The East Africa Consortium for human papillomavirus and cervical cancer in women living with HIV/AIDS.

The East Africa Consortium was formed to study the epidemiology of human papillomavirus (HPV) infections and cervical cancer and the influence of human immunodeficiency virus (HIV) infection on HPV and cervical cancer, and to encourage collaborations between researchers in North America and East African countries. To date, studies have led to a better understanding of the influence of HIV infection on the detection and persistence of oncogenic HPV, the effects of dietary aflatoxin on the persistence of HPV, the benefits of antiretroviral therapy on HPV persistence, and the differences in HPV detections among HIV-infected and HIV-uninfected women undergoing treatment for cervical dysplasia by either cryotherapy or LEEP. It will now be determined how HPV testing fits into cervical cancer screening programs in Kenya and Uganda, how aflatoxin influences immunological control of HIV, how HPV alters certain genes involved in the growth of tumours in HIV-infected women. Although there have been challenges in performing this research, with time, this work should help to reduce the burden of cervical cancer and other cancers related to HIV infection in people living in sub-Saharan Africa, as well as optimized processes to better facilitate research as well as patient autonomy and safety. KEY MESSAGESThe East Africa Consortium was formed to study the epidemiology of human papillomavirus (HPV) infections and cervical cancer and the influence of human immunodeficiency virus (HIV) infection on HPV and cervical cancer.Collaborations have been established between researchers in North America and East African countries for these studies.Studies have led to a better understanding of the influence of HIV infection on the detection and persistence of oncogenic HPV, the effects of dietary aflatoxin on HPV detection, the benefits of antiretroviral therapy on HPV persistence, and the differences in HPV detections among HIV-infected and HIV-uninfected women undergoing treatment for cervical dysplasia by either cryotherapy or LEEP.

Autocrine activation of PDGFRalpha promotes the progression of ovarian cancer.

Platelet-derived growth factor receptor (PDGFR)alpha expression was found in ovarian cancer cells and tumors by microarray hybridization. This led us to test whether ovarian cancers also produce ligands for this receptor, as this would demonstrate that such malignancies support their own growth and spread through autocrine activation. We assayed the expression of ligands for the PDGFR in ovarian tumors, cell lines and peritoneal fluid using RT-PCR, immunohistochemistry (IHC) and ELISA. We detected strong mRNA expression for the PDGFRalpha ligands in most ovarian tumors. Receptor and ligand expressions (PDGFRalpha and PDGF AB) were also detected by IHC in, respectively, 34 and 32 of 47 ovarian tumors. The stainings for PDGFRalpha and PDGF AB were strongly correlated (P-value=0.014), suggesting that an autocrine loop is functional in ovarian cancer. PDGF AA and BB were quantified in peritoneal fluid by ELISA. Both ligands are secreted at higher levels in ovarian cancer ascites specimens (n=54) than in fluid from nonmalignant disorders (n=8). PDGF was detected in media conditioned by ovarian cancer cells. Such conditioned media induced activation of the PDGFR, Akt and MAPK and stimulated cell proliferation. A neutralizing PDGF antibody blocked these effects. Specific PDGFR inhibition by siRNA or a neutralizing antibody to the receptor inhibited PDGF-stimulated receptor activation and cell proliferation, suggesting that receptor targeting has a role in ovarian cancer treatment.

Recombinant human angiostatin (rhAngiostatin) in combination with paclitaxel and carboplatin in patients with advanced non-small-cell lung cancer: a phase II study from Indiana University.

BACKGROUND: Recombinant human angiostatin (rhAngiostatin) functions as a potent inhibitor of angiogenesis. This study combined rhAngiostatin with a standard chemotherapy regimen in patients with advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Eligible patients had chemotherapy-naïve stage IIIB (with pleural effusion) or IV NSCLC, performance status (PS) 0 or 1, no history of bleeding, brain metastasis or requirements for anti-coagulation. Patients received carboplatin (AUC 5) intravenously and paclitaxel (175 mg/m2) intravenously day 1 + subcutaneous rhAngiostatin at either 15 mg or 60 mg twice daily. Cycles were repeated every 3 weeks, for up to six cycles. Patients without progression after completing at least four cycles were continued on maintenance rhAngiostatin until disease progression. RESULTS: Patient characteristics (n = 24) were: 16 males, median age 66 years (range 45-78), 54% PS 1, 83.3% stage IV and 62.5% adenocarcinoma. Grade 3/4 toxicities included: fatigue 47.8%, neutropenia 39.1%, dyspnea 39.1%, vascular 26.1% and infection 17.4%. The overall response rate was 39.1%, 39.1% stable disease and 21.7% progressive disease. Median time to progression was 144 days, and 1-year survival was 45.8%. CONCLUSIONS: rhAngiostatin in combination with paclitaxel and carboplatin is feasible and results in a high disease control rate in patients with advanced NSCLC.

Reduced intraepidermal nerve fiber density in HIV-associated sensory neuropathy.

OBJECTIVE: To explore the relationship between intraepidermal nerve fiber (IENF) density in HIV-associated sensory neuropathy (HIV-SN) to measurements of neuropathy severity and progression of HIV disease. BACKGROUND: SN affects 30% of individuals with AIDS, and treatment is often ineffective. Recombinant human nerve growth factor (rhNGF) has been proposed as a trophic factor for unmyelinated nerve fibers injured in HIV-SN, and a clinical trial has recently concluded. Skin biopsy with IENF density determination has emerged as a diagnostic test for patients with small-fiber sensory neuropathy. METHODS: Sixty-two of the 270 patients with HIV-SN who participated in the trial of rhNGF were included in a substudy examining epidermal nerve fibers. IENF density was compared with neuropathic pain intensity (measured with the Gracely Pain Scale), patient and physician global pain assessments, quantitative sensory testing, CD4 counts, and plasma HIV RNA levels both at baseline and at conclusion of the placebo-controlled phase. RESULTS: IENF density was inversely correlated with neuropathic pain as measured by patient (p = 0.004) and physician (p = 0.05) global pain assessments, but not using the Gracely Pain Scale. Decreased IENF density at the distal leg was associated with lower CD4 counts and higher plasma HIV RNA levels. IENF density measurements were stable over time. CONCLUSIONS: IENF loss at the distal leg is associated with increased neuropathic pain, lower CD4 counts, and higher plasma viral load in HIV-SN. The robustness of the longitudinal measurement of IENF density supports its use in future longitudinal studies and clinical trials.

Designs for clinical trials to test the efficacy of therapeutics in progressive multifocal leukoencephalopathy.

The design of a comparative treatment trial to evaluate the efficacy of therapeutics for progressive multifocal leukoencephalopathy (PML) is outlined. We propose a large simple randomized trial with patient survival as its primary endpoint, completed in a short period of time and involving a cohort with as few enrollment restrictions as possible. We use stratification as the counterweight to the lack of exclusion criteria and suggest that proper stratification will attenuate differences inherent in a heterogeneous subject cohort. Estimation of power, sample size, and study duration, implementation of interim analyses, toxicity management, and validation of secondary clinical measures are also addressed.

NFkappaB activation, TNF-alpha expression, and apoptosis in the AIDS-Dementia-Complex.

The role of NFkappaB activation and its relationship to inflammatory mediators and apoptosis in the HIV-infected brain have remained uncertain. The cellular and regional distribution of NFkappaB, TNF-alpha, and apoptosis was examined in the frontal cortex (FC), deep white matter (DWM) and the basal ganglia (BG) of 17 patients with ADC. Nuclear staining for NFkappaB was localized predominantly to perivascular microglia/macrophages in the BG and DWM and correlated with ADC severity. Correlations were further found with HLA-DR, iNOS, TNF-alpha, and gp41 expression in these regions. The number of TUNEL-positive cells, particularly in the BG, correlated with ADC stage. Logistic regression analysis further showed a significant relationship between the likelihood of TUNEL staining in the BG and worsening cognitive impairment.

Progressive multifocal leukoencephalopathy in AIDS: are there any MR findings useful to patient management and predictive of patient survival? AIDS Clinical Trials Group, 243 Team.

BACKGROUND AND PURPOSE: While MR findings in progressive multifocal leukoencephalopathy (PML) have been described previously, usually in retrospective studies with limited sample size, what has not been well addressed is whether any are predictive of longer survival. Our participation in a large prospective clinical trial of AIDS patients with biopsy-proved PML and MR correlation allowed us to test our hypothesis that certain MR features could be found favorable to patient survival. METHODS: The patient cohort derived from a randomized multicenter clinical trial of cytosine arabinoside for PML. Pretreatment T1- and T2-weighted noncontrast images (n = 48) and T1-weighted contrast-enhanced images (n = 45) of 48 HIV-positive patients with a PML tissue diagnosis as well as the follow-up images in 15 patients were reviewed to determine signal abnormalities, lesion location and size, and the presence or absence of mass effect, contrast enhancement, and atrophy, and to ascertain the frequency of these findings. A statistical analysis was performed to determine if any MR abnormalities, either at baseline or at follow-up, were predictive of patient survival. RESULTS: No MR abnormalities either on univariate or multivariate analysis significantly correlated with patient survival, with the exception of mass effect, which was significantly associated with shorter survival. The mass effect, however, always minimal, was infrequent (five of 48). More severe degrees of cortical atrophy and ventricular dilatation, lesion location and size, and other MR variables were not predictive of outcome. CONCLUSION: Except for mass effect, we found no MR findings predictive of the risk of death in patients with PML. The mass effect, however, was so infrequent and minimal that it was not a useful MR prognostic sign.

Relation of JC virus DNA in the cerebrospinal fluid to survival in acquired immunodeficiency syndrome patients with biopsy-proven progressive multifocal leukoencephalopathy.

The detection and semiquantitation of JC virus (JCV) DNA in cerebrospinal fluid (CSF) is prognostic of survival and is a marker of the course of progressive multifocal leukoencephalopathy (PML). CSF samples from 15 acquired immunodeficiency syndrome (AIDS) patients with biopsy-proven PML were analyzed by semiquantitative polymerase chain reaction (PCR). A low JCV burden was predictive of longer survival compared with a high JCV burden (median survival from entry, 24 [2-63] vs 7.6 [4-17] weeks). Further analyses indicated a possible threshold of 50 to 100 copies/microl separating high- and moderate-risk cases. Patients with a JCV load below this level survived longer than those with a JCV load above it.

HAART improves prognosis in HIV-associated progressive multifocal leukoencephalopathy.

Introduction of highly active antiretroviral therapy (HAART) has been associated with many changes in the complications of human immunodeficiency virus (HIV) infection. A cohort of 25 HIV patients with progressive multifocal leukoencephalopathy (PML) treated with HAART experienced a median survival of >46 weeks. This is an improvement in prognosis compared with recent historic experience and correlated with HIV RNA viral load reductions. We conclude that current HIV therapy is important in improving the outlook of PML in the setting of HIV.