Effect of TIMP1 transfection on PTEN expression in human kidney proximal tubular cells.

To explore the role of metalloproteinase-1 (TIMP-1) tissue inhibitor in the mechanisms of kidney aging, we observed the effects of sense and antisense transfection of TIMP-1 and of metalloproteinase (MMP) inhibitors on phosphatase and tensin homolog (PTEN), vascular endothelial growth factor (VEGF), and Flk-1 expression in TIMP-1 transgenic human proximal tubular epithelial cells (HKCs). Transfected HKCs were co-incubated with 100 µM MMP-2 and MMP-9 inhibitor III for 24 h to affect enzyme inhibition. TIMP-1, MMP-2, MMP-9, PTEN, VEGF, and Flk-1 mRNA expression was detected by reverse transcription-polymerase chain reaction. PTEN, VEGF, and Flk-1 protein expression in cells of each experimental group was measured by indirect immunofluorescence. We found that PTEN expression was up-regulated (P < 0.05) in the sense TIMP-1-transfected group (P < 0.05) compared with the non-transfected and empty vector groups, and that expression of VEGF and Flk-1 was down-regulated (P < 0.05). In contrast, the antisense TIMP-1 transgenic group showed the opposite results (P < 0.05). No significant differences in expression of PTEN, VEGF, or Flk-1 were observed among the MMP- 2/MMP-9 inhibitor III, non-transfected, and empty vector groups (P > 0.05). These results suggest that in the progression of renal aging, high expression of TIMP-1 up-regulates PTEN expression through an MMP-independent pathway, and subsequently down-regulates the expression of VEGF and Flk-1, indicating that PTEN and TIMP-1 are involved in the aging-associated impairment of renal angiogenesis. Our study provides a theoretical basis for further exploration of the mechanism underlying TIMP- 1 participation in renal aging progression.

Gpnmb/osteoactivin, an attractive target in cancer immunotherapy.

Cancer is a complex disease with interactions between normal and neoplastic cells. Since current therapies for cancer largely rely on drugs or radiation that kill dividing cells or block cell division, these treatments may have severe side effects on normal proliferating cells in patients with cancer. Recently, immunotherapeutic approaches for cancer therapy, by which monoclonal antibodies (Mabs) target tumor specific antigens, have shown great potential. Glycoprotein non-metastatic melanoma protein B(Gpnmb)/Osteoactivin (OA) is a transmembrane glycoprotein highly expressed in various types of cancer. Gpnmb/OA promotes the migration, invasion and metastasis of tumor cells. CR 011-vcMMAE is a Mab-drug conjugate being developed for the treatment of Gpnmb/OA-expressing cancers. Gpnmb/OA represents an attractive target in cancer immunotherapy and CR011-vcMMAE holds promise as a reagent in targeted therapy for Gpnmb/OA-expressing malignancies.

The relationship between the TGF-beta1 gene -509C/T polymorphism and tubulointerstitial damage resulting from primary nephrotic syndrome.

BACKGROUND: The aim of this study was to investigate the correlation between the transforming growth factor (TGF)-beta1 gene -509C/T polymorphism and the susceptibility to primary nephrotic syndrome (PNS), and in particular to the severe degree of tubulointerstitial damage (TID) seen in Chinese. METHODS: Ninety-eight PNS patients and 128 normal controls were studied. The extent of tubulointerstitial changes was evaluated and patients were divided into two groups according to the severe or mild degree of TID. The TGF-beta1gene -509C/T polymorphism was detected with polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique, and the serum level of TGF-beta1 was determined by enzyme-linked immunosorbent assay (ELISA). RESULTS: No statistical differences in genotype or allele frequency of the TGF-beta1 gene -509C/T were found between PNS and normal subjects. However, T allele and CT + T T genotype frequency were higher in the PNS with severe TID than the mild TID and controls. Additionally, the serum concentration of TGF-beta1 was significantly higher in the PNS with severe TID group than the other two groups and in the T T genotype individuals than the CC and CT genotype individuals. A logistic regression analysis demonstrated that TGF-beta1 gene -509C/T genotype was the risk factor of TID in PNS patients [OR (odd ratio) 2.34, confidence interval (CI) 0.98-3.46, p = 0.012]. CONCLUSION. TGF-beta1 gene -509C/T polymorphism was associated with severe TID. The higher value in serum concentration of TGF-beta1 was also associated with severe TID and the T T genotype/T allele. T allele gene might be the important risk factor for susceptibility.

Association of disease condition with changes in intestinal flora, and plasma endotoxin and vascular endothelial growth factor levels in patients with liver cancer.

OBJECTIVE: Currently, the therapeutic effect on patients with liver cancer is associated with disease development. Meanwhile, the efficacy in patients with advanced liver cancer is far from satisfactory. Therefore, the aim of this study was to explore the association of disease condition with changes in liver function indexes, intestinal flora, and plasma endotoxin (ET) and vascular endothelial growth factor (VEGF) levels in patients with liver cancer. PATIENTS AND METHODS: A total of 300 patients with primary liver cancer in our hospital were enrolled in this study. All patients were divided into three groups, including early liver cancer group, middle liver cancer group, and advanced liver cancer group. Peripheral blood was collected from each subject to detect liver function indexes, procalcitonin (PCT), plasma ET, and VEGF levels. Furthermore, mid-posterior-segment stools were collected from 15 cases in each group, and sent to the company for detection of intestinal flora. RESULTS: Liver function indexes in peripheral blood of patients with liver cancer changed with the changes in disease condition. With the progression of liver cancer, the level of aspartate aminotransferase (AST) increased significantly, and the highest was observed in advanced liver cancer patients [(91.18±10.34) U/L] (p=0.046). However, the level of plasma total protein declined significantly, which was (24.83±1.75) g/L in advanced liver cancer patients (p=0.035). The changes in total bilirubin were significantly associated with the progression of liver cancer (p=0.003). The abundance of Clostridiales, Firmicutes, and Streptococcus in the intestinal tract was high in early liver cancer group. The abundance of Ruminococcaceae, Pasteurellaceae, Tanticharoenia, and Vagococcus in the intestinal tract was high in middle liver cancer group. Meanwhile, the abundance of Bifidobacteriales, Actinobacteria, Barnesiella, Porphyromonadaceae, and Pseudomonadales in the intestinal tract was high in advanced liver cancer group. In patients with liver cancer, the level of Enterobacteriaceae was positively correlated with that of Firmicutes (r=0.36, p=0.003), whereas it was negatively correlated with Lactobacillus (r=-0.72, p=0.021). The level of Lactobacillus was positively correlated with that of Ruminococcaceae (r=0.39, p=0.043), whereas it was negatively correlated with that of Firmicutes (r=-0.27, p=0.019). In addition, the level of PCT markedly rose in advanced liver cancer group [(6.89±0.35) ng/mL] (p=0.021). The level of ET increased significantly with the development of liver cancer, with the highest level observed in advanced liver cancer group [(0.71±0.09) EU/mL] (p=0.004). The level of VEGF also increased remarkably with the aggravation of liver cancer, and the highest was found in advanced liver cancer group [(112.33±2.11) µmol/L], showing differences among groups (p<0.05). CONCLUSIONS: With the progression of liver cancer, the abundance of Barnesiella, etc., rose and that of Ruminococcaceae, etc., declined in the intestinal tract. Meanwhile, the composition of intestinal flora was changed, and the levels of plasma ET and VEGF increased.

The efficacy and safety of immune checkpoint inhibitors in non-small cell lung cancer patients of different age groups: a meta-analysis.

BACKGROUND: Age is closely related to the efficacy of treatment for non-small cell lung cancer (NSCLC) patients. Latest clinical trials have proved the better overall survival (OS) for the use of immune checkpoint inhibitors verse chemotherapy in NSCLC patients. However, we had no clear idea of the efficacy of them in elderly patients. So we conducted a meta-analysis to compare the efficacy of immune checkpoint inhibitors for NSCLC patients of different age groups and summarized overall treatment-related adverse events. MATERIALS AND METHODS: PubMed, EMBASE, Web of Science and the Cochrane Library were searched for all clinical trials in NSCLC until 30th of April 2019. Eligible studies included randomized controlled trials (RCTs) comparing immune checkpoint inhibitors with chemotherapy in NSCLC patients. The hazard ratio (HRs) and 95% confidence intervals (CIs) of OS, progression-free survival or adverse events (AEs) were used. RESULTS: A total of 4994 patients from 8 RCTs were included. Immune checkpoint inhibitors significantly prolonged the OS (HR, 0.73; 95% CI, 0.61-0.89) versus chemotherapy in NSCLC patients who were less than 65 years old. Also, they prolonged the OS (HR, 0.74; 95% CI, 0.59-0.93) in NSCLC patients who were more than 65 years old. However, there was no statistical significance of OS (HR, 0.87; 95% CI, 0.57-1.30) among NSCLC patients who were more than 75 years old. It also showed that the single use of immune checkpoint inhibitors had fewer all-grade AEs. CONCLUSION: Regardless of the NSCLC patients who were less or more than 65 years, immune checkpoint inhibitors could achieve better OS than chemotherapy. But there was no significant difference when NSCLC patients who were more than 75 years old. Older patient should be offered immune therapies if it is possible and the mechanism in old age treatment should be further studied.

Activated T cells inhibit NK cell-mediated tumour rejection.

Previous studies have described the regulation of some T-cell subsets toward natural killer (NK) cells. Naturally occurring CD4(+)CD25(+) T regulatory cells can inhibit NK cell cytotoxicity, while activated interleukin-2 (IL-2) secreting T cells can stimulate NK cells. However, little is known about the impact of the integrity T-cell population on the final outcome of NK cell cytotoxicity. We thus examined the possible role of activated T cells in affecting NK cell cytotoxicity by mixed lymphocyte co-cultures in vitro and a B16 melanoma tumour model in vivo. In our study, activated T cells were found to be able to significantly inhibit NK cell cytotoxicity in vitro and blunt NK cell-mediated tumour rejection in vivo. The inhibition of NK cell function is a cell-cell contact dependent way. Results suggest that activated T cells may play an important role in limiting NK cell functions, which might be very significant for the design of biotherapy against tumour or infection in future.

Arkadia regulates TGF-beta signaling during renal tubular epithelial to mesenchymal cell transition.

Transforming growth factor-beta (TGF-beta) signaling has been linked with tubular epithelial to mesenchymal cell transition. In this study, we examined the role of Arkadia, an E3 ubiquitin ligase that is critically required for TGF-beta signaling during epithelial to mesenchymal cell transition. We found that when normal human renal tubular epithelial cells in culture were stimulated with TGF-beta1, which increased their levels of Arkadia, Smurf2, TGF-beta type I receptor (TbetaRI), and Smad7 mRNA, but had low levels of Smad7 protein. When these cells were preincubated with Arkadia siRNA (small interfering RNA) and lactacystin (an inhibitor of proteasomal degradation), the TGF-beta(1) induced expression of Smad7, alpha-smooth muscle actin, and E-cadherin was partly reversed, but the expression of TbetaRI protein and Smad7 mRNA was not affected. In contrast, Smurf2 siRNA had no influence on the expression of these targets. Our studies suggest that Arkadia stimulates renal tubular epithelial to mesenchymal cell transition through degradation of Smad7.

Methylation of discrete regions of the O6-methylguanine DNA methyltransferase (MGMT) CpG island is associated with heterochromatinization of the MGMT transcription start site and silencing of the gene.

O6-Methylguanine DNA methyltransferase (MGMT) repairs the mutagenic and cytotoxic O6-alkylguanine lesions produced by environmental carcinogens and the chemotherapeutic nitrosoureas. As such, MGMT-mediated repair of O6-alkylguanine lesions constitutes a major form of resistance to nitrosourea chemotherapy and makes control of MGMT expression of clinical interest. The variability of expression in cell lines and tissues, along with the ease with which the MGMT phenotype reverts under various conditions, suggests that MGMT is under epigenetic control. One such epigenetic mechanism, 5-methylation of cytosines, has been linked to MGMT expression. We have used an isogenic human multiple myeloma tumor cell line model composed of an MGMT-positive parent cell line, RPMI 8226/S, and its MGMT-negative variant, termed 8226/V, to study the control of MGMT expression. The loss of MGMT activity in 8226/V was found to be due to the loss of detectable MGMT gene expression. Bisulfite sequencing of the MGMT CpG island promoter revealed large increases in the levels of CpG methylation within discrete regions of the 8226/V MGMT CpG island compared to those in 8226/S. These changes in CpG methylation are associated with local heterochromatinization of the 8226/V MGMT transcription start site and provide a likely mechanism for the loss of MGMT transcription in 8226/V.

Analysis and stability of retinol in plasma.

A simple, precise, and specific high-performance liquid chromatography (HPLC) method was developed for the simultaneous measurement of retinol (ROH), 13-cis-retinoic acid (13-cRA), and 4-oxo-13-cRA. The average recovery of ROH from serum or plasma was 95%, and the precision of the assay was less than 5%. With this HPLC method, a series of studies was carried out to evaluate the stability of ROH in various matrices. ROH was stable under our HPLC assay conditions as well as in plasma- and in serum-enriched culture media; however, ROH was not stable in aqueous matrices. Serum or heparinized plasma may be routinely used for measurement of ROH concentrations, providing EDTA, oxalate, and citrate are not used as anticoagulants. Because of ROH stability, blood samples can be kept on ice in the dark for at least 24 hours prior to separation of plasma. In addition, plasma samples containing ROH can be stored for up to 1 year at -20 degrees C without loss of stability.

Therapeutic synergism of hyperthermia-cis-platinum in a mouse tumor model.

A small-animal model was developed as a guide to whole-body hyperthermia in cancer patiens. Anesthetized DBA/2 mice were secured to a platform, and their hindlimbs were immersed in a 42.3 degrees C water bath for 30-60 minutes. Hindlimb hyperthermia reulted in steady-state rectal and femoral bone marrow and muscle temperatures of 42 degrees C and upper extremity muscle and esophagus temperatures of 41 degrees C. With this hyper thermia technique, the mouse spleen colony assay could be used to quantitate the lethality of hyperthermia and/or cis-dichloro-diammineplatinum(II) (cis-platinum) on clonogenic bone marrow and leukemia cells. Hyperthermia prior to cis-platinum administration increased cis-platinum inhibition of leukemia colony formation as much as 2 logs; however, antileukemia synergism ws greatest when cis-platinum administration immediately preceded hyperthermia and no evidence existd of synergism against normal bone marrow colonies. Correlative in vivo drug uptake studies showed a marked increase in leukemia cell uptake of 195mPt-cis-platinum at elevated temperatures, which suggested a potential mechanism for the apparent antileukemia synergism of cis-platinum and heat.

Antitumor activity and clinical pharmacology of sulofenur in ovarian cancer.

BACKGROUND: Sulofenur is a diarylsulfonylurea with demonstrated antitumor activity in patients with advanced epithelial ovarian cancer refractory to standard chemotherapy. The dose-limiting toxic effects observed in phase I clinical trials have been anemia and methemoglobinemia, resulting in cyanosis. PURPOSE: The purposes of this study were to further define the response rate, toxic effects, and pharmacokinetics and pharmacodynamics of sulofenur in patients with advanced ovarian cancer. METHODS: We conducted a phase II trial of sulofenur at a dose of 800 mg/m2 per day in 35 patients with stage III or IV ovarian cancer refractory to standard chemotherapy. Pharmacokinetics and pharmacodynamics were analyzed by comparing sulofenur parent and metabolite plasma levels with methemoglobin levels. RESULTS: Partial responses lasting 6.5-18 weeks occurred in four (15%; 95% confidence interval = 4%-35%) of the 26 patients assessable for response. In addition, 42% (11) of the assessable patients had prolonged stable disease (median, 20 weeks). The first nine patients received sulofenur as a daily oral dose for 14 days, with a 21-day treatment cycle. However, they developed substantial anemia and methemoglobinemia. As a result, the next 26 patients received sulofenur daily for 5 days followed by 2 days of rest for 3 consecutive weeks, with a 28-day treatment cycle (5/2-day schedule). Preclinical models predicted that 2 days of rest would decrease toxicity while maintaining antitumor activity. Patients treated with the 5/2-day schedule had relatively less severe anemia and methemoglobinemia and needed fewer red blood cell transfusions (31% versus 78% of patients), but 31% still required dose reductions because of these toxic effects. The hydroxy and keto metabolites of sulofenur had prolonged plasma half-lives relative to the parent compound, and the difference was statistically significant. In addition, the correlations of metabolite concentrations with methemoglobin levels were higher than the correlation of sulofenur concentrations with methemoglobin levels, and those differences were statistically significant. CONCLUSION: We conclude that sulofenur has modest clinical activity in heavily pretreated patients with ovarian cancer. IMPLICATIONS: The toxic effects of anemia and methemoglobinemia may limit the ultimate clinical utility of diarylsulfonylureas until less toxic derivatives with alternate metabolic pathways can be identified.

Reduction in plasma or skin alpha-tocopherol concentration with long-term oral administration of beta-carotene in humans and mice.

BACKGROUND: Beta-carotene is one of the most commonly used compounds in clinical trials of chemopreventive agents in various neoplastic diseases. Animal studies, including our own, have documented that dietary beta-carotene can reduce plasma alpha-tocopherol (vitamin E) levels, but few published studies have examined the clinical or pharmacokinetic ramifications of long-term, high-dose beta-carotene regimens on other fat-soluble vitamins such as alpha-tocopherol. PURPOSE: This study was designed to determine the effects of long-term beta-carotene supplementation on plasma concentrations of alpha-tocopherol in normal human subjects and in an experimental C3H/HeN mouse model. METHODS: In a double-blind study, 45 normal subjects were randomly assigned to receive 0 (placebo), 15, 30, 45, or 60 mg of oral beta-carotene daily for approximately 9 months. Monthly plasma samples were collected. Thirty-five C3H/HeN mice were fed a basal diet with or without beta-carotene and treated topically with or without alpha-tocopherol, except for the control mice, which received UV radiation for 27 weeks from week 3 to week 30. Plasma and dorsal skin samples were taken after 40 weeks and were analyzed for alpha-tocopherol and/or beta-carotene by high-performance liquid chromatography. RESULTS: Long-term dietary beta-carotene administration resulted in statistically significant reductions in levels of alpha-tocopherol in the skin and plasma of UV-irradiated mice. In the human study, the decrease in plasma alpha-tocopherol levels was progressive and significant between 6 and 9 months of beta-carotene dosing in all dosage groups. The greatest decrease was observed during the 9th (last) month of dosing, with a decrease of 40% from baseline. All oral beta-carotene doses (15-60 mg/d), however, resulted in similar decreases in steady-state plasma levels of alpha-tocopherol and in only small differences in beta-carotene plasma levels. CONCLUSION: Long-term oral administration of beta-carotene decreased steady-state plasma concentrations of alpha-tocopherol. The lack of a significant dose-response effect between doses of beta-carotene and alpha-tocopherol plasma levels is not unexpected, given the small differences in steady-state beta-carotene plasma levels in the four beta-carotene dose groups. IMPLICATIONS: Studies are needed to determine how long-term beta-carotene dosing influences tissue distribution of dietary alpha-tocopherol. Careful surveillance for this and other potentially harmful nutrient interactions should become part of all long-term intervention studies.

Molecular pharmacology of the anthracycline drug 9,10-anthracenedicarboxaldehyde bis[(4,5-dihydro-1 H-imidazol-2-yl)hydrazone] dihydrochloride (Cl 216,942).

9,10-Anthracenedicarboxyaldehyde bis[(4,5-dihydro-1H-imidazol-2yl)hydrazone] dihydrochloride (Cl 216,942) is a new anthracene bishydrazone derivative which has shown antitumor activity in Phase I trials against both hematological cancers and solid tumors. The effects of Cl 216,942 on L1210 mouse leukemia cells were studied with the nucleoid sedimentation and alkaline elution assays. Evidence for Cl 216,942 intercalation into cellular DNA was obtained in exponentially growing cells by comparing the L1210 nucleoid sedimentation behavior in neutral sucrose gradients of ethidium bromide with nucleoids from Cl 216,942-treated cells. A 1-hr treatment of exponentially growing L1210 cells with Cl 216,942 induced both protein-associated DNA single-strand breaks and DNA-protein crosslinks as detected by the alkaline elution assay. The DNA strand break and DNA-protein cross-link frequencies were found to be within a factor of 2 of each other over a range of Cl 216,942 concentrations. The dose response for the induction of DNA damage showed a linear decrease up to 10 micrograms/ml, but this was followed by a decrease in damage at dose levels greater than 10 micrograms/ml. The biphasic dose response could not be explained by changes in the cellular uptake of Cl 216,942. The kinetics of Cl 216,942 induction of DNA damage after a 1-hr treatment showed that at the dose which gave maximum damage the degree of damage (10 micrograms/ml) decreased with further incubation, but at a higher dose (20 micrograms/ml) DNA damage increased with postincubation at 37 degrees. The cytotoxicity produced by Cl 216,942 at a given frequency of protein-associated strand breaks was low. Cl 216,942 thus appeared to belong to a low-toxicity group of DNA intercalators.

Comparative molecular pharmacology in leukemic L1210 cells of the anthracene anticancer drugs mitoxantrone and bisantrene.

1,4-Dihydroxy-5,8-bis(2-[(2-hydroxyethyl)aminoethyl]amino)-9, 10-anthracenedione (mitoxantrone) and 9,10-anthracenedicarboxaldehyde bis[(4,5-dihydro-1H-imidazol-2y)hydrazone] dihydrochloride (bisantrene) were evaluated for their abilities to cause cytotoxicity and interact with cellular DNA using leukemic L1210 cells. On a molar basis mitoxantrone has been found to be 7-fold more toxic than bisantrene. Using a nucleoid sedimentation technique, bisantrene caused changes in DNA supercoiling which were characteristic of an intercalating drug, but mitoxantrone did not induce these changes. Both drugs were found to interact with cellular DNA with tight but noncovalent binding. Both drugs also induced protein-associated double- and single-strand DNA breaks, but with mitoxantrone only some of the DNA single-strand breaks were protein associated, whereas with bisantrene all the DNA single-strand breaks were protein associated. The cytotoxicity produced by bisantrene at a given frequency of protein-associated DNA strand breaks was low. However, with mitoxantrone at an equivalent DNA strand break frequency, the cytotoxicity was high. Treatment of isolated L1210 nuclei with either drug did not result in DNA single-strand breaks. It can be concluded that bisantrene binds DNA in whole cells by an intercalative mechanism, whereas mitoxantrone binds DNA by a nonintercalative, electrostatic interaction and induces non-protein-associated DNA strand breaks.

Disposition of mitoxantrone in cancer patients.

We have used a highly sensitive high-performance liquid chromatographic assay to evaluate the pharmacokinetics and tissue disposition of mitoxantrone, an investigational anthracene derivative which has shown significant activity during Phase II clinical trials in the treatment of metastatic breast cancer, unfavorable histology non-Hodgkin's lymphoma, and acute leukemia. Mitoxantrone (12 mg/sq m over 30 to 35 min in 250 ml of dextrose 5% in water) and 14C-labeled mitoxantrone (specific activity, 8.85 muCi/mg) were administered to eight patients who had advanced soft tissue cancers. The plasma disappearance of mitoxantrone concentrations measured by high-performance liquid chromatography was best described by a three-compartment model with a mean t alpha of 0.1 h, a t beta of 1.1 h, and a t gamma of 42.6 h. The mean apparent Vc was 12.2 liters/sq m, while the mean Vd was 1875 liters/sq m. The mean plasma clearance was 0.57 liters/min/sq m, and the mean renal clearance was 45 ml/min/sq m. Only 6.5% of the total mitoxantrone dose was excreted in the urine as unchanged drug over 5 days. The mean recovery of 14C-labeled material in feces over 5 days was 18.3% of the administered dose. Thirty-five days after mitoxantrone administration to a patient who died of progressive kidney cancer, approximately 15% of the 14C dose could be accounted for in seven major organs. We conclude that mitoxantrone appears to distribute into a deep tissue compartment from which it is slowly released. These data provide a pharmacological rationale for use of mitoxantrone on an intermittent dosing schedule.

Plasma pharmacokinetics of cyclophosphamide and its cytotoxic metabolites after intravenous versus oral administration in a randomized, crossover trial.

Since cyclophosphamide is used by both oral and i.v. routes in the treatment of hematological and solid malignancies, we designed a randomized, crossover clinical trial to evaluate the pharmacokinetics of this anticancer agent after either administration route. Plasma levels of cyclophosphamide and its two cytotoxic metabolites, 4-hydroxycyclophosphamide and phosphoramide mustard, were determined in seven cancer patients randomly assigned to treatment initially with either orally or i.v. administered cyclophosphamide with a 30-day interim between alternate therapy courses. Oral treatment was used initially in five patients and i.v. treatment in two patients, and the pharmacokinetic parameter, area under the plasma disappearance curve, was determined for each metabolite in each patient for both routes of drug administration. Statistical comparison of area under the plasma disappearance curve values for this set of patients indicated no significant differences for either metabolite for oral versus i.v. drug treatment, suggesting equal efficacy for these two routes of cyclophosphamide administration.

Phase I clinical and pharmacokinetic study of mitoxantrone given to patients by intraperitoneal administration.

On the basis of its high degree of cytotoxicity against fresh human ovarian cancers and its relative lack of vesicant activity, mitoxantrone administered by the i.p. route was studied in a Phase I and pharmacokinetic trial. Thirty-three patients with good performance status and diagnoses of metastatic or recurrent ovarian (31 patients) and colon (two patients) cancers were treated with 12- to 38-mg/m2 doses, administered by the i.p. route every 4 wk for up to ten treatment courses. Mitoxantrone doses were escalated at 2- to 3-mg/m2 increments in groups of three to 11 patients. Thirty-eight mg/m2 (by i.p. dwell without removal) were considered the maximally tolerated dose in that, of eight treated patients, four experienced severe leukopenia and six experienced severe abdominal pain. Response to i.p. mitoxantrone was evaluable in 17 patients. None of seven patients with clinically measurable intraabdominal or pelvic tumor masses responded; however, in three (50%) of six patients with nonmeasurable disease, there was normalization of previously elevated serum CA-125 concentrations for 3, 17, and 24 mo. Additionally, two (50%) of four patients who underwent third-look laparotomies were found to have greater than 75% reductions in i.p. tumor masses with response lasting 24 and 25 mo. At 38 mg/m2, mitoxantrone was associated with a mean concentration.time product of 100 micrograms.h/ml in the i.p. space and of 0.071 micrograms.h/ml in plasma, yielding an i.p./plasma area under the curve ratio of 1408. We conclude that chemical peritonitis is the dose-limiting toxicity of i.p. administered mitoxantrone and that a dose of 23 mg/m2 every 3 to 4 wk should be used in future Phase II trials in ovarian cancer patients with minimal residual intraabdominal and pelvic disease following second-look laparotomy.

[Effects of infant feeding practice on eczema during early childhood in Shanghai, Hohhot, and Fuzhou].

Objective: To estimate the prevalence of eczema in early childhood and effect of infant feeding practice on eczema by different regions of China with diverse climate and dietary patterns. Method: A questionnaire survey was conducted from June 2012 to October 2012 in Shanghai, Hohhot, and Fuzhou. The parent or guardian of the children aged between 2.5 to 3.5 years attending routine health visit in the chosen communities were invited to complete a modified questionnaire of the International Study of Asthma and Allergy in Childhood (ISAAC). Logistic regression model was used to analyze of the family history of allergy, duration of breastfeeding, timing of introduction of complementary foods and other potential confounders. Result: A total of 2 242 children were interviewed, 750 from Shanghai, 716 from Hohhot, and 776 from Fuzhou. The prevalence of eczema in early childhood was significantly different among Shanghai (16.9%, 95%CI 16.87-16.93), Hohhot (34.5%, 95%CI 34.46-34.54)and Fuzhou (44.3%, 95%CI 44.26-44.34). The difference was statistically significant between 3 groups (χ2=72.05, P<0.05). Introducing complementary food after the age of 6 months was associated with a decreased risk for eczema when compared to introduction between 4 to 6 months(odds ratio (OR) 0.58, 95%CI 0.41-0.81) in Fuzhou, while there was no significant association between timing of introduction of complementary foods and eczema in Shanghai and Hohhot. Conclusion: The prevalence of eczema during early childhood is various among three cities. The relationship between timing of introduction of complementary foods and eczema in Fuzhou is different from that in Shanghai and Hohhot. The role of climate and dietary patterns on prevalence of eczema needs further studies.