Gefitinib radiosensitizes stem-like glioma cells: inhibition of epidermal growth factor receptor-Akt-DNA-PK signaling, accompanied by inhibition of DNA double-strand break repair.

PURPOSE: We compared radiosensitivity of brain tumor stem cells (BTSCs) with matched nonstem glioma cells, and determined whether gefitinib enhanced BTSC radiosensitivity by inhibiting epidermal growth factor receptor (EGFR)-Akt-DNA-dependent protein kinase (DNA-PK) signaling, followed by enhanced DNA double-stand breaks (DSBs) and inhibition of DSB repair. METHODS AND MATERIALS: Radiosensitivity of stem-like gliomaspheres and nonstem glioma cells (obtained at patient neurosurgical resection) were evaluated by clonogenic assays, γ-H(2)AX immunostaining and cell cycle distribution. Survival of irradiated and nonirradiated NOD-SCID mice intracranially implanted with stem-like gliomaspheres were monitored. Glioma cells treated with gefitinib, irradiation, or both were assayed for clonogenic survival, γ-H(2)AX immunostaining, DNA-PKcs expression, and phosphorylation of EGFR and Akt. RESULTS: Stem-like gliomaspheres displayed BTSC characteristics of self-renewal; differentiation into lineages of neurons, oligodendrocytes, and astrocytes; and initiation of glioma growth in NOD-SCID mice. Irradiation dose-dependently reduced clonogenic survival, induced G(2)/M arrest and increased γ-H(2)AX immunostaining of nonstem glioma cells, but not stem-like gliomaspheres. There was no difference in survival of irradiated and nonirradiated mice implanted with stem-like gliomaspheres. The addition of gefitinib significantly inhibited clonogenic survival, increased γ-H(2)AX immunostaining, and reduced DNA-PKcs expression of irradiated stem-like gliomaspheres, without affecting irradiated-nonstem glioma cells. Gefitinib alone, and when combined with irradiation, inhibited phosphorylation of EGFR (Y1068 and Y1045) and Akt (S473) in stem-like gliomaspheres. In nonstem glioma cells, gefitinib alone inhibited EGFR Y1068 phosphorylation, with further inhibition by combined gefitinib and irradiation. CONCLUSIONS: Stem-like gliomaspheres are resistant to irradiation-induced cytotoxicity, G(2)/M arrest, and DNA DSBs, compared with nonstem glioma cells. Gefitinib differentially enhances radiosensitivity of stem-like gliomaspheres by reducing EGFR-Akt activation and DNA-PKcs expression, accompanied by enhanced irradiation-induced DNA DSBs and inhibition of DSB repair.

Changing epidemiology of enteric fevers in Singapore.

INTRODUCTION: We studied the epidemiological trends of enteric fevers (typhoid and paratyphoid fever) in Singapore from 1990 to 2009 and carried out a review of the current prevention and control measures. MATERIALS AND METHODS: Epidemiological records of all reported enteric fevers maintained by the Communicable Diseases Division, Ministry of Health from 1990 to 2009 were analysed. RESULTS: A total of 2464 laboratory confirmed cases of enteric fevers (1699 cases of typhoid and 765 cases of paratyphoid) were reported. Of these, 75% were imported, mainly from India and Indonesia. There had been a significant fall in the mean annual incidence rate of indigenous enteric fevers from 4.3 per 100,000 population in 1990 to 0.26 per 100,000 population in 2009 (P <0.005) with a corresponding increase in the proportion of imported cases from 71% between 1990 and 1993 to 92% between 2006 and 2009 (P <0.0005). Imported cases involving foreign contract workers increased significantly from 12.8% between 1990 and 1993 to 40.4% between 2006 and 2009 (P <0.0005). CONCLUSION: Singapore has experienced a marked decline in the incidence of enteric fevers that is now comparable to that of other developed countries. Continued vigilance and proactive measures that address the changing epidemiology of enteric fevers in Singapore are necessary to sustain the milestone achieved in the past 2 decades.

Salvage chemotherapy in progressive high-grade astrocytoma.

INTRODUCTION: Despite aggressive multidisciplinary interventions, patients with high-grade astrocytomas experience tumour progression or recurrence. Treatment for this group of patients remains a formidable challenge. We describe our experience of salvage chemotherapy for these patients. MATERIALS AND METHODS: A retrospective review of relevant clinical and radiographic information of patients who received at least one cycle of salvage chemotherapy for progressive high-grade astrocytoma at the National Cancer Center, Singapore, from March 2004 to September 2006, was conducted. Patients underwent regular assessment with clinical examination and magnetic resonance brain imaging to gauge response to salvage chemotherapy. Survival and progression free interval data were analysed via Kaplan-Meier method. RESULTS: Twenty-four patients (13 glioblastomas, 11 anaplastic astrocytomas) had received chemotherapy as salvage treatment following progression of their high-grade astrocytoma. Among 20 patients assessable for tumour response, there were 4 patients with partial responses and 9 with stable responses. The 12-month survival rate for the entire group from time of onset of tumour progression was 49.6%. Eight patients had survived more than 12 months at the time of writing. Among patients with glioblastoma, the 12-month survival rate was 30% and the median survival was 11.2 months. For patients with anaplastic astrocytoma, the 12-month survival rate was 73%. CONCLUSION: Durable disease control and prolonged survival were seen in a significant portion of selected patients with progressive high-grade astrocytoma who received salvage chemotherapy.

Primary central nervous system lymphoma in an Asian population: a 15-year experience.

BACKGROUND: The aim of this study was to characterize primary central nervous system lymphoma (PCNSL) among Asian patients and to determine their outcomes with different therapeutic modalities. PATIENTS AND METHODS: Between 1990 and 2005, 37 patients with PCNSL were analyzed within 5 different treatment groups: radiotherapy alone (arm A), combined chemoradiation (arm B), chemotherapy alone with methotrexate (MTX) > or = 1 g/m2 (arm C), miscellaneous therapy (arm D), and best supportive care (arm E). RESULTS: The median age at presentation was 59 years, and the majority of patients were male (68%). All patients had aggressive diffuse large B-cell lymphoma. The number of patients in arms A to E were 6, 16, 3, 8 and 4, respectively. The overall median survival was 7.4 months, 54.1 months, not reached, 8.9 months and 0.9 months, respectively. Use of MTX 1-2.5 g/m2 per cycle and an ECOG performance status of 0-2 were each associated with improved survival on univariate analysis (p = 0.022 and p = 0.049, respectively). Compared to radiotherapy alone, use of combined chemo-radiation was associated with a trend towards improved overall median survival (7.4 vs. 54.1 months, p = 0.058). CONCLUSION: The clinical characteristics and treatment outcomes in our Asian patients were comparable to those reported in Western series. Use of MTX 1-2.5 g/m2 per cycle and an ECOG performance status of 0-2 were associated with improved survival.

Detection of subclinical diabetic neuropathy: Potential factors affecting electrodiagnostic parameters

OBJECTIVES: To identify the factors that can potentially affect the ability of electrodiagnostic tests such as sural/radial amplitude ratio or SRAR and the presence of carpal tunnel syndrome or CTS to detect early subclinical neuropathy in diabetes mellitus (DM). Likewise, to investigate the likelihood of developing subclinical neuropathy that can be detected by a positive CTS or SRAR abnormalities, because of the presence of anthropometric factors and sugar levels, in addition to DM duration METHODOLOGY: A retrospective cohort study was undertaken among 144 DM type 2 patients with confirmed subclinical neuropathy. Demographic data such as age, height and age, body mass index (BMI) and blood glucose profiles were obtained. Nerve conduction findings (SRAR and CTS protocols) were statistically analyzed using two sample t-test and multiple logistic regression ratios RESULTS: Patients who were positive in the CTS protocols were taller and had lower BMI. They had shorter duration of DM but with extreme elevations in blood glucose. Variables that are independently associated with a (+) CTS are duration of DM, FBS, BMI, height and weight. Patients with SRAR abnormalities were older and obese, with longer duration of DM and less marked elevations in blood glucose. Variables that are independently associated with SRAR abnormalities are age, duration of DM, weight and BMI CONCLUSION: Factors such as age, duration of DM, weight and height, BMI as well as glucose control can potentially affect the ability of various electrodiagnostic tests (SRAR and the presence of CTS) to detect early subclinical neuropathy. Since confounding factors was different between CTS and SRAR, the pathogenesis of these conditions may be different. The likelihood of developing subclinical neuropathy that can be detected by a (+) CTS or SRAR abnormalities because of the presence of certain factors, were documented.