Treatment of mesothelioma with gene-modified PA1STK cells and ganciclovir: a phase I study.

Mesothelioma is an incurable cancer of the pleura with a life expectancy of less than 1 year. On the basis of in vivo efficacy seen with the herpes simplex virus type 1 thymidine kinase (HSVtk) suicide gene-modified PA1STK cell line and ganciclovir (GCV) in a murine model of mesothelioma, a first in humans, clinical trial was designed for this therapeutic concept. The study was a phase I clinical trial using direct infusion of escalating doses of HSVtk suicide gene-modified PA1STK cells directly into tumor-associated pleural effusions followed by 7 days of intravenous GCV infusion. Therapeutic levels of GCV in both serum and pleura were achieved within 1 h, and GCV trough levels remained above the therapeutic threshold for the duration of GCV treatment. The treatment was well tolerated without any Grade 3 or 4 toxicity observed. Significant inductions of both Th1 and Th2 cytokines up to 20-fold over baseline were observed. No significant differences were seen between serum and pleura cytokine profiles, with the exception of interleukin-10, which was consistently elevated in the pleura specimens. No objective radiographic responses were observed. The data indicate significant immunological responses and validate the principal anti-tumor mechanisms observed in preclinical models of mesothelioma in a human clinical trial.

The treatment of malignant mesothelioma with a gene modified cancer cell line: a phase I study.

Malignant mesothelioma is a tumor of the pleura for which there is no satisfactory treatment. It is almost universally fatal, regardless of the stage of the tumor at the time of diagnosis. Current treatment modalities include surgery, chemotherapy, and radiation therapy, although in some series none of these modalities is superior to no treatment at all. Because of the dismal prognosis for patients with malignant mesothelioma, a new mode of treatment is desperately needed. A promising area of research into the treatment of various malignancies is gene therapy. Recent studies have demonstrated the utility of exposing tumor cells to cells transduced to express the Herpes simplex virus gene for thymidine kinase (HSV-tk). By virtue of their expression of HSV-tk, the transduced cells are rendered susceptible to the antiviral drug, ganciclovir (GCV). and nearby tumor cells are killed by a phenomenon termed the bystander effect. In this protocol we propose a Phase I trial to study the safety and determine the maximal tolerated dose of an HSV-tk-transduced ovarian cancer cell line (PA1-STK cells) infused into the pleural cavities of patients with malignant pleural mesothelioma, followed by systemic administration of ganciclovir. The hope is that administration of ganciclovir will result in killing of the HSV-tk transduced ovarian cancer cells as well as the nearby malignant mesothelioma cells. This is a standard dose-escalation protocol.

Gene therapy for malignant mesothelioma: a novel approach for an incurable cancer with increased incidence in Louisiana.

Malignant mesothelioma (MM) is a tumor of the pleura for which there is no satisfactory treatment. It is an almost universally fatal disease, regardless of the stage of the tumor at the time of diagnosis. Current treatment modalities include surgery, chemotherapy, and radiation therapy, although in some series none of these modalities is superior to no treatment at all. Because of the dismal prognosis for patients with MM, new modes of treatment are desperately needed. A promising area of research into the treatment of various malignancies is gene therapy. Recent studies have demonstrated the utility of exposing tumor cells to cells transduced to express the Herpes simplex virus gene for thymidine kinase (HSV-TK). By virtue of their expression of HSV-TK, the transduced cells are rendered susceptible to the antiviral drug, ganciclovir (GCV). Nearby untransduced tumor cells are killed by a so-called bystander effect. We are describing a Phase I clinical gene therapy trial for MM, which we are presently conducting at the Louisiana State University Medical Center of New Orleans. The purpose is to study the safety and to determine the maximal tolerated dose of an HSV-TK-transduced ovarian cancer cell line (PA1-STK cells) that is infused into the pleural cavities of patients. This infusion is followed by systemic administration of GCV. The hope is that administration of GCV will result in killing of both the transduced ovarian cancer cells as well as the nearby malignant cells.

Relationship of coping style to affective state and perceived social support in asymptomatic and symptomatic HIV-infected persons: implications for clinical management.

The authors describe the relationship of three coping styles to affective state (mood) and perceived social support in 29 human immunodeficiency virus (HIV)-infected homosexual/bisexual men between the ages of 18 and 45 years. Active-behavioral coping was significantly related to enhanced mood and greater perceived social support. Avoidance coping was significantly related to greater mood disturbance and lower social support. No relationships were found for active-cognitive coping. Recommendations for clinical management of HIV-infected persons and their traditional and/or nontraditional family follow from the findings.

A biopsychosocial examination of symptomatic and asymptomatic HIV-infected patients.

This study evaluated twenty-nine symptomatic and asymptomatic HIV-infected homosexual/bisexual men between eighteen and forty-five in the areas of psychiatric/psychosocial, neuropsychological, family, and immunological functioning. The subjects were referred by physicians, nurses, and mental health professionals from the Tulane/Louisiana State University AIDS Clinical Trials Unit and the C-100 outpatient Primary Care Clinic for HIV-infected patients served within the Charity Hospital of Louisiana at New Orleans. All subjects and their significant others were evaluated between November 1987 and October 1988 at the C-100 Clinic. The outcome measures were mood disturbance, psychological distress, and CD4 cell count. The most significant other family member, as selected by each subject, completed family measures. The subjects experienced psychological distress and neuropsychological problems. Active-behavioral coping appeared adaptive (related to enhanced mood) as did perceived social support (related to positive mood and lower psychological distress). Higher levels of neuropsychological functioning (verbal memory, visual memory, motor speed, and visual-motor sequencing) were associated with enhanced psychosocial functioning and/or immunological status. The findings from this study highlight the importance of conducting longitudinal studies using a multidimensional approach in which HIV-infected persons and their most significant other family members are evaluated within a biopsychosocial model.

The immune system in hereditary hemochromatosis: a quantitative and functional assessment of the cellular arm.

The objective of this investigation was to evaluate certain quantitative and functional characteristics of the effector cells of the cellular arm of the immune system in hereditary hemochromatosis (HH) with respect to treatment status. Two observations were consistent with the postulate that the elevated levels of storage iron has in vivo immunoregulatory properties: (1) the absolute number of CD8-positive T cells were significantly elevated in untreated HH patients (n = 7) and reduced in treated patients (n = 7), as compared with controls; and (2) the proliferative response of peripheral blood mononuclear cells from untreated HH patients to mitogens was suboptimal but the response of peripheral blood mononuclear cells (PBM) from treated HH patients was normal. Furthermore, immunoglobulin secretion by PBM from treated HH patients as compared to controls was altered. Finally, one T effector cell abnormality was unrelated to treatment status in that a subset of mature, non-activated T lymphocytes aberrantly formed thermostable erythrocyte-rosettes (TE-R), a lymphoid surface marker usually expressed on thymocytes or activated T cells. Taken together these data define certain immune alterations that are consistent with the interpretation that cellular immunity may be influenced by the high level of storage iron in HH patients.

Human immunodeficiency virus: risk of exposure among health care workers at a southern urban hospital.

To assess the risk of exposure to the human immunodeficiency virus (HIV) among health care workers in a southern urban setting, random screening for antibodies to HIV was undertaken. Patients who were admitted for major trauma, for medical emergencies, or in labor were screened. Of 534 sera screened, 11 (2%) were seropositive. All but two of the seropositive patients were men. Rates were similar among black and white patients. Seven patients could be placed into an established risk group, but only one patient was known to have AIDS upon presentation to the emergency room. The mean age of seropositive individuals was 30.9 years; there were similar seroprevalence rates in each of four age groups among men. We conclude that there is a substantial risk of exposure to HIV in trauma and medical emergency centers; therefore all health care workers should practice universal barrier precautions whenever exposure to a patient's blood or body fluids is likely.

Thermostable erythrocyte rosette-forming lymphocytes in hereditary hemochromatosis. I. Identification in peripheral blood.

Although the immunoregulatory role of iron has been demonstrated in vitro, evidence for a similar role in vivo is controversial. We have, therefore, studied certain functional and structural properties of lymphocytes in hereditary (idiopathic) hemochromatosis (HH), a disease characterized by iron overload. T- and B-lymphocyte percentages in peripheral blood, serum immunoglobulin levels, and proliferative responses of peripheral blood mononuclear cells (PBM) to lectins were comparable with those of controls. Furthermore, HH serum with elevated iron concentrations did not significantly alter proliferative responses of normal lymphocytes to mitogens. In contrast to those normal findings was the identification of a subset of T lymphocytes in HH that formed rosettes with sheep red blood cells (SRC) at 37 degrees C in abnormally high numbers. Those lymphocytes that formed thermostable erythrocyte rosettes (TE-R) were not immature thymocytes, activated T lymphocytes, or an artifact of passive attachment of anti-SRC antibodies to the HH lymphocyte surface. Their presence did not correlate with a concentration of iron in the serum, the length of treatment, or the presence of the HLA antigen, A3. We conclude that the cellular expression of HH may be detected not as an immunological abnormality, but rather as an abnormality in receptor expression.