Interleukin-2 as a modulator of 5-fluorouracil in hepatic arterial immunochemotherapy for liver metastases

BACKGROUND/AIMS: Hepatic arterial infusion of interleukin-2-based immunochemotherapy has yielded a high response rate (> 75%) in patients with unresectable liver metastases. In order to clarify the mechanisms that underlie the apparent benefit of combination treatment, the role of IL-2 as a modulator of 5-fluorouracil metabolism was investigated. METHODOLOGY: A single dose of 5-fluorouracil (50 mg/kg) with or without IL-2 (3500 Japan Reference Units/kg) was given via the hepatic artery to rats bearing liver metastases. Thirty minutes later samples of liver metastatic foci or surrounding normal liver tissue were removed for the measurement of thymidylate synthase, thymidine kinase and dihydropyrimidine dehydrogenase activity, and 5-fluorouracil content. RESULTS: 5-fluorouracil levels in tumor were significantly higher than in normal liver. Although the addition of IL-2 reduced 5-fluorouracil levels in both tumor and normal liver tissues by the activation of dihydropyrimidine dehydrogenase, the ratio of tumor/normal liver 5-fluorouracil levels was unchanged. Both thymidylate synthase and thymidine kinase activities were significantly inhibited in tumor tissue when the combination of 5-fluorouracil and IL-2 was administered. CONCLUSIONS: IL-2 increases 5-fluorouracil cytotoxicity through the inhibition of thymidylate synthase/thymidine kinase activities in the hepatic arterial infusion.     

Impaired synthesis of retinol-binding protein and transthyretin in rat liver with bile duct obstruction

To gain further insight into the protein metabolism in bile duct-obstruction, we examined the synthesis of retinol-binding protein (RBP) and transthyretin (TTR) in rats with common bile duct-ligation. In these rats, liver and plasma levels of RBP and TTR decreased markedly, whereas liver retinoid contents remained unchanged. Although there appeared no decrease in the total amount of RBP or TTR mRNA expressed in the liver, the subcellular distribution of these mRNAs changed from the membrane-bound polysome fraction to the membrane-unbound polysome fraction. This abnormal distribution recovered rapidly after biliary drainage, resulting in the subsequent recovery of the plasma RBP and TTR levels. These observations suggest that cholestasis inhibits the synthesis and secretion of RBP and TTR by disrupting the binding of their mRNAs to membrane-bound polysomes. Plasma levels of RBP and TTR might be sensitive indicators of the recovery of protein synthesis after biliary drainage in patients with obstructive biliary disorders.Supported in part by Grant-in-Aids from the Ministry of Education, Science and Culture (05770350 to M.O.; 05670463 to H.M.; 07780553 to S.K.) and by a grant from the Ryoichi Naito Foundation for medical research (to S.K.).     

Unusual trihydroxy bile acids in the urine of patients treated with chenodeoxycholate, ursodeoxycholate or rifampicin and those with cirrhosis

Urinary bile acids from 20 patients treated with chenodeoxycholate, 18 treated with ursodeoxycholate, 15 treated with rifampicin and 8 patients with advanced cirrhosis were analyzed by gas-liquid chromatography and gas-liquid chromatography-mass spectrometry. Occurrence rates and amounts of three so-called unusual trihydroxy bile acids, hyocholate, ursocholate and omega-muricholate, were increased in patients treated with chenodeoxycholate, ursodeoxycholate or rifampicin and decreased in cirrhotic patients as compared with those in untreated healthy adults. These data suggest that chenodeoxycholate and ursodeoxycholate are hydroxylated to produce unusual trihydroxy bile acids in bile acid-loaded humans and that this metabolism may be related to the induction of hepatic microsomal enzymes by rifampicin. In contrast, the hydroxylation of chenodeoxycholate and ursodeoxycholate may be impaired by severe hepatic damage. Because the urine is a secretory pathway for internal bile acids, the occurrence of unusual trihydroxy bile acids in the urine may be used as an indicator of hepatic ability to metabolize "hydrophobic" dihydroxy bile acids to their secretory forms.     

Rhabdoid tumor predisposition syndrome with renal tumor 10 years after brain tumor

We report a case of rhabdoid tumor predisposition syndrome with a renal tumor developing 10 years after a brain tumor, which demonstrated an unexpectedly favorable outcome. A 2-year-old boy underwent gross total resection of a brain tumor located in the fourth ventricle, and received adjuvant chemotherapy and radiotherapy. At the age of 11 years, a renal tumor was found and nephrectomy was performed. He is currently alive without evidence of disease over 2 years without postoperative therapy. Histologically, rhabdoid cells were observed in both brain and renal tumors. Loss of SMARCB1 (also known as INI1) expression was found in the nucleus of both tumor cells. Genetic testing revealed pathogenic variants of SMARCB1 exon 5 in the renal tumor and SMARCB1 exon 9 in the brain tumor. In addition, heterozygous deletion of 22q11.21-q11.23 containing the SMARCB1 locus was shared by both tumors and this deletion was identified in normal peripheral blood. Considering the histopathological and genetic findings, our case was considered to be rhabdoid tumor predisposition syndrome with atypical teratoid/rhabdoid tumor and late-onset rhabdoid tumor of the kidney.     

A Survey of the FAERS Database Concerning the Adverse Event Profiles of α1-Adrenoreceptor Blockers for Lower Urinary Tract Symptoms

Purpose: Current guidelines recommend α1-adrenoreceptor blockers (A1Bs) for treating lower urinary tract symptoms suggestive of benign prostatic hyperplasia, but their adverse effects can be problematic. In this study, reports submitted to the US Food and Drug Administration Adverse Event Reporting System (FAERS) between 1997 and 2011 were reviewed to assess the safety profiles of A1Bs.Methods: After deleting duplicated submissions and revising arbitrary drug names, reports involving A1Bs for male patients were analyzed. Data mining algorisms were used for the quantitative detection of signals, where a signal represents an association between a drug and an adverse event or a drug-associated adverse event, including the proportional reporting ratio, reporting odds ratio, information component given by a Bayesian confidence propagation neural network, and empirical Bayes geometric mean.Results: The total number of reports used was 1,260,182. Signal scores suggested the associations of alfuzosin, doxazosin, tamsulosin, and terazosin with dizziness/vertigo, orthostatic hypotension, erectile dysfunction, ejaculation dysfunction (EjD), thirst/dry mouth, and constipation; however, reports on naftopidil, silodosin, and urapidil were not enough to compare with the other 4 A1Bs. Signal scores for EjD were higher for tamsulosin, and those for dizziness/vertigo were lower for doxazosin than for the other 3 drugs.Conclusions: Tamsulosin-associated EjD, which was found in clinical studies, was reproduced in this analysis with markedly higher signal scores, and these results strongly suggest the necessity of well-organized clinical studies on A1B-associated adverse events.     

Clinicopathological evaluation of T2-gastric cancer among age groups

BACKGROUND/AIMS: Although the recent results of surgical treatments for T2-gastric cancer (defined as: tumor invasion of the muscularis propria or the subserosa) have been comparatively favorable, frequency of lymph node metastasis is high and recurrence often happens. METHODOLOGY: A retrospective study on T2-gastric cancer in 347 patients who underwent curative resection between 1975 and 1995 was performed to address this issue. These 347 patients were divided into 3 groups according to age: group I (72 cases) < 50 years old; group II (202 cases) not < 50 years but < 70 years old; and group III (73 cases) > or = 70 years old. RESULTS: There was an apparent tendency that gastric cancer in aged patients is more likely to become differentiated cancer and spread easily to the liver. CONCLUSIONS: The data suggest that aged patients should be more carefully followed for any hematogenous metastases including liver metastases. Removal of hepatic metastases or regional hepatic infusion chemotherapy may then salvage some patients even elderly patients.     

Effects of bypass on ocular ischaemic syndrome caused by reversed flow in the ophthalmic artery

Superficial temporal to middle cerebral artery bypass was useful for ocular ischaemic syndrome caused by reversed flow in the ophthalmic artery as shown by ophthalmic-artery colour doppler flow imaging.     

Thrombocytosis in patients with tumors producing colony-stimulating factor.

We investigated the cause of thrombocytosis in 14 patients with tumors producing colony-stimulating factor (CSF). Of the 14 patients, 10 had tumors producing granulocyte-CSF (G-CSF) and 4 had tumors producing granulocyte-macrophage--CSF (GM-CSF). Thrombocytosis of greater than 400 x 10(9)/L was noted in 8 of 10 patients with G-CSF-producing tumors and all 4 patients with GM-CSF-producing tumors. Median peak platelet counts were, respectively, 511 x 10(9)/L (range, 384 to 694 x 10(9)/L) and 579 x 10(9)/L (range, 526 to 910 x 10(9)/L) in patients with tumors producing G-CSF and GM-CSF. In most patients, thrombocytosis declined towards the terminal stage. High interleukin-1 (IL-1) and IL-6 levels were found in addition to CSFs in the plasma or culture supernatants of tumor cells obtained from most patients. In patients with GM-CSF-producing tumors, these specimens had megakaryocyte-CSF (Meg-CSF) activity, which was abolished by anti-GM-CSF antibody. These specimens also had megakaryocyte potentiating (Meg-Pot) activity attributable to both GM-CSF and IL-6. In patients with G-CSF-producing tumors, only Meg-Pot activity due to IL-6 was detected. These results indicate that the thrombocytosis in GM-CSF-producing tumors was caused by both the Meg-CSF activity of GM-CSF and the Meg-Pot activity of IL-6 plus GM-CSF, while that in G-CSF-producing tumors was due to the Meg-Pot activity of IL-6.     

Endotoxin-induced hypercoagulability: a possible aggravating factor of alcoholic liver disease

The present experiments were designed to study the effect of chronic ethanol consumption on endotoxin toxicity. The intravenous injection of endotoxin produced a more pronounced increase of serum AST and ALT activities in chronic ethanol-fed rats, when compared to controls. The activities of hepatic mitochondrial enzymes, succinate dehydrogenase and cytochrome oxidase, were also distinctly decreased by endotoxin treatment in chronic ethanol-fed rats. Consistent with these biochemical alterations, light and electron microscopic examinations revealed severe liver injury after endotoxin injection in chronic ethanol-fed rats. Furthermore, the increase of blood BUN and creatinine levels accompanied by the degeneration of the renal tubulus and slight infiltration of neutrophils into the glomerule were produced by endotoxin treatment and were more conspicuous in chronic ethanol-fed rats than controls. Therefore, the biochemical and histological evidence indicates that endotoxin markedly potentiates organ injury after chronic ethanol consumption. In addition, a more pronounced decrease in blood antithrombin III activity accompanied by an increase in fibrin degradation product level in blood was recognized in chronic ethanol-fed rats receiving endotoxin, when compared to controls receiving endotoxin. This increase of blood fibrin degradation product level correlated well with the decrease of antithrombin III activity (r = -0.6116; p less than 0.005). These findings of blood antithrombin III activity and fibrin degradation product level indicate that the coagulation-fibrinolysis system is more activated by endotoxin treatment after chronic ethanol consumption. Furthermore, the activation of the coagulation-fibrinolysis system was well correlated with biochemical and histological alterations representing hepatorenal involvement.(ABSTRACT TRUNCATED AT 250 WORDS)     

Impact of cytomegalovirus serostatus on outcome of unrelated cord blood transplantation for adults: a single-institute experience in Japan

Cytomegalovirus (CMV) disease is one of the major infectious complications after allogeneic hematopoietic stem cell transplantation (SCT). Several studies have shown that CMV-seropositive patients have a substantial survival disadvantage after bone marrow transplantation (BMT) or peripheral blood SCT (PBSCT). Between August 1998 and February 2006, 101 adult patients underwent myeloablative cord blood transplantation (CBT) from unrelated donors at our institution. Sixteen and 85 patients were CMV-seronegative and CMV-seropositive, respectively, prior to CBT. Outcomes of CBT were compared between CMV-seronegative and CMV-seropositive patients. The cumulative incidences of neutrophil engraftment at 60 d after CBT did not differ between CMV-seronegative and CMV-seropositive patients (100% and 94%, P = 0.09); however, the cumulative incidence of platelet engraftment at 100 d was higher in CMV-seronegative patients than CMV-seropositive patients (100% vs. 86%, P < 0.005). The cumulative incidence of CMV antigenemia at 100 d was lower in CMV-seronegative patients than CMV-seropositive patients (0% vs. 77%, P < 0.001); however, the cumulative incidences of CMV disease did not differ between CMV-seronegative and CMV-seropositive patients (0% vs. 1%, P = 0.84). The probabilities of disease-free survival at 2 yr also did not differ between CMV-seronegative and CMV-seropositive patients (92% vs. 72%, P = 0.16). The outcomes of CBT for CMV-seropositive patients as well as CMV-seronegative patients in our series were favorable. This might be due to effective antiviral therapy for CMV infection. Large-scale studies are needed to determine the impact of recipient CMV serostatus on the outcome of CBT for adults.