Effect of wheat fiber and vitamins C and E on rectal polyps in patients with familial adenomatous polyposis.

Over a 4-year period in a chemoprevention trial on large bowel neoplasia, 58 patients with familial adenomatous polyposis were treated with 4 g of ascorbic acid (vitamin C)/day plus 400 mg of alpha-tocopherol (vitamin E)/day alone or with a grain fiber supplement (22.5 g/day). In this randomized, double-blind, placebo-controlled study, we determined the effects of these supplements on rectal polyps in these patients. Analysis by intent to treat suggested that the high-fiber supplement had a limited effect. Analysis adjusted for patient compliance showed a stronger benefit from the high-fiber supplement during the middle 2 years of the trial. The results provide evidence for inhibition of benign large bowel neoplasia by grain fiber supplements in excess of 11 g/day in this study population. The findings are consistent with the hypothesis that dietary grain fiber and total dietary fat act as competing variables in the genesis of large bowel neoplasia.

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.

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.

Prediction of early relapse in patients with operable breast cancer by detection of occult bone marrow micrometastases.

We used monoclonal antibodies to identify occult micrometastases in the bone marrow of 49 patients with operable (stage I and II) breast carcinoma. Follow-up (mean, 29 months; median, 30 months) revealed that 12 patients recurred. The presence of bone marrow micrometastases (BMM) was significantly associated with early recurrence (P less than .04). The estimated 2-year recurrence rate for patients with no BMM detected (BMM-) was 3%; in patients with BMM, the 2-year recurrence rate was 33%. When BMM and axillary lymph node (LN) status were combined, groups of patients at low risk (LN-, BMM-; 2-year recurrence rate, 0%) and high risk (LN+, BMM+; 2-year recurrence rate, 42%) for early recurrence were identified. Bone marrow tumor burden was related to early recurrence. Among patients with BMM, those who did not recur had on average fewer extrinsic cells in their marrow than those who recurred (15 v 43 cells, respectively). Multivariate analysis comparing BMM, LN+ versus LN-, and tumor size (less than or equal to 2 cm v greater than 2 cm) revealed no factor independently associated with early recurrence. Peripheral tumor burden of BMM (0 or less than 10 extrinsic cells v greater than or equal to 10 extrinsic cells) was the only independent predictor of early recurrence (P less than .003). In conjunction with conventional prognostic factors, particularly axillary LN status, evaluation for BMM might be used to stratify patients for adjuvant treatment programs. Because this pilot study involved few patients with short-term follow-up, the results should be interpreted with caution. The examination of bone marrow for micrometastases remains an experimental procedure; the clinical usefulness of the test will be established through larger studies with long-term follow-up.

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.

Luteinizing hormone pulsatility in subjects with 5-alpha-reductase deficiency and decreased dihydrotestosterone production.

The pattern of LH pulsatility in male pseudohermaphrodites with inherited 5 alpha-reductase-2 deficiency (5 alpha RD) and decreased levels of plasma dihydrotestosterone was compared to that in normal males. Analysis of 10-min plasma LH sampling during either a 10- or 24-h period demonstrated that the subjects with 5 alpha RD had 1) a mean plasma LH level, mean LH pulse amplitude, and mean plasma LH nadir that were approximately twice normal; and 2) a mean LH pulse frequency similar to that in normal males, whether described as pulses per h or pulses per study period. An increased plasma LH response to GnRH administration was also noted. The findings suggest that a deficiency of DHT results in decreased negative feedback at the level of the hypothalamus and/or pituitary, resulting in an increase in mean plasma LH, LH pulse amplitude, and LH responsiveness to GnRH. In response to increased LH, mean plasma testosterone (T), free T, and plasma estradiol (E2) are increased. The pulse amplitude is increased despite elevated plasma T and E2 levels; this underscores the importance of DHT in pulse amplitude regulation. LH pulse frequency is not decreased despite elevated plasma T and E2, raising the possibility that DHT deficiency increased pulse frequency that was normalized by increased T and/or E2. In conclusion, studies of LH pulsatility in subjects with 5 alpha RD suggest a role for DHT in the modulation of LH.

The two patterns of reactive astrocytosis in postischemic rat brain.

The distribution and time course of postischemic astrocyte hypertrophy and hyperplasia and the relationship to neuronal viability or necrosis was studied in rats subjected to 30 min of carotid and vertebral artery occlusion followed by reperfusion from 3 h to 5 weeks. Intermediate filaments (IFs) were evaluated by electron microscopy, IF proteins by immunohistochemistry, and astrocyte division by [3H]thymidine uptake. Glial fibrillary acidic protein (GFAP) increased in damaged and nondamaged brain regions by 2 days and was associated with cell enlargement, increases in IF, and transformation of GFAP-negative into GFAP-positive glia. Cell hypertrophy and increased GFAP persisted only in regions of neuronal necrosis whereas the number and size of GFAP-positive astrocytes returned to control levels in nondamaged regions by 2 weeks. Astrocyte hyperplasia was not seen until 3 days and was confined to damaged brain regions. Vimentin-positive astrocytes were numerous by 2 days in damaged brain and remained only in those regions at 5 weeks. The data demonstrate that reactive astrocytosis develops in undamaged brain, but is reversible with prolonged survival, whereas reactive astrocytosis that accompanies structural brain damage persists for prolonged periods and is associated with hyperplasia, as well as hypertrophy. In addition, the results show that astrocyte expression of vimentin is more specific than GFAP in identifying regions of permanent ischemic injury during the early postischemic period.

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.

Early seizures following intracerebral hemorrhage: implications for therapy.

Seizures occurred in 19 of 112 patients (17%) with nontraumatic, supratentorial intracerebral hemorrhage (ICH). All seizures occurred at ICH onset; patients without seizures at hemorrhage onset remained seizure-free until the last recorded follow-up. Seizures were significantly associated with extension of blood into the cerebral cortex. We found no association between seizures and hemorrhage size or the presence of subarachnoid or intraventricular blood. These data suggest that (1) seizures, in ICH, occur at hemorrhage onset, (2) patients without seizures at hemorrhage onset are at very low risk for subsequent seizures during their hospitalization, (3) hemorrhage involving the cerebral cortex, regardless of site of origin, predisposes to seizures, and (4) the prophylactic use of anticonvulsants in the acute management of these patients appears unwarranted, especially in patients without cortical extension.

Dysphagia therapy following stroke: a controlled trial.

OBJECTIVE: To determine the effect of graded levels of intervention by a dysphagia therapist on the occurrence of pneumonia, dehydration, calorie-nitrogen deficit, recurrent upper airway obstruction, and death following stroke. DESIGN: A randomized control trial. SETTING: Inpatient stroke rehabilitation unit. PATIENTS: All patients met the following eligibility criteria: (1) stroke defined by clinical history and neurologic examination with compatible CT or MRI, (2) ages 20 to 90 years inclusive, (3) no known history of significant oral or pharyngeal anomaly, (4) laboratory values below end point criteria, (5) failure on the Burke Dysphagia Screening Test, and (6) modified barium swallow evaluation evidence of dysphagia (patients who aspirated > or = 50% of all consistencies presented, even using compensatory swallowing techniques, were excluded). Of 123 eligible patients, eight refused study participation. One hundred fifteen patients were randomized. INTERVENTIONS: Three graded levels of dysphagia therapist control of diet consistency and reinforcement of compensatory swallowing techniques were provided during the inpatient rehabilitation stay. MAIN OUTCOME MEASURES: Pneumonia, dehydration, calorie-nitrogen deficit, recurrent upper airway obstruction, and death. RESULTS: The log rank statistic showed no significant difference between the three treatment groups for the distribution of time until end point during the inpatient stay or to 1 year post-stroke. CONCLUSION: Limited patient and family instruction regarding use of diet modification and compensatory swallowing techniques during inpatient rehabilitation is as effective as therapist control of diet consistency and daily rehearsal of compensatory swallowing techniques for the prevention of medical complications associated with dysphagia following stroke.

Immunohistochemical detection of cathepsin D in T2N0M0 breast carcinoma.

Recent studies have reported significant but inconsistent correlations between tumor cathepsin D (CD) concentration and prognosis in breast carcinoma. To investigate the tissue distribution and a prognostic utility of CD in breast carcinoma, 159 cases of T2N0M0 breast carcinoma with a minimum of 10 years' follow-up were studied for CD expression by immunohistochemistry. This group of patients was chosen for study because of current interest in prognostic markers for stage I breast carcinoma and the likelihood that there would be sufficient recurrences in this group to detect significant differences. Seventy-two carcinomas (45%) showed prominent staining of cells composing the tumor. Neoplastic cell staining for CD correlated with well-differentiated architecture, and lack of neoplastic cell CD expression correlated with high nuclear grade and the medullary carcinoma category. Stromal cell (primarily histiocyte) staining in carcinomas was the major contributor to CD expression in 67 of the 159 cases (42%). Intense intratumoral stromal cell staining correlated with absence of estrogen receptors and the medullary carcinoma subtype. There was no significant correlation between disease-free or overall survival and (a) intensity of overall staining for CD, (b) staining of carcinoma cells alone, or (c) staining of nonneoplastic cells within the region of the carcinoma. These results show that a significant proportion of CD activity detected within a tumor by immunohistochemistry may be contributed by nonneoplastic cells, and there is no significant correlation between survival and immunohistochemical detection of CD in T2N0M0 breast cancer.

Rug shampoo and Kawasaki disease.

Following personal interviews with 63 families of children with Kawasaki disease and with 63 control families with children paired for race, sex, and age, no epidemiologic differences were seen except for use of rug shampoo within 1 month of onset in 16 episodes in 15 children with Kawasaki disease in 14 families (24% of children, 22% of families) compared with two families of control children (3%, P less than .005). Explanations for this strong association of recent rug shampoo and Kawasaki disease include the question of recall bias as well as the possibility that an agent in the shampooing process does cause or does contribute to illness.

Nursery privileges of the private attending pediatrician in the care of critically sick neonates in New York state.

To determine the role of the private attending pediatrician in caring for newborns who require intensive, intermediate, or continuing care in New York state, a request was sent to New York state institutions to select the statement best describing private attending pediatrician privileges. Privileges were graded from 1 to 6 with category 1 allowing the private attending pediatrician to care for all newborns and category 6 not allowing the private attending pediatrician to care for any newborns. Nurseries were classified (per New York State Department of Health) as regional, nonregional intensive care, intermediate care, and continuing care centers. A total of 97% (88/90) of institutions responded, representing 2,040 private attending pediatricians. In 95% (79/83) of the New York state institutions with staff private attending pediatricians, the pediatricians' privileges were limited. In 18% (15/83), the private attending pediatrician does not supervise any newborns receiving special care, whereas in an additional 77%, pediatricians' privileges have been limited. Despite this, the majority of institutions encourage the private attending pediatrician to continue communication with the family. Limited hospital privileges coupled with continued family communication may be the future trend for private attending pediatricians in the hospital setting.

Epidemiologic aspects of Kawasaki disease in a Manhattan hospital.

Epidemiologic and clinical features of Kawasaki disease in 106 patients seen between 1980 and 1986 at The New York Hospital in midtown Manhattan were compared with those in large series from the United States, Canada, and Japan. Dissimilarities in our Kawasaki disease experience included ethnic heterogeneity of our patients (50% white, 18% black, 16% Hispanic, and 16% Oriental) and, in comparison with the Japanese experience, an older mean age (3 1/2 vs 1 1/2 years) with fewer children less than 2 years of age (32% vs 50% to 60%). In comparison with the general population of the geographic urban and suburban referral area for our hospital and in comparison with our general pediatric population, Oriental children with Kawasaki disease were overrepresented (16% vs 2%). More families of children with Kawasaki disease were members of the upper and middle class (73%) than were the population seen in general pediatrics (31.7%) at our hospital. Personal interviews with 63 families of children with Kawasaki disease and 63 control families with children paired for ethnic group, sex, and age revealed no epidemiologic differences except for use of rug shampoo within 1 month of onset in 16 episodes in 15 children with Kawasaki disease in 14 families (22% of families) compared with two families of control children (3%) (P less than .001).

Female external genitalia and müllerian duct derivatives in a 46,XY infant with the smith-lemli-Opitz syndrome.

We report on a 46,XY newborn infant with Smith-Lemli-Opitz (SLO) syndrome with female external genitalia, intraabdominal testes with epididymides and deferent ducts and a normally shaped uterus and vagina. Polydactyly, cleft palate, and several internal organ malformations were also present, and the patient died shortly after birth. Data on six reported male infants with SLO syndrome and female external genitalia suggest a correlation between degree of genital involvement and overall degree of severity. Scoring systems to quantify overall degree of severity (SLO score) and degree of genital involvement in males (genital score) were devised and applied to 122 reported cases from the literature. Statistical analyses showed a unimodal distribution of the SLO severity scores, and positive correlations between the SLO score and the genital score in males, the presence of polydactyly, and the presence of cleft palate. In 19 multiplex families the affected sibs were generally similar in their SLO scores. The above analyses suggest that the wide phenotypic variability in the SLO syndrome is determined by variable expressivity of the same entity as opposed to genetic heterogeneity. The observed phenotypic correlations naturally determine that males with complete feminization are among the more severe patients and tend to have polydactyly and cleft palate.

Late effects of bone marrow transplantation on pulmonary function in children.

This study was undertaken to evaluate in a primarily pediatric population whether the late effects of bone marrow transplantation (BMT) on pulmonary function in patients having undergone the procedure for treatment of acute leukemia or lymphoma are worse than that of patients having undergone transplant for treatment of aplastic anemia. Forty-six patients were studied. We did not demonstrate statistically significant differences in group mean forced expiratory flow in one second/forced vital capacity (FEV1/FVC) and percentage predicted forced expiratory volume in one second (FEV1), forced vital capacity (FVC), forced expiratory flow at 25-75% of the forced vital capacity (FEF25-75) and total lung capacity (TLC) values between the two groups of patients before BMT and to 7 years post-transplant. Individual patients with pulmonary function abnormalities were identified. Furthermore, there were no significant differences between the two study groups or within the group of patients with aplastic anemia from pre-transplant to 9-12 months and from pre-transplant to 18-24 months after BMT. However, within the group of patients treated for acute leukemia or lymphoma, there was a significant decline in the group mean percentage predicted FVC (p = 0.0001), FEV1 (p = 0.0006) and FEF25-75 (p = 0.0063) from pre-transplant to 9-12 months and in the FVC (p = 0.004) and FEV1 (p = 0.0006) from pre-transplant to 18-24 months after BMT. The greater decline in the FVC relative to the FEV1 suggests the development of a restrictive process in this group of patients.

Multicentricity and bilaterality in invasive breast carcinoma.

Multicentricity and bilaterality are well-established characteristics of breast carcinoma, but little is known about the relationship of these variables with each other. This question was explored by analyzing the data pertaining to 880 women with invasive breast carcinoma. Patients with multicentric carcinoma had bilateral disease more often than those whose carcinoma was apparently limited to a single quadrant. Among women who had lobular carcinoma in situ coexisting with infiltrating duct carcinoma or infiltrating lobular carcinoma, bilaterality and multicentricity were significantly more common than they were among patients whose only lesion was infiltrating duct or medullary cancer. Other variables associated with bilaterality and multicentricity were degree of ductal differentiation, tumor size, nodal status, type of tumor margin, intensity of lymphoid infiltrate, and menstrual status. Age at diagnosis and estrogen receptors were related to bilaterality but not to multicentricity. The following variables proved to be unrelated to bilaterality and multicentricity: family history of breast carcinoma, height, weight, and parity. The data obtained in this study tend to support a conclusion that multicentricity and bilaterality are manifestations of similar factors involved in the neoplastic transformation of mammary gland epithelium leading to the development of breast cancer.

Gleason grading of prostate cancer: a predictor of survival.

The Gleason grading system was employed in the pathologic assessment of 82 patients with carcinoma of the prostate diagnosed between 1962-1965 and subsequently followed to death. The data suggest that the Gleason grade gives long-term prognostic information independent of stage with a direct correlation between increasing Gleason grade and cancer death rate index. Furthermore, the sum of clinical stage plus Gleason grade is a more significant prognostic factor than either stage or grade alone.

Lobar vs thalamic and basal ganglion hemorrhage: clinical and radiographic features.

One hundred and twelve patients with spontaneous supratentorial intracerebral hemorrhages were reviewed to identify features which distinguish lobar intracerebral hemorrhage (LH; n = 42) from thalamic or basal ganglionic hemorrhage (TGH; n = 70). Chronic hypertension occurred more commonly in TGH (TGH 67%; LH 48%) while bleeding diathesis was more common in LH (LH 19%; TGH 6%). Clinical presentations were extremely variable and not associated with the type of hemorrhage. Bleeding into the ventricles and hydrocephalus occurred more often with TGH. At last follow-up, there were minimal differences between LH and TGH in overall mortality and functional outcome of the survivors. Alertness on admission was associated with a good outcome regardless of the type of hemorrhage, while a low Glasgow Coma Scale score, coma, ataxic respiration, abnormal pupil reactions, acute hypertension, large hemorrhage size and intraventricular blood were associated with a poor outcome. These data confirm etiological distinctions between LH and TGH, but fail to confirm previously reported differences in clinical presentation and outcome.