Association of hyperglycemia and markers of hepatic dysfunction with dextrose infusion rates in Korean patients receiving total parenteral nutrition.

The association of hyperglycemia and markers of hepatic dysfunction with dextrose infusion rates in Korean patients receiving total parenteral nutrition (TPN) was studied. A retrospective study of 122 patients with normal glucose levels and liver function tests (LFTs) was conducted. Pharmacy and medical records of all patients who received TPN from three university-affiliated teaching hospitals in Korea between January 1998 and December 1999 were reviewed. Each patient was categorized as receiving dextrose at (1) < or = 5 or > 5 mg/kg/min and (2) < or = 4, 4.1-5, 5.1-6, or > 6 mg/kg/min. Fifty-five patients received dextrose at a rate of > 5 mg/kg/min for 15.1 +/- 12.8 days and 67 patients at a rate of < or = 5 mg/kg/min for 10.1 +/- 6.8 days. Two patients in each group did not have follow-up glucose levels. Of the 53 patients in the > 5 mg/kg/min group, 16 exhibited hyperglycemia, compared with 21 of the 65 receiving lower rates of dextrose infusion. Elevated aspartate transaminase was the most common abnormal LFT value in both groups (25% and 29% in the < or = 5- and > 5-mg/kg/min groups, respectively). In the group receiving dextrose at > 5 mg/kg/min, 22.2% had two hepatic enzyme levels elevated concurrently, while 18.5% had two hepatic enzyme levels elevated in the group receiving dextrose at < or = 5 mg/kg/min. Regression analysis revealed that duration of TPN and dextrose infusion rate were positively correlated with blood glucose levels and that duration of TPN was positively correlated with abnormal LFT values. A retrospective study of Korean patients revealed no significant difference in the risk of hyperglycemia or hepatic dysfunction between those receiving < or = 5 and > 5 mg/kg/min dextrose infusion in their TPN.     

Self-assembled nanoparticles of hydrophobically-modified polysaccharide bearing vitamin H as a targeted anti-cancer drug delivery system.

Vitamin H (biotin) was incorporated into a hydrophobically modified polysaccharide, pullulan acetate (PA), in order to improve the cancer-targeting activity and internalization of self-assembled nanoparticles. The biotinylated pullulan acetate (BPA) nanoparticles were prepared by a diafiltration method and the mean diameter was approximately 100 nm. Three samples of biotinylated pullulan acetate (BPA), comprising 7 (BPA 1), 20 (BPA 2), and 39 (BPA 3) vitamin H groups per 100 anhydroglucose units of PA, were synthesized. The critical aggregation concentrations (CAC) of the BPA nanoparticles in distilled water were 3.1 x 10(-3), 4.3 x 10(-3) and 6.8 x 10(-3) mg/ml for BPA 1, BPA 2, and BPA 3, respectively. Adriamycin (ADR) was loaded into the BPA nanoparticles as a model drug. The loading efficiencies and ADR content in the BPA nanoparticles decreased with increasing vitamin H content due to a lower hydrophobicity. The RITC-labeled BPA nanoparticles exhibited very strong adsorption to the HepG2 cells, while the RITC-labeled PA nanoparticles did not show any significant interaction. The degree of the interaction increased with increasing vitamin H content. Confocal laser microscopy also revealed that internalization of the BPA nanoparticles into the cancer cells depended on the vitamin H content.     

Extent and zonal distribution of prostatic intraepithelial neoplasia in patients with prostatic carcinoma in Japan: analysis of whole-mounted prostatectomy specimens

BACKGROUND: Prostatic intraepithelial neoplasia (PIN), an intraluminar proliferation of epithelial cells in ducts and acini, is divided into high-grade (HGPIN) and low-grade (LGPIN), based on morphologies. HGPIN is considered to be a putative precursor of prostatic adenocarcinoma (PCA). Information on PIN has been limited in Japan, because PIN had not been regarded as a precursor lesion for PCA. METHODS: In this study, extent and zonal distribution of PIN together with its relationship with PCA were examined in totally embedded radical prostatectomy specimens obtained from 70 patients with PCA. Fifty-three patients received androgen deprivation therapy (castrated) and remaining 17 did not (noncastrated). RESULTS: Frequency of HGPIN in noncastrated cases (76%) was much higher than that in castrated cases (26%) (P < 0.001). LGPIN showed the same tendency, but the difference was smaller. Difference in mean number of HGPIN in noncastrated and castrated cases (12.0 and 6.4, respectively) was more marked than in LGPIN (6.4 and 5.1, respectively). Reduction rate of mean size in HGPIN (26%) by the androgen deprivation therapy was larger than in LGPIN. When evaluated in noncastrated cases, the coexistence of PCA and HGPIN was found in 76% of cases in the nontransition and 53% in the transition zone. Close association of PCA and PIN (相似文献   

Expression of constitutively active Notch4 (Int-3) modulates myeloid proliferation and differentiation and promotes expansion of hematopoietic progenitors.

The Notch family of transmembrane receptors has been implicated in the regulation of many developmental processes. In this study, we evaluated the role of Notch4 in immature hematopoietic progenitors by inducing, with retroviral transduction, enforced expression of Int-3, the oncogenic and constitutively active form of mouse Notch4. Int-3-transduced human myeloid leukemia (HL-60) cells demonstrated significantly delayed expression of differentiation markers following retinoic acid and 12-0-tetradecanoylphorbol 13-acetate treatment. Furthermore, HL-60 cells expressing Int-3 displayed a slower growth rate than cells infected with void virus, and accumulation in the G0/G1 phases of cell cycle. Transduction with deletion mutants of Int-3 defined the importance of individual domains of the protein (in particular, the ANK domain and the C-terminal domain) in the inhibition of differentiation and growth arrest of HL-60 cells. When mouse bone marrow enriched for stem cells (5-fluorouracil-resistant, lineage negative) was transduced and cultured for two weeks, the Int-3-transduced population displayed a lower expression of differentiation markers and a three- to five-fold higher frequency of colony-forming cells (CFU-GM/BFU-E) than control cultures. These results strongly support the notion that Notch signaling inhibits differentiation and promotes expansion of hematopoietic stem/progenitor cells.     

Prognostic significance of c-kit mutation in localized gastrointestinal stromal tumors.

PURPOSE: Constitutive mutational activation of c-kit has been found to be associated with the pathogenesis of gastrointestinal stromal tumors (GISTs). The prognostic significance of c-kit mutations, however, is still controversial. EXPERIMENTAL DESIGN: We examined 86 patients curatively resected for localized GIST. Genomic DNA was extracted from paraffin-embedded tumor tissues. Exons 9, 11, 13, and 17 of the c-kit gene were amplified by PCR and sequenced. RESULTS: Mutations in exon 11 were detected in 61 tumors, and mutations in exon 9 were observed in three tumors, whereas no mutations were detected in exons 13 or 17. The overall c-kit mutation frequency was 74%. Amino acid alterations in the 61 tumors with exon 11 mutations were deletion in 33 tumors, substitution in 20, both deletion and substitution in 4, insertion in 1, and duplication in 3. Histologically, tumors with c-kit mutations showed higher mitotic counts and higher cellularity. The 5-year relapse-free survival (RFS) in patients having GISTs with c-kit mutations was 21%, compared with 60% in those without c-kit mutations. Significantly higher RFS rates were observed in patients with tumors having mitotic counts < 5 mitoses/50 high power field, spindle-cell histology, tumor size < 5 cm, or gastric GISTs. Multivariate analyses indicated association of poorer RFS with a higher mitotic count > or = 5 of 50 high power fields; odds ratio (OR) = 3.0], presence of c-kit mutations (OR = 5.6), and a larger tumor size (> or = 5 cm; OR = 4.2). CONCLUSIONS: The presence of c-kit mutation, along with high mitotic count and larger tumor size, was an independent factor for poor prognosis in patients with localized GISTs.     

Phase II study of pemetrexed with and without folic acid and vitamin B12 as front-line therapy in malignant pleural mesothelioma.

PURPOSE: This phase II clinical study evaluated the efficacy of pemetrexed for the treatment of malignant pleural mesothelioma (MPM). PATIENTS AND METHODS: Patients with a histologically proven diagnosis of MPM, chemotherapy-naive measurable lesions, and adequate organ function received pemetrexed (500 mg/m2) intravenously over 10 minutes every 3 weeks. After a protocol change, most patients also received folic acid and vitamin B12 supplementation to improve safety. RESULTS: A total of 64 patients were enrolled. Nine (14.1%) of the 64 patients had a partial response. The Kaplan-Meier estimate for median overall survival was 10.7 months. Forty-three patients received vitamin supplementation for all courses of therapy, and 21 patients did not. Seven of the nine responders were vitamin supplemented. The median overall survival was 13.0 months for supplemented patients and 8.0 months for nonsupplemented patients. Vitamin-supplemented patients completed more cycles of therapy than nonsupplemented patients (median, six v two cycles, respectively). Grade 3/4 neutropenia (23.4%) and grade 3/4 leukopenia (18.8%) were the most common laboratory toxicities. Fatigue and febrile neutropenia were the most commonly reported nonlaboratory events (grade 3, 6.3%; grade 4, 0.0% each). The incidence of these toxicities was generally lower in the supplemented patients. CONCLUSION: Single-agent pemetrexed for MPM resulted in a moderate response rate (14.1%) and median overall survival of 10.7 months. Patients supplemented with folic acid and vitamin B12 tolerated treatment better (less toxicity and more cycles of treatment) and had a 5-month greater median overall survival than nonsupplemented patients. These results indicate that patients with MPM could benefit from single-agent pemetrexed treatment combined with vitamin supplementation.