Induction of cell stress through gene transfer of an engineered heat shock transcription factor enhances tumor immunogenicity.

Heat shock protein expression and release is closely associated with immunogenic forms of cell death. We show that activation of the stress response within tumor cells during cell death, using an engineered form of the heat shock transcription factor, leads to an immunogenic death. Cells dying through 'stressful death' show decreased phagocytosis by macrophages in vitro. Moreover, cells expressing heat shock proteins during cell death are significantly more protective against subsequent tumor challenge. These data demonstrate the utility of activating cellular stress programs over the course of cytotoxic therapies to enhance immune responses to dying cells.

Macrophages orchestrate the immune response to tumor cell death.

The mechanisms by which the immune system distinguishes normal developmental cell death from pathological immunogenic cell killing are central to effective cancer immunotherapy. Using HSVtk suicide gene therapy, we showed that macrophages can distinguish between tumor cells dying through classical apoptosis and tumor cells engineered to die through nonapoptotic mechanisms, resulting in secretion of either immunosuppressive cytokines (interleukin 10 and transforming growth factor beta) or inflammatory cytokines (tumor necrosis factor alpha or interleukin 1beta), respectively. Additionally heat shock protein 70 acts as one component of a bimodal alarm signal that activates macrophages in the presence of stressful, immunogenic tumor cell killing. These differential responses of macrophages can also be used to vaccinate mice against tumor challenge, using adoptive transfer, as well as to cure mice of established tumors.

Psychosocial consequences of bone marrow transplantation in donor and nondonor siblings.

We investigated the psychosocial effects of bone marrow transplantation (BMT) on siblings of transplant recipients. We asked how donor siblings compared with nondonor siblings on quantitative measures of behavior, psychological distress, and sense of self. Participants included 44 siblings (21 donors and 23 nondonors, ages 6-18 yr) of surviving pediatric BMT patients. On self-report measures, donors reported significantly more anxiety and lower self-esteem than nondonors. On teacher-rated scales, donors showed significantly more adaptive skills in school. On these same scales, nondonors showed significantly more school problems than donors. One-third of the siblings in each group reported a moderate level of post-traumatic stress reaction. Exploratory multiple regression analyses point to factors that might influence sibling adjustment and suggest counseling strategies and avenues for future research.

Cognitive and adaptive behavior 1 and 3 years following bone marrow transplantation.

Children receiving a bone marrow transplant (BMT) are at risk for neuropsychological late effects because of potentially neurotoxic chemotherapy and total body irradiation. The goal of this study was to prospectively and longitudinally assess the intellectual and adaptive functioning of children receiving a BMT. This study examined 67 children whose development was evaluated at baseline prior to BMT and at 1 year follow-up. Mean age at BMT was 45 months. Repeated-measures ANOVA indicated a significant decline in IQ between baseline and the 1 year follow-up evaluation. Multivariate and exploratory univariate analyses examined the potential influence of diagnosis, treatment regimen, cranial radiation dose, age at time of transplant, and sex of child but none of these independent variables predicted outcome. Twenty-six children (mean age at BMT of 28.4 months) were also given developmental evaluations 3 years post-BMT. Although IQ at the 1 year follow-up was significantly lower than baseline, no further changes were evident at the 3 year follow-up evaluation. Scores on the Vineland Adaptive Behavior Scales also dropped significantly between baseline and the 1 year follow-up, but did not change between the 1 year and 3 year evaluations.

Toxicities of total-body irradiation for pediatric bone marrow transplantation.

PURPOSE: To determine the acute and late effects, including cognitive function, of total body irradiation (TBI) and chemotherapy for bone transplant (BMT) in children with immunodeficiency or hematologic disorders. METHODS AND MATERIALS: At UCSF, 15 children with immunodeficiency disorders and 58 children with leukemia received chemoradiotherapy between July 1982 and November 1993 and were evaluated for toxicity. Patients with severe combined immunodeficiency disorder (SCID) received 7 Gy TBI while leukemia patients received 12 Gy TBI. RESULTS: Eight immunodeficient patients (53%) are alive at 4 months to 11 years posttransplant. Acute toxicity was limited and treatment well tolerated. Most patients developed mild nausea and vomiting, skin rash, or erythema. Transient fever/chills, oral mucositis, and alopecia were noted in approximately 50% of patients. Seventy-three percent of all patients demonstrated acute liver dysfunction, but only four (27%) developed veno-occlusive disease. All children had decreased growth velocity but normal growth hormone levels. Other endocrinologic evaluations including adrenocorticotropic hormone (ACTH), cortisol, and thyroid hormones were normal. Only one evaluable girl had delayed puberty with late onset of secondary sexual characteristics. Neuropsychological testing demonstrated an intelligence quotient (IQ) reduction between the baseline and 1 year post-BMT, with some recovery at 3 years. Only one patient developed a clinically significant cataract. Thirteen percent of patients had chronic interstitial lung disease. Four children developed exostosis. Only 1 of the 15 children developed a second malignancy (acute myelogenous leukemia) at age 5, 51 months posttransplant for SCID. For patients with leukemia, similar toxicities were observed. Twenty-nine percent disease-free survival was noted with a mean follow-up of 4.7 years. Twenty-two percent had chronic interstitial lung disease and two patients were diagnosed with cataracts. Graft-vs.-host-disease (GVHD), pubertal development arrest, and delayed puberty were seen. One child developed papillary thyroid carcinoma, 49 months post-BMT. Similar neuropsychological testing decrements were also observed. CONCLUSION: Our experience suggests that intensive chemoradiotherapy, even at a young age, does not cause severe, acute, or late toxicities but does result in a small IQ decrement and the risk of secondary malignancy in children with long-term follow-up.

The developmental implications of prenatal and/or postnatal crack cocaine exposure in preschool children: a preliminary report.

Previous studies examining the development of prenatally cocaine-exposed children through 3 years of age have found no significant differences between exposed and control groups. This study explored the developmental correlates of prenatal and/or postnatal crack cocaine exposure in children between 4 and 6 years of age. Three groups were studied: Group 1, 18 prenatally-exposed children whose mothers continue to use crack; Group II, 28 children without prenatal exposure whose mothers presently use crack; and Group III, 28 children whose mothers never used crack. Mothers were street-recruited and were comparable in race and socioeconomic status. The three groups of children did not differ on neurological gross motor and expressive language measures. However, prenatally exposed children performed significantly worse than others on receptive language and visual motor drawing tests. Prenatal crack exposure predicted poor visual motor performance even after control for intrauterine alcohol and marijuana exposure, age, birth weight, and duration of maternal crack use.

A prospective study of cognitive functioning following low-dose cranial radiation for bone marrow transplantation.

This study prospectively examined the effects of low doses of cranial irradiation on psychological development in children. The subjects were 22 children receiving bone marrow transplantation. Fifteen children receiving cranial doses ranging from 350 to 1200 cGy as part of their conditioning regimen were contrasted to seven children who were not irradiated. Measures of intellectual and psychosocial development were administered to all subjects prior to transplant and again at one-year posttransplant. There were no decrements in psychological functioning at the one-year follow-up, regardless of the dose of cranial radiation received or the age at which radiation was administered. In addition, there were no significant differences in test scores relative to baseline in a smaller cohort of children followed up for 3 years. Although no significant between-group findings were found, examination of individual cases revealed a high degree of variability, with decrements in IQ of 10 points or more found in 7 children at the one-year follow-up. Findings suggest that doses less than 1500 cGy may prove to be relatively well tolerated with respect to long-term cognitive and psychosocial development, even in young children, although caution is urged in light of the limited length of follow-up.

Physical growth and behavioral adaptations of children with renal insufficiency.

The purpose of this study was to explore the relationship between physical growth and behavioral adaptations of children in the early stages of renal insufficiency. Twenty children between the ages of two and ten years were evaluated along with their parents. The results showed that there was a relationship between growth velocity and the balance of stresses to supports.

Psychosocial factors associated with physical growth and behavior adaptations of children with renal dysfunction.

To probe factors related to growth in children with renal insufficiency, who often grow poorly, 21 patients age 2 to 10 yr. were studied. Relationships among height rates, calorie intake, and staff ratings of compliance were positive but nonsignificant. The balance of stresses and supports was significantly related to growth and ratings of adjustment. Variables related to parent-child-staff communications were explored.

Visibility of handicap, self-concept, and social maturity among young adult survivors of end-stage renal disease.

This study examined the relationship between visibility of handicap and both self-image and social maturity in young adult survivors of end-stage renal disease. Ratings of visibility of handicap, social maturity, and a self-report measure of self-image were obtained through interviews with 31 patients. Results showed that visibility was inversely correlated with identity stability (p less than 0.05), social maturity (p less than 0.025), and self-esteem (p greater than 0.10), while jointly controlling for patients' age and years since last transplant. Although patients with visible handicaps remain at risk for maladjustment, many developed positive coping strategies in order to face the developmental challenges of adulthood.

Intellectual development of children with renal insufficiency and end stage disease.

Sixty six pediatric nephrology patients, age 6 months to 20 years, were given individual psychometric tests of intelligence two or more times during the course of treatment; 24 were retested within the stage of conservative management, dialysis or post-transplantation, 42 were retested between those stages. The first IQ scores ranged from three standard deviations below the test mean of 100 to two above (first sample mean 85.91). The second mean IQ was significantly higher (91.96). Paired t tests showed that significant increases in mean IQ scores occurred between the pre- to post-transplantation stages of treatment. No significant changes occurred within stages or between conservative management and dialysis. Equivocal changes existed between dialysis and transplantation. Four patients with prolonged central nervous system complications and serious family problems had scores which declined more than one standard deviation. Issues related to age, medical condition, socioeconomic status, and cohort changes were evaluated.

Self-concept in the diethylstilbestrol daughter.

To evaluate the possible psychologic impact of diethylstilbestrol (DES) in utero exposure on young women, the authors studied self-concept as a multifaceted construct in 25 known DES in utero exposed young women compared with 25 age-matched controls. Psychologic inventories used included Rosenberg's Self-Esteem Scale, Adjective Check List, Who Am I Test, Wyeth 's Self-Satisfaction Ladder, and the Draw Yourself Test, as well as semi-structured personal interview. Diethylstilbestrol subjects differed significantly from controls on the adjective check list subscales of Defensiveness, Nurturance, and Affiliation (P less than or equal to .05), as well as in the Draw Yourself Test, by omitting or obscuring body parts, especially sexual characteristics (P = .001). Subjects with known physical sequelae associated with DES were less satisfied with their lives (P = .05). On other measures of self-concept, no peer differences between DES subjects and controls were found. In fact, a trend for DES subjects to describe themselves more positively emerged. Most women also mentioned that they trusted physicians and were concerned about their future fertility and about the possibility of developing cancer. These findings suggest that young women exposed to DES may be using protective denial in their attempt to cope with their DES exposure. Physicians need to be aware of the possible psychologic impact of DES exposure, especially as more data become available regarding decreased fertility in these women and as new attention is focused on young men exposed to DES in utero.