Prediction of hepatic graft viability before reperfusion: an analysis of effluent from porcine allografts

Rapid and reliable assessment of hepatic graft viability is important for successful orthotopic liver transplantation (OLTx). OLTx was performed in 11 pairs of pigs via a venovenous bypass. Six of these grafts were transplanted immediately (group A), while the other five were preserved in University of Wisconsin (UW) solution for 24 h and then transplanted (group B). All grafts were flushed with 300 ml of chilled (4°C) Ringer's lactate solution before reperfusion of the graft, when 20 ml of effluent from the graft was collected and the concentrations of ammonia, lactic acid, GOT, and LDH were measured. Four of the six pigs in group A survived longer than 3 days, while the other two pigs died of causes other than graft dysfunction. All five pigs in group B died either of hemoperitoneum or hemodynamic instability due to liver failure. The histology of postperfusion biopsies in group A showed minimal pathological changes, while the grafts in group B revealed moderate to severe ischemic injuries. Ammonia and lactic acid in the effluent of group B were significantly higher than those of group A (1511±216 vs 417±333 g/dl and 114.1±12.2 vs 91.4±12.2 mg/dl, respectively; P<0.05 in both cases). Before reperfusion, the rate of total adenine nucleotides in all of the substances in the graft, which were measured using high performance liquid chromatography (HPLC), inversely correlated with the ammonia levels in the effluent. We conclude that an analysis of the effluent, (i.e. the levels of ammonia and lactic acid), flushed from a hepatic graft before reperfusion could serve as a predictor of hepatic graft viability.     

Confluent BALB/c 3T3 cells monolayer provides selective and efficient growth of neoplastic cells

In an attempt to further characterize non-irradiated contact-inhibited confluent monolayer of BALB/c 3T3 cells (= Contact-Sensitive Plates; CSP) as substrata for in vitro drug sensitivity testing, we compared the efficiency of colony formation with panels of cell lines on CSP with that on plastic dishes or in agar. Tumorigenicity in athymic nude mice was also examined. We found that: (1) HeLa cells, 2 esophageal cancer lines, rat 3Y1 fibroblasts transformed by either adenovirus type 12, mouse polyoma virus, Rous avian sarcoma virus, or plasmid DNA carrying v-Ha-ras oncogene all formed colonies on CSP and in agar and at the same time was tumorigenic. The efficiency of colony formation on CSP proved always to be higher than that in agar. (2) None of the 4 "normal" fibroplastic cell lines formed colonies on CSP or in agar and were tumorigenic. (3) Simian virus 40 and adenovirus E1A gene transformed rat 3Y1 fibroblasts formed colonies on CSP but not in agar, and were not tumorigenic. Therefore, CSP was found to provide selective and efficient growth of neoplastic cells when compared to other substrata and is also helpful in detecting incompletely transformed cells.     

Efficacy of postoperative adjuvant therapy for stage ilia breast cancer: Futraful vs futraful+tamoxifen for er-positive patients and futraful vs futraful + adriamycin for er-negative breast cancer

A multi-center, randomized controlled collaborative study was conducted in 310 institutions located throughout Japan for 3 years and 9 months from February 1985 until October 1988 to evaluate the efficacy of post-operative adjuvant therapy for patients who had previously undergone curative surgery for treatment of Stage IIIa breast cancer. Patients with estrogen receptor-positive [ER( + )] breast cancer were treated with two types of regimens, ie, cyclophosphamide + adriamycin + fluorouracil (CAF; 2 cycles) + Futraful (FT) or CAF (2 cycles) + FT + tamoxifen (TAM), and the clinical benefit of additional use of TAM was evaluated. Of the 509 ER( + ) patients registered for the trial, 473 patients (92.9%) were eligible for evaluation. The 5-year survival rate was 77.2% for the CAF + FT group and 74.6% for the CAF + FT+TAM group, and the 5-year disease-free survival rate was 56.7% for the CAF+FT group and 59.2% for the CAF + FT + TAM group. Neither the survival rate nor the disease-free survival rate differed significantly between the groups. Analyses by factor revealed that the 5-year disease-free rate for lymph node-negative patients in the CAF + FT + TAM group was significantly higher than that for the corresponding patients in the CAF + FT group. No differences were noted in the incidence of adverse reactions between the two treatment groups, other than an increase in LDH (the frequency of which was higher in the CAF + FT+TAM group than in the CAF + FT group). Patients with estrogen receptor-negative [ER( -)] breast cancer were treated with two types of regimens, ie, CAF + FT or CAF + FT + adriamycin (ADR), and the clinical benefit of the combined use of intermittent doses of ADR was evaluated. Of the 514 ER(-) patients registered in the trial, 478 (93.0%) were eligible for evaluation. The 5-year survival rate was 64.9% for the CAF + FT group and 63.0% for the CAF + FT + ADR group, and the 5-year disease-free survival rate was 59.2% for both CAF + FT and CAF + FT + ADR groups. Neither the survival rate nor the disease-free survival rate differed significantly between the groups. There were no significant differences between these groups in analyses by nodal or menopausal status. The incidences of adverse reactions including anorexia, nausea/vomiting and alopecia were higher in the CAF + FT+ADR group than in the CAF + FT group.     

Pharmacokinetics and boron uptake of BSH (Na2B12H11SH) in patients with intracranial tumors

We evaluated retrospectively the pharmacokinetics and boron uptakeof BSH (mercaptoundecahydrododecarborate) for Boron Neutron Capture Therapy(BNCT) in 123 patients undergoing craniotomy for intracranialtumors. The pharmacokinetics revealed that BSH could moveeasily from blood to the peripheral organs; itwas retained there and elimination was very slow.BSH after intra-arterial infusion (IA) was found tomove into the peripheral organs more easily thanafter intra-venous (IV) infusion.In patients with malignant glioma, the average valuesof boron concentration in tumor and the tumorto blood ratio (T/B ratio) after IA infusionwere 26.8 ± 19.5 g/g (range, 6.1–104.7 g/g)and 1.77 ± 1.30 (range, 0.47–6.65) respectively. Onthe other hand, after IV infusion the valueswere 20.9 ± 12.2 g/g (range, 7.0–39.7 g/g)and 1.30 ± 0.65 (range, 0.61–2.94) respectively. Thedifferences are not statistically significant. Boron uptake inmalignant glioma was about three times higher thanlow grade glioma. We found a good correlationbetween boron uptake and time interval from BSHinfusion, and 15–20 hours after BSH infusion theboron concentration in tumor was above 20 g/g¹⁰B in 69% of the malignant glioma patients;T/B ratio was above one in 75%, andabove two in 44% of them.We recommend intra-venous infusion of BSH clinically sinceit is safer, and results in sufficient boronconcentration in tumor, and the planned irradiation mightbe optimal around 15–20 hours after the BSHinfusion for treating malignant glioma.     

Disseminated intravascular coagulation in a man with metachronous bone metastasis from gastric-cancer - case-report

We report on a case of multiple bone metastasis and disseminated intravascular coagulation (DIG) in a 49-year-old Japanese man. He underwent total gastrectomy for advanced gastric cancer in July 1992, He was diagnosed as a case of multiple bone metastasis in August 1993. Severe anemia, thrombocytopenia, and elevated fibrinogen degradative products were indicative of DIG. He was treated with sequential i.v. administration of methotrexate (MTX) and 5-fluorouracil (5-FU) and continuous i.v. infusion of heparin and gabexate mesilate. After two weeks of treatment with MTX combined with 5-FU, the findings of DIC disappeared and his general condition improved dramatically.     

Synergism of cytotoxicity between cis-diaminedichloro-platinum-(ii) and cis-diamine(1,1-cyclobutanedicarboxylate)-platinum-(ii)

In an attempts to increase the antitumor effect and to reduce normal tissue toxicity, the combined cytotoxic effect of cis-Diamminedichloroplatinum (II) (CDDP) and cis-diammine(1,1-cyclobutane dicarboxylate) platinum (II) (CBDCA) was investigated using HeLa and colon 26 cell lines and the combination index (CI). Cytotoxicity of the combination of CDDP and CBDCA on 27 surgically resected specimens of human gastric and colorectal adenocarcinomas was also evaluated using the in vitro succinate dehydrogenase inhibition (SDI) test. The CI values varied with the dose ratio examined (1:1-1:6) of CDDP and CBDCA, with findings that CI<1, synergy, was obtained at fraction affected (Fa)>0.75 for HeLa cells and at Fa<0.9 for colon 26 cells in cases of a dose ratio of 1:1 to 1:2. Of all 27 clinical human adenocarcinomas, the succinate dehydrogenase (SD) activity was significantly lower in cancer cells concomitantly exposed to both CDDP and CBDCA than in those exposed to either drug alone. These positive effects of a combination of two platinum analogues on human malignant tissues have heretofore not been reported, which would warrant the clinical application of this combination for human malignant tumors.     

Multiple tumor-suppressor-1 gene and esophageal-carcinoma

The multiple tumor suppressor 1 (MTS1) gene is homozygously deleted frequently in cell lines derived from a wide variety of tumors. We investigated the deletion of the MTS1 gene in esophageal cancer cell lines and primary esophageal squamous carcinomas using the polymerase chain reaction. Sixteen and 15 of 23 esophageal cancer cell lines showed homozygous deletion of MTS1 exon 1 and exon 2, respectively, while none of 21 primary esophageal carcinomas showed the deletion. An analysis of MTS1 gene mutations was carried out by direct DNA sequencing in 8 cell lines and 21 primary carcinomas showing no homozygous deletion. In contrast to previous reports of esophageal carcinoma, there were no mutations recognized in the region sequenced. Our study suggests that the inactivation of the MTS 1 gene may play an important role in esophageal carcinoma cell lines but may be less important in primary carcinomas of the human esophagus.     

The significance of stromal desmoplasia in intrahepatic cholangiocarcinoma: a special reference of 'scirrhous-type' and 'nonscirrhous-type' growth.

Fifty-eight surgically resected cases of intrahepatic cholangiocarcinoma (ICC) were examined grossly and microscopically. We microscopically categorized the ICC into two groups, "scirrhous-type" ICC (SICC) and "nonscirrhous-type" ICC (NSICC), according to the degree of the stromal desmoplasia in the tumor. We next assessed the histologic characteristics including proliferative activities and prognoses. Additionally, the prognostic factors of ICC were examined by univariate and multivariate analyses. Histologically, the incidences of lymphatic permeation and perineural invasion in SICC (85.7% and 100.0%, respectively) were significantly higher than those in NSICC (47.7% and 45.6%, respectively). The mean MIB-1 labeling index of SICC (mean+/-standard deviation, 29.9%+/-14.3%) was significantly higher than that of NSICC (mean+/-standard deviation, 19.1%+/-14.3%). Additionally, the 1- and 3-year survival rates of the SICC were 64.3% and 22.0%, respectively, and those of NSICC were 72.8% and 55.8%, respectively. The survival rate of SICC was significantly lower than that of NSICC. Overall, lymphatic permeation, intrahepatic metastasis, and lymph node metastasis were all considered to be independent prognostic factors for a worse prognosis based on the multivariate analyses, whereas our new category based on stromal desmoplasia or other variables were not. Our study thus indicates that lymphatic permeation, perineural invasion, and a higher proliferative activity of tumor cells carry a poorer prognosis in SICCs than in NSICCs. Although the overall independent prognostic factors were lymphatic permeation, intrahepatic permeation, and lymph node metastasis based on a multivariate analysis, a detailed histologic examination related to the stromal desmoplasia in the tumor is also considered to be useful for evaluating the biologic behavior of the ICC.     

Assessment of hepatic graft injury by graft effluent in rodents: N-acetyl-β-glucosaminidase and type III procollagen peptide

We studied the significance of N-acetyl--glucosaminidase (-NAG) and type III procollagen peptide (P-III-P) in the effluent of rodent hepatic grafts. After total hepatectomy, the livers were preserved in chilled, lactated Ringer's solution and then divided into five groups (n=10 each): group 1, 4 h preservation only; group 2, 4 h preservation and rewarming; group 3, 6 h preservation only; group 4, 6 h preservation and rewarming; and group 5, minimal preservation only. The -NAG of groups 2 and 4 was significantly higher than that of groups 1 and 3 (0.98±0.5 U/l vs 0.21±0.12 U/l; P<0.01 and 1.76±0.67 U/l vs 0.38±0.25 U/l, respectively; P<0.01), while that of group 4 was significantly higher than that of group 2 (1.76±0.67 U/l vs 0.98±0.50 U/l; P<0.05). The P-III-P of group 4 was significantly higher than that of group 2 (0.133±0.008 U/ml vs 0.110±0.015 U/ml; P<0.01). We conclude that -NAG is a novel parameter of parenchymal and nonparenchymal cells, while P-III-P reflects the integrity of the hepatic sinusoidal extracellular matrix.     

Spontaneous submucosal dissection of the esophagus. A case report

A forty year-old Japanese woman complained of slight hematemesis and severe pain on swallowing. Fluoroscopic examination showed typical esophagograms of "double barreled esophagus" or "mucosal stripe". An esophageal ulceration, probably where the dissection re-entered the usual lumen, was endoscopically evident at the lower end of the mucosal bulging. A large, shallow ulcer of unknown cause was also identified in the just anal area from the esophago-gastric junction. She recovered with conservative treatment of fasting, cimetidine and sodium alginate.