Influence of tumor size on outcomes following pelvic exenteration.

OBJECTIVE: Pelvic exenteration (PE) is often the only curative option for locally advanced or recurrent pelvic malignancies. Despite radical surgery, recurrence risk and morbidity remain high. In this study, we sought to determine tumor size effect on perioperative outcomes and subsequent survival in patients undergoing PE. METHODS: Retrospective chart review was performed for female patients who underwent PE at two comprehensive cancer centers from 2000 to 2015. Demographics, complications and outcomes were recorded. Statistical analyses were performed using chi-square, student's t-test, logistic regression, non-parametric tests, log-rank test, and Cox proportional hazards. RESULTS: Of 151 women who underwent PE, 144 had available pathologic tumor size. Gynecologic oncology, surgical oncology, and urology performed 84, 29, and 31 exenterations, respectively. Tumor dimensions ranged from 0 to 25.5cm. Perioperative complications, 30-day mortality, reoperation, and readmission rates were not associated with tumor size. Obesity and prior radiation increased risk for major perioperative complication while anterior exenterations decreased risk. Larger tumors were more likely to undergo total pelvic exenteration (OR 1.14; 95%CI 1.03-1.27), have positive margins (OR 1.11; 95%CI 1.02-1.22), and recur (65%, 42% and 20% for tumors >4cm, ≤4cm and no residual tumor respectively, p=0.016). Tumor size >4cm and positive margins were associated with worse overall survival amongst gynecologic oncology patients. CONCLUSION: Tumor size was not associated with perioperative morbidity. Larger tumors were associated with positive margins, more extensive resection, and worse survival in gynecologic oncology patients. Larger studies are needed to further understand tumor size impact on PE outcomes within specific tumor types.

Genotoxicity studies on licorice flavonoid oil (LFO).

Licorice flavonoid oil (LFO) is a new functional food ingredient. In this study, the genotoxicity of LFO was investigated using a test battery of three different methods. In a reverse mutation assay using four Salmonella typhimurium strains and Escherichia coli, LFO did not increase the number of revertant colonies in any tester strain with or without metabolic activation by rat liver S9 mix. In a chromosomal aberration test using Chinese hamster lung (CHL/IU) cells, LFO did not induce any chromosomal aberrations either in the short period test without rat liver S9 mix or in the continuous treatment (24 h or 48 h) test. However, in the short-period test with rat liver S9 mix, LFO induced structural chromosomal aberrations at concentrations higher than 0.6 mg/mL. A bone marrow micronucleus test using male F344 rats was initially conducted. The animals were dosed by oral gavage at doses up to 5000 mg/kg/day. No significant or dose-dependent increases in the frequency of micronucleated polychromatic erythrocytes (MNPCE) were observed and the high dose suppressed the ratio of polychromatic erythrocytes (PCE) to total erythrocytes. Subsequently, a liver and peripheral blood micronucleus test using male F344 rats was conducted. No micronuclei induction either in hepatocytes or PCE was observed even at the highest dose of 5000 mg/kg/day. From the findings obtained from the genotoxicity assays performed in this study and the published pharmacokinetic studies of LFO, it appears unlikely that dietary consumption of LFO will present any genotoxic hazard to humans.

90-Day repeated-dose toxicity study of licorice flavonoid oil (LFO) in rats.

Licorice flavonoid oil (LFO) is a new functional food ingredient consisting of licorice hydrophobic polyphenols in medium-chain triglycerides (MCT). As part of a safety evaluation, a 90-day oral toxicity study in rats was conducted using an LFO concentrate solution (2.90% glabridin). Male and female animals were assigned to one of 12 groups (10 males or females per group) and received corn oil (negative control), MCT (vehicle control), or 400, 600, 800 or 1600 mg/kg of the LFO concentrate solution. In conclusion, LFO concentrate solution induced an anticoagulation effect in both sexes, although there was a clear sex difference. Based on these findings, it is concluded that the no-observed-adverse-effect level (NOAEL) for the LFO concentrate solution is estimated to be 800 mg/kg/day for female rats, and approximately 400 mg/kg/day for male rats.

28-Day repeated dose toxicity study of dried microorganism in rats.

Ubidecarenone, also known as CoQ(10), is currently sold as a dietary supplement in the United States, with a majority of these products derived from the fermentation of carbohydrates or tobacco leaf extracts. In addition to its availability in dietary supplements, CoQ(10) is now being considered for use in foods. Accordingly, as part of the process for attaining "Generally Recognized as Safe" status, and to supplement information already available regarding the safety of CoQ(10) per se, a 28-day oral toxicity study in rats was conducted to evaluate the subacute safety of a microorganism biomass used as a new source in CoQ(10) production. Groups of Crj:CD(SD) rats (SPF) (6 males or females per group, 4 groups per sex) received dried microorganism at doses of 0, 500, 1000 or 2000 mg/kg/day via intragastric intubation. Clinical observations were recorded, and body weight, and food and water consumptions measured throughout the study. At the end of the study, aortic blood samples were collected from all animals for analysis of hematological and clinical chemistry parameters, and gross pathologic examination was performed. Histopathologic examination was performed on select tissues from the control and high-dose groups. There were no treatment-related changes that were considered to be of toxicological significance. Since rats treated with 2000 mg/kg of dried microorganism did not demonstrate any treatment-related changes, the no-observable-adverse-effect level (NOAEL) for dried microorganism was estimated to be greater than 2000 mg/kg/day under the present study conditions.

Genotoxicity of gardenia yellow and its components.

Gardenia fruit (Gardenia jasminoides ELLIS) is widely used as a natural food colorant and as a traditional Chinese medicine for treatment of hepatic and inflammatory diseases. "Gardenia yellow" is a natural food colorant which is extracted by ethanol from gardenia fruit. The purpose of this study was to evaluate the genotoxicity of gardenia yellow. Genotoxicity of gardenia yellow and its components, crocetin, gentiobiose (a component of crocin), geniposide and genipin (formed by hydrolysis of geniposide), was studied by Ames test, rec-assay, and sister chromatid exchange (SCE) using V79 cells. Gardenia yellow and its components were found not to be mutagenic in the Salmonella reverse mutation assay. Gardenia yellow and genipin caused damage of DNA in rec-assay. Gardenia yellow induced a significant dose-dependent increase of SCE frequency (8.6 times at 1000 microg/ml as the value for the solvent control). Only genipin induced SCEs significantly among the components of gardenia yellow. Moreover, genipin induced a significant increase of tetraploids at all doses tested (95% at 8 microg/ml). Gardenia yellow preparation was analyzed by capillary electrophoresis (CE), and geniposide was detected. However, genipin was not observed. In conclusion, we have shown that genipin possesses genotoxicity. Furthermore, there were unidentified genotoxicants in gardenia yellow.

Chemopreventive effects of coumaperine from pepper on the initiation stage of chemical hepatocarcinogenesis in the rat.

This study was designed to investigate the chemopreventive action of three natural products, coumaperine, aurapten and an extract from rosemary, against the initiation stage of rat hepato-carcinogenesis. Coumaperine has been isolated from white pepper as a naturally occurring antioxidative agent, but its potential modifying effects on carcinogenesis remain unclear. In experiment 1, a modification of the model developed by Tsuda et al. was applied, with assessment of numbers and areas of induced glutathione S-transferase placental form (GST-P)-positive hepatocellular foci in male F344 rats. Coumaperine, aurapten and the extract from rosemary were administered i.g. at 100 mg / kg / day once daily for 5 days with initiation by diethylnitrosamine (DEN) on day 4 (20 mg / kg, i.p.). Numbers and areas of GST-P-positive foci in each group given test chemicals tended to be decreased as compared to the vehicle control group values, significance being achieved for number with coumaperine. Experiment 2 was planned to investigate the mechanism of the inhibitory effects of coumaperine. Livers at 8 h after initiation by DEN were examined with coumaperine administered at 100 mg / kg / day once daily for 3 days. Proliferating cell nuclear antigen (PCNA)-positive cells tended to be decreased as compared to the vehicle control, but no effects on apoptosis or cytochrome P-450 (CYP) 2E1 expression were apparent. Our results suggest that coumaperine provides protection against initiation of hepatocarcinogenesis, and that this is related to inhibition of cell proliferation.

Suppressive activity of lycoricidinol (narciclasine) against cytotoxicity of neutrophil-derived calprotectin, and its suppressive effect on rat adjuvant arthritis model.

Calprotectin is a calcium- and zinc-binding protein complex that is abundant in cytosol of neutrophils. The concentration of calprotectin in extracellular fluids is greatly increased under various inflammatory conditions in vivo. We recently demonstrated that calprotectin inhibited cell growth and induced apoptosis of various cell types including tumor cells and normal fibroblasts; therefore, extracellular calprotectin might cause tissue destruction in severe inflammatory diseases. We previously found that an alkaloid, lycorine inhibits induction of apoptosis by calprotectin. In this paper, we examined the inhibitory activities of other Amaryllidaceae alkaloids, namely, lycoricidinol, hippeastrine and ungerine against the cytotoxicity of calprotectin. Lycoricidinol (narciclasine) inhibited calprotectin-induced cytotoxicity at more than 10-fold lower concentration (IC50=0.001-0.01 microg/ml) than lycorine, while the effects of the latter two alkaloids were very weak. Therefore, we next checked the prophylactic effect of lycorine and lycoricidinol on the adjuvant arthritis model in rats. Lycoricidinol, but not lycorine, significantly suppressed the degree of swelling of adjuvant-treated as well as untreated feet, suggesting that lycoricidinol might be a candidate as a the drug having marked suppressive activity for inflammation which might be influenced by calprotectin.

Enhancing effects of organosulfur compounds from garlic and onions on hepatocarcinogenesis in rats: association with increased cell proliferation and elevated ornithine decarboxylase activity.

Four organosulfur compounds from garlic and onions were examined for modifying effects on diethylnitrosamine (DEN)-induced neoplasia of the liver in male F344 rats using the medium-term bioassay system based on the two-step model of hepatocarcinogenesis. Carcinogenic potential was scored by comparing the numbers and areas per cm2 of induced glutathione S-transferase placental form-positive foci. Isothiocyanic acid isobutyl ester (IAIE), dipropyl trisulfide (DPT), and allyl mercapton (AM) exerted enhancing effects on their development, while dimethyl trisulfide also tended to increase them. To investigate possible mechanisms of the modifying influence, sequential changes in ornithine decarboxylase activity (ODC) over 24 h were measured in AM-treated liver tissue without prior DEN initiation. The activity started to increase by 4 h after AM-treatment, and reached maximum at 16 h, compared to controls. Spermidine/spermine N1-acetyltransferase activity was not significantly changed. An increase in proliferating cell nuclear antigen-positive cells followed the elevation of ODC activity. These results suggest that IAIE, DPT, and AM promote rat hepatocarcinogenesis and their promoting effect might be caused by increased cell proliferation with increased polyamine biosynthesis. In evaluating relationships between diet and cancer, it is thus appropriate to consider not only a possible protective role of garlic and onions, but also enhancing effects.

In vivo evaluation of NM441, a new thiazeto-quinoline derivative.

NM441 is a lipophilic prodrug of a new thiazeto-quinoline carboxylic acid derivative NM394, and when it is administered orally it is readily absorbed and hydrolyzed to its parent compound. After oral administration of NM441 at a dose of 20 mg/kg to dogs, the peak concentration of NM394 in plasma was 2.39 micrograms/ml, whereas it was 0.63 micrograms/ml for NM394 administered alone. The in vivo activity of NM441 was compared with those of ciprofloxacin, ofloxacin, and enoxacin in mouse protection studies. NM441 was as effective as ofloxacin and was twice as effective as ciprofloxacin against systemic infection with Staphylococcus aureus. Against infections with streptococci, NM441 was two to three times as effective as ofloxacin and five times as effective as ciprofloxacin. Against infection with Escherichia coli, NM441 was as effective as ciprofloxacin and ofloxacin, but against infections with Klebsiella pneumoniae, Serratia marcescens, and Pseudomonas aeruginosa, NM441 was two to four times as effective as ciprofloxacin and ofloxacin. NM441 was three to seven times as effective as enoxacin in systemic infections. Against urinary tract infections with E. coli, NM441 reduced the number of bacterial CFU per gram of kidney by 1 to 2 log10 more and, with P. aeruginosa, by 1 to 6 log10 more than did ciprofloxacin and ofloxacin. Against respiratory tract infections with K. pneumoniae, NM441 was as effective as ofloxacin and was twice as effective as ciprofloxacin.

Location of a DBS-electrode in lateral thalamus for deafferentation pain. An autopsy case report.

Pain relief was obtainable when deep brain stimulation was tried in the sensory thalamic nucleus in a patient with deaffereantation pain to cervical myelopathy. The electrode was histologically verified in post-mortem examination after 20 months and the localization of contact points of the implanted electrode was estimated. The cathode appeared to have been placed in the region from Vim to the rostral border of Vci while the anode was in the medical lemniscus region. Stimulation of the Vim nucleus might have had a pain relieving effects because no facial paraesthesiae was evoked by stimulation. The implanted electrode caused only minor histological changes.

[Multiple malignant schwannoma treated with a multidisciplinary therapy--a case report].

A 32-year-old man, complaining of an abdominal mass, was admitted to hospital where, on undergoing examination, the mass, which had spread widely through the abdominal cavity and the retroperitoneal space, was diagnosed as a malignant schwannoma with a liver metastasis. Thus, a multidisciplinary treatment was initiated and a remission was achieved. Later, however, he developed a multiple, local recurrence and died forty months after onset of his clinical symptoms. Since the prognosis of patients with a malignant schwannoma that do not undergo radical surgery is extremely poor, the authors emphasize the necessity of research for an effective adjuvant therapy.

[Drug sensitivity test of cultured human cancer cells--assay for microcolonies inhibition test].

The sensitivity of anti-cancer drugs against cultured human lung cancer cells and the first cultured xenograft tumor has been measured by the microcolonies inhibition test in microplates (Falcon, Micro Test II). The results obtained were as follows; 1). The drug sensitivity of cancer cells has differed in each case. The established cancer cell lines of the same cell type and the same growth speed have also showed a different sensitivity. Therefore, it suggests that the measurement of drug sensitivity of cultured human cancer cells is usefull for the clinical application. 2). The drug sensitivity of cancer cells has been elevated when they changed their character during the passage cultures. On the other hand, the successful culture of cancer cells has been elevated when they were purified with discontinuous density gradients and a hypotonization. 3). In future, further efforts to develop a better medium for the colonies inhibition test, i. e., a conditioned medium containing the specific growth factor for the colony of cancer cells are imperative.

Taking the role of retarded children: effects of familiarity and similarity.

As a first step in improving social relations between nonhandicapped and retarded children, this study was designed to investigate children's ability to take a retarded child's role and the effects of two variables on this ability: (a) familiarity with the characteristics of retarded children and (b) similarity of experiences to those of retarded youngsters. Findings were interpreted as indicating that children's ability to take the perspective of retarded children may be a productive area for further research.