Phase I trial of gemtuzumab ozogamicin in intensive combination chemotherapy for relapsed or refractory adult acute myeloid leukemia (AML): Japan Adult Leukemia Study Group (JALSG)-AML206 study

In order to investigate better molecular-target therapy for acute myeloid leukemia (AML), we conducted a phase I trial of a combination of gemtuzumab ozogamicin (GO) with conventional chemotherapy. Between January 2007 and December 2009, a total of 19 adult Japanese patients with relapsed or refractory CD33-positive AML (excluding acute promyelocytic leukemia) were enrolled. All registered patients received a standard dose of cytarabine (Ara-C) (100 mg/m(2) × 7 days), combined with either idarubicin (IDR) (10-12 mg/m(2) × 3 days) or daunorubicin (DNR) (50 mg/m(2) × 3-5 days), and then GO (3-5 mg/m(2) ), which was administered 1 day after the last infusion of IDR (IAG regimen) or DNR (DAG regimen). While doses of both GO and IDR and the administration period of only DNR were increased, the dose-limiting toxicity (DLT) was assessed. Among 19 patients (nine in the IAG regimen, 10 in the DAG regimen), the median age was 59 years (range 33-64), and the relapsed/refractory ratio was 13/6. In the therapy using 3 mg/m(2) GO in the IAG or DAG regimen, grade 3/4 leukopenia and neutropenia were observed in all patients, but none had grade 3/4 non-hematological toxicities, except febrile neutropenia. Three patients in the IAG regimen who were administered 5 mg/m(2) GO showed DLT. No patients had veno-occlusive disease or sinusoidal obstructive syndrome. In conclusion, 3 mg/m(2) GO combined with Ara-C and IDR or DNR can be safely administered, and phase II trials should be conducted to investigate the clinical efficacy of the combination therapy.     

Persistent roles of signal transduction of platelet-derived growth factor B in genesis,growth, and anaplastic transformation of gliomas in an in-vivo serial transplantation model

We previously reported that retrovirally transduced platelet-derived growth factor-B (PDGFB) in glial progenitors of the rat cerebral white matter, subventricular zone, or brain stem induced malignant brain tumors closely resembling human glioblastoma (GBM). While human GBMs may progress over the period of several months to a few years, prospective, long-term in-vivo observation of histological changes of the tumor tissues is not feasible in these models, because the animals undergo rapid tumor progression and mortality within approximately 1 month. We thus performed successive, long-term in-vivo transplantation of the PDGFB-induced tumor cells into the rat cerebrum. Primary retroviral transduction of PDGFB in the glial progenitors of the rat basal ganglia induced malignant glioma resembling human GBM or anaplastic oligodendroglioma (AOL) consisting of relatively monomorphous tumor cells expressing markers for the oligodendrocyte lineage. In the course of long-term successive transplantation, tumor cells presented pleomorphism as well as focal GFAP expression. This suggests that secondary chromosomal aberration and dysregulation of gene expression following accelerated cell cycle by PDGFB stimulation would induce morphological and immunophenotypic changes in tumor cells. Furthermore, while the primary tumors contained only a minor fraction of proviral GFP-expressing or hemagglutinin-expressing cells, most tumor cells came to express these proviral genes in the course of serial transplantation suggesting a persistent role of PDGFB-expressing cells in maintenance and growth of the tumors. This model would be useful for investigation of the long-term effects of PDGFB stimulation in glioma tissues on anaplastic evolution.     

A new molecular targeted therapeutic approach for renal cell carcinoma with a p16 functional peptide using a novel transporter system

Molecular targeting agents have become formidable anticancer weapons showing much promise against refractory tumors and functional peptides and are among the more desirable of these nanobio-tools. Intracellular delivery of multiple functional peptides forms the basis for a potent, non-invasive mode of delivery, providing distinctive therapeutic advantages. We examine the growth suppression efficiency of human renal cell carcinoma (RCC) by single-peptide targeting. We simultaneously introduced p16INK4a tumor suppressor peptides by Wr-T-mediated peptide delivery. Wr-T-mediated transport of p16INK4a functional peptide into 10 RCC lines, lacking expression of the p16INK4a molecule, reversed the specific loss of p16 function, thereby drastically inhibiting tumor growth in all but 3 lines by >95% within the first 96?h. In?vivo analysis using SK-RC-7 RCC xenografts in nude mice demonstrated tumor growth inhibition by the p16INK4a peptide alone, however, inoculation of Wr-T and the p16INK4a functional peptide mixture, via the heart resulted in complete tumor regression. Thus, restoration of tumor suppressor function with Wr-T peptide delivery represents a powerful approach, with mechanistic implications for the development of efficacious molecular targeting therapeutics against intractable RCC.     

Expression of thrombospondin-1 and Ski are prognostic factors in advanced gastric cancer

Background  

It has been suggested that thrombospondin-1 (TSP-1) plays a role in angiogenesis in many cancers. In addition, TSP-1 has been shown to suppress tumor growth by activating transforming growth factor-β (TGF-β). Recent studies have shown that Ski protein suppresses TGF-β signaling. The aim of this study was to investigate the role of TSP-1 and Ski expression in advanced gastric cancer.     

The Kampo medicine,Goshajinkigan, prevents neuropathy in patients treated by FOLFOX regimen

Background  

Oxaliplatin is now considered a standard treatment for advanced or unresectable colorectal cancer, but its main dose-limiting toxicity is sensory neuropathy. The OPTIMOX (stop and go) approach offers a reasonable strategy, but the preventive agent is not established. It is reported that the Kampo medicine, Goshajinkigan (GJG), has recently been considered an effective agent for the neuropathy of taxanes and for vibration sensation in patients with diabetic neuropathy. The aim of this study was to clarify the efficacy of GJG for peripheral neuropathy associated with oxaliplatin therapy.     

Tooth loss and intakes of nutrients and foods: a nationwide survey of Japanese dentists

Wakai K, Naito M, Naito T, Kojima M, Nakagaki H, Umemura O, Yokota M, Hanada N, Kawamura T. Tooth loss and intakes of nutrients and foods: a nationwide survey of Japanese dentists. Community Dent Oral Epidemiol 2010; 38: 43–49. © 2009 John Wiley & Sons A/S   Abstract – 
Objectives:  To clarify the association of tooth loss with dietary intakes among dentists, for whom sufficient dental care is available.
Methods:  We analyzed the data from 20 366 Japanese dentists (mean age ± SD, 52.2 ± 12.1 years; women 8.0%) who participated in a nationwide cohort study from 2001 to 2006. The baseline questionnaire included a validated food-frequency questionnaire to estimate intakes of foods and nutrients. We computed the geometric means of daily intakes by the number of teeth, adjusting for age, sex, smoking, physical activity, and history of diabetes.
Results:  The mean intakes of some key nutrients and food groups, such as carotene, vitamins A and C, milk and dairy products, and vegetables including green-yellow vegetables, decreased with the increasing number of teeth lost ( P for trend <0.05). On the contrary, mean intakes of carbohydrate, rice, and confectioneries were increased among those with fewer teeth ( P for trend <0.05). The difference in the geometric mean (%) between totally edentulous subjects and those with ≥25 teeth, that is [(Geometric mean for ≥25 teeth) — (Geometric mean for 0 teeth)]/(Geometric mean for ≥25 teeth) × 100, was 14.3%, 8.6%, 6.1%, and –6.1% for carotene, vitamin C, vitamin A, and carbohydrate, respectively. For food groups, it was 26.3%, 11.9%, 5.6%, –9.5%, and –29.6% for milk and dairy products, green-yellow vegetables, total vegetables, rice, and confectioneries, respectively.
Conclusions:  Tooth loss was linked with poorer nutrition even among dentists.     

Potential of Periodontal Ligament Cells to Regenerate Alveolar Bone

Regeneration of periodontal tissues, lost as a result of periodontal disease, is a key objective of periodontal treatment. Although several periodontal regeneration therapies have been devised, the origin of the undifferentiated cells that regenerate periodontal tissues remains unknown. Therefore, in the present study, to clarify the existence of osteoblast progenitor cells in the periodontal ligament, as well as to investigate the mechanism of alveolar bone regeneration without any effects from the original bone, we evaluated osteoblast differentiation induced by transplantation of GFP-transgenic rat molars into the subcutaneous tissues of wild-type rats. Ten days after transplantation, initial alveolar bone was formed apart from the cementum in the bifurcation region. After 20 days, this bone tissue had expanded to almost all of the bifurcation. GFP localization showed that the osteoblasts were derived from the transplant. Alpha-SMA- and BMP4-positive cells were observed near the root surface at 5 days after transplantation. With the progress of alveolar bone regeneration, osteoblasts expressing Runx2 and Osterix appeared in the bone-forming region. These results indicate that periodontal ligament tissue remaining on the root surface after a tooth extraction contains undifferentiated cells that have the ability to regenerate alveolar bone. The process of osteoblast differentiation in this model might be similar to that for normal alveolar bone formation. Thus, periodontal ligament cells might be useful for the regeneration of alveolar bone in tissue engineering applications.     

Can Daytime Use of Bed Nets Not Treated with Insecticide Reduce the Risk of Dengue Hemorrhagic Fever Among Children in Vietnam?

The purpose of this study was to investigate the prevalence of bed net use and elucidate the effect of daytime bed net use on preventing dengue hemorrhagic fever (DHF) among children in Vietnam. We conducted a population-based cross-sectional survey and a matched case–control study in Khanh Hoa Province where not only some pre-schoolchildren but also some school children, who take a nap during lunch break prior to returning to school, used bed nets during the day. Among 36,901 children 2–10 years of age, most used untreated bed nets during the night (98.3%) compared with 8.4% during the day. The results of the case–control study, which defined 151 cases who were hospitalized with DHF in the provincial hospitals and 604 age-matched neighborhood controls, did not support our hypothesis that children using untreated bed nets during the day are less likely to be hospitalized with DHF (adjusted odds ratio = 0.56, 95% confidence interval = 0.23–1.39).Dengue hemorrhagic fever (DHF), a life-threatening syndrome caused by any one of four dengue virus (DENV) infections, is a rapidly increasing public health problem in the tropical and subtropical regions of the world.¹ The pathogenesis of DHF has been hypothesized to involve a complex interaction of several factors including the host immune response, virus virulence, and host genetic background.^2,3 However, antibody-dependent enhancement caused by secondary heterologous DENV infections is widely accepted as a principal risk factor for DHF, except in infants who acquire maternal dengue antibodies.⁴ Dengue infection is highly endemic in the urban/peri-urban areas of Vietnam, and all four serotypes of DENV (DEN-1 to DEN-4) have been identified.⁵ The breeding sites of dengue vector mosquitoes (i.e., Aedes aegypti) are located in and around households and may include indoor water jars, basins, and vases.^6–9 Because such containers are often indispensable, it is difficult to limit their use.⁹ As a result, household residents are highly susceptible to Ae. aegypti bites and subsequent dengue infection.Insecticide-treated bed nets, promoted for malaria control in the rural areas of Vietnam,¹⁰ are usually not used in urban/peri-urban areas, where malaria is not endemic. However, residents of urban/peri-urban areas commonly use untreated bed nets (not treated with insecticides) for protection against Culex mosquitoes and other nuisance insects during the night. If daytime bed net use for children could decrease the frequency of Ae. aegypti bites, the incidence of dengue may be reduced. To investigate the prevalence of bed net use and elucidate the effect of daytime bed net use on preventing DHF among children, we conducted a population-based cross-sectional study and a matched case–control study in Khanh Hoa Province in central Vietnam.The province has a hot-dry season from May through October and a cool-wet season from November through April. Although the province includes suburban communes surrounded by rice fields, most residents in the province live in urban communes. The study area covered 33 communes in this province. A population-based cross-sectional survey was conducted in July 2006 to collect information on the demography and socioeconomic statuses of all residents. The detailed study methods and the characteristics of this population have been described.¹¹ The study was reviewed and approved by the Institutional Review Board of the National Institute of Hygiene and Epidemiology, Hanoi, Vietnam, and the Institutional Review Board of the Institute of Tropical Medicine, Nagasaki University, Nagasaki, Japan.All houses were geo-referenced using a handheld global positioning system unit with a resolution of 2–5 meters. We obtained admission records of two principal hospitals (provincial-level hospitals) in Khanh Hoa Province that provide medical care exclusively to patients with severe illnesses such as DHF. Patients with DHF were diagnosed by well-experienced local clinicians as part of routine procedures in the hospitals; diagnosis was based on the World Health Organization classification criteria.¹² Hospital records during the 16-month period preceding the census and population census data were linked by using the individual''s name, sex, age, contact person, and address.Among the identification-confirmed DHF patients, children 2–10 years (24–119 months) of age at the time of the interview were included in our case-control study. For each patient, four age-matched neighbor controls (the first- to fourth-nearest age-matched neighbors living in different households) were selected from the study population by using the census database and data from a geographic information system (ArcGIS version 9.3; Environmental Systems Research Institute, Redlands, CA). Information on child bed net practices was collected during household interviews with mothers. To evaluate the effect of daytime bed net use on DHF, we performed a case–control analysis by using a conditional logistic-regression model.A total of 52,671 children 2–10 years of age were enumerated in the census. Among these children, we excluded 4,028 preschool children (2–5 years of age) who attended kindergarten, 2,304 school age children (6–10 years of age) who had not attended primary school, and 9,438 for whom we had no information on bed net use or other socioeconomic variables. Thus, we included 36,901 children (70.1%) in the analysis. Almost all mothers of the children mentioned that their children used bed nets during the previous night of the household interview (36,259 of 36,901, 98.3%). However, few mothers of the children mentioned that their children used bed nets during the day on the previous day of the interview (3,107 of 36,901, 8.4%). Because insecticide treatment of bed nets and long-lasting insecticide-treated bed-nets were not available, all bed nets in the study area were not treated with insecticide.We identified 251 patients 2–10 years of age who were hospitalized with DHF from our study area within the 16-month period preceding the census. Among these patients, we obtained matched census data for 212 (47.6%). Among the matched 212 DHF patients, we included 151 (71.2%) patients in the case–control study except the minorities (i.e., attending kindergarten among preschool children and not attending primary school among school age children) and patients without complete information about bed net use or other variables. Among the 151 DHF patients and 604 age-matched neighbor controls, the mean age of persons in each group was 7.0 years. Children (cases and controls) had similar demographic and bed net use patterns (