Gene therapy strategies for AIDS-related malignancies

AIDS-related malignancies (ARM) include AIDS-defining cancers such as Kaposi's sarcoma, non-Hodgkin's lymphoma and cervical carcinoma. In addition, certain other malignancies are also increased with human immunodeficiency virus (HIV) infection. New antiretroviral agents and better prophylaxis and treatment of HIV-related opportunistic infections are prolonging the lives of HIV-infected individuals. There will thus likely be a continued rise in the incidence and prevalence of ARM in the long term, even if effective antiretroviral and other AIDS-related therapies reduce their appearance in the short term. There are presently no curative regimens for the common ARM, with the possible exception of some lymphomas. Survival is shortened by most, and treatment is often toxic and poorly tolerated. Gene therapies may thus offer a useful adjunct to conventional treatment strategies for selected ARM. Although some gene therapy strategies may work well in the HIV setting, the chronic viral infection, immunodeficient status of the host, the tendency for HIV-infected individuals to have altered drug metabolism and an increased rate of adverse drug reactions will likely present special challenges. This review summarizes the state-of-the-art in the fledgling field of gene therapy for ARM, and explores areas for future research.     

Experimental and theoretical comparison of NIR spectroscopy measurements of cerebral hemoglobin changes

Two near-infrared spectroscopy (NIRS) methods are available for measuring changes (Delta) in total cerebral hemoglobin concentration (CHC): 1) a continuous measurement of the changes in total hemoglobin concentration (Delta[Hb]tot) and 2) the difference between two absolute measurements of CHC, each derived from a small, controlled change in inspired O2 fraction. This paper investigates the internal consistency of these two methods by using an experimental and theoretical comparison. NIRS was used to measure [Hb]tot in five newborn piglets before and after a change in arterial PCO2. Delta[Hb]tot demonstrated a low coefficient of variation of 2.8 +/- 2.8 (SD) % which allowed changes in CO2-cerebral blood volume reactivity to be clearly discriminated. However, a high coefficient of variation of 22.8 +/- 3.5% on the DeltaCHC measurements obscured any CO2 reactivity changes. A theoretical analysis demonstrates the effects of optical pathlength, background absorption, scatter, and blood vessel diameter on both methods. For more accurate monitoring of CHC, individual measurements of optical pathlength and more accurate pulse oximetry are required.     

Mature teratoma identified after postchemotherapy surgery in patients with disseminated nonseminomatous testicular germ cell tumors: a plea for an aggressive surgical approach

BACKGROUND: Mature teratoma is often found in resected retroperitoneal residual tumor masses (RRTM) after chemotherapy for disseminated nonseminomatous testicular germ cell tumors (NSTGCT). The aim of this report is to describe the clinical course of patients after resection of residual teratoma, with particular emphasis on relapse with either growing mature teratoma or secondary non-germ cell malignancy. METHODS: During the period 1979-1995, 113 patients underwent a laparotomy for resection of RRTM after chemotherapy for NSTGCT. Only patients with mature teratoma in the RRTM were included in the current study, and data on the patients who experienced relapse were studied in detail. RESULTS: Mature teratoma was found in 51 patients (45.1%) with RRTM resected after chemotherapy. Nine of these 51 patients (17.6%) relapsed; the relapses resulted from growing mature teratoma in 5 patients (9.8%), secondary non-germ cell malignancy in 3 patients (5.9%), and recurrent germ cell malignancy in 1 patient (2.0%). The primary treatment for all relapsing patients was surgical excision. All five patients with growing mature teratoma are alive without evidence of disease, as is the patient with recurrent germ cell malignancy. One of the three patients with non-germ cell malignancy died of disease, and the remaining two are alive with disease. CONCLUSIONS: Long term follow-up after resection of postchemotherapy residual teratoma is indicated because a proportion of patients develop growing mature teratoma or a secondary non-germ cell malignancy. The treatment for these recurrences should be complete surgical excision.     

Differential susceptibility of primary and established human glioma cells to adenovirus infection: targeting via the epidermal growth factor receptor achieves fiber receptor-independent gene transfer

Adenovirus (Ad) vectors are promising for gene therapy of glioma due to their ability to achieve efficient gene transfer upon intratumoral administration. Yet in this context, Ad mediates widespread gene transfer to both tumor and surrounding parenchyma. Ad entry is dependent upon the expression of fiber receptors, such as coxsackie/adenovirus receptor, and alpha(v) integrins on the target cells for binding and internalization, respectively. We hypothesized that the susceptibility of human gliomas to Ad would likely be heterogeneous due to variable expression of these receptors. It was found that established human glioma cell lines exhibited differential susceptibility to Ad-mediated gene transfer, which correlated directly with the level of radiolabeled Ad binding and with the expression of coxsackie/adenovirus receptor but not with the expression of alpha(v) integrins. To circumvent the lack of fiber receptors and to target Ad gene transfer specifically to tumor cells, we used a bispecific antibody conjugate to ablate Ad binding to fiber receptors and retarget binding to the epidermal growth factor receptor (EGFR), a tumor-associated marker negligibly expressed in normal, mitotically quiescent neural tissues. The results demonstrate that EGFR-targeted Ad gene transfer was EGFR specific and independent of fiber-fiber receptor interactions. Furthermore, EGFR targeting significantly enhanced Ad gene delivery to 7 of 12 established glioma cell lines and to 6 of 8 cultured primary gliomas. Interestingly, EGFR-targeted Ad gene transfer did not correlate with EGFR expression across cell lines, suggesting the importance of other factors. This study establishes that fiber receptor expression limits the utility of Ad vectors for gene transfer to glioma cells and suggests that targeting Ad via EGFR may prove valuable for tumor-specific gene transfer to high-grade gliomas. These findings have key relevance in the context of Ad vector-based approaches for glioma gene therapy.     

Guidelines for the treatment of cytomegalovirus diseases in patients with AIDS in the era of potent antiretroviral therapy: recommendations of an international panel. International AIDS Society-USA

OBJECTIVE: To provide recommendations for the treatment of acquired immunodeficiency syndrome-related cytomegalovirus (CMV) end-organ diseases, including retinitis, colitis, pneumonitis, and neurologic diseases. PARTICIPANTS: A 17-member panel of physicians with expertise in clinical and virological research and inpatient care in the field of CMV diseases. EVIDENCE: Available clinical and virological study results. Recommendations are rated according to the quality and strength of available evidence. Recommendations were limited to the treatment of CMV diseases; prophylaxis recommendations are not included. PROCESS: The panel was convened in February 1997 and met regularly through November 1997. Subgroups of the panel summarized and presented available information on specific topics to the full panel; recommendations and ratings were determined by group consensus. CONCLUSIONS: Although the epidemiological features of CMV diseases are changing in the setting of potent, combination antiretroviral therapy, continued attention must be paid to CMV diseases in patients infected with the human immunodeficiency virus to prevent irreversible endorgan dysfunction. The initial and maintenance treatment of CMV retinitis must be individualized based on the characteristics of the lesions, including location and extent, specific patient factors, and characteristics of available therapies among others. Management of relapse or refractory retinitis must be likewise individualized. Ophthalmologic screening for patients at high risk for retinitis or who have a prior diagnosis of extraretinal disease is recommended. Recommendations for gastrointestinal, pulmonary, and neurologic manifestations are included.     

Estimates of the prevalence of arthritis and selected musculoskeletal disorders in the United States

OBJECTIVE: To provide a single source for the best available estimates of the national prevalence of arthritis in general and of selected musculoskeletal disorders (osteoarthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, the spondylarthropathies, systemic lupus erythematosus, scleroderma, polymyalgia rheumatica/giant cell arteritis, gout, fibromyalgia, and low back pain). METHODS: The National Arthritis Data Workgroup reviewed data from available surveys, such as the National Health and Nutrition Examination Survey series. For overall national estimates, we used surveys based on representative samples. Because data based on national population samples are unavailable for most specific musculoskeletal conditions, we derived data from various smaller survey samples from defined populations. Prevalence estimates from these surveys were linked to 1990 US Bureau of the Census population data to calculate national estimates. We also estimated the expected frequency of arthritis in the year 2020. RESULTS: Current national estimates are provided, with important caveats regarding their interpretation, for self-reported arthritis and selected conditions. An estimated 15% (40 million) of Americans had some form of arthritis in 1995. By the year 2020, an estimated 18.2% (59.4 million) will be affected. CONCLUSION: Given the limitations of the data on which they are based, this report provides the best available prevalence estimates for arthritis and other rheumatic conditions overall, and for selected musculoskeletal disorders, in the US population.     

Mechanism of cardiovascular actions of the chromogranin A fragment catestatin in vivo

Catestatin (bovine chromogranin A(344-364); RSMRLSFRARGYGFRGPGLQL), reduces catecholamine secretion from chromaffin cells in vitro. We investigated the effects of this peptide on catecholamine release and blood pressure in vivo. Intravenous catestatin reduced pressor responses to activation of sympathetic outflow by electrical stimulation in rats, and the catestatin effect persisted even after adrenergic (alpha plus beta) blockade. Catestatin did not alter plasma norepinephrine levels, but increased plasma epinephrine 11-fold. Catestatin also blunted pressor responses to exogenous neuropeptide Y agonists. A control peptide (chromogranin A(141-160)) did not alter pressor or catecholamine responses to electrical stimulation. Pretreatment with a histamine H1 receptor antagonist blocked both the vasodepressor response to catestatin and the elevation in plasma epinephrine. Catestatin elevated endogenous circulating histamine 21-fold, and exogenous histamine mimicked both the epinephrine elevation and the vasodepressor actions of catestatin. We conclude that catestatin is a potent vasodilator in vivo whose actions appear to be mediated, at least in part, by histamine release and action at H1 receptors.