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Facilitative glucose transporter-1 (GLUT1) is abundant in trophoblast cells and is responsible for glucose transport in the placenta. However, the change in GLUT expression in human placenta upon trophoblast differentiation remains to be clarified. Therefore, we first examined the localization of GLUT1 and GLUT3 using human first-trimester chorionic villi. We found that GLUT1 and GLUT3 were mainly localized to syncytiotrophoblast and cytotrophoblast cells respectively. We analyzed whether placental GLUT1 and GLUT3 expression changes during differentiation using a human choriocarcinoma (BeWo) cell line which is known to show functional and morphological differentiation in response to cAMP in culture. Treatment of BeWo cells with 8-bromo-cyclicAMP (8-bromo-cAMP) increased the level of hCG secretion and induced cell fusion leading to the formation of large syncytia. Treatment of BeWo cells with 8-bromo-cAMP also resulted in a significant increase in glucose uptake on days 2-3 of culture. The stimulating effect of 8-bromo-cAMP on glucose uptake was concentration dependent. Northern and immunoblot analyses revealed that the levels of mRNA and protein of GLUT1, but not of GLUT3, were significantly increased by 8-bromo-cAMP. These findings suggest that 8-bromo-cAMP stimulates GLUT1 expression with differentiation in BeWo cells.

Percutaneous microwave coagulation therapy (PMCT) is a new technique for the treatment of hepatocellular carcinoma (HCC). However, it is difficult to distinguish those lesions in which necrosis has been induced from the viable residual lesions during the procedure, because the margin of the tumor becomes unclear during PMCT. We determined the area of necrotic lesions during the procedure using color Doppler imaging. PMCT was performed on 10 patients (17 lesions) with recurrent HCC. The electrode of the microwave delivery system was moved around the tumor and the surrounding area until color mosaic images disappeared from the entire area of the tumor. The areas in which necrotic tissue was indicated by color Doppler imaging were later confirmed by other modalities such as angiography or contrast-enhanced computed tomography. This leads us to believe that real-time, effective evaluation of PMCT is possible with color Doppler imaging.

The FIB-4 index is a simple formula to predict liver fibrosis based on the standard biochemical values (AST, ALT and platelet count) and age. We here investigated the utility of the index for noninvasive prediction of progression in liver fibrosis. The time-course alteration in the liver fibrosis stage between paired liver biopsies and the FIB-4 index was examined in 314 patients with chronic hepatitis C. The average interval between liver biopsies was 4.9 years. The cases that showed a time-course improvement in the fibrosis stage exhibited a decrease in the FIB-4 index, and those that showed deterioration in the fibrosis stage exhibited an increase in the FIB-4 index with a significant correlation (P0.001). Increase in the ΔFIB-4 index per year was an independent predictive factor for the progression in liver fibrosis with an odds ratio of 3.90 (P = 0.03). The area under the receiver operating characteristic curve of the ΔFIB-4 index/year for the prediction of advancement to cirrhosis was 0.910. Using a cut-off value of the ΔFIB-4 index/year0.4 or ≥ 0.4, the cumulative incidence of fibrosis progression to cirrhosis at 5 and 10 years was 34% and 59%, respectively in patients with the ΔFIB-4 index/year ≥0.4, whereas it was 0% and 3% in those with the ΔFIB-4 index/year0.4 (P0.001). In conclusion, measurement of the time-course changes in the FIB-4 index is useful for the noninvasive and real-time estimation of the progression in liver fibrosis.

There is an increasing need for accurate prediction methods of assessing individual risk for breast cancer for both clinical and research purposes. The purpose of this study is to compare the Gail and Claus model risk estimates of breast cancer among women with a family history of breast cancer. This study presents risk estimates from two models of breast cancer risk in 491 women 18 to 74 years of age with a family history of breast cancer who were recruited to risk counseling clinical trials in Seattle, Washington between 1996 and 1997. These trials included women from the general population and additional samples of Ashkenazi Jewish, African-American, and lesbian women. We estimated and compared lifetime (to age 79) and 5-year risk for developing breast cancer using the National Surgical Adjuvant Breast and Bowel Project adaptation of the Gail model and the Claus model. About one-quarter of participants fell into the Gail "high" risk category (or =1.7% risk of developing breast cancer in the next 5 years). The average lifetime risk was estimated at 13.2% by the Gail model and 11.2% by the Claus model. Estimates from the two models were moderately and positively correlated (r = 0.55) with the Gail model yielding a higher estimate than the Claus model for most participants. If women with a family history of breast cancer are being counseled regarding decisions on genetic testing, tamoxifen use, or other preventive measures, presenting both Claus and Gail estimates may be the best option.

We report on results of an interview study assessing women's attitudes toward and hypothetical interest in genetic susceptibility testing for breast cancer. Data are from 246 interviews with women of varying ethnicity (African American, European American, Native American, and Ashkenazi Jewish), family history of breast cancer (negative, positive, and borderline), and educational level. Semistructured interviews included questions on general health beliefs; attitudes, experiences, and concerns about breast cancer; and hypothetical interest in genetic testing. Influence of specific test characteristics was assessed with 14 Likert scales varying negative and positive predictive value, timing of disease, possible medical interventions following a positive result. Results reported include both statistical and qualitative analysis. We found that women had a high level of interest in testing which, in general, did not vary by ethnicity, level of education, or family history. Interest in testing appeared to be shaped by an exaggerated sense of vulnerability to breast cancer, limited knowledge about genetic susceptibility testing, and generally positive views about information provided through medical screening. However, study participants were most interested in a test that didn't exist (high positive predictive value followed by effective, noninvasive, preventive therapy) and least interested in the test that does exist (less than certain positive predictive value, low negative predictive value, and limited, invasive, and objectionable therapeutic options). Our data suggest that without a careful counseling process, women could easily be motivated toward interest in a test which will not lead to the disease prevention they are seeking.

Our aim was to describe and identify factors associated with breast cancer screening among Cambodian American women. We conducted a cross-sectional survey of 1,365 households using bilingual and bicultural interviewers. We found that low proportions of Cambodian American women were up to date on their clinical breast examinations (CBE; 42%) and mammograms (40%). More than 80% of women with female physicians have had at least one prior screening, and 52% have had the tests recently. Women with male Asian American physicians were less likely to have had screening as compared to women with female non-Asian physicians: ever had CBE (odds ratio [OR], 0.26); recent CBE (OR, 0.39); ever had mammogram (OR, 0.36); and recent mammogram (OR, 0.22). Breast cancer screening among Cambodian American women lags behind the general U.S. population. Tailored promotion efforts should address barriers and promote cancer screening by physicians, staff, and organizations serving this population.

Parallel to its established causal association with both infectious mononucleosis (IM) and young adulthood Hodgkin disease (YAHD), we propose a hypothesis that "delayed" primary EBV infection (i.e., primary infection occurring during adolescence or adulthood) is associated with elevated breast cancer risk. We evaluated this hypothesis with two investigations, one descriptive and the other analytic. The descriptive study used international/United States cancer registry data to assess the association between incidence rates of breast cancer and those of YAHD. The incidence rates of the seemingly unrelated neoplasms were strongly correlated (correlation coefficients of 0.74 and 0.88 for international and United States data, respectively; these were higher than the correlation coefficients of YAHD with two other cancers that we considered). Populations with higher incidence rates corresponded to those with higher likelihood of delayed primary EBV infection. The analytical study was based on a population-based case-control study of breast cancer in middle-aged women. Age-adjusted odds ratios of breast cancer in women who reported a history of IM, relative to women who did not, increased monotonically from 0.55 [95% confidence interval (CI), 0.05-6.17] for women with 0-9 years of age at IM onset to 2.67 (CI, 1.04-6.89) for women withor =25 years of age at IM onset (P = 0.016). An older age at tonsillectomy, another surrogate of delayed EBV exposure, was also associated with increased risk of breast cancer: odds ratios, 0.92 (CI, 0.57-1.48) and 1.76 (CI, 1.15-2.69) for women with tonsillectomy at 0-4 years of age andor =15 years of age, respectively (P = 0.018). Adjusting for additional potential confounders did not modify the associations appreciably. The implications of the findings and a potential biological mechanism are presented.

Colorectal hyperplastic polyps are benign lesions that share many risk factors with colorectal adenomas and cancers. Low folate intakes are associated with an increased risk of colon cancer. The enzyme 5,10-methylene-tetrahydrofolate reductase (MTHFR) may be linked to DNA methylation and nucleotide synthesis and thus play a role in the etiology of colorectal neoplasia. We investigated an association between the common MTHFR polymorphism (C677T) and colorectal hyperplastic polyps within the Minnesota Cancer Prevention Research Unit case-control study. Cases (n = 200) were diagnosed with colonoscopically confirmed hyperplastic polyps; controls (n = 645) were derived from the same gastroenterology practice and were polyp-free at colonoscopy. Dietary intakes were estimated from a self-administered food-frequency questionnaire prior to colonoscopy. Multivariate adjusted odds ratios (ORs) and 95% confidence intervals for MTHFR status were 0.8 (0.6-1.2; CT versus CC wild-type) and 0.9 (0.5-1.6; TT versus CC). In subgroup analyses stratified on dietary intakes of folate, vitamin B12, vitamin B6, or methionine, those with the TT genotype and either low intakes of folate or vitamin B6 were at increased risk relative to those with normal or high vitamin intake. However, most 95% confidence intervals included 1.0, and no consistent trends were observed. In contrast to our findings on colorectal adenomas, increasing alcohol consumption was associated with an elevated risk of colorectal hyperplastic polyps, regardless of genotype. The MTHFR (C677T) variant genotype does not appear to be related to risk of colorectal hyperplastic polyps, and there is no convincing evidence that MTHFR shows a different relation to risk, dependent on dietary intakes of nutrients related to its pathway.

5,10-Methylene-tetrahydrofolate reductase (MTHFR), an enzyme in folate metabolism, may play a role in the etiology of colorectal adenomas via effects on DNA methylation and nucleotide synthesis. We investigated the association between a common polymorphism (C677T, reduced MTHFR activity) and colorectal adenomas within the Minnesota CPRU case-control study. Cases (n = 527) were diagnosed with colonoscopically confirmed adenomas; controls (n = 645) were derived from the same gastroenterology practice and were polyp free at colonoscopy. Dietary intakes were obtained from a self-administered food-frequency questionnaire prior to colonoscopy. Age- and sex-adjusted odds ratios (ORs) and 95% confidence intervals for the MTHFR genotype were 0.9 (0.7-1.2; CT versus CC wild-type) and 0.8 (0.6-1.3; TT versus CC). The associations between dietary intakes of folate, vitamin B12, vitamin B6, or methionine and risk of adenomas showed consistent patterns dependent upon MTHFR genotype. Individuals with the TT genotype and intakes of any of these nutrients in the lowest tertile were at elevated risk for adenomas (about 2-3-fold when compared with TT genotype with high intakes). These trends were more pronounced among individuals over age 60, resulting in a 3-6-fold increase for low intakes of folate, B12, and B6. An increased risk with increasing alcohol consumption was observed only among those with the CC genotype (P-trend = 0.005); among those with the TT genotype, those with moderate alcohol consumption were at lowest risk (P for interaction P = 0.02). In conclusion, nutrients involved in the MTHFR metabolic pathway may modify the relationship between the MTHFR C677T polymorphism and colorectal adenomas. Low intakes of folate, vitamin B12, and vitamin B6 increase risk among those (particularly the elderly) with the MTHFR TT genotype.

Vietnamese have higher liver cancer rates than any other racial/ethnic group in the United States. Approximately 80% of liver cancers are etiologically associated with hepatitis B virus (HBV) infection, which is endemic in Southeast Asia.A telephone survey of randomly selected Vietnamese households (n = 75) was conducted during 1998 to examine HBV knowledge among Seattle's Vietnamese community. The questionnaire included items related to the transmission of HBV, the possible sequelae of infection, and disease prevention.The response rate was 70% among reachable and eligible households. Prior to being provided with a description of the disease, two thirds of our respondents had heard of HBV infection. Less than 60% knew that asymptomatic individuals can transmit the disease to others. Most thought that HBV infection can cause liver cancer (63%) and death (80%). However, only a minority knew that infection can be lifelong (38%) and incurable (22%). Finally, 28% had never heard of the HBV vaccine. There were significant associations between knowledge and educational level as well as home ownership.The findings suggest that Vietnamese immigrants have low levels of knowledge about HBV infection, and indicate a need for targeted educational interventions aimed at reducing HBV-related liver cancer mortality.

To improve the response and decrease toxicity of the treatment non-Hodgkin's lymphomas, a prospective single-arm trial was initiated using cyclophosphamide, epirubicin, vincristine, prednisone, bleomycin, eoposide (CEOP-BE). From March 1994 to August 1997, 29 previously untreated patients with intermediate- or high-grade non-Hodgkin's lymphomas, stage II to IV, were included in the study. Complete remissions (CR) were observed in 26 patients. The 4-year overall survival (OS) was 71.3%, and the 4-year disease free survival (DFS) was 61.8%. Recurrences occurred in 11 of 26 patients. Seven of 11 patients with recurrences showed bone marrow or other extranodal lesions. CEOP-BE is an active and feasible regimen for most patients with intermediate- and high-grade non-Hodgkin's lymphomas.

Surgical stapling techniques are widely used in gastrointestinal surgery. These procedures are excellent in convenience and safety. We describe here a new practical application of the surgical disposable stapler, Auto Suture Premium Plus CEEA 34 circular stapler, for the operative drainage of a large symptomatic pancreatic pseudocyst. A 68 year-old man underwent an operative cystogastrostomy using this instrument. His post-operative recovery was uneventful. He is free from symptoms, and abdominal tomography shows complete disappearance of the cystic cavity. We believe that this is the first clinical paper that reports on the stapled cystogastrostomy. This instrument is very useful for creating a stapled cystogastrostomy, similar to one created in the standard open approach.

Cloning, expression and phenotype studies of the defective gene for delta-aminolaevulinate dehydratase (ALAD) in a family with an asymptomatic girl who had ALAD deficiency were carried out. The proband was identified by neonatal ALAD screening, and had erythrocyte ALAD activity at 12% of the normal control. She was heterozygous for ALAD deficiency, which was inherited from her father. Nucleotide sequence analysis of the cloned ALAD cDNA revealed C36 to G and T168 to C mutations on the same allele. The former mutation resulted in F12L substitution, whereas the latter was a silent mutation. All family members who had decreased ALAD activity had the same mutation. Expression of the mutant ALAD cDNA in Chinese hamster ovary cells produced an ALAD protein without significant enzyme activity. Additionally, the mutant ALAD cDNA which encodes F12L substitution produced an aberrant migration pattern in polyacrylamide gel electrophoresis under denaturing conditions. This finding probably reflects an abnormal folding of the F12L protein, since the mutation occurred in the alpha1 helix of the N-terminal arm of the enzyme, which is involved in the extensive quaternary interactions among the subunits. This is also the first report of ALAD gene mutation in an asymptomatic subject.

The goal of this paper is to provide a preliminary description of the marital status for a large number of childhood cancer survivors participating in the Childhood Cancer Survivor Study (CCSS).This report includes children and adolescents (21 years of age) diagnosed with cancer between 1970 and 1986 at 25 oncology centers in the United States and Canada who survived at least 5 years from diagnosis. Self-reported data from 10,425 survivors are used in this preliminary descriptive summary. The proportion of survivors ever married and divorced/separated is compared to the U.S. population according to age-specific groups. The median age of the survivor population at diagnosis was 7 years and 26 years at the time martial status was ascertained. Excluded from this assessment are children15 years of age at the time of study, those whose martial status was unknown, and those married prior to diagnosis. Data for marital status of the U.S. population, as tabulated in the Bureau of Census 1995 Update, is used as a general comparison to the survivor population.Overall, 32% of the survivors reported being married or living as married, 6% being divorced or separated, 0% being widowed, and 62% having never been married. In general, compared to the U.S. population, survivors were less likely to have ever married, particularly females and whites, but, once married, were less likely to divorce/separate, again particularly females and whites. Black survivors were generally found to be more likely to have married, with males and blacks more likely to divorce/separate once married. Comparison of childhood tumor types suggested that survivors of CNS tumors, particularly males, were less likely to have ever married and more likely to divorce/separate compared to those with other cancer diagnoses and the general U.S. population.This interim evaluation of the CCSS cohort provided preliminary data describing a suggested decreased likelihood of marriage, which may be influenced by gender and/or race. These patterns must be confirmed within the entire CCSS cohort and comparisons made with an appropriate sibling comparison group before making final conclusions.

We report a solitary intraperitoneal recurrence in a long-term survivor after rupture of hepatocellular carcinoma. Ultrasonography demonstrated the finding of a lobulated mass with a “mosaic” appearance. The patient underwent resection of this implant and is currently disease free. We emphasize the importance of periodic surveillance of disseminated metastases of this condition.

Southeast Asian women have higher invasive cervical cancer incidence rates and lower Pap testing frequencies than most other racial/ethnic groups in the United States. However, there is little information about the cervical cancer screening behavior of Cambodian-American women. Cambodian residents of Seattle were surveyed in person during late 1997 and early 1998. The PRECEDE model was used to guide the development of items that assessed predisposing, reinforcing, and enabling factors associated with cervical cancer screening participation. The estimated overall survey response was 72%. Four hundred thirteen women completed our questionnaire. Approximately one-quarter (24%) of the respondents had never had a Pap test, and over one-half (53%) had not been screened recently. The following variables were positively associated with a history of at least one Pap smear: younger age, greater number of years since immigration, belief about Pap testing for postmenopausal women, prenatal care in the United States, and physician recommendation. Women who believed in karma were less likely to have ever been screened for cervical cancer than those who did not. Six variables independently predicted recent screening: age; beliefs about regular checkups, cervical cancer screening for sexually inactive women, and the prolongation of life; having a female doctor; and a previous physician recommendation for Pap testing. The study findings indicate that culturally specific approaches might be effective in modifying the cervical cancer screening behavior of immigrant women. Programs targeting Cambodian-Americans are likely to be more effective if they are multifaceted and simultaneously address predisposing, reinforcing, and enabling factors.

OBJECTIVE: To examine the impact of a policy restricting reimbursement for Medicaid anti-ulcer drugs on anti-ulcer drug use and peptic-related hospitalizations. DATA SOURCES/STUDY SETTING: In addition to U.S. Census Bureau data, all of the following from Florida: Medicaid anti-ulcer drug claims data, 1989-1993; Medicaid eligibility data, 1989-1993; and acute care nonfederal hospital discharge abstract data (Medicaid and non-Medicaid), 1989-1993. STUDY DESIGN: In this observational study, a Poisson multiple regression model was used to compare changes, after policy implementation, in Medicaid reimbursement for prescription anti-ulcer drugs as well as hospitalization rates between pre- and post-implementation periods in Medicaid versus non-Medicaid patients hospitalized with peptic ulcer disease. PRINCIPAL FINDINGS: Following policy implementation, the rate of Medicaid reimbursement for anti-ulcer drugs decreased 33 percent (p < .001). No associated increase occurred in the rate of Medicaid peptic-related hospitalizations. CONCLUSIONS: Florida's policy restricting Medicaid reimbursement for anti-ulcer drugs was associated with a substantial reduction in outpatient anti-ulcer drug utilization without any significant increase in the rate of hospitalization for peptic-related conditions.

Efficiency of urine sediment analysis was evaluated in 423 specimens including 86 documented renal disorder ones using three methods; a traditional centrifugal and microscopic one, an image-scanning one and a flow cytometric one. Among the three methods, good correlations were observed in white blood cells and epithelial cells. Between white blood cells and bacterial counts a good correlation was observed only in the flow cytometry one. Female specimens usually demonstrated high values in white blood cells except with the microscopic method. Casts in patients with renal disorder exhibited significantly high in the flow cytometric method. In all methods, proteinuria specimens showed high cast count in the sediment. From these results we concluded that the flow cytometric method was clinically useful, especially in urinary tract disorder specimens.

To evaluate the pain experience of seriously ill hospitalized patients and their satisfaction with control of pain during hospitalization. To understand the relationship of level of pain and dissatisfaction with pain control to demographic, psychological, and illness-related variables.Prospective, cohort study.Five teaching hospitals.Patients for whom interviews were available about pain (n = 5,176) from a total of 9,105 patients in the Study to Understand Prognoses and Preferences for Outcomes and Risks of Treatments (SUPPORT).None.Patients were interviewed after study enrollment about their experiences with pain. When patients could not be interviewed due to illness, we used surrogate (usually a family member) responses calibrated to patient responses (from the subset of interviews with both patient and surrogate responses). Ordinal logistic regression was used to study the association of variables with level of pain and satisfaction with its control. Nearly 50% of patients reported pain. Nearly 15% reported extremely severe pain or moderately severe pain occurring at least half of the time, and nearly 15% of those patients with pain were dissatisfied with its control. After adjustment for confounding variables, older and sicker patients reported less pain, while patients with more dependencies in activities of daily living, more comorbid conditions, more depression, more anxiety, and poor quality of life reported more pain. Patients with colon cancer reported more pain than patients in other disease categories. Levels of reported pain varied among the five hospitals and also by physician specialty. After adjustment for confounding variables, dissatisfaction with pain control was more likely among patients with more severe pain, greater anxiety, depression, and alteration of mental status, and lower reported income; dissatisfaction with pain control also varied among study hospitals and by physician specialty.Pain is common among severely ill hospitalized patients. The most important variables associated with pain and satisfaction with pain control were patient demographics and those variables that reflected the acute illness. Pain and satisfaction with pain control varied significantly among study sites, even after adjustment for many potential confounders. Better pain management strategies are needed for patients with the serious and common illnesses studied in SUPPORT.

Human bone marrow mononuclear cells (BMMNCs) and enriched CD34 positive (CD34+) cells were transduced with adenovirus vectors encoding Escherichia coli beta-galactosidase gene. Tranductions were carried out by 24-hour coincubation with adenovirus vectors at different multiplicities of infections (moi). Efficacy of gene transfer into BM cells and expression of the gene product (ie, beta-galactosidase) were studied using X-Gal histochemical staining and flow cytometric analysis. X-Gal staining demonstrated that the percentage of positive cells at mois of 5 to 500 was 3.4% to 34.5% for BMMNCs and 6.0% to 20.0% for enriched CD34+ cells. Similar results (1.5% to 35.7% for BMMNCs and 5.4% to 24.2% for enriched CD34+ cells) were obtained with flow cytometric analysis using fluorescein di-beta-D-galactopyranoside (FDG). Multicolor flow cytometry analysis, which included FDG, demonstrated that BM progenitors (CD34+ or CD34+CD38-), T cells (CD2+), B cells (CD19+), natural killer cells (CD56+), granulocytes, and monocytes all expressed the adenovirus transgene. To ascertain the effects of adenovirus vectors on normal BM progenitors, the numbers of colony forming unit-granulocyte/macrophage (CFU-GM), burst-forming unit-erythrocyte (BFU-E), and high-proliferative potential-colony-forming cells (HPP-CFC) after 24-hour coincubation with adenovirus vectors were determined. When BMMNCs or enriched CD34+ cells were incubated with adenovirus vectors at mois of 5 and 50, no significant differences in the numbers of CFU-GM, BFU-E, and HPP-CFC were observed compared with the uninfected control cells. However, the numbers of CFU-GM were significantly (P.01) decreased when BMMNCs or enriched CD34+ cells were incubated with adenovirus vectors at a moi of 500, compared with the uninfected control cells. The adenovirus infected cells, purified by cell sorting for FDG expression, were capable of growing in culture and gave rise to various colonies (ie, CFU-GM, BFU-E, and HPP-CFC). These data indicate that recombinant adenovirus vectors can be used to transfer genes to human BM hematopoietic cells with expression of the exogenous gene at a high transduction efficiency.

A 23-year old woman was admitted to our hospital because of fever, leukocytopenia, thrombocytopenia and cervical lymphadenopathy. From pathological findings of the cervical lymphnode she was diagnosed as subacute necrotizing lymphadenitis (SNL). Bone marrow aspiration was hypocellular with proliferation of mature histiocytes with hemophagocytosis. Lactate dehydrogenase was elevated to 1863 IU/l and mild liver dysfunction was observed. Hepatosplenomegaly, lymphnode swelling in abdominal cavity, pleural effusion and pericardial effusion were detected. After glucocorticoid therapy all such disorders were normalized. In this course, Epstein-Barr (EB) virus genome was detected by a polymerase chain reaction method from peripheral mononuclear cells. After normalization, EB virus genome became not to be detected. From present case we concluded that EB virus was expanded in clinical course and was associated with pathogenesis of SNL.

A 6-year-old-boy with epidermolysis bullosa underwent plastic surgeries for the scar contraction of hands. Anesthesia was induced with inhalation of sevoflurane in combination with nitrous oxide and oxygen. The tracheal was not intubated. Anesthesia was maintained with sevoflurane, nitrous oxide and oxygen with continuous intravenous infusion of ketamine. The courses of anesthesia and the operations were uneventful. The most important point in the anesthetic management of the patient with this disease is to avoid mechanical stimulation to skin and mucous membrane.

A case of invasive lung cancer was reported, in which operation partial resection and reconstruction of the invaded superior vena cava (SVC) was performed. During procedure in SVC, a two stage venous return catheter, which is ordinary used in cardiac operations, was used as a temporary SVC-right atrial internal bypass. This new application of the catheter was convenient and effective for resection and reconstruction of SVC.

Analysis of lymphocyte subsets and determination of leukemic cells by flow cytometry has now become an important clinical test. With recent technological developments, reliability was improved and the procedure became easier. To establish quality assurance procedures for flow cytometry, standardization is necessary. In the United States, the National Committee for Clinical Laboratory Standards (NCCLS) has been working actively and has published several tentative guidelines. However, in Japan, such work lags behind that in western countries. The results of quality control surveys show that differences in data exist among instruments and laboratories. To minimize such differences, nation-wide surveillance must be established. Also, efforts should be made to establish reference methods and reference materials that will lead to standardized results. We hope standardization will ensure precision and accuracy in flow cytometric results in clinical laboratories.

A 52-year-old man, who complained of tarry stool and systemic lymphadenopathy, was admitted to our hospital on July 2, 1992. Biopsy showed diffuse large cell lymphoma. Leukocytosis with atypical lymphocytes was not shown in the peripheral blood, but there was an elevated serum LDH level. The man was found to have both HTLV-I antibody and the monoclonal integration of proviral DNA in malignant lymph node cells obtained at biopsy. The diagnosis was lymphoma-type adult T-cell leukemia (ATLL). The chemotherapy regimens of MI-FP, CHOP and modified DHAP were used for the treatment, but were not effective. So, he was treated with etoposide 75 mg orally for 25 days (chronic oral etoposide therapy) and achieved partial remission. This chemotherapy induced myelosuppression with neutropenia, but there was no documented infection. Chronic oral etoposide therapy is an effective regimen for patients with relapse or refractory lymphoma.

The effect of granulocyte-colony stimulating factor (G-CSF) or macrophage-colony stimulating factor (M-CSF) on patients with malignant lymphoma was analyzed. G-CSF was administered for ten days after conventional chemotherapy causing an increase in the granulocyte and monocyte counts. The increase in these cells shortened the duration of a leukocyte count lower than 2000 or 3000/mm3. There were no detectable effects from G-CSF on other blood cells. M-CSF had no effect on any of these cells. Receptors of these cytokines on various types of leukemic cells were also analyzed by flow-cytometry using fluorescent isothianate-labelled G-CSF or M-CSF. With this simplified method, G-CSF receptors were detected on almost all of the myeloid acute leukemia cells, but not on the nonmyeloid leukemic cells. M-CSF receptors were also detected on all of the monocytic acute leukemic cells, but not on myelocytic or lymphocytic leukemic cells.

A 53-year-old man was hospitalized for the development of watery diarrhea associated with decreased appetite and progressive weight loss and was found to have leukocytosis. The white blood cell count was 14,600/microliters with 66 percent abnormal lymphocytes. Serum anti-HTLV-I was positive and monoclonal insertion of HTLV-I provirus into the atypical cell genome was confirmed with the southern blotting hybridization technique. A diagnosis of ATL was made. Examination of fresh stool specimens revealed Isospora belli (I. belli) oocysts. Initial treatment for I. belli consisted of oral trimethoprim 160mg and sulfamethoxazole 400mg given twice daily for nine days. Diarrhea ceased within 2 days of the start of treatment, but I. belli oocysts were again detected after 20 days. Trimethoprim 160mg and sulfamethoxazole 400mg were reinstituted four times daily for 10 days, and then twice daily for 21 days. The clinical response was again dramatic, with rapid clearance of oocysts from the stool. There has been no recurrence of diarrhea. The patient's leukemia was refractory to chemotherapy; the white blood cell count continued to rise, pneumonia developed, and the patient died. I. belli is a previously unrecognized opportunistic pathogen that must be considered in the clinical setting of chronic diarrhea in patients with ATL.

Clinicopathological analysis was performed in 19 patients diagnosed clinically with malignant histiocytosis. Ultimately, 9 patients died and 10 are still alive. All 19 had fever of unknown origin. Among the 10 surviving patients, 6 recovered with only supportive therapy such as antibiotic treatment. One recovered with steroid therapy and 2 with VP (vincristine and prednisolone) therapy. Complications due to immunodeficiency were detected in one surviving patient and 2 who died. All 9 patients who died had anemia, and 8 had thrombocytopenia. However, among survivors, only one had anemia and only 2 had thrombocytopenia. Chromosomal abnormality was detected in one patient who died. Histiocytic cells were classified morphologically into 3 types: immature, intermediate and mature. In 4 patients who died, histiocytic cells were immature, but in 4 others mature histiocytic cells were detected. In 5 of the 10 surviving patients, histiocytic cells were of the immature type. Immuno-histochemical analysis of the origin of histiocytic cells in 8 deceased patients showed T-zone histiocytes in one, T cells in one, monocyte phagocytic system (MPS) in 5, and histiocytes of unknown origin in one. Thus, malignant histiocytosis is a heterogenous entity including reactive histiocytic disorder, lymphocytic neoplasm and true histiocytic neoplasm. In histiocyte proliferative disorders, red blood cell counts and platelet counts are useful for assessing prognosis, while cytological findings only confuse this evaluation.

The efficacy and safety of a combination regimen using flomoxef (FMOX) and tobramycin (TOB) were evaluated in the treatment of infections complicated with hematological disorders. The primary diseases in 40 patients included acute leukemia, malignant lymphoma and others. Complicated infections included 35 cases with suspected septicemia, 4 cases with septicemia and 1 case with pleuritis. Clinical responses were excellent in 10 (25.0%), good in 14 (35.0%), fair in 2 (5.0%) and poor in 14 (35.0%). The efficacy rate was 73.1% in patients with neutrophil counts higher than 501/microliters after administration, but it was 35.7% in patients with counts less than 501/microliters; the difference was statistically significant. No side effects were observed in any of the 40 patients. Abnormal laboratory data in liver functions were identified in 1 patient (2.5%). Degree of this abnormality was very slight, and the continuation of treatment was not disturbed. In conclusion, this combination therapy of FMOX and TOB thus appears to be useful and safe in therapies for infections complicated with hematological disorders.

Forty-three patients with severe infections which were complicating hematological disorders were treated with panipenem/betamipron, and the efficacy and the safety of the drug were evaluated. The results obtained are summarized below. 1. Out of 40 patients in whom efficacies are evaluable, the clinical responses were excellent in 17 patients, good in 4, fair in 7 and poor in 12, and the total clinical efficacy rate was 52.5%. 2. The efficacy rate in 7 patients who had failed to respond to prior treatment with other antibiotics was 57.1%. Thus, no significant difference was observed in efficacy rates between the patients who had failed to respond to prior treatment with other antibiotics and the patients who received no preceding antibiotics therapy. 3. Out of the 43 patients in whom the safety was evaluable, no side effects nor abnormal laboratory findings were found.

CD56 antigen (detected by NKH-1) is distributed on NK cells, monocytes, and ectodermal neural cells. In this study, the blasts of 29.2% of 27 patients with acute nonlymphocytic leukemia (ANLL) expressed CD56 antigen, but not CD16, CD2, or CD3 antigen. Leukemic cells isolated from 3 patients with CD56-positive ANLL did not have NK activity. There were no significant differences between CD56-positive and CD56-negative ANLL in CD13-positive cases, CD33-positive cases, and HLA-DR-positive cases. These results suggest that CD56-positive ANLL could be so-called mixed-lineage leukemia (lymphoid-associated antigen in ANLL).

We studied the effects of granulocyte-colony stimulating factor (G-CSF) on human erythropoiesis in vivo. Changes in the peripheral blood were analyzed in 9 subjects; 3 healthy volunteers, 3 patients with pancytopenia and hypersplenism and 3 patients with chronic renal failure and severe anemia being treated with hemodialysis. We monitored erythropoiesis according to the number of highly fluorescent cells (HFC) present in the peripheral blood after staining with Auramine 0. These cells are relatively immature reticulocytes that contain much RNA. All subjects received recombinant human G-CSF at a daily dose of 100 micrograms/m2 administered intravenously for 3 to 5 days. Plasma erythropoietin was measured in patients receiving dialysis before and several times after its administration. The number of HFC increased significantly in all subjects. In 1 of 3 patients receiving dialysis, the plasma erythropoietin increased transiently but insignificantly. These findings show that G-CSF affects human erythropoiesis in vivo, but that the mechanism of its effect did not involve an increase in plasma erythropoietin.

A case of an adult T-cell leukemia (ATL) with double negative (CD4-, CD8-) phenotype is reported. A-57-year-old man was consulted by his home doctor with us because of leucocytosis, splenomegaly and systemic lymphadenopathy. On admission, white blood cell count was 87,500/microliters with 77% of convoluted atypical cells. Serum anti-HTLV-1 antibody was positive and monoclonal insertion of HTLV-1 provirus into the atypical cell-gene was proved with southern blotting hybridization technique. A diagnosis of an ATL was made. Immunophenotypic analysis of leukemic cells showed CD3 (-), CD4 (-), CD8 (-) and genes encoding both TCR alpha and beta chains were rearranged. Though the patient responded to some degree to the combination chemotherapies including VEPA, he died of infectious complications about 4 months after admission.

A 52-year-old man, who came from Kagoshima prefecture, was hospitalized because of lumbago and lymphadenopathy. On admission, mild anemia and leukocytosis with atypical lymphoid cells were seen in the peripheral blood. Flow cytometry of the abnormal lymphocytes showed that they expressed CD4, and CD25, but not CD8. Anti HTLV I antibody was expressed in the serum. Atypical lymphoid cells had proviral DNA with restriction enzyme EcoRI. Lymphnode biopsy was performed and the specimens of lymphnode showed diffuse infiltration of abnormal lymphocytes. So we diagnosed Adult T-cell leukemia lymphoma. The patient's serum calcium level was increased, so he lost consciousness and became oliguric and developed acute renal failure. Hemodialysis was required to control azotemia. During the time of hemodialysis, cardiac arrest was occurred and he died. Autopsy confirmed the presence of a metastatic calcification in various organs, such as myocardium, alveolar septa of the lungs, and gastric mucosa. A metastatic calcinosis was found in the myocardium, which was thought to be the cause of his heart failure. But at the ATLL cells didn't infiltrate in the myocardium. Calcinosis was a significant complication of neoplastic disease in these patients and contributed to morbidity and mortality.

A 33-year-old man was hospitalized because of thrombocytopenia and severe splenomegaly. On admission 78% of peripheral lymphoid cells were abnormally large, with pale cytoplasm. Flow cytometry of the abnormal lymphocytes showed that they expressed CD 2, CD 3, CD 11, CD 16, and CD 56, but not CD 4 nor CD 8, so they were T-cell large granular lymphocytes (T-LGL). Abnormal lymphocytes obtained from a lymph node expressed CD 2, CD 16, CD 38, and CD 56, but not CD 3, CD 4, and CD 8, so they were natural killer(NK) cells. Splenectomy was performed and the operative specimen showed diffuse infiltration of pleomorphic lymphocytes, probably chronic lymphocytic leukemia cells. After splenectomy, the platelet count returned to normal but the lymphocytosis continued. Two years after discharge, chemotherapy was done because of thrombocytopenia and hepatomegaly. The patient died of disseminated intravascular coagulation arising from sepsis. The differences and similarities between peripheral and lymph-node lymphocytes suggest that LGL and NK cells may be differentiated from the same kind of cell, somewhat differentiated from stem cells.

It is generally difficult to treat patients with ovarian cancer. A Tenckhoff catheter was implanted in eighteen patients for intraperitoneal chemotherapy and drainage of ascites. Sixteen cases including 5 recurrent cases were treated with anticancer drug. It could not be used in two cases by bowel adhesion, so immediately catheters were removed. CDDP (100-150 mg/body) with or without Etoposide (180-300 mg/body) in 2 liters of saline was administered via Tenckhoff catheter over 30 minutes with a dwell time of 4 hours. We have studied the kinetics of CDDP and Etoposide in ascites and blood after intraperitoneal chemotherapy. High concentrations of free-CDDP and Etoposide were reached for 4 hours in the ascites but concentrations in the blood varied. These results showed obviously high values and direct effects on the tumor cells in the abdominal cavity and the peritoneal clearance depended on the severity of carcinomatous peritonitis in each case. Twelve cases showed decrease, but 4 cases increase of ascites. Five recurrent cases and one patient of stage IV died. Seven cases are outpatients and the disease free duration of their ranges are from 1 to 24 months. Three patients are now under treatment. Intraperitoneal chemotherapy elicited only mild nausea, myelosuppression and no significant changes of renal function. No patients had signs of catheter infection and peritonitis. These findings suggested that a Tenckhoff catheter was valuable to treat and manage ovarian cancer patients with little side effect.

We evaluated the effects of recombinant human granulocyte colony stimulating factor (rhG-CSF) given to 30 patients with hematological malignancies after cytotoxic chemotherapy. The first course of chemotherapy was not treated with rhG-CSF (control), and in the second to fourth courses, rhG-CSF was given by one of the following three ways to the patients (not necessarily in this order): 1) 10 days of administration starting 48 hr after chemotherapy, 2) 5 days of administration starting 48 hr after chemotherapy, and 3) 5 days of administration after the leukocyte counts reached to less than 2,000/microliters. The leukocyte nadirs were significantly higher in the course with 10 days of administration compared with the control course. The time needed for recovery from the leukocyte nadir was significantly shorter in 10-day course and 5-day course after the leukocyte counts reached to less than 2,000/microliters. The therapy spans became significantly shorter with all of the three patterns of administration of rhG-CSF compared with the control course. The number of days on which the leukocyte counts became less than 2,000/microliters were significantly fewer in 10-day course and 5-day course after the leukocyte counts became less than 2,000/microliters. These findings showed that rhG-CSF prevented severe neutropenia after cytotoxic chemotherapy, and (or) assisted the rapid recovery from neutropenia. These effects depend on the timing of its administration.

Twenty cases of myelodysplastic syndrome (MDS) were treated with ubenimex. Seventeen cases were treated with the drug over 90 d. Among these, 10 showed improvement of anemia, 12 an increase in platelet count which had decreased before treatment and 10 an increase in neutrophil count; however, 14 showed an increase in blast percentage in bone marrow aspirate. CD4/CD8 ratio was increased in 4 cases and shifted to a normal from an abnormal range in 6 cases. When the MDS cases were observed in refractory anemia (RA) and refractory anemia with excess blasts (RAEB), great improvement was seen, but in RAEB increase in blast percentage was also observed. CD4 increased mostly in RA and CD8 increased in RAEB. Ten cases of chronic myelocytic leukemia (CML) were first treated with ubenimex and cytostatics, then with ubenimex only. Six cases attained partial remission within 3 months, but one case showed a marked increase in white cell count and blast count and in another case a progression of splenomegaly associated with increase in white cell count. From these findings we conclude that ubenimex could be utilized in MDS or CML if the patient was at risk for strong chemotherapy.

We did a retrospective statistical study of 117 patients with non-Hodgkin's lymphoma admitted to our hospital from January 1979 to December 1988. Five-year survival was 83% for patients in stage I at diagnosis, which was significantly better than the 55% in stage II, 37% in stage III, and 34% in stage IV. Five-year survival was 74% for patients with B-cell lymphoma (74%), which was significantly better than with the 32% for T-cell lymphoma. For patients in stage I or II, five-year survival was 46% for those with nasal lymphoma, which was significantly worse than the 72% with nodal lymphoma and the 82% for those with Waldeyer's lymphoma. Sixty-eight patients were treated initially with radiation only. The relapse frequency was 20% in stage I and 40% in stage II. All of the relapses occurred outside the irradiated area treated on the other side of the diaphragm. Of all 48 patients with combination chemotherapy such as vincristine, cyclophosphamide, predonisolone, and Adriamycin (VEPA), mitoxantrone, cyclophosphamide, vincristine, and predonisolone (MCOP), and mitoxantrone, ifosfamide, vindesine, and predonisolone (MIFP), 33 (69%) achieved complete remission.

Nephrotoxicity is the major side effect of cisplatinum (CDDP) and it is often the dose limiting factor. We have studied the effect of urinastatin (US) to decrease the nephrotoxicity of CDDP administration. 28 patients with gynecological cancer treated by chemotherapy including CDDP (13 mg/m2 daily for 5 days) were assigned to two groups, the group with US (n = 14) and the group without US (n = 14). The former was added each 150,000 units of US before and after administration of CDDP. The BUN, serum creatinine (Cre), creatinine clearance (Ccr) and the excretion of beta 2-microglobulin (beta 2-MG) index and N-acetyl-beta-glucosaminidase(NAG)index were measured. The BUN, Cre and Ccr were within normal range during four cycles. However NAG index rose remarkably when CDDP was treated by CDDP. And the increase in NAG index, which reflect the magnitude of renal tubal damage, was less in the group with US than in the group without US. It was suggested that US had effects to reduce nephrotoxicity of CDDP in chemotherapy, and that we could treat patients by high dose CDDP.

The efficacy and safety of a combination regimen using cefmetazole (CMZ) and netilmicin (NTL) were evaluated in the treatment of infections complicated with hematological disorders. Primary diseases in 31 patients included in the evaluation were acute myelocytic leukemia (3 cases), acute lymphocytic leukemia (2 cases), malignant lymphoma (14 cases), chronic myelocytic leukemia (2 cases), chronic myelocytic leukemia blast crisis (4 cases), myelodysplastic syndrome (2 cases), aplastic anemia (3 cases), and malignant histiocytosis (1 case). Complicated infections included 29 cases of suspected septicemia, 1 case of septicemia and 1 case of pneumonia. Clinical responses were excellent in 6 (19.4%), good in 12 (38.7%), fair in 1 (3.2%) and poor in 12 (38.7%). The total clinical efficacy rate was 58.1%. No significant effect of initial neutrophil counts was observed on response rates. Patients who showed increasing neutrophil counts during therapy had higher response rates than those in whom the neutrophil count decreased or remained unchanged at levels less than 500/mm3 in after neutrophil counts. No side effects were observed in any of the 31 patients. In conclusion, this combination therapy of CMZ and NTL thus appears to be useful and safe in therapies for infections complicated with hematological disorders.

A 20-year-old woman was hospitalized because of abdominal distention. She had developed facial edema about one year earlier, and recently amenorrhea and red verrucae on the chest and abdomen. Neurological examination disclosed hypesthesia, paresthesia, and diminished tendon reflexes in the arms and legs. The level of serum immunoglobulin A (IgA) was elevated and an M protein was detected. Examination of the bone marrow disclosed abnormal increase in plasma cells. Results of glucose tolerance test were mildly abnormal. The patient was diagnosed as Crow-Fukase syndrome. Plasma exchange was done four times and melphalan was given orally for two weeks, but the level of serum IgA increased further. Then one bolus injection of methylprednisolone decreased the serum IgA with improvement in other signs. The disorder is now controlled satisfactory with a low dose of prednisolone.

An intraarterial high-dose CDDP, using a balloon catheter, has been infused into five patients with a recurrent ovarian cancer. The dose of CDDP was 150 mg-200 mg/body. Two patients experienced a partial tumor regression, whereas three showed no change. With regard to the toxicity, the NAG index (NAG activity/urinary creatinine) rose markedly in all patients, but toxicity was almost similar to that seen from a systemic administration. No significant catheter complication occurred.

In our series of investigations concerning immunopotentiators, we evaluated the host immunocompetence of patients triggered by PSK. Our subjects for screening consisted of seven patients with malignant tumors of female reproductive organs chosen at random from our patients. Four of them were treated with chemotherapy (CAPF) alone and served as controls, whereas the other three were administered PSK, 3.0 g/day, plus chemotherapy as above. Cellular and humoral immunities were measured at three points. Firstly prior to chemotherapy, secondly, two weeks after the start of chemotherapy, and thirdly, prior to next chemotherapy. The results indicated higher values of T-cell subset ratio OKT-4/8 of 2.73 +/- 0.56 on the average for cellular immunocompetence as compared to 1.35 +/- 0.45 for normal subjects in the PSK-administered group, whereas there was no increase in the non-PSK-administered group, in which the value was 1.28 +/- 0.30. Thus, PSK was considered to extert an immunopotentiating effect on the T-lymphocytes.

A continuous subcutaneous infusion of peplomycin was performed on 15 patients with cervical cancer. Eight patients received 5 mg of peplomycin a day and 7 patients received 2.5 mg a day. The peplomycin concentrating in the serum after infusion for 24 hours thus were 0.094 microgram/ml and 0.056 microgram/ml, respectively. The concentration of peplomycin in the tumor was found to be higher than in normal cervical tissue, and in the lymph nodes it was equal or higher than in the serum. Histological changes were minimum. A Grade IIa determination, however, was found in one patient, which may have been due to the total dose and/or the time of the examination. No pulmonary toxicity developed in any patients.