Neutrophil and monocyte adhesion molecules in bronchopulmonary dysplasia, and effects of corticosteroids.

AIMS: To study a longitudinal change in the expression of adhesion molecules CD11b, CD18, and CD62L on neutrophils and monocytes in very low birth weight babies who develop respiratory distress syndrome, to compare these levels between bronchopulmonary dysplasia (BPD) and non-BPD infants, and to assess the effect of corticosteroid treatment on these adhesion molecules. METHODS: Of 40 eligible neonates, 11 neonates were oxygen dependent at 36 weeks (BPD 36 weeks), 16 infants were oxygen dependent at 28 days, but not at 36 weeks (BPD d28), and 13 infants did not develop BPD. Seventeen neonates received a six day course of steroid treatment. Expression of CD11b, CD18, and CD62L was measured on neutrophils and monocytes in arterial blood on days 1, 3, 7, 14, 21, and 28, and before and 2-3 days after initiation of dexamethasone treatment by flow cytometry. RESULTS: CD18 expression on neutrophils and monocytes and CD62L on neutrophils, measured as mean fluorescent intensity, was significantly decreased in BPD neonates compared to non-BPD neonates on days 1-28. Dexamethasone treatment significantly decreased CD11b, CD18, and CD62L expression on neutrophils, and CD11b and CD18L expression on monocytes. CONCLUSIONS: Decreased CD18 expression on neutrophils and monocytes, and decreased CD62L expression on neutrophils, measured as mean fluorescent intensity during the first four weeks of life in micropremies may be risk factors and early predictors of BPD. Dexamethasone use was associated with decreased expression of CD11b, CD18, and CD62L.

Assessment of a bronchoscopy simulator.

The study objective was to validate a flexible bronchoscopy simulator by determining if it could differentiate between expert and novice bronchoscopists. A subsequent evaluation phase was then done to determine whether use of the simulator would improve the rate of bronchoscopy skill acquisition for new pulmonary fellows. A multicenter prospective cohort study was performed using a bronchoscopy simulator. Three cohorts were evaluated based on the number of bronchoscopies previously performed: "experts" (> 500, n = 9), "intermediates" (25 to 500, n = 8), and "novices" (none, n = 11). Each participant performed two simulated cases with performance measures being recorded by the simulator. Performance measures that distinguished between groups were then used to evaluate the learning curve for new fellows training on the simulator. A randomized-controlled trial was then conducted comparing the quality of bronchoscopy performance for new pulmonary fellows who were trained either with conventional methods or with the simulator. Expert bronchoscopists performed better on the simulator than intermediates who performed better than novices in terms of procedure time, percentage of segments visualized, time in red-out, and wall collisions. Training of new fellows demonstrated that after performing 20 bronchoscopic simulations, the skill level acquired with the simulator significantly improved in terms of speed, percentage of segments visualized, time in red-out, and collisions. Fellows trained on the simulator performed better than fellows trained using conventional methods during their first actual bronchoscopies as assessed by procedure time (815 versus 1,168 s, p = 0.001), a bronchoscopy nurse's subjective quality assessment score (7.7 +/- 0.3 versus 3.7 +/- 2.5, p = 0.05), and by a quantitative bronchoscopy quality score (percentage of segments correctly identified/procedure time, 0.119 +/- 0.015 versus 0.046 +/- 034, p = 0.03). In conclusion, the bronchoscopy simulator was able to accurately assess bronchoscopy experience level. Training new fellows on the bronchoscopy simulator leads to more rapid acquisition of bronchoscopy expertise compared with conventional training methods. This technology has the potential to facilitate bronchoscopy training and to improve objective evaluations of bronchoscopy skills.

Comparison of the auditory and visual privacy of emergency department treatment areas with curtains versus those with solid walls.

STUDY OBJECTIVE: The design and function of emergency departments may allow breaches of privacy that could adversely affect patient satisfaction and medical care. We sought to determine whether patients perceive less privacy in ED treatment areas with curtains than in rooms with solid walls. METHODS: Patients 18 years and older at a university hospital ED who received care in a room with solid walls and a door, a curtained area next to the nurses' station, or a curtained area away from the nurses' station were surveyed. Patients responded on a 5-point Likert scale to 11 questions regarding privacy. Differences between areas were determined by using the Kruskal-Wallis and Mann-Whitney tests and were considered significant at P values of less than.05. RESULTS: Structured interviews were conducted with 108 ED patients. Responses from those in the curtained areas were similar. Compared with those in the rooms with walls, these patients more often believed that they could overhear others and that others could hear them, view them, hear personal information, and view personal parts of their bodies (P < or =.04 for all). They also perceived a lower overall sense of privacy (P <.01). Of all those surveyed, 85.2% reported "a lot of" or "complete" respect for privacy by the staff, and 92.6% experienced at least as much privacy as they expected, with no difference between areas. CONCLUSION: Patients perceive significantly less auditory and visual privacy in ED treatment areas with curtains compared with a room with solid walls. Consideration of these findings in current practice and in future ED design and construction is suggested.

A dose of 75 microg/kg/d of i.v. anti-D increases the platelet count more rapidly and for a longer period of time than 50 microg/kg/d in adults with immune thrombocytopenic purpura.

Treatment with 75 microg/kg/d intravenous (i.v.) anti-D was compared with 50 microg/kg/d in a prospective randomized study of 27 RhD-positive, human immunodeficiency virus-negative, adult, acute, non-splenectomized patients with immune thrombocytopenic purpura (ITP) and platelet counts < or = 30 x 109/l. The higher dose resulted in greater median d 1 (43 x 109/l vs. 7.5 x 109/l; P = 0.012) and d 7 (153 x 109/l vs. 64.5 x 109/l; P = 0.001) platelet increases despite no greater haemoglobin decrease. Children with acute ITP receiving 75 microg/kg/d had overnight platelet increases in seven out of nine cases. The duration of effect at the 75 microg/kg/d dose was 46 d vs. 21 d (P = 0.03). Adverse events were mild to moderate and ameliorated with prednisone and acetaminophen premedication.

Effect of antenatal steroid administration on the fetal biophysical profile.

PURPOSE: Our objective was to determine whether antenatal steroid administration affects the biophysical profile score in fetuses. METHODS: A prospective study was conducted in 84 fetuses between 28 and 34 weeks' menstrual age at risk of preterm delivery. Two intramuscular injections of 12 mg of betamethasone were given to the mother 24 hours apart. All fetuses underwent biophysical profile testing prior to and between 24 and 48 hours after steroid administration. Biophysical profiles (including nonstress tests) were evaluated by two maternal-fetal medicine specialists blinded to the timing of steroid administration. Neonatal outcome, including Apgar score, menstrual age at delivery, admission to and length of stay in the neonatal intensive care unit, and mortality, was analyzed in all subjects. RESULTS: In 31 (37%; 95 confidence interval, 26.6-47.2%) of 84 cases, the biophysical profile score decreased at least 2 points after steroid administration. The most commonly affected variables were fetal breathing and the nonstress test. There was no significant difference in the neonatal outcome between the fetuses whose biophysical profile decreased and those whose did not. CONCLUSIONS: Biophysical profile scores were decreased in more than one third of fetuses within 48 hours of antenatal steroid administration, but neonatal outcome was not affected. Knowledge of this occurrence could avoid incorrect decision making regarding fetal well-being.

Angiogenesis gene therapy: phase I assessment of direct intramyocardial administration of an adenovirus vector expressing VEGF121 cDNA to individuals with clinically significant severe coronary artery disease.

BACKGROUND: Therapeutic angiogenesis, a new experimental strategy for the treatment of vascular insufficiency, uses the administration of mediators known to induce vascular development in embryogenesis to induce neovascularization of ischemic adult tissues. This report summarizes a phase I clinical experience with a gene-therapy strategy that used an E1(-)E3(-) adenovirus (Ad) gene-transfer vector expressing human vascular endothelial growth factor (VEGF) 121 cDNA (Ad(GV)VEGF121.10) to induce therapeutic angiogenesis in the myocardium of individuals with clinically significant coronary artery disease. METHODS AND RESULTS: Ad(GV)VEGF121.10 was administered to 21 individuals by direct myocardial injection into an area of reversible ischemia either as an adjunct to conventional coronary artery bypass grafting (group A, n=15) or as sole therapy via a minithoracotomy (group B, n=6). There was no evidence of systemic or cardiac-related adverse events related to vector administration. In both groups, coronary angiography and stress sestamibi scan assessment of wall motion 30 days after therapy suggested improvement in the area of vector administration. All patients reported improvement in angina class after therapy. In group B, in which gene transfer was the only therapy, treadmill exercise assessment suggested improvement in most individuals. CONCLUSIONS: The data are consistent with the concept that direct myocardial administration of Ad(GV)VEGF121.10 to individuals with clinically significant coronary artery disease appears to be well tolerated, and initiation of phase II evaluation of this therapy is warranted.

Variability of human systemic humoral immune responses to adenovirus gene transfer vectors administered to different organs.

Administration of adenovirus (Ad) vectors to immunologically naive experimental animals almost invariably results in the induction of systemic anti-Ad neutralizing antibodies. To determine if the human systemic humoral host responses to Ad vectors follow a similar pattern, we evaluated the systemic (serum) anti-Ad serotype 5 (Ad5) neutralizing antibodies in humans after administration of first generation (E1(-) E3(-)) Ad5-based gene transfer vectors to different hosts. AdGVCFTR.10 (carrying the normal human cystic fibrosis [CF] transmembrane regulator cDNA) was sprayed (8 x 10(7) to 2 x 10(10) particle units [PU]) repetitively (every 3 months or every 2 weeks) to the airway epithelium of 15 individuals with CF. AdGVCD.10 (carrying the Escherichia coli cytosine deaminase gene) was administered (8 x 10(8) to 8 x 10(9) PU; once a week, twice) directly to liver metastasis of five individuals with colon cancer and by the intradermal route (8 x 10(7) to 8 x 10(9) PU, single administration) to six healthy individuals. AdGVVEGF121.10 (carrying the human vascular endothelial growth factor 121 cDNA) was administered (4 x 10(8) to 4 x 10(9.5) PU, single administration) directly to the myocardium of 11 individuals with ischemic heart disease. Ad vector administration to the airways of individuals with CF evoked no or minimal serum neutralizing antibodies, even with repetitive administration. In contrast, intratumor administration of an Ad vector to individuals with metastatic colon cancer resulted in a robust antibody response, with anti-Ad neutralizing antibody titers of 10(2) to >10(4). Healthy individuals responded to single intradermal Ad vector variably, from induction of no neutralizing anti-Ad antibodies to titers of 5 x 10(3). Likewise, individuals with ischemic heart disease had a variable response to single intramyocardial vector administration, ranging from minimal neutralizing antibody levels to titers of 10(4). Evaluation of the data from all trials showed no correlation between the peak serum neutralizing anti-Ad response and the dose of Ad vector administered (P > 0.1, all comparisons). In contrast, there was a striking correlation between the peak anti-Ad5 neutralizing antibody levels evoked by vector administration and the level of preexisting anti-Ad5 antibodies (P = 0.0001). Thus, unlike the case for experimental animals, administration of Ad vectors to humans does not invariably evoke a systemic anti-Ad neutralizing antibody response. In humans, the extent of the response is dictated by preexisting antibody titers and modified by route of administration but is not dose dependent. Since the extent of anti-Ad neutralizing antibodies will likely modify the efficacy of administration of Ad vectors, these observations are of fundamental importance in designing human gene therapy trials and in interpreting the efficacy of Ad vector-mediated gene transfer.

Adolescent physical abuse: risk for adolescent psychiatric disorders.

OBJECTIVE: The present study examined whether physical abuse functions as an additional risk factor for adolescent psychopathology after other important known risk factors are controlled for. METHOD: The authors recruited 99 adolescents aged 12 to 18 years directly from the New York State Department of Social Services after official documentation of physical abuse. The abused adolescents were compared to 99 nonabused adolescents matched for age, gender, race, and community income. Diagnostic interviews and measures of selected risk factors for psychopathology were administered to the adolescents and their parents and then entered into a multiple logistic regression model testing the added risk contributed by physical abuse to adolescent psychopathology. RESULTS: Physical abuse added significantly to other risk factors in accounting for lifetime diagnoses of major depression, dysthymia, conduct disorder, drug abuse, and cigarette smoking. Physical abuse also contributed significantly to prediction of current adolescent unipolar depressive disorders, disruptive disorders, and cigarette smoking. CONCLUSIONS: Since physically abused adolescents are at greater risk for the development of psychiatric disorders, recognition of adolescent abuse and the provision of psychiatric and substance abuse services may reduce morbidity.

PIP: The association between physical abuse of adolescents and adolescent psychopathology was investigated in a case-control study conducted in Long Island, New York (US). 99 White adolescents 12-18 years of age identified from the New York State Department of Social Services Central Register for Child Abuse in 1989-91 and 99 nonabused adolescents matched for age, gender, race, and community income were enrolled. Diagnostic interviews and measures of selected risk factors for psychopathology were administered to the adolescents and their parents and then entered into a multiple logistic regression model testing the added risk contributed by physical abuse. Physical abuse added significantly to other risk factors in accounting for lifetime diagnoses of major depression, dysthymia, conduct disorder, drug abuse or dependence, and cigarette smoking. Physical abuse also contributed significantly to the prediction of current adolescent unipolar depressive disorders, disruptive disorders, and cigarette smoking. These findings underscore the importance of increased identification of physically abused adolescents so that mental health and substance abuse services can be provided.

BRCA-associated breast cancer in young women.

PURPOSE: To delineate the clinical characteristics and outcomes of breast cancer that arises in the setting of a germline BRCA mutation and to compare BRCA-associated breast cancers (BABC) with those that arise in women without mutations. PATIENTS AND METHODS: We reviewed the clinical records of 91 Ashkenazi Jewish women ascertained during studies of the genetics of early-onset breast cancer. All women underwent testing for the BRCA1 mutations 185delAG and 5382insC. After the discovery of BRCA2, 79 women were also tested for the BRCA2 mutation 6174delT. RESULTS: Mutations were identified in 30 women (33%). BABC were less likely to present with stage I disease than cases in women without mutations (27% v 46%), more likely to have axillary nodal involvement (54% v46%), and more likely to have extensive axillary involvement (25% v 17%). These differences were not statistically significant. BABC were significantly more likely to be histologic grade III (100% v 59%, P=.04) and to be estrogen receptor-negative (70% v 34%, P=.04). In the entire cohort, there were no significant differences between BABC and non-BRCA-associated cancers in 5-year relapse-free survival (65% v 69%, P=not significant [NS]), 5-year event-free survival (57% v 68%, P=NS), or 5-year overall survival. However, among cases diagnosed within 2 years of study entry, there was a trend toward shorter event-free survival in BRCA heterozygotes, but not relapse-free survival. Women with germline BRCA mutations were significantly more likely to develop contralateral breast cancer at 5 years (31% v 4%, P=.0007). CONCLUSION: BABC present with adverse clinical and histopathologic features when compared with cases not associated with BRCA mutations. However, the prognosis of BABC appears to be similar to that of nonassociated cancer. Further studies of incident cases are necessary to define the independent prognostic significance of germline BRCA mutations.

Impact of minimum hematocrit during cardiopulmonary bypass on mortality in patients undergoing coronary artery surgery.

BACKGROUND: The hematocrit on cardiopulmonary bypass (CPB) frequently falls to a low level during many cardiac surgical procedures. This study was designed to explore the impact on mortality of minimum hematocrit level achieved during the CPB after coronary artery surgery. METHODS AND RESULTS: Two thousand seven hundred thirty-eight sequential isolated coronary artery surgery patients during a 42-month period at a tertiary academic center were included in this study. Thirty-one standardized preoperative risk factors used in a multiple logistic regression revealed eight statistically significant independent predictors for postoperative mortality. Minimum hematocrit level during CPB was then added to the regression model and was found to be an independent risk factor for mortality. The entire patient population was divided into dichotomous groups using different minimum hematocrit levels on CPB for the determination of cutoff points by multiple logistic regression. After adjusting for other risk factors, the minimum hematocrit level of 14% was found to be a statistically significant cutoff point. Patients with minimum hematocrit levels < or =14% were found to have an increased probability of risk-adjusted mortality (odds ratio, 2.70; P=.002). A subgroup analysis revealed that high-risk patients with minimum hematocrit levels < or =17% were found to have a significantly increased probability of postoperative mortality (odds ratio, 2.20; P=.017). CONCLUSIONS: Minimum hematocrit level during CPB is an independent risk factor for mortality after coronary artery surgery. There is a significantly increased risk of mortality for hematocrit levels < or =14%. For high-risk patients, there is a significantly increased risk of mortality for hematocrit levels < or =17%.

Guidelines for budgeting biostatistics involvement in research projects.

This paper seeks to help biostatisticians develop realistic budgets for their involvement in research projects. The approach is to list categories of expenses and associated questions about the types and levels of projected costs that the budget planner needs to consider. I subdivide the expense categories into smaller subcomponents that should provide for better planning. I also propose an algorithm for determining hourly rates.

Statistical and methodological issues in the evaluation of case management studies.

For the past 3 years, the nursing case management team at North Shore University Hospital in Manhasset, NY, has been involved in a project to implement more than 50 clinical pathways, which provide a written "time line" for clinical events that should occur during a patient's hospital stay. A major objective of this project was to evaluate the efficacy of these pathways with respect to a number of important outcomes, such as length of stay, hospital costs, quality of patient care, and nursing and patient satisfaction. This article discusses several statistics-related issues in the design and evaluation of such case management studies. In particular, the role of a research approach in implementing and evaluating hospital programs, the choice of a comparison (control) group, the exclusion of selected patients from analysis, and the problems of equating pathways with diagnosis-related groups are addressed.

Antenatal management of alloimmune thrombocytopenia with intravenous gamma-globulin: a randomized trial of the addition of low-dose steroid to intravenous gamma-globulin.

OBJECTIVES: Our purposes were to investigate maternal infusions of intravenous gamma-globulin, to prevent intracranial hemorrhage, and to determine whether 1.5 mg dexamethasone and 60 mg prednisone per day add to the effect of intravenous gamma-globulin. STUDY DESIGN: Fifty-four women with alloimmune thrombocytopenia and thrombocytopenic fetuses were randomized to intravenous gamma-globulin 1 gm/kg per week with or without dexamethasone. Nonresponders after 4 to 6 weeks received continued intravenous gamma-globulin plus 60 mg of prednisone per day ("salvage"). RESULTS: Dexamethasone did not add to the effect of intravenous gamma-globulin. Overall, there was a mean platelet increase from the first to the second fetal blood sampling of 36,000/microliters (n = 47) and from the first fetal blood sampling to birth of 69,000/microliters (n = 54). A total of 62% to 85% of fetuses responded. There were no intracranial hemorrhages. "Salvage" increased the platelet count in 5 of 10 nonresponders to intravenous gamma-globulin. CONCLUSION: Intravenous gamma-globulin treatment is appropriate for thrombocytopenic fetuses with alloimmune thrombocytopenia before use of weekly in utero platelet transfusions, even in severe thrombocytopenia.

Antiplatelet antibody testing in thrombocytopenic pregnant women.

OBJECTIVE: The purpose of the study was to attempt to distinguish pregnant women with gestational thrombocytopenia from those with idiopathic immune thrombocytopenia by eight different platelet antibody assays. STUDY DESIGN: Sera from pregnant women with presumed gestational thrombocytopenia (n = 160) and idiopathic immune thrombocytopenia (n=90) were prospectively tested for indirect and platelet-associated immunoglobulins G and M and complement C3, as well as for serotonin release. After the results were analyzed, a subset of patients were subsequently analyzed for circulating antiplatelet antibody directed against platelet membrane glycoprotein GPIIb/IIIa. RESULTS: Indirect immunoglobulin G was significantly greater in the 85 women with idiopathic immune thrombocytopenia than in the 129 women with gestational thrombocytopenia (p<0.001). Platelet-associated immunoglobulin G was elevated in the majority of women, both those with gestational thrombocytopenia and those with idiopathic immune thrombocytopenia. There were also no statistically significant difference in the values for platelet-associated C3 or indirect immunoglobulin M and C3. Levels of platelet-associated immunoglobulin M showed a tendency to be higher in women with gestational thrombocytopenia (p=0.04), as did the values in the serotonin release assay (p=0.06). CONCLUSION: Our data demonstrate that patients with gestational thrombocytopenia had surprisingly high levels of platelet-associated immunoglobulin despite mild thrombocytopenia. Comparison of a relatively large number of patients with idiopathic immune thrombocytopenia and gestational thrombocytopenia indicates that women with idiopathic immune thrombocytopenia cannot be distinguished from those with gestational thrombocytopenia by means of one or more of the prototypic platelet antiglobulin tests currently in use. Our preliminary data with glycoprotein-specific assays indicate that they may be more useful.

Laboratory diagnosis of infection status in infants perinatally exposed to human immunodeficiency virus type 1.

Accurate and timely diagnosis of infection status in infants born to women infected with human immunodeficiency virus (HIV) is of paramount importance. The comparative accuracy of five diagnostic decision rules was evaluated in 208 HIV-exposed infants (32 infected, 176 uninfected) based on laboratory testing during the first 6 months of life. Diagnostic rules A and B, which required single blood samples analyzed by culture and polymerase chain reaction (PCR) (rule A) or culture, PCR, and p24 antigen detection (rule B) were more prone to incorrect diagnoses than were rules requiring 2 blood samples analyzed by a single assay (rule C) or combinations of culture and PCR (rules D and E). Rule D, which used PCR as the initial test, established the most useful algorithm: a positive PCR result followed by a positive culture in the second sample confirmed infected status, while two consecutive negative PCR results reconfirmed as negative at 6 months of age established uninfected status.

Immunophenotype of intraductal carcinoma.

OBJECTIVE: Mammography and breast-conserving therapy have focused attention on the classification of intraductal carcinoma (IDC) and emphasized the prognostic importance of comedo versus noncomedo variants. We used histochemical markers to define the immunophenotype of 43 IDCs with respect to comedo versus noncomedo status and patterns of angiogenesis. RESULTS: Reactions in comedo carcinomas were significantly negative for estrogen receptor and progesterone receptor, and positive for p53 and HER-2/neu more often than the noncomedo variant. All seven IDCs associated with Paget's disease showed positive reactions for HER-2/neu. Basement membrane immunoreactivity for type IV collagen and laminin was discontinuous in most examples of IDC regardless of type, with a trend toward more intense staining in comedo than in noncomedo carcinomas. Periductal angiogenesis was not significantly related to the type of IDC but was more pronounced with comedo carcinomas. CONCLUSIONS: These observations indicate that there are immunophenotypic correlates to the current structural classification of IDC. The immunophenotype of IDC is helpful in subclassifying an IDC and could prove useful as a prognostic indicator for local control in patients treated by breast-conserving therapy.

Pathological gambling among methadone patients.

This paper examines the correlates of problem gambling among a population of 220 methadone patients receiving treatment in the New York metropolitan area. Like most methadone patients, respondents were primarily adult males, ethnically mixed, of limited educational accomplishment and had long experiences with intravenous drug use. More than two-thirds of subjects had been convicted of one or more criminal offences. Analysis of the data showed seven percent of respondents to be probable pathological gamblers according to the South Oaks Gambling Screen (SOGS), indicating a high rate of gambling problems among this treatment population. Consistent with past studies, problem gamblers are more likely to be men, with histories of alcohol abuse, and with extensive criminal participation dating back to their teenage years. The data also suggested that problem gamblers who were also drug dependent were more likely to show greater evidence of social dysfunctionality compared to those who were exclusively substance abusers. More dually addicted respondents reported higher levels of recent heroin use, greater unemployment, and more reported hallucinations. Probable pathological gamblers who were substance abusers were also more likely to report being in conflict with their close friends. A multiple regression analysis suggested this to be the closest linked correlate to being a pathological gambler. Evidently, pathological gamblers create antipathy towards themselves as their compulsion to gamble is expressed; this in turn, may drive them toward further gambling, as they respond to this perceived opposition. These last preliminary findings will require further confirmation in future research.

The biostatistician in medical research: allocating time and effort.

Biostatisticians in research juggle many responsibilities: short-term consulting; long-term collaboration; teaching/training, and statistical research. In an institutionally-supported service group, the biostatistician frequently faces allocation of limited resources (time and effort) over multiple projects, none of which individually supports the biostatistician. In addition to the level of support provided by a specific project, there are several major issues with resource allocation: the quality of the science and data in the project; the possibility that long-term support develops from the work; personal and institutional considerations that involve the specific investigator or project. In this paper, we discuss these considerations along with some examples. We present guidelines for making decisions about allocation of time and effort and the possible implications of setting such priorities.

p53 in node-negative breast carcinoma: an immunohistochemical study of epidemiologic risk factors, histologic features, and prognosis.

PURPOSE: The present study explores p53 in relation to the following four aspects of node-negative breast carcinoma: epidemiologic risk factors, tumor histopathology, prognosis, and HER2/neu (HER) expression. MATERIALS AND METHODS: Immunohistochemical (IH) staining for p53 was performed on formaldehyde-fixed, paraffin-embedded primary invasive carcinomas from 440 node-negative patients with a median follow-up duration of 119 months. RESULTS: The IH expression, or lack thereof, of p53 separately or in combination with HER did not prove to be prognostically significant and there was no consistent association of p53 with epidemiologic risk factors. p53 was expressed in 68% of medullary carcinomas (MEDs), which is a significantly higher frequency (P < .001) than in lobular (9%) and duct (23%) carcinomas. p53 was not found in some types of low-grade carcinomas (tubular and papillary), and was observed in a minority of mucinous carcinomas. p53 was present significantly more often in carcinomas with high-grade or poorly differentiated nuclear grade than in low- or intermediate-grade tumors. There was an inverse statistically significant relationship between estrogen receptor (ER) positivity and p53 expression. Tumors with the p53(+)/HER(-) immunophenotype tended to be MEDs or duct carcinomas with a marked lymphoplasmacytic reaction. Infiltrating lobular carcinomas (IFLCs) were largely p53(-)/HER(-). p53(+)/HER(+) carcinomas had the best prognosis. The poorest outcome was associated with the p53(-)/HER(+) immunophenotype. This trend was statistically significant for recurrence-free and overall survival in patients with T1NOMO infiltrating duct carcinoma (IFDC). CONCLUSION: The IH demonstration of p53 was not a reliable prognostic indicator in the node-negative breast carcinoma patients studied and it was not associated with major epidemiologic risk factors. The combined immunophenotypic expression of p53 and HER was significantly associated with some histologic types of breast carcinoma and with prognosis in T1NOMO breast carcinoma.

Immunochemotherapy for a systemic intracellular infection: accelerated response using interferon-gamma in visceral leishmaniasis.

To determine if cytokine immunotherapy accelerates the response to conventional treatment in visceral leishmaniasis (kala-azar), previously untreated Indian patients were given antimony for 30 days (n = 15) or antimony plus interferon-gamma (IFN-gamma; n = 16). After 10 days, 10 (63%) of 16 patients treated with antimony plus IFN-gamma versus 1 (7%) of 15 randomized to antimony alone were considered cured of parasites (P < .005). On day 20, 14 (93%) of 15 versus 6 (40%) of 15 patients, respectively, were apparent clinical cures (P < .006), and treatment was discontinued early in the 14 IFN-gamma treated responders. Day 30 apparent cure rates (100% vs. 73%) and 6-month ultimate cure responses (87% vs. 60%) were higher in IFN-gamma-treated patients but not statistically different from controls (P > .05). All 13 IFN-gamma-treated subjects who were cured (12 of whom received therapy for 20 days) have remained healthy with follow-up of 14-24 months (mean, 18.9). These results indicate that IFN-gamma successfully accelerates the parasitologic and clinical response to antimony treatment, an effect that should permit shortening the duration of conventional therapy in previously untreated kala-azar.