Standardization of preoperative stoma site marking and its utility for preventing stoma leakage: a retrospective study of 519 patients who underwent laparoscopic/robotic rectal cancer surgery.

PURPOSE: Stoma site marking is an important preoperative intervention for preventing various stoma-associated complications. In our institution, standardized stoma site marking is routinely performed before rectal cancer surgery with stoma creation, and various stoma-associated factors are recorded in the ostomy-record template. The present study investigated risk factors for stoma leakage. METHODS: Our stoma site marking is standardized so that it can be performed by non-stoma specialists. To identify risk factors of stoma leakage at 3 months after surgery, various preoperative factors associated with stoma site marking in our ostomy-record template were retrospectively analyzed in 519 patients who underwent rectal cancer surgery with stoma creation from 2015 to 2020. RESULTS: Stoma leakage was seen in 35 of the 519 patients (6.7%). The distance between the stoma site marking and the umbilicus was less than 60 mm in 27 of the 35 patients (77%) who experienced stoma leakage, so a distance of less than 60 mm was identified as an independent risk factor for stoma leakage. Aside from preoperative factors, stoma leakage was also caused by postoperative skin wrinkles or surgical scars near the stoma site in 8 of 35 patients (23%). CONCLUSION: Preoperative standardized stoma site marking is necessary to achieve reliable marking that is easy to perform. To reduce the risk of stoma leakage, a distance of 60 mm or more between the stoma site marking and the umbilicus is ideal, and surgeons need to contrive ways to keep surgical scars away from the stoma site.

Diagnostic test accuracy of antigenaemia assay for PCR-proven cytomegalovirus infection-systematic review and meta-analysis.

OBJECTIVES: We aimed to assess diagnostic test accuracy of antigenaemia assay for PCR-proven cytomegalovirus (CMV) infection. METHODS: We systematically searched studies that provide data both on sensitivity and specificity of the CMV antigenaemia assay using the PCR as the reference standard. Adults, children, infants, individuals who were immunocompromised for any reason, symptomatic patients and asymptomatic individuals were all included. A hierarchical summary receiver operating characteristics model was used for diagnostic meta-analysis. Study quality was assessed by Revised Tool for the Quality Assessment of Diagnostic Accuracy Studies. Protocol registration identification is CRD42016035892. RESULTS: We identified 75 eligible articles including 9058 CMV PCR-positive individuals and 22 232 PCR-negative individuals. The diagnostic odds ratio for positive antigenaemia was 30 (95% CI 24-38, I2 = 28%) and the area under the hierarchical summary receiver operating characteristic curve was 0.86 (95% CI 0.83-0.88). The summary estimates of sensitivity and specificity were 0.65 (95% CI 0.59-0.70) and 0.94 (95% CI 0.93-0.95), respectively. The positive likelihood ratio of 10.9 (95% CI 8.5-14.0) suggested that a positive result from the antigenaemia assay greatly increased the probability of PCR-proven CMV infection, but a negative likelihood ratio of 0.38 (95% CI 0.32-0.44) indicated that a negative result led to a small decrease in the probability of PCR-proven CMV infection. Sensitivity and subgroup analyses replicated these results. CONCLUSIONS: The antigenaemia assay overlooked 35% of PCR-proven CMV infections; hence, a negative result of an antigenaemia assay could not rule out a CMV infection.

Impact of stillbirths on international comparisons of preterm birth rates: a secondary analysis of the WHO multi-country survey of Maternal and Newborn Health.

OBJECTIVE: To evaluate the extent to which stillbirths affect international comparisons of preterm birth rates in low- and middle-income countries. DESIGN: Secondary analysis of a multi-country cross-sectional study. SETTING: 29 countries participating in the World Health Organization Multicountry Survey on Maternal and Newborn Health. POPULATION: 258 215 singleton deliveries in 286 hospitals. METHODS: We describe how inclusion or exclusion of stillbirth affect rates of preterm births in 29 countries. MAIN OUTCOME MEASURES: Preterm delivery. RESULTS: In all countries, preterm birth rates were substantially lower when based on live births only, than when based on total births. However, the increase in preterm birth rates with inclusion of stillbirths was substantially higher in low Human Development Index (HDI) countries [median 18.2%, interquartile range (17.2-34.6%)] compared with medium (4.3%, 3.0-6.7%), and high-HDI countries (4.8%, 4.4-5.5%). CONCLUSION: Inclusion of stillbirths leads to higher estimates of preterm birth rate in all countries, with a disproportionately large effect in low-HDI countries. Preterm birth rates based on live births alone do not accurately reflect international disparities in perinatal health; thus improved registration and reporting of stillbirths are necessary. TWEETABLE ABSTRACT: Inclusion of stillbirths increases preterm birth rates estimates, especially in low-HDI countries.

A global reference for caesarean section rates (C-Model): a multicountry cross-sectional study.

OBJECTIVE: To generate a global reference for caesarean section (CS) rates at health facilities. DESIGN: Cross-sectional study. SETTING: Health facilities from 43 countries. POPULATION/SAMPLE: Thirty eight thousand three hundred and twenty-four women giving birth from 22 countries for model building and 10,045,875 women giving birth from 43 countries for model testing. METHODS: We hypothesised that mathematical models could determine the relationship between clinical-obstetric characteristics and CS. These models generated probabilities of CS that could be compared with the observed CS rates. We devised a three-step approach to generate the global benchmark of CS rates at health facilities: creation of a multi-country reference population, building mathematical models, and testing these models. MAIN OUTCOME MEASURES: Area under the ROC curves, diagnostic odds ratio, expected CS rate, observed CS rate. RESULTS: According to the different versions of the model, areas under the ROC curves suggested a good discriminatory capacity of C-Model, with summary estimates ranging from 0.832 to 0.844. The C-Model was able to generate expected CS rates adjusted for the case-mix of the obstetric population. We have also prepared an e-calculator to facilitate use of C-Model (www.who.int/reproductivehealth/publications/maternal_perinatal_health/c-model/en/). CONCLUSIONS: This article describes the development of a global reference for CS rates. Based on maternal characteristics, this tool was able to generate an individualised expected CS rate for health facilities or groups of health facilities. With C-Model, obstetric teams, health system managers, health facilities, health insurance companies, and governments can produce a customised reference CS rate for assessing use (and overuse) of CS. TWEETABLE ABSTRACT: The C-Model provides a customized benchmark for caesarean section rates in health facilities and systems.

Maternal body mass index and risk of birth and maternal health outcomes in low- and middle-income countries: a systematic review and meta-analysis.

We conducted a systematic review and meta-analysis of population-based cohort studies of maternal body mass index (BMI) and risk of adverse birth and health outcomes in low- and middle-income countries. PubMed, Embase, CINAHL and the British Nursing Index were searched from inception to February 2014. Forty-two studies were included. Our study found that maternal underweight was significantly associated with higher risk of preterm birth (odds ratio [OR], 1.13; 95% confidence interval [CI], 1.01-1.27), low birthweight (OR, 1.66; 95% CI, 1.50-1.84) and small for gestational age (OR, 1.85; 95% CI, 1.69-2.02). Compared with mothers with normal BMI, overweight or obese mothers were at increased odds of gestational diabetes, pregnancy-induced hypertension, pre-eclampsia, caesarean delivery and post-partum haemorrhage. The population-attributable risk (PAR) indicated that if women were entirely unexposed to overweight or obesity during the pre-pregnancy or early pregnancy period, 14% to 35% fewer women would develop gestational diabetes, pre-eclampsia or pregnancy-induced hypertension in Brazil, China, India, Iran or Thailand. The highest PAR of low birthweight attributable to maternal underweight was found in Iran (20%), followed by India (18%), Thailand (10%) and China (8%). Treatment and prevention of maternal underweight, overweight or obesity may help reduce the burden on maternal and child health in developing countries.

Species differences in the metabolism of ritobegron in vitro and assessment of potential interactions with transporters and cytochrome P450 enzymes.

Ritobegron, a selective ß3-adrenoceptor agonist, is the prodrug of the active compound, KUC-7322. We investigated species differences in its metabolism in vitro and the potential for drug-drug interactions with ritobegron. In rat, dog, monkey, and human liver microsomes, ritobegron was not metabolized by cytochrome P450 enzymes (CYPs). KUC-7322 was the only metabolite observed. Hydrolysis of ritobegron to KUC-7322 was likely catalyzed by carboxylesterases in human liver microsomes. The maximum velocity of the reaction (V(max))/Michaelis-Menten constant (K(m)) for hydrolysis of ritobegron to KUC-7322 was much higher in rat serum than those in other species. There were also species differences in the conjugation of KUC-7322. Sulfate conjugates of ritobegron were detected in all species, whereas glucuronide and glutathione conjugates of KUC-7322 were only observed in rat liver subcellular fractions. Ritobegron and KUC-7322 did not affect the CYP-mediated metabolism of probe substrates in human liver microsomes and organic anion transporter 1 (OAT1)-, OAT2-, OAT3-, organic cation transporter 2 (OCT-2)-, OCT3-, or organic cation/carnitine transporter 1 (OCTN1)-mediated uptake of probe substrates in S2 cells. Ritobegron, but not KUC-7322, inhibited P-glycoprotein-mediated digoxin transport in Caco-2 cells. Significant uptake of KUC-7322 was observed in OAT3-expressing S2 cells. Therefore, CYP-mediated drug-drug interactions are not likely when ritobegron is administered with CYP substrates or inhibitors. Ritobegron may increase the plasma concentrations of P-glycoprotein substrates, such as digoxin, and the plasma concentration of KUC-7322 may increase when it is administered in combination with OAT inhibitors such as probenecid.

Primary prophylaxis to prevent obstetric complications in asymptomatic women with antiphospholipid antibodies: a systematic review.

OBJECTIVE: Obstetric complications are common in patients with antiphospholipid syndrome. However, the impact of antiphosholipid antibodies (aPL) in the pregnancy outcomes of asymptomatic aPL carriers is uncertain. The aim of this systematic review is to assess whether primary prophylaxis is beneficial to prevent obstetric complications during pregnancy in asymptomatic women positive for aPL who have no history of recurrent pregnancy loss or intrauterine fetal death. METHODS: Studies evaluating the effect of prophylactic treatment versus no treatment in asymptomatic pregnant aPL carriers were identified in an electronic database search. Design, population and outcome homogeneity of studies was assessed and meta-analysis was performed. The pooled Mantel-Haenszel relative risk of specific pregnancy outcomes was obtained using random effects models. Heterogeneity was measured with the I(2) statistic. All analyses were conducted using Review Manager 5.3. RESULTS: Data from five studies involving 154 pregnancies were included and three studies were meta-analysed. The risk ratio and 95% confidence interval (CI) of live birth rates, preterm birth, low birth weight and overall pregnancy complications in treated and untreated pregnancies were 1.14 (0.18-7.31); 1.71 (0.32-8.98); 0.98 (0.07-13.54) and 2.15 (0.63-7.33),respectively. Results from the meta-analysis revealed that prophylactic treatment with aspirin is not superior to placebo to prevent pregnancy complications in asymptomatic aPL carriers. CONCLUSION: This systematic review did not find evidence of the superiority of prophylactic treatment with aspirin compared to placebo or usual care to prevent unfavourable obstetric outcomes in otherwise healthy women with aPL during the first pregnancy.

Pregnancy and childbirth outcomes among adolescent mothers: a World Health Organization multicountry study.

OBJECTIVE: To investigate the risk of adverse pregnancy outcomes among adolescents in 29 countries. DESIGN: Secondary analysis using facility-based cross-sectional data of the World Health Organization Multicountry Survey on Maternal and Newborn Health. SETTING: Twenty-nine countries in Africa, Latin America, Asia and the Middle East. POPULATION: Women admitted for delivery in 359 health facilities during 2-4 months between 2010 and 2011. METHODS: Multilevel logistic regression models were used to estimate the association between young maternal age and adverse pregnancy outcomes. MAIN OUTCOME MEASURES: Risk of adverse pregnancy outcomes among adolescent mothers. RESULTS: A total of 124 446 mothers aged ≤24 years and their infants were analysed. Compared with mothers aged 20-24 years, adolescent mothers aged 10-19 years had higher risks of eclampsia, puerperal endometritis, systemic infections, low birthweight, preterm delivery and severe neonatal conditions. The increased risk of intra-hospital early neonatal death among infants born to adolescent mothers was reduced and statistically insignificant after adjustment for gestational age and birthweight, in addition to maternal characteristics, mode of delivery and congenital malformation. The coverage of prophylactic uterotonics, prophylactic antibiotics for caesarean section and antenatal corticosteroids for preterm delivery at 26-34 weeks was significantly lower among adolescent mothers. CONCLUSIONS: Adolescent pregnancy was associated with higher risks of adverse pregnancy outcomes. Pregnancy prevention strategies and the improvement of healthcare interventions are crucial to reduce adverse pregnancy outcomes among adolescent women in low- and middle-income countries.

Maternal and institutional characteristics associated with the administration of prophylactic antibiotics for caesarean section: a secondary analysis of the World Health Organization Multicountry Survey on Maternal and Newborn Health.

OBJECTIVE: To illustrate the variability in the use of antibiotic prophylaxis for caesarean section, and its effect on the prevention of postoperative infections. DESIGN: Secondary analysis of a cross-sectional study. SETTING: Twenty-nine countries participating in the World Health Organization Multicountry Survey on Maternal and Newborn Health. POPULATION: Three hundred and fifty-nine health facilities with the capacity to perform caesarean section. METHODS: Descriptive analysis and effect estimates using multilevel logistic regression. MAIN OUTCOME MEASURES: Coverage of antibiotic prophylaxis for caesarean section. RESULTS: A total of 89 121 caesarean sections were performed in 332 of the 359 facilities included in the survey; 87% under prophylactic antibiotic coverage. Thirty five facilities provided 0-49% coverage and 77 facilities provided 50-89% coverage. Institutional coverage of prophylactic antibiotics varied greatly within most countries, and was related to guideline use and the practice of clinical audits, but not to the size, location of the institution or development index of the country. Mothers with complications, such as HIV infection, anaemia, or pre-eclampsia/eclampsia, were more likely to receive antibiotic prophylaxis. At the same time, mothers undergoing caesarean birth prior to labour and those with indication for scheduled deliveries were also more likely to receive antibiotic prophylaxis, despite their lower risk of infection, compared with mothers undergoing emergency caesarean section. CONCLUSIONS: Coverage of antibiotic prophylaxis for caesarean birth may be related to the perception of the importance of guidelines and clinical audits in the facility. There may also be a tendency to use antibiotics when caesarean section has been scheduled and antibiotic prophylaxis is already included in the routine clinical protocol. This study may act as a signal to re-evaluate institutional practices as a way to identify areas where improvement is possible.

Mode and timing of twin delivery and perinatal outcomes in low- and middle-income countries: a secondary analysis of the WHO Multicountry Survey on Maternal and Newborn Health.

OBJECTIVE: To describe the mode and timing of delivery of twin pregnancies at ≥34 weeks of gestation and their association with perinatal outcomes. DESIGN: Secondary analysis of a cross-sectional study. POPULATION: Twin deliveries at ≥34 weeks of gestation from 21 low- and middle-income countries participating in the WHO Multicountry Survey on Maternal and Newborn Health. METHODS: Descriptive analysis and effect estimates using multilevel logistic regression. MAIN OUTCOME MEASURES: Stillbirth, perinatal mortality, and neonatal near miss (use of selected life saving interventions at birth). RESULTS: The average length of gestation at delivery was 37.6 weeks. Of all twin deliveries, 16.8 and 17.6% were delivered by caesarean section before and after the onset of labour, respectively. Prelabour caesarean delivery was associated with older maternal age, higher institutional capacity and wealth of the country. Compared with spontaneous vaginal delivery, lower risks of neonatal near miss (adjusted odds ratio, aOR, 0.63; 95% confidence interval, 95% CI, 0.44-0.94) were found among prelabour caesarean deliveries. A lower risk of early neonatal mortality (aOR 0.12; 95% CI 0.02-0.56) was also observed among prelabour caesarean deliveries with nonvertex presentation of the first twin. The week of gestation with the lowest rate of prospective fetal death varied by fetal presentation: 37 weeks for vertex-vertex; 39 weeks for vertex-nonvertex; and 38 weeks for a nonvertex first twin. CONCLUSIONS: The prelabour caesarean delivery rate among twins varied largely between countries, probably as a result of overuse of caesarean delivery in wealthier countries and limited access to caesarean delivery in low-income countries. Prelabour delivery may be beneficial when the first twin is nonvertex. International guidelines for optimal twin delivery methods are needed.

Risk factors for spontaneous and provider-initiated preterm delivery in high and low Human Development Index countries: a secondary analysis of the World Health Organization Multicountry Survey on Maternal and Newborn Health.

OBJECTIVE: To evaluate how the effect of maternal complications on preterm birth varies between spontaneous and provider-initiated births, as well as among different countries. DESIGN: Secondary analysis of a cross-sectional study. SETTING: Twenty-nine countries participating in the World Health Organization Multicountry Survey on Maternal and Newborn Health. POPULATION: 299 878 singleton deliveries of live neonates or fresh stillbirths. METHODS: Countries were categorised into very high, high, medium and low developed countries using the Human Development Index (HDI) of 2012 by the World Bank. We described the prevalence and risk of maternal complications, their effect on outcomes and their variability by country development. MAIN OUTCOME MEASURES: Preterm birth, fresh stillbirth and early neonatal death. RESULTS: The proportion of provider-initiated births among preterm deliveries increased with development: 19% in low to 40% in very high HDI countries. Among preterm deliveries, the socially disadvantaged were less likely, and the medically high risk were more likely, to have a provider-initiated delivery. The effects of anaemia [adjusted odds ratio (AOR), 2.03; 95% confidence interval (CI), 1.84; 2.25], chronic hypertension (AOR, 2.28; 95% CI, 1.94; 2.68) and pre-eclampsia/eclampsia (AOR, 5.03; 95% CI, 4.72; 5.37) on preterm birth were similar among all four HDI subgroups. CONCLUSIONS: The provision of adequate obstetric care, including optimal timing for delivery in high-risk pregnancies, especially to the socially disadvantaged, could improve pregnancy outcomes. Avoiding preterm delivery in women when maternal complications, such as anaemia or hypertensive disorders, are present is important for countries at various stages of development, but may be more challenging to achieve.

Absorption, disposition, metabolism, and excretion of ritobegron (KUC-7483), a novel selective ß3-adrenoceptor agonist, in rats.

The pharmacokinetic profile of ritobegron, a novel, selective ß3-adrenoceptor agonist, was investigated in rats. Ritobegron, an ethyl ester prodrug of the active compound KUC-7322, or KUC-7322 itself was orally administered (10 mg/kg). Ethyl esterification resulted in a 10-fold increase in the area under the plasma concentration-time curve (AUC(0-t)), as compared to KUC-7322. Following intravenous administration of KUC-7322 (1 mg/kg), total blood clearance was 1.36 L/h/kg, suggesting that intrinsic hepatic clearance is the rate-limiting step in KUC-7322 excretion. When ritobegron was orally administered (0.3, 1, 3, and 10 mg/kg), plasma concentrations of KUC-7322 rapidly increased and reached a maximum concentration (C(max)) at 0.25 to 0.31 h. KUC-7322 levels rapidly decreased, with a half-life (t 1/2) of 0.42 to 1.37 h thereafter. AUC(0-t) did not show a dose-dependent increase. The bioavailability of KUC-7322 was estimated to be 4%. Following oral administration of [14C]ritobegron (3 mg/kg), radioactivity concentrations in tissues rapidly increased and declined in parallel with changes in plasma concentration. In most of tissues, excluding the liver, kidney, urinary bladder, stomach and small intestine, radioactivity concentrations were lower than that in plasma. In plasma, bile, urine, and feces, KUC-7322 and its glucuronide, sulfate, and glutathione conjugates were detected. The glucuronide conjugate of KUC-7322 was the predominant metabolite in bile, plasma, and urine, and KUC-7322 was predominant in feces. Ritobegron was not detected in any of the samples. The cumulative excretion of radioactivity in urine and feces were 28.7% and 68.3% of the dose, respectively, up to 120 h after administration.

Maternal and perinatal outcomes among nulliparous adolescents in low- and middle-income countries: a multi-country study.

OBJECTIVE: To investigate the risk of adverse pregnancy outcomes and caesarean section among adolescents in low- and middle-income countries. DESIGN: Secondary analysis using facility-based cross-sectional data from the World Health Organization (WHO) Global Survey on Maternal and Perinatal Health. SETTING: Twenty-three countries in Africa, Latin America, and Asia. POPULATION: Women admitted for delivery in 363 health facilities during 2-3 months between 2004 and 2008. METHODS: We constructed multilevel logistic regression models to estimate the effect of young maternal age on risks of adverse pregnancy outcomes. MAIN OUTCOME MEASURES: Risk of adverse pregnancy outcomes among young mothers. RESULTS: A total of 78 646 nulliparous mothers aged ≤24 years and their singleton infants were included in the analysis. Compared with mothers aged 20-24 years, adolescents aged 16-19 years had a significantly lower risk of caesarean section (adjusted OR 0.75, 95% CI 0.71-0.79). When the analysis was restricted to caesarean section indicated for presumed cephalopelvic disproportion, the risk of caesarean section was significantly higher among mothers aged ≤15 years (aOR 1.27, 95% CI 1.07-1.49) than among those aged 20-24 years. Higher risks of low birthweight and preterm birth were found among adolescents aged 16-19 years (aOR 1.10, 95% CI 1.03-1.17; aOR 1.16, 95% CI 1.09-1.23, respectively) and ≤15 years (aOR 1.33, 95% CI 1.14-1.54; aOR 1.56, 95% CI 1.35-1.80, respectively). CONCLUSIONS: Adolescent girls experiencing pregnancy at a very young age (i.e. <16 years) have an increased risk of adverse pregnancy outcomes.

Synthesis of diaminobutane derivatives as potent Ca(2+)-permeable AMPA receptor antagonists.

We synthesized diaminobutane derivatives as potent Ca(2+)-permeable AMPA receptor antagonists with non-hypotensive activity. Compound 10c showed selective Ca(2+)-permeable AMPA receptor antagonist activity and neuroprotective effects in transient global ischemia models in gerbils.

An Interlaboratory Validation Study of the Improved Transformation Assay Employing Balb/c 3T3 Cells: Results of a Collaborative Study on the Two-stage Cell Transformation Assay by the Non-genotoxic Carcinogen Study Group.

The Non-genotoxic Carcinogen Study Group of the Environmental Mutagen Society of Japan organised the first step of an interlaboratory validation study on an improved cell transformation assay employing Balb/c 3T3 A31-1-1 cells. Nineteen laboratories participated in this study. The modified transformation assay was evaluated for its responsiveness, its interlaboratory reproducibility and its transferability. In this study, a mixture of Dulbecco's modified Eagle's medium and nutrient mixture F12, supplemented with insulin-transferrin-ethanolamine-sodium selenite and 2% fetal bovine serum (FBS) was used during the period of expression of transformed foci, intead of the usual minimum essential medium with 10% FBS. 20-Methylcholanthrene (MCA) and 12-O-tetradecanoylphorbol-13-acetate (TPA) were selected as a prototype initiator and a tumour promoter, respectively. Two series of experiments were conducted. In the first series, the transformation activity of MCA was examined at various concentrations. In the absence of the promoting treatment with TPA, exposure to MCA only weakly induced transformed foci. In the presence of 0.1µg/ml TPA, all laboratories observed significant dose-dependent increases in the number of transformed foci with increasing MCA concentrations. In the second series of experiments, various concentrations of TPA were tested. In the absence of initiating treatment with MCA, exposure to TPA weakly induced transformed foci in about half of the laboratories. In the presence of 0.2µg/ml MCA, all the laboratories observed significant dose-dependent increases in the number of transformed foci with increasing TPA concentrations. The results from this study support the usefulness of this modified two-stage transformation assay with Balb/c 3T3 cells.

P-glycoprotein-mediated acquired multidrug resistance of human lung cancer cells in vivo.

We examined whether the increased expression of P-glycoprotein (P-gp) encoded by the human multidrug resistance gene MDR1 is related to the acquired multidrug resistance of lung cancer in vivo. We estimated the chemosensitivity of lung cancer xenografts (LC-6, adenocarcinoma; Lu-24, small-cell cancer) by calculation of relative tumour growth (T/C%, treated/control) in vivo, based on statistical significance determined by the Mann-Whitney U test (P < 0.01, one-sided). MDR1 gene expression levels were evaluated by reverse transcription-polymerase chain reaction (RT-PCR) assay. P-gp production and P-gp localisation were examined by Western blotting and by immunohistochemical analysis respectively. LC-6 and Lu-24 were initially sensitive to both vincristine (VCR, 1.6 mg kg-1: LC-6, 45%; Lu-24, 39%) and doxorubicin (DOX, 12 mg kg-1: LC-6, 26%; Lu-24, 27%) in vivo. VCR-resistant variants (LC-6R, 66% and Lu-24R, 68%) selected with VCR (0.4 mg kg-1, x 9) significantly acquired cross-resistance to DOX (LC-6R, 55% and Lu-24R, 55% respectively). RT-PCR assay showed increased levels of MDR1 expression in LC-6R and Lu-24R with stable MDR1 expression levels. P-gp expression levels were elevated, and the percentage of P-gp-positive tumour cells increased in both LC-6R and Lu-24R. These results suggest that P-gp/MDR1 overexpression is related to acquired multidrug resistance in lung cancer in vivo.

[Clinicopathological study of pulmonary hamartoma with special reference to 6 patients who also had another tumor].

We studied 22 patients in whom intrapulmonary hamartoma was diagnosed between 1975 and 1994. Twelve were men and 10 were women, and their ages ranged from 20 to 72 years (averaged: 52.5). The sizes of the hamartomas ranged from 5 mm to 3 cm. Five patients also had other types of cancer (ling 3, colon 1, thyroid 1) and one had a mediastinal tumor (1). In those 6 patients, the hamartomas had to be distinguished from intrapulmonary metastasis. In 2 of those 6, thoracoscopic surgery was useful for obtaining sufficient materials for diagnosis. In one patient immunohistochemical analysis with anti-PCNA (proliferative cell nuclear antigen) antibody was useful in distinguishing leiomyomatous hamartoma from benign metastatic leiomyoma.

Advantage of in vivo chemosensitivity assay to detect vincristine-resistance in a human epidermoid carcinoma xenograft.

We examined both in vitro and in vivo chemosensitivity of the human epidermoid carcinoma xenograft xeKB3-1-R which shows overexpression of the multidrug resistance gene (MDR1). XeKB3-1-R was sensitive to vincristine (VCR, 6%) and doxorubicin (DOX, 9%) in the adhesive tumor cell culture system in vitro. However, this xenograft showed decreased sensitivity to VCR (65%) and DOX (42%) in an in vivo chemosensitivity assay. The in vivo resistance of xeKB3-1-R to both VCR and DOX was reversed by coadministration of cyclosporin A (VCR 22%, DOX 11%). The xenograft xeKB3-1-R expressed significantly higher levels of MDR1 than xeKB3-1. The results confirmed that multidrug resistance in xeKB3-1-R was related to enhanced MDR1 expression in vivo. The observed discrepancies between in vitro and in vivo chemosensitivities suggest that the in vivo sensitivity assay more accurately reflects drug resistance as a result of low-level MDR1 overexpression in solid tumors.

Expression of the multidrug resistance-associated protein (MRP) gene in non-small-cell lung cancer.

We examined the levels of expression of the multidrug resistance-associated protein (MRP) gene quantified by Northern blot analysis in comparison with those of the MDR1 gene determined by reverse transcription-polymerase chain reaction (RT-PCR) in 104 non-small-cell lung cancer (NSCLC) specimens [59 adenocarcinoma (Ad), 40 squamous cell carcinoma (Sq), four large cell carcinoma (La) and one adeno-squamous carcinoma (AdSq)]. Thirty-three (31.7%) of the 104 NSCLC expressed the MRP gene at various levels. The NSCLC showing high (++) levels of MRP gene expression (19 out of 33, 57.6%) were predominantly squamous cell carcinomas (Ad, 5; Sq, 13; La, 1) (P < 0.05). Six of the eight NSCLCs expressing high levels of MRP mRNA and no MDR1 (MRP ++, MDR1-) were squamous cell carcinomas. Sixty-one of the 104 NSCLC patients received chemotherapy with MRP-related anti-cancer drugs [vindesine (VDS) and etoposide (VP-16)]. Twenty-three patients (37.7%) with tumour expressing high or moderate levels of MRP showed significantly worse prognoses than those with non- or low-MRP-expressing tumours (P < 0.05). These results suggest that the level of MRP gene expression is related to the histopathology and prognosis of NSCLC.

Omega-3 fatty acids in Hawaii seafood.

Omega-3 fatty acids, the most potent of which are found in seafood, are of interest because of their effects on cardiovascular and inflammatory diseases and their possible effects on cancer. However, consumers in Hawaii wishing to increase their dietary omega-3 to omega-6 fatty acid ratio are faced with the difficulty that several types of seafood popular in Hawaii and aquacultured seafood new in the marketplace have unknown omega-3 fatty acid levels. The purpose of this work is to determine omega-3 fatty acid levels of selected seafood and fish oil capsules. Several seafoods and some over-the-counter fish oil capsules were sampled and analyzed. Aku eggs, aquacultured hamachi (yellowtail jack from Japan), one sample of turbot, and EPA Plus, Promega, and Omega-3 Super EPA capsules were found to contain high levels of omega-3 fatty acids. Levels were comparable to those in the fatty fishes such as salmon and mackerel. Butterfish, mahimahi eggs; other fish oil capsules (ProEPA and Omega 3) contained moderate levels of omega-3 fatty acids. Fish cakes, seaweed, several lean fishes, and cod liver oil capsules had small quantities of omega-3 fatty acids. It appeared that the omega-3 fatty acid content of aquacultured species studied was significantly higher than in wild caught species. There was a substantial difference between claimed and actual omega-3 fatty acid levels in commercially available fish oil capsules. These findings can help consumers when selecting types of seafood for their diet that are good sources of omega-3 fatty acids.