Effects of intermittent Pringle's manoeuvre on cirrhotic compared with normal liver.

BACKGROUND: Although patients with liver cirrhosis are supposed to tolerate ischaemia-reperfusion poorly, the exact impact of intermittent inflow clamping during hepatic resection of cirrhotic compared with normal liver remains unclear. METHODS: Intermittent Pringle's manoeuvre was applied during minor hepatectomy in 172 patients with a normal liver, 59 with chronic hepatitis and 97 with liver cirrhosis. To assess hepatic injury, delta (D)-aspartate aminotransferase (AST) and D-alanine aminotransferase (ALT) (maximum level minus preoperative level) were calculated. To evaluate postoperative liver function, postoperative levels of total bilirubin, albumin and cholinesterase (ChE), and prothrombin time were measured. RESULTS: Significant correlations between D-AST or D-ALT and clamping time were found in each group. The regression coefficients of the regression lines for D-AST and D-ALT in patients with normal liver were significantly higher than those in patients with cirrhotic liver. Irrespective of whether clamping time was 45 min or less, or at least 60 min, D-AST and D-ALT were significantly lower in patients with cirrhosis than in those with a normal liver. Parameters of hepatic functional reserve, such as total bilirubin, prothrombin time, albumin and ChE, were impaired significantly after surgery in patients with a cirrhotic liver. CONCLUSION: Patients with liver cirrhosis had a smaller increase in aminotransferase levels following portal triad clamping than those with a normal liver. However, hepatic functional reserve in those with a cirrhotic liver seemed to be affected more after intermittent inflow occlusion.

Impact of a left-lobe graft without modulation of portal flow in adult-to-adult living donor liver transplantation.

In adult-to-adult living donor liver transplantation (LDLT), left-lobe grafts can sometimes be small-for-size. Although attempts have been made to prevent graft overperfusion through modulation of portal inflow, the optimal portal venous circulation for a liver graft is still unclear. Hepatic hemodynamics were analyzed with reference to graft function and outcome in 19 consecutive adult-to-adult LDLTs using left-lobe grafts without modulation of graft portal inflow. Overall mean graft volume (GV) was 398 g, which was equivalent to 37.8% of the recipient standard liver volume (SV). The GV/SV ratio was less than 40% in 13 of the 19 recipients. Overall mean recipient portal vein flow (PVF) was much higher than the left PVF in the donors. The mean portal contribution to the graft was markedly increased to 89%. Average daily volume of ascites revealed a significant correlation with portal vein pressure, and not with PVF. When PVP exceeds 25 mmHg after transplantation, modulation of portal inflow might be required in order to improve the early postoperative outcome. Although the study population was small and contained several patients suffering from tumors or metabolic disease, all 19 patients made good progress and the 1-year graft and patient survival rate were 100%. A GV/SV ratio of less than 40% or PVF of more than 260 mL/min/100 g graft weight does not contraindicate transplantation, nor is it necessarily associated with a poor outcome. Left-lobe graft LDLT is still an important treatment option for adult patients.

Increased frequency of CD45 negative T cells (T zone cells) in older Golden retriever dogs.

T zone lymphoma (TZL) is characterized by the clonal expansion of T cells lacking expression of the pan-leukocyte antigen CD45 (TZ cells). A strong breed predisposition is observed in Golden retrievers. This study aimed to confirm aberrant CD45 mRNA expression and determine if Golden retrievers without clinical lymphoma have an increased frequency of circulating TZ cells. Gene expression analysis on confirmed TZL cases showed a significant decrease in CD45 expression compared to normal dogs. Peripheral blood samples from senior dogs, 242 Golden retrievers and 42 non-Golden retrievers, without evidence of lymphoproliferative disease were assessed for the presence of TZ cells by flow cytometry. Thirty-one percent of Golden retrievers had TZ cells compared to 14% of non-Golden retrievers. Thirty-four percent of Golden retrievers with TZ cells had a clonal T cell receptor gamma (TRG) gene rearrangement. Interestingly, 20% of Golden retrievers without TZ cells also had a clonal TRG rearrangement. Golden retrievers may have an increased risk of TZL due to an increased frequency of TZ cells.

Clinicopathologic features of lingual canine T-zone lymphoma.

Canine T-zone lymphoma (TZL) is a subtype of T-cell lymphoma characterized by unique histologic pattern and cytomorphology, immunophenotypic loss of CD45 expression, and an indolent clinical behaviour. Dogs with TZL typically present with 1 or more enlarged lymph nodes and/or lymphocytosis. We describe a novel extranodal presentation of TZL involving the tongue. Twelve dogs with tongue masses were diagnosed with lingual TZL based on a variable combination of immunophenotyping via flow cytometry, cytology, histopathology, immunohistochemistry and/or PCR for antigen receptor rearrangement (PARR) assay. Eleven dogs exhibited concurrent lymphocytosis and/or lymph node enlargement. Three cases were initially diagnosed as plasma cell tumours based on histology alone, thereby revealing a potential diagnostic challenge. Seven dogs achieved clinical remission and 4 achieved stable disease following variable treatment, consistent with the indolent nature of typical TZL involving the lymph nodes and peripheral blood. In 1 case the TZL resulted in progressive disease and failure to respond to treatment. In this case, the TZL exhibited histologic features of a higher grade neoplasm. This case series highlights a unique presentation of TZL and identifies a new differential diagnosis for lingual neoplasia. In this study, we characterize the clinical presentation, diagnostic features and patient outcomes of 12 dogs with lingual TZL.

Breed Distribution and Clinical Characteristics of B Cell Chronic Lymphocytic Leukemia in Dogs.

BACKGROUND: B-cell chronic lymphocytic leukemia (B-CLL) is the most common hematopoietic malignancy in humans in the developed world and the primary risk factor is genetic. Dogs also develop B-CLL, but there is no systematic description of the disease in dogs. Understanding the epidemiology of B-CLL in dogs may help practitioners recognize the disease and position the dog as a model for future genetic studies. OBJECTIVES: To describe B-CLL presentation in dogs, its clinicopathologic findings, and breed predisposition. ANIMALS: Four hundred and ninety-one dogs with B-CLL and 5,673 control dogs with suspicion of a lymphoproliferative disorder (LPD). METHODS: Retrospective cross-sectional study of dogs for which samples were submitted to the Colorado State University Clinical Immunology Laboratory for immunophenotyping between 2010 and 2014. To assess breed predilection, dogs with B-CLL were compared to those with suspicion of other LPDs using logistic regression. RESULTS: The median age was 11 years with no sex predilection. Half of the dogs presented with peripheral lymphadenopathy or splenomegaly and 26% had anemia. Eleven small-breed dogs had significantly increased odds of B-CLL. In addition, English Bulldogs had an increased risk and a unique presentation: these dogs were diagnosed at a median of 6 years and expressed lower class II MHC and CD25. CONCLUSIONS: B-cell chronic lymphocytic leukemia is overrepresented in small-breed dogs. Future genetic studies of these breeds may identify genetic risk factors. The unique presentation of English Bulldogs provides evidence of multiple forms of this disease. Additional studies are necessary to determine whether presenting signs are associated with survival.

Prophylactic intravesical instillation therapy with adriamycin and mitomycin C in patients with superficial bladder cancer.

Intravesical instillation of adriamycin (ADM) or mitomycin C (MMC) was carried out for the purpose of preventing the recurrence of superficial bladder cancers (Ta and T1) after transurethral resection or transurethral coagulation. First, eligible patients were divided into two groups (solitary and multiple) and then they were randomized into the following three groups: (1) ADM group, intravesical instillation with 50 mg ADM dissolved in 100 ml physiological saline; (2) MMC group, intravesical instillation with 30 mg MMC dissolved in 100 ml physiological saline; (3) control, transurethral resection or transurethral coagulation alone. The drugs were given six times by instillation within 2 weeks after TUR or TUC; after 2 weeks the drugs were administered for 2 consecutive days every 4 weeks for 2 years. Of the 134 patients admitted to the study, 103 were evaluable and 31 were eliminated as non-evaluable patients. The cumulative nonrecurrence rates were 73.6% for ADM, 63.4% for MMC, and 22.5% for controls after a follow-up of 24 months. The cumulative non recurrence rates of the ADM and MMC groups were significantly higher than that of the control group. The incidence of side effects was low and the grade of these side effects mild. This instillation therapy with ADM and MMC was considered useful for preventing the recurrence of superficial bladder cancers.

Intravesical chemotherapy with 4'-epi-Adriamycin in patients with superficial bladder tumors.

We evaluated the effects of 4'-epi-Adriamycin (EPI), a derivative of Adriamycin (ADR), in intravesical instillation chemotherapy. The patients received two courses of three daily instillations of 50-80 mg EPI dissolved in 30 ml physiological saline on 3 consecutive days, with an interval of 4 days between courses. Full evaluation was possible in 33 of 35 patients with superficial bladder tumors treated with EPI. Complete response was observed in 4 cases and partial response in 14 cases, giving a response rate of 55%. Side effects such as pollakiuria and pain on micturition occurred in 9 cases. EPI appears to be an effective agent for intravesical instillation chemotherapy in patients with superficial bladder tumors.

Usefulness of p53 protein, Bcl-2 protein and Ki-67 as predictors of chemosensitivity of malignant tumors.

In various types of human malignant tumors, the presence or absence of expression of apoptosis-associated gene products (p53 protein and Bcl-2 protein) and the tumor proliferation activity-related factor (Ki-67) was assessed by immunohistochemical staining and the correlation between this expression and chemosensitivity to anticancer drugs was investigated. Study subjects comprised 55 preoperative patients with untreated malignant tumors (9 with esophageal cancer, 11 with stomach cancer, 11 with colon cancer, 13 with hepatic cancer and 11 with breast cancer). A chemosensitivity test was carried out with the histoculture drug response assay (HDRA) method using 4 drugs, mitomycin C (MMC), 5-fluorouracil (5-FU), doxorubicin hydrochloride (ADM), and cisplatin (CDDP). Immunohistochemical staining was used to assess expression of p53 protein, Bcl-2 protein and Ki-67. The tumor growth inhibition index (I.I.) of the 4 drugs was significantly lower in a group of the patients with p53 protein overexpression-type (mutant p53 protein positive expression-type) tumors than in a group with p53 protein negative expression-type tumors (p<0.05). No significant correlation was found between the expression of the Bcl-2 protein by and the I.I. of any drug studied in any type of cancer. A negative correlation was found between the labeling index (L.I.) for Ki-67 in all cases and I.I. for MMC and ADM and thus, chemosensitivity of the tumors with high growth activity was lower. Furthermore, a positive correlation existed between the L.I. for Ki-67 and that for p53 protein. The patients with p53 protein overexpression-type (mutant p53 protein positive) tumors showed low chemosensitivity. In addition, overexpression of p53 protein is suggested to be one of the factors involved in the lowered chemosensitivity of the tumors with high growth activity. Summarizing these findings, the p53 protein can play an important role in cancer therapy.

Development of anti-influenza drugs: II. Improvement of oral and intranasal absorption and the anti-influenza activity of stachyflin derivatives.

The in-vivo anti-influenza-virus activity of Stachyflin derivatives (III and its phosphate ester, III-Phos), a new class of haemagglutinin fusion inhibitor, and the improvement of their absorption after oral or intranasal administration were studied in mice, rats, and ferrets. The absorption of III in PEG 4000 and III-Phos aqueous solution increased about three and four fold in AUC after oral administration to uninfected mice compared with that of 0.5% HPMC (hydroxypropyl-methylcellulose) suspension. Using a mouse influenza virus infection model, significant anti-influenza-virus activity was observed in infected mice treated orally with these compounds dissolved in PEG 4000 or distilled water, respectively, but not in mice treated with 0.5% HPMC. The in-vivo anti-influenza-virus activity in ferrets, a good model for influenza virus infection in man, was also studied. Although the concentration of III in plasma was above the IC50 against the influenza virus strain used for 6h after the oral administration of III in PEG 400 to uninfected ferrets, no in-vivo anti-influenza-virus activity was observed at the same dosage given 4 times daily for 3 days. The intranasal administration of III-Phos, which was expected to have a more notable in-vivo anti-influenza-virus activity, was examined. III-Phos, whose intranasal absorption had been improved by the modification of III with phosphate ester in rats, inhibited viral replication in the nasal cavity and suppressed influenza-virus-induced fever when administered intranasally to infected ferrets. This study demonstrates that intranasally administered compounds with anti-influenza-virus activity must permeate the nasal membranes to produce their anti-influenza-virus effect.

Cytological alteration of cultured rat liver cells by 3'-methyl-4-dimethylaminoazobenzene with special reference to chromosome changes, changes of growth patterns at a colony level and alpha-fetoprotein production.

A near diploid clone derived from a rat liver cell line was continuously treated with various concentrations of 3'-methyl-4-dimethylaminoazobenzene (3'-Me-DAB) in culture. By treatment with 2.8 micrograms/ml, cells with 41 chromosomes formed a mode and which then shifted to 39. The chromosome numbers of cells treated with 5.4 micrograms/ml were widely distributed at early stages, but later the mode shifted to hypotetraploid region. Untreated control cells were confirmed as near diploid. Increased plating efficiency by 3'-Me-DAB as well as the appearance of large sized colonies was obtained. The production of alpha-fetoprotein (AFP) by the cells was slightly enhanced by treatment with 3'-Me-DAB. The cells treated with and without 3'-Me-DAB did not produce any tumor in rats 6 months after their intraperitoneal injection.

The effects of intravesical instillation of Thio-Tepa on the recurrence rate of bladder tumors.

Seventy-eight patients were treated with intravesical instillation of Thio-Tepa in an attempt to prevent postoperative recurrences of bladder tumors. Fifty-six patients who were given no preventive treatment against recurrences were taken as the control group. The patients in this series presented at the Okayama University Hospital between 1961 and 1976 and only the first recurrence after the primary operation was taken into consideration. There was no significant difference in the recurrence rates of the control and instillation groups.

Effects of steroid sex hormones and adriamycin on human bladder cancer cells in culture.

The effects of steroid sex hormones on the established cell lines derived from human urinary bladder cancer, T24, and from human transitional cell cancer of the urinary tract, 253J, were examined using the colony formation method. Of the seven kinds of steroid hormones tested, estradiol-17 beta was intensively cytotoxic for both cells. The cytotoxic effect was depended on the dose and time of treatment. The combined effect of Adriamycin and estradiol-17 beta on T24 cells could be recognized at low concentrations of Adriamycin (less than or equal to 10(-3) micrograms/ml) after exposure for 24 h.

Field infestation of rambutan fruits by internal-feeding pests in Hawaii.

More than 47,000 mature fruits of nine different varieties of rambutan (Nephelium lappaceum L.) were harvested from orchards in Hawaii to assess natural levels of infestation by tephritid fruit flies and other internal feeding pests. Additionally, harvested, mature fruits of seven different rambutan varieties were artificially infested with eggs or first-instars of Mediterranean fruit fly, Ceratitis capitata (Wiedemann), or oriental fruit fly, Bactrocera dorsalis (Hendel) (Diptera: Tephritidae) to assess host suitability. When all varieties were combined over two field seasons of sampling, fruit infestation rates were 0.021% for oriental fruit fly, 0.097% for Cryptophlebia spp. (Lepidoptera: Tortricidae), and 0.85% for pyralids (Lepidoptera). Species of Cryptophlebia included both C. illepida (Butler), the native Hawaiian species, and C. ombrodelta (Lower), an introduced species from Australia. Cryptophlebia spp. had not previously been known to attack rambutan. The pyralid infestation was mainly attributable to Cryptoblabes gnidiella (Milliere), a species also not previously recorded on rambutan in Hawaii. Overall infestation rate for other moths in the families Blastobasidae, Gracillariidae, Tineidae, and Tortricidae was 0.061%. In artificially infested fruits, both species of fruit fly showed moderately high survivorship for all varieties tested. Because rambutan has such low rates of infestation by oriental fruit fly and Cryptophlebia spp., the two primary internal-feeding regulatory pests of rambutan in Hawaii, it may be amenable to the alternative treatment efficacy approach to postharvest quarantine treatment.

[Clinical effect of UFT on bladder cancer].

UFT (a mixture of futraful and uracil) was administered orally to 15 cases of recurrent and superficial bladder cancer principally for more than 4 weeks at the doses of 300 or 600 mg per day. The result was evaluated by Koyama-Saito's response criteria. Of 14 evaluable cases, complete remission was noted in 5. Two cases of advanced bladder cancer were treated with UFT combined with irradiation therapy, and one case was found that cancer cells degenerated severely in the primary lesion pathologically. Another case was recognized that lung metastasis disappeared completely. As the side effects, anorexia occurred in 2 cases with 600 mg per day and 1 case with 300 mg, but it was not so severe to terminate UFT therapy. From above-mentioned results, UFT seems to be a useful drug for the treatment of bladder cancers.

[Intravesical chemotherapy with 4'-Epi-Adriamycin in patients with superficial bladder tumors].

Intravesical instillation of anticancer agents is one of the most effective methods for treating superficial bladder cancer. We evaluated the effects of including 4'-Epi-Adriamycin, a derivative of Adriamycin, in intravesical instillation chemotherapy. Thirty-five patients with superficial bladder tumors were treated with 4'-Epi-Adriamycin. The patients received 2 courses of 3 consecutive daily instillations of 50-80 mg 4'-Epi-Adriamycin dissolved in 30 ml of physiological saline, with an interval of 4 days. Of the 33 cases which could be fully evaluated, complete regression was observed in 4 cases and partial regression (greater than 50%) in 14 cases, showing an effectiveness rate of 55%. Side effects such as pollakisuria and miction pain occurred in 9 cases. The rate of effectiveness of this treatment was approximately equivalent to the results that we reported using Adriamycin and the occurrence and degree of side effects were lower.

[Effects of etoposide in testicular tumors].

A clinical study of a new semisynthetic podophyllotoxin etoposide (NK 171) was performed by administering the drug to four patients with testicular tumors. The drug was given intravenously at a dose of 80-120 mg/m2/day for five days or orally at a dose of 200 mg/body/day for five days. Among the four patients, 1 CR, 1 NC and 2 PD were observed. One patient with a testicular tumor who was given oral etoposide achieved complete remission for 23 months. Patients experienced the following side effects: alopecia (75%); anorexia (50%): stomatitis, phlebitis, anemia and liver dysfunction (25%). None of these side effects, however, was serious or permanent. Currently, we are testing etoposide in combination chemotherapy.

[Alternating combination chemotherapy (VIP-DMF) in patients with advanced adenocarcinoma of the prostate].

Eleven patients with advanced adenocarcinoma of the prostate were treated with a cyclic alternating chemotherapy (VIP-DMF therapy), consisting of a three-drug combination of vincristine, ifosfamide, and peplomycin; and a three-drug combination of adriamycin, mitomycin C and 5-fluorouracil. Each cycle was repeated every 3 or 4 weeks. Of these patients, 9 were refractory to prior hormonal therapy and 8 (89%) achieved an objective response (3 partial, 6 stable) using the criteria of the U.S. National Prostatic Cancer Project. In the patients showing objective response, the duration was from 3 to 18 months with a median duration of 6 months. The survival periods from the initiation of chemotherapy in effective cases ranged from 6 to 20+ months with a median duration of 11 months. The major toxicity was myelosuppression, although no patients suffered life-threatening toxicity. We consider that VIP-DMF therapy is a useful regimen for the treatment of advanced prostatic cancer.

[Phase II study of recombinant human leukocyte A interferon on urogenital cancer patients].

A phase II study on recombinant human leukocyte A interferon (rIFN-alpha A) was carried out in 30 patients with urogenital cancers. Each patient received rIFN-alpha A by i.m. injection every day for at least 4 weeks. The initial daily dose was 3 X 10(6) U, being escalated at intervals of 3 days or more up to 50 X 10(6) U. The results are summarized as follows: In aged patients, the daily dose appropriate for everyday i.m. injection was considered to be 9 X 10(6) U or below, judging from the adverse reactions observed. According to Koyama and Saito's response criteria, partial response (PR) and minor response (MR) were obtained, respectively, in 3 and 1 out of 12 patients with renal cell carcinoma, while PR was seen in 1 out of 9 with urothelial cancer. No response was observed in patients with testicular cancer and in those with prostatic cancer. Various kinds of adverse reactions were recognized and each patient showed one reaction or more. Fever, fatigue, leukopenia, anemia, thrombocytopenia and elevation of GOT and GPT were observed relatively frequently. Among these, fatigue and thrombocytopenia were regarded as dose limiting factors.

[Combination chemotherapy with cisplatin, ifosfamide and adriamycin in patients with advanced transitional cell carcinoma of the urinary tract].

A combined chemotherapy with cisplatin, ifosfamide and adriamycin (CIA therapy) was performed in 20 patients with advanced transitional cell carcinoma of the urinary tract. Adriamycin 30mg/m2 and ifosfamide 1.5g/m2 were administered on day 1 and cisplatin 50 mg/m2 on day 2, which was repeated at intervals of 3 weeks, in principle. According to Koyama and Saito's response criteria, complete response (CR), partial response (PR) and minor response (MR) were obtained in 1, 4 and 5 cases, respectively; CR+PR+MR in 10 cases out of 18 evaluable cases (56%). The duration of response was 2 to 14 months (median; 4 months) in the cases with CR and PR. The survival time of the responders ranged from 3 to 23 months (median; 11 months), being significantly longer than that of the non-responders (p less than 0.05, Generalized Wilcoxon test). Adverse reactions observed were of a slight or moderate degree, with only a few cases of damage to renal function.

[Intravesical chemotherapy with interferon in superficial bladder tumors].

Interferon (IFN) was used in the treatment of superficial bladder tumors. Interferon (IFN-beta, IFN-gamma) was instilled into the bladder at dosages ranging from 16 billion to 36 billion U IFN per 30 ml physiological saline. The IFN was instilled into the bladder once a day or twice a day for 10 to 20 days. In this trial, ten patients with superficial bladder tumors were treated at Okayama City Hospital, and of these, 1 CR, 3 PR, 2 MR and 4 NC were obtained. There were no signs of either irritable bladder or general side effects. IFN (especially IFN-beta) is considered a useful drug for superficial bladder tumors in intravesical chemotherapy.