p53 protein accumulation predicts poor response to tamoxifen therapy of patients with recurrent breast cancer.

PURPOSE: Mutations of the p53 gene are frequently observed in primary breast cancer and accumulation of p53 protein has been used as a surrogate marker of p53 inactivation. Previous studies have shown that p53 accumulation is related to poor prognosis in primary breast cancer. We studied whether p53 protein accumulation is a predictive factor for response to tamoxifen treatment in patients with recurrent breast cancer. PATIENTS AND METHODS: Levels of p53, estrogen receptor (ER), progesterone receptor (PgR), and urokinase-type plasminogen activator (uPA) were assayed in cytosolic extracts derived from primary tumors of 401 tamoxifen-naive patients who developed recurrent disease. All patients in the study received tamoxifen therapy upon relapse (median follow-up, 69 months). Association of tested factors with response to tamoxifen treatment was studied by logistic regression analysis, and with survival after the start of treatment by Cox univariate and multivariate regression analysis. RESULTS: p53 levels (median, 0.23 ng/mg protein) were not related to ER or PgR levels, but positively correlated with uPA (P < .0001). In a test for trend, we observed an association of p53 protein levels with response to tamoxifen therapy. When dichotomized (at the median value), 42% in the p53-high versus 56% in the p53-low group showed a response. In multivariate analysis, including patient and tumor characteristics, p53 accumulation retained significance with the rate of response (odds ratio [OR], 0.48; 95% confidence interval [CI], 0.31 to 0.74; P < .001). Also in multivariate analysis, reduced survival after the start of tamoxifen therapy was observed in the p53-high group (relative hazards rate [RHR], 1.56, 95% CI, 1.17 to 2.10; P = .002). A statistically significant association between p53 levels and decreased tamoxifen response was seen only in the subset of patients whose tumors expressed low levels of ER or PgR (<75 fmol/mg protein). CONCLUSION: Measurement of primary tumor p53 levels may be effective in predicting response to tamoxifen therapy in recurrent breast disease. However, more confirming studies on the association between p53 protein accumulation and response to antiestrogen therapy are needed before tumor p53 levels can be used in routine clinical practice.

Dacarbazine-vindesine versus dacarbazine-vindesine-cisplatin in disseminated malignant melanoma. A randomised phase III trial.

In a multicentre phase III study of disseminated malignant melanoma performed in Sweden and Norway, 326 patients were randomised to receive treatment with the combination dacarbazine [DTIC] (D) and vindesine (V) with or without the addition of cisplatin (P). D was given intravenously (i.v.) at a dose of 250 mg/m2 days 1-5 every 4 weeks and V was given i.v. at a dose of 3.0 mg/m2 day 1 weekly. P was given i.v. at a dose of 100 mg/m2 day 1 every 4 weeks. There was no statistically significant difference in overall survival between the treatment arms (P = 0.22). Increased toxicity was observed in the treatment arm containing P of which leucopenia, alopecia and nausea/vomiting were the most pronounced. The median time to progression was significantly longer in patients treated with DVP (4.2 versus 2.2 months, P = 0.007). In conclusion, adding P to DV did not change overall survival but did significantly increase toxicity.

Radiation induced height impairment in pediatric Hodgkin's disease.

PURPOSE: To quantitate the impairment in skeletal growth from radiation treatment, we reviewed height measurements among children with Hodgkin's disease irradiated at Stanford University Medical Center between 1965 and 1986. METHODS AND MATERIALS: One hundred and twenty-four children with Hodgkin's disease, in whom long-term follow-up data were available, became the subjects for this analysis. They all had baseline height measurements within 1 year of radiation treatment, a final height measurement beyond age 15 for boys and 13 for girls, and a minimum time interval between baseline and final measurement of 2 years. A baseline and final percent height, as compared to a reference standard, was calculated for each patient. The difference between these two figures was used to assess height impairment. The study group was divided into age and treatment groups and a comparative analysis between these groups was performed. RESULTS: Height impairment was most severe among children who were given high dose radiation to the entire spine when pre-pubertal in age. These patients demonstrated a 7.7% (p < 0.0001) average height impairment, which equates to a height loss of 13 cm or two standard deviations of the U.S. population mean. Pubertal and post-pubertal patients given similar heavy treatment as well as pre-pubertal patients given light treatment also demonstrated some impairment of skeletal growth, however, the loss was not deemed clinically significant. Comparison of standing versus sitting height impairment did not show evidence of disproportionate final growth impairment. CONCLUSION: Treatment regimens that use low doses of radiation for pediatric Hodgkin's disease are thus not associated with clinically significant impairment of skeletal growth, as measured by standing and sitting heights.

Prognostic value of TP53 protein accumulation in human primary breast cancer: an analysis by luminometric immunoassay on 1491 tumor cytosols.

The tumor suppressor gene TP53 is implicated in the regulation of normal cell growth and division, DNA repair and apoptosis. Mutations in this gene usually give rise to a conformationally altered protein which is stably expressed at high levels. We have studied TP53 protein accumulation in routinely prepared cytosols from 1491 human primary breast cancer specimens (median follow-up of patients alive, 66 months), using a quantitative luminometric immunoassay (LIA). The TP53-LIA values varied between 0 and 153.53 (median 0.20 ng/mg protein). Median TP53 levels were significantly higher in ER- and PgR-negative tumors. In Cox univariate regression analysis, when analyzed as a continuous variable, increasing TP53 levels were related with a poor relapse-free survival (p < 0.01). In multivariate analysis for relapse-free survival, including age, menopausal status, tumor size, nodal status and steroid hormone receptor status, TP53 accumulation, when analyzed as a dichotomized variable, was an independent factor for predicting the rate of relapse with a relative relapse rate (95% confidence limits) of 1.39 (1.19-1.63). In conclusion, the LIA for the TP53 protein can easily be performed on cytosols routinely prepared for steroid hormone receptor analysis, it is a quantitative assay, and it may be useful in establishing the relation of TP53 accumulation and breast cancer prognosis.

Partition of sodium dodecyl sulfate into stratum corneum lipid liposomes.

Synthetic detergents produce deleterious effects on human skin as the result of being taken up by the stratum corneum (SC). The present study aimed to determine to what extent a typical detergent enters the SC lipid lamellae, and what effect this might have on the physical properties of the lipids. These effects were studied in large unilamellar liposomes prepared from SC lipids (50% by weight of epidermal ceramides, 28% cholesterol, 17% free fatty acids, and 5% cholesteryl sulfate) by extrusion through successive polycarbonate filters of decreasing pore size, finally 400 nm. Freeze-fracture electron microscopy and light-scattering particle size analysis indicated a uniform liposome diameter averaging 230 nm. Partitioning of sodium dodecyl sulfate (SDS) into the lipid phase from aqueous buffer solutions was measured using the SC lipid liposomes and [U-14C]SDS. The partition coefficient was 416, 450, and 588 at pH 8.5 and 524, 507, and 807 at pH 7 for three different concentrations (0.1%, 0.02%, and 0.004%) of SDS. This high degree of partitioning into the liposomes is consistent with the high level of SDS partitioning seen in full SC. At the maximum, the SDS represented 18% of the liposomal lipids. Preparation of stable liposomes from SC lipids to which 10% or 20% of SDS had been added confirmed the ability of the liposomes to survive these high concentrations of surfactant. The permeability of the liposomes was enhanced as a result of SDS partitioning into the bilayers, as measured by the increased release of trapped [U-14C]glucose from these vesicles, and by their increased permeability to water in osmotic shock experiments.(ABSTRACT TRUNCATED AT 250 WORDS)

Restricting the time of injury in fatal inflicted head injuries.

OBJECTIVE: To determine the normal clinical progression of fatal head injuries in children. Such information can then be used to estimate the time of injury in cases with obscure histories and will thus aid investigations of nonaccidental trauma. METHOD: A retrospective chart review design was used. One hundred and thirty eight accidental fatalities involving head injury were identified and 95 of these were used as the study group. Details of the cases were reviewed and cases in which a child either had a Glasgow Coma Scale (GCS) of 14-15 or was described as having a "lucid interval" or as being "conscious" were further studied. RESULTS: One "lucid interval" case was identified. This case involved an epidural hematoma. Three other cases that partially met the criteria for a lucid interval were also identified; one of these cases did not meet the criteria for inclusion in the study group. Review of head CTs revealed that brain swelling could be detected as early as 1 hour and 17 minutes post injury. CONCLUSIONS: The children studied were in obvious serious medical condition from the time of injury until death. If a history purports a lucid interval in a fatal head injury case that does not involve an epidural hematoma, that history is likely false and the injury is likely inflicted. The time of most fatal head injury events can be restricted to the time period after the last confirmed period of wellness for the child. In addition, the presence of brain swelling on a head CT scan is not helpful in restricting the time of injury.

Stress hormones, lipids, and factors of hemostasis in trauma patients with and without fat embolism syndrome: a comparative study at least one year after severe trauma.

The pathophysiologic mechanism of fat embolism syndrome (FES) has been thought to depend on mechanical blockage of capillaries by fat emboli or on the toxic effect of free fatty acids on the capillary endothelium. Aggregation of platelets, microembolism, disseminated intravascular coagulation, and vasoactive amines are considered to be involved. The question of why some patients develop fat embolism while other patients with similar injuries do not remains to be solved. Blood tests in ten patients who developed FES and their reaction to stress were compared to the same tests in ten patients with similar injuries without FES at least 1 year after trauma. The following were measured: blood Hb, leucocytes, platelets, protein and lipid electrophoresis, ACTH, cortisol, TSH, GH, insulin, glucose, NEFA, certain coagulation and fibrinolytic studies, alpha 1 antitrypsin, and antithrombin III. The platelet values, especially after stress, and P + P values were higher in the FES-patients. The alpha-beta lipoprotein ratio was lower and the blood glucose values were higher in half of those FES-patients in whom a diabetic heredity was discovered. The U-catecholamines were also somewhat higher in the FES-patients. Disturbances of the lipid and carbohydrate metabolism as well as a high platelet count and high P + P values may predispose to thrombosis and DIC. More numerous petechiae in Rumpel-Leede's stasis test in fat embolism patients suggest increased capillary fragility. Low growth hormone values in FES-patients and a different cortisol reaction to stress compared to control patients suggests a disturbed neurohumoral regulation in FES.

Immunoelectroosmophoresis (IEOP) for detection of bacterial antigens in cerebrospinal fluid.

365 cerebrospinal fluid specimens from 259 patients were tested by the immunoelectroosmophoretic (IEOP) method to detect bacterial antigens. 25 patients had bacterial meningitis. The bacterial agent was identified by IEOP in 16 of 21 cases with aetiological agents detectable with the antisera employed. No false positive reactions occurred. The test gave true negative results in 340 instances. The rapidity, simplicity, sensitivity, reliability and low cost are emphasized.

The relationship between uterine volume, plasma progesterone and intrauterine pressure. A preliminary report.

PIP: 8 nulliparous women, all approximately 15 weeks pregnant, were administered 350 ml Macrodex intraamniotically during a period of 15-30 minutes to increase uterine volume. 4 of the patients aborted following a decrease in plasma progesterone and an increase in resting pressure, active pressure, and oxytocin response. In 2 patients, plasma progesterone increased while resting pressure, active pressure, and oxytocin response did not increase, and pregnancy continued undisturbed. It is concluded that increasing uterine volume may induce a compensatory synthesis of progesterone in the palcenta provided that: 1) the osmotic action of the injected hypertonic solution does not suppress placental function to a degree equal to that of the stimulatory effect of increasing volume; 2) the osmotic increase in volume is slow enough to permit the time-dependent increase in progesteronegenesis; and 3) the increase in intrauterine pressure and clinical progress in abortion does not suppress placental endocrine function. Further experiments are necessary to verify this interpretation.^ieng