Hereditary pancreatic cancer.

Hereditary pancreatic cancer (PC) appears to be exceedingly heterogeneous, as evidenced by its association with a variety of integrally associated diverse cancers and/or differing mendelian inherited cancer syndromes, which include the Lynch syndrome II variant of hereditary nonpolyposis colorectal cancer, hereditary breast-ovarian cancer syndrome in families with the BRCA2 mutation, hereditary pancreatitis, Peutz-Jeghers polyposis and the familial atypical multiple-mole melanoma syndrome in families with the CDKN2A (p16) germline mutation. Because of this heterogeneity, we provide a conservative estimate that about 5% (1,460) of PC cases in the US annually are hereditary. Although this number is relatively small, members of hereditary PC families serve as excellent models for studying the etiology, natural history, biomarkers, pathogenesis, potential carcinogenic exposures and their perturbation of underlying genetic events, and treatment of PC. These individuals would benefit greatly from method(s) capable of detecting cancer at an early stage, and such knowledge would also be useful for improving the diagnosis of the much more common 'sporadic' form of PC.

Clinical impact of molecular genetic diagnosis, genetic counseling, and management of hereditary cancer. Part II: Hereditary nonpolyposis colorectal carcinoma as a model.

Hereditary nonpolyposis colorectal carcinoma (HNPCC) is the most common hereditary form of colorectal carcinoma (CRC) and may account for 5-10% of the total CRC burden. The discovery of DNA mismatch repair (MMR) genes, inclusive of hMSH2, hMLH1, hPMS2, and hMSH6, has enabled the identification of who has and who does not have inordinately increased susceptibility to CRC as well as a litany of extracolonic cancers. Mutation testing has focused on hMSH2 and hMLH1, the most common mutations in HNPCC. The protocol for DNA testing and DNA-based genetic counseling is described in Part I of this study. One hundred ninety-nine bloodline relatives were tested and counseled from five hMLH1 and two hMSH2 families. Their major reason for seeking genetic counseling and DNA testing was to inform their children and other loved ones of their mutation status. Those who sought counseling overestimated their risk for inheriting the mutation and showed a high rate of interest in prophylactic surgery, and many were greatly concerned about insurance discrimination. Knowledge about HNPCC, its molecular genetic diagnosis, surveillance and management opportunities, and genetic counseling implications are still emerging, all in the face of a greater need for physician education regarding all facets of hereditary cancer.

Clinical impact of molecular genetic diagnosis, genetic counseling, and management of hereditary cancer. Part I: Studies of cancer in families.

Hereditary cancer represents approximately 5-10% of the total cancer burden and may account for 60,000 to 120,000 new cancer occurrences this year in the United States. New developments in molecular genetics and the cloning of cancer-prone genes have intensely fueled interest in dealing with hereditary forms of cancer. The authors provide an algorithm that depicts the process for the identification, study, and DNA-based genetic counseling of families being investigated under a research proposal at the Hereditary Cancer Institute of Creighton University School of Medicine. They have studied 56 hereditary nonpolyposis colorectal carcinoma families; in 18 of them, associated genomic mutations have been identified in affected members. DNA-based genetic counseling has been provided for seven of these families. The authors have also evaluated 131 hereditary breast-ovarian carcinoma families. BRCA1 and BRCA2 mutation searches have been performed for 76 of these families; BRCA1 mutations were found in 38 families and BRCA2 mutations in 9. The study of cancer-prone families is a powerful approach to cancer control, particularly when the germ-line mutation is identified in the family and individuals at high risk can be tested, once they provide informed consent, and receive DNA-based genetic counseling. Discovery of the germ-line mutation for cancer proneness provides an unparalleled opportunity to predict patients' life-time risk for cancer of specific anatomic sites, inclusive of a pattern of multiple primaries. Surveillance and management protocols, when melded to the particular syndrome's natural history, can be life-saving.

Neurobehavioral symptoms and family functioning in traumatically brain-injured adults.

Traumatic brain injury (TBI) often results in a myriad of symptoms across physical, cognitive, and neurobehavioral domains. Despite inherent limitations associated with physical or cognitive impairments, the extant literature suggests that neurobehavioral symptoms tend to be the most distressing symptoms for the family and are more strongly related to poor outcome for the patient. The Neuropsychology Behavior and Affect Profile (NBAP) along with the General Functioning subscale of the Family Assessment Device (FAD-GF) and the Perceived Stress Scale were administered to 153 family members of persons who had sustained a TBI. The results provide new normative data and statistical support for the NBAP as a promising measure of neurobehavioral symptomatology following TBI. The correlation of.54 (p <.01) between FAD-GF and Full Scale NBAP scores provides powerful support for the hypothesis that family dysfunction is related to the presence of neurobehavioral symptoms in the patient. NBAP domains of Depression, Inappropriateness, Pragnosia, and Indifference appear most strongly related to family functioning and also bear a significant relationship to caregiver stress level and patient unemployment, whereas injury severity had little impact on either family functioning or neurobehavioral symptoms. The findings reinforce the significance of neurobehavioral symptoms and fortify their proposed link to family dysfunction post-TBI.

Emotional behavior as an agenda in neuropsychological evaluation.

In an effort to objectify neuropsychologic evaluations, consideration of a patient's emotional behavior has often been neglected. An extensive literature review is undertaken in an effort to document lateralized emotional behaviors commonly found in brain injury populations. This evidence is contrasted with the psychiatric symptoms and lateralized neuropsychologic impairments seen in major depression and schizophrenia. A theoretical model is then proposed that attempts to integrate these "functional" vs. "organic" symptoms based upon reciprocal inhibition of lateralized emotional functioning in brain injury and psychiatric disorders. This opponent process model not only seems to account for some of the discrepant findings in the literature, but additionally provides a cogent and useful marker to neurophychologically differentiate "neuronal" vs. "metabolic" disorders. The model further suggests new ways of envisioning treatment and recovery from both psychiatric illness and brain injury.

Cerebral blood flow changes in benign aging and cerebrovascular disease.

Cross-sectional analysis of CBF values was carried out among 668 volunteers and patients. Subjects were subdivided according to age, gender, and degree of cerebrovascular disease, ranging from healthy volunteers with or without risk factors for stroke to patients with multi-infarct dementia. Four-year longitudinal analysis was also carried out on 230 individuals from the original sample. Decrements in CBF values were evidenced by both cross-sectional and longitudinal analysis in relation to advancing age, progressive cerebrovascular disease, and dementia. Regional, age-related CBF declines in healthy volunteers were heterogeneous, possibly related to changes in levels of functional activity within different brain regions.

Xenon contrast CT-CBF scanning of the brain differentiates normal age-related changes from multi-infarct dementia and senile dementia of Alzheimer type.

Local cerebral blood flow (LCBF) and partition coefficients (L lambda) were measured during inhalation of stable xenon gas with serial CT scanning among normal volunteers (N = 15), individuals with multi-infarct dementia (MID, N = 10), and persons with senile dementia of Alzheimer type (SDAT, N = 8). Mean gray matter flow values were reduced in both MID and SDAT. Age-related declines in LCBF values in normals were marked in frontal cortex and basal ganglia. LCBF values were decreased beyond normals in frontal and temporal cortices and thalamus in MID and SDAT, in basal ganglia only in MID. Unlike SDAT and age-matched normals, L lambda values were reduced in fronto-temporal cortex and thalamus in MID. Multifocal nature of lesions in MID was apparent. Coefficients of variation for LCBFs were greater in MID compared with SDAT and/or age-matched normals.

The effects of chronic cigarette smoking on cerebrovascular responsiveness to 5 per cent CO2 and 100 per cent O2 inhalation.

Effects of chronic cigarette smoking on cerebrovascular responsiveness of volunteers at risk for stroke and not at risk for stroke were evaluated by serial measurements of cerebral blood flow using the 133Xe inhalation method. Resting gray matter blood flow values (Fg) measured while breathing room air were compared with Fg values measured during inhalation of either 5 per cent CO2 in air or 100 per cent O2. Changes in Fg values during inhalation of 5 per cent CO2 were used to estimate cerebral vasodilator capacitance, and those during inhalation of 100 per cent O2 were used to estimate cerebral vasoconstrictor capacitance. Results indicated that chronic cigarette smokers have both reduced vasodilator (P less than 0.01) and reduced vasoconstrictor (P less than 0.02) capacitance when compared with nonsmokers of the same ages regardless of whether or not other risk factors for stroke were present. Vasodilator capacitance to 5 per cent CO2 inhalation was reduced among smokers compared with nonsmokers of the same age by 48 per cent in non-risk subjects and 56 per cent in risk-factored subjects, while vasoconstrictor capacitance to 100 per cent O2 inhalation among smokers was decreased by 24 per cent in non-risk subjects and 34 per cent in risk-factored subjects. In risk-factored subjects, combined effects of smoking and other risks appeared to be additive.

Cigarette smoking decreases cerebral blood flow suggesting increased risk for stroke.

Effects of chronic cigarette smoking on cerebral blood flow were investigated by measuring gray matter blood flow (Fg) using xenon 133 inhalation among 192 volunteers without cerebrovascular symptoms. There were 108 normal, healthy volunteers; 84 had risk factors for stroke (hypertension, hyperlipidemia, diabetes mellitus, and/or heart disease). Of both risk and nonrisk groups, 75 were habitual smokers (0.5 to 3.5 packs per day for 25 years). Comparisons of mean Fg values for both hemispheres showed significant reductions related to tobacco consumption and risk factors for stroke. Multiple-regression equations using smoking, age, risk, and alcohol consumption indicated a combined R2 value of 0.22. Smoking seems to be a potent risk factor decreasing cerebral blood flow probably by enhancing cerebral arteriosclerosis. Chronic cigarette smoking in persons with other risk factors further reduced Fg values in an additive manner when compared with subjects who had corresponding risk factors who did not smoke.

Reductions in regional cerebral blood flow associated with chronic consumption of alcohol.

Neurotoxic effects of habitual alcohol consumption were investigated by correlating the subjects' estimates of abstinence or frequency and amount of alcohol consumed with measurements of gray matter blood flow utilizing the 133Xe inhalation method. Two hundred and twenty-two subjects were studied, including 136 healthy subjects, 82 subjects with well-established risk factors for stroke (hypertension, hyperlipidemia, heart disease, and diabetes mellitus), and four subjects with chronic alcoholic dementia of the Wernicke-Korsakoff type. Subjects were classified according to average quantitative amounts of alcohol consumed per day, week, or month for the past five years. Comparisons of mean values for hemispheric gray matter blood flow indicated significant inverse relationships with the average amounts of alcohol consumed. This linear relationship occurred regardless of whether or not other risk factors were present and indicated that alcohol itself was a risk factor reducing gray matter blood flow and had additive effects of reducing cerebral blood flow further when combined with other risk factors. Patients who had chronic Wernicke-Korsakoff syndrome had the most severely reduced blood flow levels, as might be predicted from extrapolation of the regression line comparing cerebral blood flow values with the degree of chronic alcohol consumption.

Double-blind trial of oral papaverine in chronic cerebrovascular ischemia.

A preliminary analysis of the effect of long-term therapy with oral papaverine has been made in 11 patients with chronic cerebral ischemia due to cerebral arteriosclerosis. The cases were classified as remote cerebral infarction (6 patients) or vertebrobasilar arterial insufficiency (5 patients). The patients received 225 mg or 450 mg daily, assigned in a double-blind manner. Most showed clinical improvement and improvement on the EEG. There was a statistically significant increase in regional cerebral blood flow in the vertebrobasilar arterial distribution, including the brain stem and cerebellar and posterior cerebral regions, particularly in the right hemisphere. Evidence appears to indicate that zones of severe remote cerebral infarction are refractory to pharmacologically induced vasodilation.