troponin-exchange in skinned fibers and properties of troponin isoforms thereafter clarified under physiological conditions, 4) recent studies on the functional consequences of the mutations in human cardiac troponins T and I that cause genetic disorders, familial hypertrophic cardiomyopathy (HCM), and familial dilated cardiomyopathy (DCM).     

Tumor-specific novel taxoid-monoclonal antibody conjugates

Taxoids bearing methyldisulfanyl(alkanoyl) groups for taxoid-antibody immunoconjugates were designed, synthesized and their activities evaluated. A highly cytotoxic C-10 methyldisulfanylpropanoyl taxoid was conjugated to monoclonal antibodies recognizing the epidermal growth factor receptor (EGFR) expressed in human squamous cancers. These conjugates were shown to possess remarkable target-specific antitumor activity in vivo against EGFR-expressing A431 tumor xenografts in severe combined immune deficiency mice, resulting in complete inhibition of tumor growth in all the treated mice.     

Catechol and hydroquinone have different redox properties responsible for their differential DNA-damaging ability.

We examined the redox properties of the "carcinogenic" catechol and the "noncarcinogenic" hydroquinone in relation to different DNA damaging activities and carcinogenicity using 32P-labeled DNA fragments obtained from the human genes. In the presence of endogenous NADH and Cu2+, catechol induces stronger DNA damage than hydroquinone, although the magnitudes of their DNA damaging activities were reversed in the absence of NADH. In both cases, DNA damage resulted from base modification at guanine and thymine residues in addition to strand breakage induced by Cu+ and H2O2, generated during the oxidation of catechol and hydroquinone into 1,2-benzoquinone and 1,4-benzoquinone, respectively. EPR and 1H NMR studies indicated that 1,2-benzoquinone is converted directly into catechol through a nonenzymatic two-electron reduction by NADH whereas 1,4-benzoquinone is reduced into hydroquinone through a semiquinone radical intermediate through two cycles of one-electron reduction. The reduction of 1,2-benzoquinone by NADH proceeds more rapidly than that of 1,4-benzoquinone. This study demonstrates that the rapid 1,2-benzoquinone two-electron reduction accelerates the redox reaction turnover between catechol and 1,2-benzoquinone, resulting in the enhancement of DNA damage. These results suggest that the differences in NADH-mediated redox properties of catechol and hydroquinone contribute to their different carcinogenicities.     

Absolute stereostructures of three new sesquiterpenes from the fruit of Alpinia oxyphylla with inhibitory effects on nitric oxide production and degranulation in RBL-2H3 cells

The 80% aqueous acetone extract and the ethyl acetate-soluble portion from the dried fruit of Alpinia oxyphylla MIQUEL were found to show inhibitory effects on nitric oxide production in lipopolysaccharide-activated macrophages and antigen-induced degranulation in RBL-2H3 cells. A new eudesmane-type sesquiterpene, oxyphyllol A, and two eremophilane-type sesquiterpenes, oxyphyllols B and C, were isolated from the ethyl acetate-soluble portion, together with 16 known constituents. The absolute stereostructures of oxyphyllols A, B, and C were determined on the basis of chemical and physicochemical evidence. The effects of isolated components on nitric oxide production were examined, and nine constituents including oxyphyllol A and nootkatone were found to show inhibitory activity. On the other hand, five constituents inhibited the release of beta-hexosaminidase from RBL-2H3 cells.     

Role of hypomagnesemia in chronic cyclosporine nephropathy

BACKGROUND: Hypomagnesemia is a common finding of cyclosporine (CsA)-treated patients and has been proposed as both a cause and a consequence of CsA-induced nephrotoxicity. This experiment was conducted to elucidate the role of hypomagnesemia in the pathogenesis of chronic CsA nephropathy. METHODS: CsA (15 mg/kg/day subcutaneously) was administered to rats maintained on a low-sodium diet for 1, 2, and 4 weeks, and the effects of magnesium (Mg) supplementation on renal function, renal histology, and renal gene expression profile of fibrogenic molecules and vasoconstrictors was examined. RESULTS: CsA elicited hypomagnesemia and induced a progressive decline in glomerular filtration. At 28 day, renal tubular atrophy and cortical striped interstitial fibrosis were evident with CsA treatment. Dietary supplementation of Mg ameliorated CsA-induced hypomagnesemia and almost completely abolished CsA-induced chronic fibrotic lesions. Neither CsA nor Mg supplementation affected blood pressure. Renal cortical mRNA of transforming growth factor beta, plasminogen activator inhibitor (PAI)-1, and extracellular matrix started to increase at 14 days and elevated further at 28 days. In contrast, the increase in mRNA of tissue inhibitor of matrix metalloproteinase-1 and renin was evident early at 7 days and reached peak at 14 days. These mRNA increases, except that of renin, were almost abolished when hypomagnesemia was corrected. Magnesium supplementation also improved glomerular dysfunction, at least in part, through inhibition of up-regulated mRNA of endothelin-1. CONCLUSION: CsA-induced hypomagnesemia contributes to chronic renal fibrotic lesions seen during CsA treatment through up-regulation of fibrogenic molecules, most notably early activation of tissue inhibitor of matrix metalloproteinase-1 expression.     

Glucagon-like peptide-1 evokes action potentials and increases cytosolic Ca2+ in rat nodose ganglion neurons

We previously reported that the intraportal appearance of glucagon-like peptide-1 (GLP-1) facilitates the afferent activity (the spike discharge firing rate) of the rat hepatic vagus in a dose-dependent fashion. To examine whether GLP-1 directly activates single neurons isolated from the rat nodose ganglion, GLP-1-induced changes of the membrane potential and cytosolic-free Ca2+ concentration ([Ca2+]i) in the cells were measured using whole-cell patch-clamp and microfluorometric techniques, respectively. GLP-1 application (3 x 10(-12) - 3 x 10(-9) M) induced a gradual depolarization from a mean resting membrane potential of - 55.0 +/- 3.1 mV and evoked a burst of action potentials with a time lag of 7.5 +/- 4.5 min after its starting (n = 4). The burst of action potentials continued during the application and even up to 13 min or more after its cessation. GLP-1 at a concentration of 10(-12) - 10(-8) M induced an increase of [Ca2+]i. The GLP-1-induced [Ca2+]i responses were often oscillatory and lasted even up to 10 min or more after the washout of GLP-1. An adenylate cyclase activator, forskolin, mimicked the GLP-1-induced increase in [Ca2+]i. The present results indicate that GLP-1 activates nodose ganglion neurons as manifested by membrane depolarization, a burst of action potentials and [Ca2+]i increase, possibly via the cAMP pathway. Together with our previous observations, the results strongly suggest cellular mechanisms by which the postprandial humoral information, intraportal appearance of GLP-1, is uniquely converted to the neural information in the hepatoportal area.     

Multiple synchronous primary malignant tumors of fibrosarcoma and squamous cell carcinoma in the urinary bladder: a case report

A 65-year-old housewife presented with a diagnosis of malignant spindle cell tumor of the bladder which had been diagnosed by work up for chance hematuria. Urine cytology revealed a small number of squamous epithelial cells showing dyskeratosis but no spindle cells. Computed tomography and magnetic resonance images showed a markedly enhanced mass, 4 cm in diameter, on the anterior wall of the urinary bladder, which appeared to be adhesive to the pubic bone. However, no metastasis was found. Under the suspicion of sarcoma of the urinary bladder, we performed anterior pelvic exenteration with construction of an ileal conduit. Although the anterior wall of the urinary bladder was mildly adhesive to the pubic bone, the surgical margin was negative for malignant cells. The tumor corresponded to a fibrosarcoma that infiltrated the adipose tissue surrounding the urinary bladder. The entire mucosa of the bladder showed diffuse squamous metaplasia, and well differentiated squamous cell carcinoma with pearl formation was found in part. These two malignant tumors were clearly apart from each other, resulting in the histologic diagnosis of synchronous multiple malignant tumors of the bladder. The patient developed a local relapse and pulmonary metastasis of fibrosarcoma one month postoperatively and died two month later without any response to chemotherapy (CYVADIC) and radiotherapy. The current case seems to be the first one in Japan (third in the world) of a patient with multiple synchronous primary malignant tumors, carcinoma and sarcoma, airsing in the urinary bladder.     

Abnormalities of rate-corrected QT intervals in Parkinson's disease-a comparison with multiple system atrophy and progressive supranuclear palsy

A number of patients with Parkinson's disease (PD) and multiple system atrophy (MSA), in whom sudden death does occur occasionally, have QT or rate-corrected QT (QTc) interval prolongation on electrocardiogram (ECG). Although these QT or QTc interval abnormalities are likely related to autonomic dysfunction, the pathophysiology remains unknown. The aim of this study was to compare the degree of QTc interval prolongation among akinetic-rigid syndromes, namely PD and related disorders, and to evaluate the relationship between QTc prolongation and severity of autonomic dysfunction. Thirty-four patients with PD, 22 with MSA, 11 with progressive supranuclear palsy (PSP) and 30 healthy controls underwent standard autonomic function tests, and electrocardiography variables (RR, QT and QTc intervals) were measured by an ECG recorder with an automated analyzer. The relationship between QTc interval and cardiovascular reflex tests were also analyzed. Orthostatic hypotension and decreased heart rate in response to respiratory stimuli were prominent in MSA, while these were relatively mild in PD. Unlike the RR and QT intervals, the QTc interval significantly differed among all groups (p<0.01). The QTc interval was significantly prolonged in PD (409+/-17 ms; p<0.001) and MSA (404+/-14 ms; p<0.05) compared with healthy controls (394+/-19 ms). Neither autonomic dysfunction nor QTc interval prolongation was evident in PSP. QTc intervals and cardiovascular reflexes did not correlate, except for Valsalva ratio. The QTc interval was obviously prolonged in PD patients to an extent that could not be accounted for simply by autonomic dysfunction levels. MSA patients showed slightly prolonged QTc intervals in spite of marked cardiovascular autonomic dysfunction. Abnormalities of the QTc may reflect the degeneration of cardioselective sympathetic and parasympathetic neurons that cannot be fully captured by cardiovascular autonomic function tests.     

New bone-seeking agent: Animal study of Tc-99m-incadronate

OBJECTIVE: Disodium cycloheptylaminomethylenediphosphonate monohydrate (incadronate disodium) is a third-generation bisphosphonate compound which potently inhibits bone resorption, and a highly effective drug in the treatment of metastatic bone disease. We first labeled incadronate disodium with 99mTc, and examined its biodistribution and bone uptake after intravenous injection in rats to assess its potential for clinical use as a bone-seeking agent for judgment of the therapeutic effect of incadronate on bone metastases. Bone scan with 99mTc-labeled incadronate (99mTc-incadronate) may yield important information prior to the use of incadronate for treatment of bone metastases. METHODS: Synthesis of 99mTc-incadronate was carried out by reduction of 99mTc-pertechnetate in the presence of SnCl2 and N2 gas. Normal rats were injected with 18.5 MBq (0.5 mCi) 99mTc-incadronate in a volume of 0.1 ml intravenously and then sacrificed at 15 min, 30 min, 1 h or 2 h (six rats at each time point) after injection. Samples of muscle, stomach, small intestine, kidney, liver and bone (femur) were taken and weighed. In addition, a 1-ml sample of blood was drawn from the heart, and urine was taken from the urinary bladder immediately after sacrifice. Samples were measured for radioactivity and expressed as percent uptake of injected dose per gram or per milliliter (% ID/g or ml). Bone-to-blood and bone-to-muscle uptake ratios were determined from the % ID/g or ml values for these organs. RESULTS: The greatest accumulation of 99mTc-incadronate was found in bone. Radioactivity in bone was as high as 3.22 +/- 0.68% ID/g at 2 hours after injection. Scintigraphic images of 99mTc-incadronate in normal rats revealed highly selective skeletal uptake. CONCLUSION: 99mTc-incadronate exhibited high uptake in bone, and relatively low uptake in soft tissue, suggesting that it may be useful as a bone-seeking agent for judgment of the therapeutic effect of incadronate on bone metastases, by determining the degree of its accumulation in metastatic bone lesions.