Enhancement of the anti-tumor activity of therapeutic monoclonal antibodies by CXCR4 antagonists.

The interaction between CXCR4 on the surface of tumor cells and CXCL12 in the stroma is believed to contribute to tumor cell survival and protection against drug treatment. Inhibition of stromal survival signals by CXCR4 antagonists has been reported to render tumor cells more sensitive to chemotherapy, but little is known about potential synergy with monoclonal antibodies. In this study, administration of the small molecule CXCR4 antagonists plerixafor and GENZ-644494 was found to enhance the anti-tumor activity of the monoclonal antibodies alemtuzumab and rituximab in disseminated lymphoma models. The observed enhancement in therapeutic efficacy by CXCR4 antagonists appeared to involve several factors, including interference with the tumor-promoting signals delivered by CXCL12, disruption of the tumor/stroma interaction and mobilization of effector neutrophils capable of mediating antibody-dependent cell-mediated cytotoxicity. The involvement of neutrophils was further supported by the observed reversal in therapeutic benefit upon neutrophil depletion.

Five-year experience with scaling-up access to antiretroviral treatment in an HIV care programme in Cambodia.

OBJECTIVES: To evaluate a 5-year HIV care programme (2003-2007) in the Sihanouk Hospital Center of HOPE, Phnom Penh, Cambodia. METHODS: Analysis of routine programme indicators per year: number of new patients, active patients, antiretroviral therapy (ART) coverage in the cohort, mortality and loss to follow-up. Comparison of mortality before and after the start of ART using Kaplan-Meier survival curves. Analysis of risk factors using Cox regression for the combined endpoint of mortality and loss to follow-up in patients on ART. RESULTS: 3844 patients were registered in the hospital between March 2003 and December 2007. The mortality and loss to follow-up rate fell and paralleled the rise of ART coverage from 23% in 2003 to 90% in 2007. The mortality and the loss to follow-up rate was significantly higher in patients not on ART but eligible (Log rank P < 0.001). The combined endpoint of mortality and loss to follow-up was 48.7% after one year in patients who were waiting for ART. 1667 patients were started on ART. The combined endpoint (mortality and loss to follow-up) in this group was 11.5% at 12 months and 14.2% at 24 months. Risk factors for mortality in the ART group were male sex, CD4 count <50 cells/microl, BMI <18 and haemoglobin levels <10 g/dl. CONCLUSION: Better access to ART is associated with lower mortality and fewer losses to follow-up. Pre-ART attrition remains significant. Strategies are needed to enable an earlier start of ART and to promote retention in care.

Validation of primary CD4 gating as an affordable strategy for absolute CD4 counting in Cambodia.

OBJECTIVE: To validate primary CD4 gating in lysed whole blood for absolute CD4 counts in fresh and aged blood using an affordable compact volumetric commercial flow cytometer. DESIGN: Comparison of CD4 counts between the FACSCount and the 2-parameter CyFlow SL Green. METHODS: One hundred twenty fresh blood samples from patients likely to be infected with HIV were simultaneously run on a FACSCount at the Pasteur Institute of Cambodia and on a CyFlow SL Green at the Sihanouk Hospital Center of Hope (SHCH), Phnom Penh, Cambodia. Intra- and interrun precision was assessed using 2 blood samples. Stability of CD4 counting in blood stored up to 96 hours at room temperature was assessed using 27 blood samples. RESULTS: CD4 counts on the CyFlow SL Green and on the FACSCount correlated well apart from a relative bias (R = 0.993, bias of -9.5%, 95% confidence interval [CI]: -11.8% to -7.1%, limits of agreement: -32.5% to 13.6%). Intra- and interrun variability ranged from 3% to 5% and from 5% to 6%, respectively. CD4 counts on aged blood using the CyFlow SL Green showed an interassay variability of <10%. CONCLUSIONS: Primary CD4 gating in lysed whole blood using the CyFlow SL Green is an affordable and precise method for CD4 counting. Because the fluorescence (FL) and light scatter signals have to be analyzed manually, however, intensive training of the technician and/or operator is imperative.

The added value of a CD4 count to identify patients eligible for highly active antiretroviral therapy among HIV-positive adults in Cambodia.

In a retrospective study of 648 persons with HIV infection in Cambodia, we determined the sensitivity, specificity, and accuracy of the 2003 World Health Organization (WHO) criteria to start antiretroviral treatment based on clinical criteria alone or based on a combination of clinical symptoms and the total lymphocyte count. As a reference test, we used the 2003 WHO criteria, including the CD4 count. The 2003 WHO clinical criteria had a sensitivity of 96%, a specificity of 57%, and an accuracy of 89% to identify patients who need highly active antiretroviral therapy (HAART). In our clinic, with a predominance of patients with advanced disease, the 2003 WHO clinical criteria alone was a good predictor of those needing HAART. A total lymphocyte count as an extra criterion did not improve the accuracy. Nine percent of patients were wrongly identified to be in need of HAART. Among them, almost 50% had a CD4 count of more than 500 cells/muL, and 73% had weight loss of more than 10% as a stage-defining condition. Our data suggest that, in settings with limited access to CD4 count testing, it might be useful to target this test to patients in WHO stage 3 whose staging is based on weight loss alone, to avoid unnecessary treatment.

Telemedicine by email in remote Cambodia.

An email-based telemedicine service was implemented in two remote village communities in Cambodia. Volunteer physicians at the Brigham and Women's Hospital, Massachusetts General Hospital and the Sihanouk Hospital Center of Hope in Phnom Penh provide monthly consultations to the local clinicians. Between February 2001 and May 2005, there were 469 teleconsultations. The 214 telemedicine cases involving new patients managed in the first 28 months were reviewed. The mean duration of the chief complaint at the initial patient visit was 37 months for the first six months and had dropped to eight months by the end of the study period. Of 63 adult patients surveyed, all were either satisfied (54%, n = 34) or very satisfied (46%, n = 29) with their experience in the telemedicine clinic. About 78% (n = 49) were willing to pay, on average, 0.63 US dollars for their visits. The introduction of basic point-of-care laboratory testing in November 2004 was associated with a reduction in patients requiring off-site referral for completion of laboratory testing (69% before to 35% afterwards, P < 0.001). The success of the pilot telemedicine programme confirms the value of email support for non-physician health-care workers in the developing world.

Delivering health care in rural Cambodia via store-and-forward telemedicine: a pilot study.

Since 2001, a monthly telemedicine clinic has helped provide health care to residents in a remote region in Cambodia. Physicians at Massachusetts General Hospital and Brigham and Women's Hospital in Boston, Massachusetts, and Sihanouk Hospital of HOPE in Phnom Penh, Cambodia, provide consultations via e-mail to a mobile nurse in the district of Rovieng, Cambodia. We describe the operations of the monthly clinic and report the results of a retrospective case review of the first 28 months of consultations. We also report the results of a satisfaction and willingness to pay survey. A total of 264 visits were made during the 28 monthly sessions. Mean duration of chief complaint at initial visit declined from 37 months to 8 months during the first and last 6 months of the study period, respectively. Thirty-six percent (n = 76) of new patients complained of abdominal pain. Nine percent (n = 20) of new patients were given an empiric diagnosis of goiter. The percent of patients requiring referral to a hospital outside of the village decreased over time. All patients surveyed were either "very satisfied" or "satisfied" with their care, and most patients were willing to pay for a visit, with a median amount of USD 0.63. We conclude that store-and-forward e-mail consultative support for mobile nonphysician health care workers is a feasible model for delivering care in the developing world. Further research is needed to demonstrate improvement in health status, cost effectiveness, and sustainability.

Disseminated nocardiosis presenting with cardiac tamponade in an HIV patient.

The incidence of nocardial infection in HIV-positive patients is increasing. In immune suppression the infection is often disseminated and can present as cardiac tamponade.