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.

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.

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.

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.