Galantamine treatment in outpatients with mild Alzheimer's disease.

OBJECTIVE: To assess long-term effectiveness of galantamine in community-dwelling persons with mild Alzheimer's disease. METHODS: Prospective open-label trial including patients with mild AD (NINCDS-ADRDA criteria) treated with galantamine for up to 36 months. Outcome parameters included ADAS-cog/11, Bayer-ADL scale (self- and caregivers' ratings), 10-item NPI and CGI-change, safety and tolerability measures. Data are presented based on ITT analyses (LOCF). RESULTS: Seventy-five patients (55% women; mean ADAS-cog 22.3; mean age 70.2 years) were treated with galantamine for approximately 36 months. About 60% (n=45) received a total daily dose of 24 mg galantamine at final visit. After 3, 6, and 12 months of treatment, mean improvements in ADAS-cog ranged between 2.2 and 3.0 points (all P<0.05). After 24-month treatment, ADAS-cog returned to baseline value and at 3-year follow-up, patient deteriorated on average by 2.9 points. There was significant improvement on the NPI scale between baseline and 3- to 12-month follow-up (all P<0.05) and at 3-year endpoint, a slight deterioration was noted. Activities of daily living (B-ADL) decreased significantly after 24 months in self-ratings and after 12 months in caregivers' ratings. Fifty-four patients reported at least one AE, most of them occurring during the first 2 years of treatment. Among the most frequently (>10%) reported AEs irrespective of causal relationship to study medication were nausea (17.3%), dizziness (12%), and vomiting (10.7%). CONCLUSION: Galantamine was generally safe and well tolerated during the 3-year observation period. Cognition, behavior, and activities of daily living improved during 12 months treatment. At 3-year follow-up, worsening in all outcomes was measured; however, cognition remained improved compared with an untreated population.

Two galantamine titration regimens in patients switched from donepezil.

OBJECTIVES: In addition to inhibiting acetylcholinesterase, galantamine has allosteric-modulating activity at nicotinic receptors. This may make galantamine an attractive option for patients starting treatment for Alzheimer's disease (AD), but also for those who have not benefited from their current therapy. This study explored outcomes in subjects with AD transitioning from donepezil because of insufficient tolerability or efficacy. MATERIALS AND METHODS: Subjects previously receiving donepezil for mild-to-moderate AD were enrolled in a 12-week randomized, open-label study. After screening and a 7-day washout, subjects were randomly allocated to galantamine fast (8 mg/week increments) or slow (8 mg/4 week) titration to 16-24 mg. Efficacy outcomes included the Alzheimer's Disease Assessment Scale - cognitive subscale (ADAS-cog/11), Mini-Mental State Examination (MMSE), Clinician's Interview-Based Impression of Change - Plus Caregiver's Input (CIBIC-plus) and Alzheimer's Disease Cooperative Study - Activities of Daily Living Inventory (ADCS-ADL). RESULTS: Eighty-six of 89 patients (fast titration, n = 44; slow titration, n = 45) completed the study. At week 12, ADAS-cog/11 score improved from screening by 2.6 and 0.6 in the fast- and slow-titration arms, respectively (overall, -1.6; P = 0.002). MMSE scores improved slightly in both arms (overall, +0.9; P = 0.002). Two-thirds of patients had improvement or no change on the CIBIC-plus at week 12. ADCS-ADL scores did not change significantly from screening in either treatment arm. Galantamine was generally well tolerated; nausea (5.6%) and bradycardia (4.5%) were the most commonly reported adverse events. CONCLUSIONS: Patients in whom donepezil is ineffective or poorly tolerated may benefit from a switch to galantamine.

Functional improvement and correlations with symptomatic improvement in adults with attention deficit hyperactivity disorder receiving long-acting methylphenidate.

BACKGROUND: Data on the relationship between core symptoms and daily functioning in adults with attention deficit hyperactivity disorder (ADHD) are limited. Daily functioning was assessed as part of an open-label extension, and associations with symptom scores were evaluated. METHOD: After a 5-week double-blind study with adults with ADHD receiving osmotic-controlled release oral delivery system (OROS) methylphenidate (MPH) 18, 36 or 72 mg/day, or placebo, participants were eligible for a 7-week open-label extension in which all patients received OROS MPH. Data for the Conners' Adult ADHD Rating Scale - Observer: Screening Version (CAARS-O:SV) (primary endpoint) have been presented previously. Secondary endpoints included the observer self-reported short version of the CAARS (CAARS-S:S) and the Clinical Global Impressions - Severity Scale (CGI-S). Daily functioning and quality of life were assessed using the Sheehan Disability Scale (SDS) and the Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q) respectively. In post-hoc analyses, changes in CAARS-O:SV were evaluated in subgroups. Relationships between symptom and functional outcomes were evaluated in a multivariate regression analysis. RESULTS: A total of 370 patients entered the open-label extension. Significant improvements from baseline in CAARS-O:SV were similar regardless of sex, ADHD subtype, prior treatment or psychiatric co-morbidity. Significant improvements from double-blind baseline were also seen for the CAARS-S:S, CGI-S, SDS and Q-LES-Q. Improvements in the CAARS-O:SV Hyperactivity/Impulsivity subscale were associated with improvements in SDS total and subscale scores, and in the Q-LES-Q score at open-label endpoint. Improvements in CAARS-O:SV Inattention subscale and CGI-S scores were not significantly associated with functional changes. CONCLUSIONS: Improvements in ADHD symptoms relating to hyperactivity and impulsivity in adults receiving OROS MPH are associated with improvements in daily functioning and quality of life.

Effects of galantamine in Alzheimer's disease: double-blind withdrawal studies evaluating sustained versus interrupted treatment.

To evaluate the effects of galantamine withdrawal, and compare this with uninterrupted therapy, two 6-week double-blind withdrawal studies (Studies 1 and 2) were performed. These enrolled individuals who had completed one of two 3- or 5-month randomized clinical trials (parent trials) involving patients with mild to moderate Alzheimer's disease (AD). In Study 1 (GAL-USA-11; n'723), patients continuously treated with galantamine 16 mg/day exhibited a mean (± standard error [SE]) improvement in 11-item cognitive subscale of the Alzheimer's Disease Assessment Scale score of 1.8 (± 0.46) points at Week 6 compared with the parent trial baseline, (p < 0.001 vs placebo; observed cases analysis). Over the same period, patients switched from galantamine to placebo and those who had received continuous placebo, exhibited mean (± SE) deteriorations of 0.7 (± 0.49) and 1.2 (± 0.49) points, respectively. Similar trends were apparent in Study 2 (GAL-USA-5; n=118). In Study 1, subgroup analyses demonstrated cognitive benefits with continuing galantamine treatment and deterioration associated with galantamine withdrawal in patients with advanced moderate AD (baseline Mini-Mental State Examination score ≤14) and in individuals deemed non-responsive in terms of Clinician's Interview-Based Impression of Change-plus Caregiver Input (CIBIC-plus) evaluation at the end of the parent trial (CIBIC-plus score > 4). No safety issues were identified. In patients with mild to moderate AD who have exhibited cognitive benefits from up to 5 months' galantamine treatment, continuing therapy reinforces previously achieved benefit, whereas in patients in whom galantamine is discontinued, although no safety concerns arise, the natural progression of AD is apparent.

Galantamine and behavior in Alzheimer disease: analysis of four trials.

OBJECTIVES: Many individuals with Alzheimer's disease (AD) experience behavioral and neuropsychiatric symptoms, which may cause caregiver distress and lead to the institutionalization of the patient. This analysis characterized behavioral symptoms and caregiver distress in trials of galantamine and their response to treatment. MATERIALS AND METHODS: Data were pooled from four randomized, placebo-controlled clinical trials of galantamine in patients with mild to moderate AD (three studies) or AD plus cerebrovascular disease (one study) (n = 2177). Behavior and associated caregiver distress were assessed in each study using the Neuropsychiatric Inventory (NPI) and NPI distress (NPI-D), respectively. RESULTS: After 5/6 months, but not after 3 months, NPI score was significantly improved with galantamine vs placebo (P = 0.013). The benefit was particularly pronounced in patients categorized as having advanced moderate AD. At 5/6 months, there was a numerical benefit of galantamine over placebo in terms of caregiver distress; the difference was statistically significant in patients with moderate or advanced moderate AD. CONCLUSIONS: Galantamine reduces behavioral symptoms in patients with mild to moderate AD, leading to reduced caregiver burden. The reductions were greatest in patients with moderate or advanced moderate disease.

Prevention of episodic migraine with topiramate: a prospective 24-week, open-label, flexible-dose clinical trial with optional 24 weeks follow-up in a community setting.

OBJECTIVE: To explore efficacy and safety outcomes of topiramate for episodic migraine prevention in community practice. RESEARCH DESIGN AND METHODS: Open-label, multicenter, flexible-dose clinical trial consisting of a 4-week baseline phase, 24-week core phase and an optional 24-week follow-up phase in patients (18-80 years) with episodic migraine treated in community practices outside tertiary care centers. MAIN OUTCOME MEASURES: The primary efficacy endpoint was the change in the number of migraine days/28 days (baseline vs. the last 4 weeks of core treatment) Secondary efficacy parameters included aspects of quality of life (QoL) and subjective patient ratings. RESULTS: A total of 360 patients entered the core phase (ITT population); 37.6% (97 patients) discontinued prematurely, mainly due to adverse events (AEs; 23.6%). Mean topiramate dosage was 90 mg/day. Migraine days decreased from 8.30/28 days to 5.65/28 days and QoL (HIT-6 and MIDAS) was improved. Efficacy, tolerability and satisfaction were rated as 'good' or better by 56, 61 and 63% of patients, respectively. A total of 321 of 364 patients (88.2%) reported at least one treatment emergent AE, and the most common during the core phase were paraesthesia (46.4% of 364 patients), fatigue (17.0%), nausea (15.4%), dizziness (12.9%), viral infection (12.9%), weight decrease (12.6%) and impaired concentration (10.2%). Of 227 patients completing the core phase, 199 (88%) participated in the follow-up phase. A total of 187 patients received topiramate and 38 (20.3%) of these stopped treatment prematurely due to insufficient efficacy (6.4%), AEs (4.8%) or other reasons (10.2%). Reduction in migraine days and improvements in QoL (HIT-6) were maintained or improved (MIDAS) during follow-up, and 84% rated their satisfaction with topiramate therapy as 'good to very good'. CONCLUSIONS: This community practice study showed that long-term treatment with topiramate in the prevention of episodic migraine was effective and well-tolerated, and it was associated with clinically relevant improvements in several aspects of QoL.

Migraines with and without aura and their response to preventive therapy with topiramate.

Data from the Prolonged Migraine Prevention (PROMPT) with Topiramate trial were evaluated post hoc to determine whether topiramate could prevent migraine auras, and whether its efficacy in preventing migraine headaches was similar in patients with (MA; n = 269) and without (MoA; n = 542) aura. Migraines and auras were recorded during prospective baseline, 6-month open-label (OL) topiramate and 6-month double-blind (DB), placebo-controlled phases. In the last 28 OL days, migraines without aura and migraine auras decreased by 43.1% and 54.1%, respectively, in MA patients. MoA patients experienced a 44.3% reduction in migraines. In the DB phase, increases in migraines with placebo vs. topiramate were similar to the full study, but were generally not statistically significant, probably due to lack of power in the subgroup analysis. Similarly, there were no statistically significant changes in number of auras between groups. Thus, topiramate appears to reduce migraine auras in parallel with headache reductions, which are similar in patients with and without aura.

Effectiveness of low dose of topiramate following rapid titration in multiply handicapped children and difficult-to-treat epilepsy.

This prospective, observational, single arm, monocentric study explored efficacy and tolerability outcomes of rapid oral initiation of topimarate in children with difficult to treat epilepsy. The study population consisted of 19 multiply handicapped children (mean age 4.4 years, range 0.6-15.3 years). The observation period was 12 weeks and included 7 visits. The mean initial dose of topiramate was 1.1 mg/kg body weight/d (range: 0.66-2.67 mg/kg/d) following rapid titration. The mean final dose was 3.3 mg/kg/d (range 0.5-6.7 mg/kg/d). An at least 50% reduction of seizure frequency compared to baseline was observed in 9 of 19 patients (47.4%). Six patients (31.6%) had a slight reduction of seizure frequency (<50%) and 4 patients (21.1%) experienced an increase of seizure frequency. A total number of 29 adverse events were documented in 17 of 19 patients. Most frequently captured were fatigue (26.3% of patients), decreased appetite (15.8%) and psychiatric disturbances (15.8%). No serious adverse events were reported. These data might suggest that in certain clinical circumstances rapid dose escalation with topiramate followed by a low maintenance dose might be a good therapeutic option for pediatric patients with difficult to treat epilepsy.

Exploring efficacy and tolerability outcomes in patients with difficult-to-treat epilepsy receiving adjunctive topiramate at different titration rates--an exploratory study.

OBJECTIVE: To compare rapid vs regular titration of topiramate concerning efficacy and safety. MATERIALS AND METHODS: Open-label, prospective, single-center study exploring efficacy and tolerability of two adjunctive dosing regimens of topiramate (TPM) in adult patients with difficult-to-treat epilepsy. Based on investigator judgment, 21 of 50 consecutive patients received a rapid titration (starting dose 50 mg/day, stepwise increase with 50 mg/day after 3 days each until reaching the target dose), while the other 29 patients received titration according to the German prescribing information (starting dose 25 mg/day, stepwise increase with 25-50 mg/day every 7 days). Patients were observed until the target dose was reached and 3 months thereafter. RESULTS: Mean final dosages were 136 mg/day (regular titration) and 213 mg/day (rapid titration). Efficacy and tolerability measures did not differ significantly. Forty-six percent of all patients experienced a seizure reduction of > or = 50%; 14% became seizure free. No serious adverse events occurred. The most common adverse effects were tiredness (20%), memory and language difficulties (18% each), slowness in thinking and speech (10%), psychomotor disturbance (8%) and paresthesia (8%). CONCLUSIONS: This study suggests that rapid and conventional titration generate similar tolerability, safety and effectiveness in selected patients.

Conversion from valproic acid onto topiramate in adolescents and adults with epilepsy.

OBJECTIVE: To explore efficacy and tolerability outcomes of topiramate (TPM) in patients with epilepsy transitioning from valproic acid (VPA) because of insufficient efficacy and/or tolerability onto TPM. METHODS: Multicenter, open label, single arm, non-interventional study examining patients (> or =12 years) with epilepsy, transitioning onto TPM from baseline mono-or combination therapy with VPA. TPM was added onto the existing antiepileptic drug (AED) treatment and started at a dose of 25 mg once daily. The dose was titrated up with 25 mg/day increments, once every 1-2 weeks, until a final dose between 50-200 mg/day was reached. Based on clinical judgment, the treating physician decided whether or not and when the existing AED treatment especially with VPA could be withdrawn. Documented were type and frequency of seizures, TPM dose, quality of life (QOLIE-10 questionnaire), subjective perception of improvement, and adverse events (AE). RESULTS: One hundred and forty-seven patients (59% women, mean age 41 years) switched from baseline VPA treatment onto TPM because of insufficient efficacy (61%) and/or poor tolerability (81%). Average duration of follow-up was 20.3 weeks with an overall discontinuation rate of 16.3% of patients, mainly because of AE (in 8.2% of 147 patients). At study endpoint, the intended shift to TPM monotherapy was achieved in 70% of patients at a median dose of 150 mg/day. A seizure reduction of > or =50% was achieved in 75% of patients in the last scheduled period (week 8-20), and 51% of patients entering that period remained seizure-free. Quality of life improved significantly as compared with baseline for all domains of QOLIE-10 (P < 0.001). Most frequent AEs were weight decrease (4.8%), paraesthesia and fatigue (4.1% each), speech disorder and headaches (2.7% each). CONCLUSIONS: In patients with epilepsy not satisfactorily treated with VPA, conversion to TPM was associated with improved seizure control as well as improvement in several aspects of quality of life.

Epilepsy outcomes in elderly treated with topiramate.

OBJECTIVES: To explore effectiveness, tolerability and quality of life in elderly patients with epilepsy treated with topiramate. METHODS: One year, open-label, flexible-dosing clinical trial. RESULTS: One hundred and seven patients (mean age 69 years, 53% men) were studied during 273 +/- 141 days. The average final dose in monotherapy was 98 mg/day vs 153 mg/day in adjunctive treatment. Mean monthly cumulative seizure frequency decreased from 3.7 +/- 15 to 1.6 +/- 7.7 (n = 101, P < 0.0001), 78% of patients with seizures at baseline (n = 102) achieved at least 50% reduction in seizure frequency, 44% were seizure-free throughout the trial. Total scores on the quality of life in epilepsy inventory (QOLIE-31) improved from 57 +/- 17 to 68 +/- 18 (n = 64, P < 0.0001). The most frequently reported adverse events included convulsions, dizziness and tiredness. CONCLUSIONS: Elderly patients treated with topiramate showed marked reductions in seizures, good tolerability and significant improvements in several aspects of quality of life.

Conversion from carbamazepine or oxcarbazepine to topiramate in adolescents and adults with epilepsy.

OBJECTIVE: To explore effectiveness, tolerability and changes in quality of life in patients with epilepsy converting to topiramate (TPM) from carbamazepine (CBZ) or oxcarbazepine (OXC) due to insufficient effectiveness and/or tolerability. METHODS: A multicenter, open-label, non-interventional trial was used to examine patients (> or = 12 years) with epilepsy, changing to TPM monotherapy from baseline mono- or combination therapy with CBZ or OXC. TPM was added to the existing antiepileptic drug (AED) treatment and started at a dose of 25 mg once daily. The dose was titrated up with 25 mg/day increments, once every 1-2 weeks, until a final dose between 50 and 200 mg/day was reached. On the basis of clinical judgment, the treating physician decided whether or not the existing AED treatment with CBZ or OXC could then be withdrawn. Type and number of seizures, preferred TPM dose, quality of life (QOLIE-10 questionnaire), subjective perception of improvement and adverse events (AE) were documented. RESULTS: 140 patients (53.5% women, mean age 47 years) decided to switch to TPM due to insufficient effectiveness (75% of patients) and/or poor tolerability (80%) of the CBZ/OXC treatment. Average duration of follow-up was 24 weeks with an overall discontinuation rate of 19.3%, mainly due to AEs (12.1%). At study endpoint, the intended shift to TPM monotherapy was achieved in 73% of patients at a median TPM dose of 100 mg/day. A seizure reduction of > or = 50% was achieved in 91% of patients in the last scheduled period (weeks 12-26); 62% of patients entering that period remained seizure free. Quality of life at endpoint improved significantly when compared with baseline for all domains of QOLIE-10 (P < 0.001). Most frequent AEs (reported by > or = 5% of patients) were paresthesia (9.3%), weight loss (7.9%), convulsions (5.7%) and memory disorders (5.0%). CONCLUSION: In patients with epilepsy, previously not satisfactorily treated with CBZ or OXC, conversion to TPM may result in an improvement in seizure control as well as in quality of life.

Topiramate in add-on therapy: results from an open-label, observational study.

An open-label, observational prospective study assessed the effectiveness of topiramate (TPM) as add-on therapy. A total of 450 patients aged 12 and above with a diagnosis of epilepsy and at least one epileptic seizure during the 12-week retrospective baseline were to be documented. After baseline evaluation, topiramate was added. Ninety-five percent of patients had at least one baseline AED, most commonly Carbamazepine (53%) or Valproate (34%). In 5% TPM was started in monotherapy. Topiramate dose titration and target dose was determined by clinical response and side effect profile. Patients were intended to be followed for a total of 1 year which included 6 visits during which seizure frequency, adverse events, weight as well as clinical global impression were recorded. During the 12 weeks retrospective baseline, a median of 2.8 seizures per month were recorded which reduced significantly to 0.7 per month during the complete treatment phase (p < 0.0001). Seventy-two percent of patients had a > or =50% seizure reduction. Ten percent of patients were seizure free during the study. The most commonly reported adverse events were difficulties with memory (4.2%), somnolence (3.6%), and dizziness (2.7%). Overall, topiramate was well tolerated, and only 5% of patients discontinued treatment due to an adverse event. Retention in the study was higher than previously reported during randomized, dose controlled studies and is likely due to individualized doses as well as slower titration used.

Seizure outcomes after stereotactic radiosurgery for cerebral arteriovenous malformations.

OBJECTIVES: To determine the effect of stereotactic radiosurgery on seizure outcomes for patients with intracerebral arteriovenous malformations (AVM). METHODS: Between May 1990 and December 1998, 65 patients with a history of single or recurrent seizures underwent AVM radiosurgery, had more than 1 year of follow-up, and sufficient data to record an Engel seizure frequency score. The authors reviewed their records and updated clinical information when necessary with direct patient contact. Follow-up ranged from 12 to 144 months (median, 48 months). Seizure frequency was compared before and after radiosurgery with the Engel Seizure Frequency Scoring System. RESULTS: Overall, 26 patients (51%) were seizure-free (aura-free) after radiosurgery at 3-year follow-up; 40 patients (78%) had an excellent outcome (non-disabling simple partial seizures only) at 3-year follow-up. Factors associated with seizure-free or excellent outcomes include a low seizure frequency score (<4) before radiosurgery and smaller size and diameter AVM. Twenty-three patients had intractable partial epilepsy prior to treatment. Twelve (52%) of 23 and 11 of 18 (61%) patients with medically intractable partial epilepsy had excellent outcomes at years 1 and 3. CONCLUSION: Overall, stereotactic radiosurgery improves seizure outcomes in the majority of patients and more than half of the patients with medically intractable partial epilepsy had an excellent seizure outcome after radiosurgery.

Diagnosis of hyperlipidemia and treatment with a statin in the outpatient stroke clinic.

The aim of this study was to assess a stroke clinic's performance in the diagnosis of hyperlipidemia and more specifically to evaluate the effectiveness of statins in patients with cerebrovascular disease not enrolled in a research study. The records of 370 consecutive patients seen at a stroke clinic over a 4-year period were reviewed, and information regarding neurologic diagnosis, lipid profile, and use and type of cholesterol-lowering medication was abstracted. Hyperlipidemia was defined as a total cholesterol level equal to or more than 200 mg/dL. Forty-eight patients meeting specific criteria were further analyzed to monitor the effects of statins. Cholesterol testing was obtained in 324 patients (88%) and 178 (55%) were hyperlipidemic, but only 86 (48%) patients received treatment. The mean cholesterol level of the 48 patients dropped from 246.2 mg/dL to 197.1 mg/dL (P < .0001) after the initiation of statin therapy, and significant reductions were present in subgroups with pretreatment levels of 200 to 249 mg/dL and 250 to 299 mg/dL. Of the 21 patients with repeated cholesterol testing more than 6 months after the first posttreatment test, only 11 (52%) maintained a level below 200 mg/dL. Effective control of hyperlipidemia can be achieved in patients with cerebrovascular disease, but not all are adequately tested or treated. Improved physician awareness and more effective health care delivery systems are needed.

Ophthalmic artery microembolism in giant cell arteritis.

A 70-year-old man presented with a history of headache and sudden loss of vision of the left eye. Funduscopic examination showed sector retinal edema and hemorrhage as well as optic disc swelling consistent with anterior ischemic optic neuropathy. The Westergren sedimentation rate was 66 mm/h. Temporal artery biopsy was consistent with giant cell arteritis. Routine transcranial Doppler testing performed on a Pioneer 2020 instrument (Nicolet Vascular, Inc., Golden, CO) equipped with special software for microembolus detection showed a microembolic signal in the left ophthalmic artery. During a subsequent monitoring study, microembolic signals were detected in the anterior and middle cerebral arteries, bilaterally. Microembolism can occur in giant cell arteritis. Ophthalmic artery microembolism can be detected in vivo by transcranial Doppler ultrasonography. This new imaging capability can potentially be useful when evaluating patients with vascular disorders of the eye.

Tumors associated with p53 germline mutations: a synopsis of 91 families.

Although inherited p53 mutations are present in all somatic cells, malignant transformation is limited to certain organs and target cells. The analysis of 475 tumors in 91 families with p53 germline mutations reported since 1990 shows that breast carcinomas are most frequent (24.0%), followed by bone sarcomas (12.6%), brain tumors (12.0%), and soft tissue sarcomas (11.6%). The sporadic counterparts of these tumors also carry a high incidence of p53 mutations, suggesting that in these tissues p53 mutations are capable of initiating the process of malignant transformation. Hematological neoplasms (acute lymphoblastic leukemia and Hodgkin's lymphoma) and adrenocortical carcinomas occurred at a frequency of 4.2 and 3.6%, respectively. One-half of the families fulfilled the diagnostic criteria of the Li-Fraumeni syndrome. There were marked organ-specific differences in the mean age at which carriers of p53 germline mutations present with neoplastic disease: 5 years for adrenocortical carcinomas, 16 years for sarcomas, 25 years for brain tumors, 37 years for breast cancer, and almost 50 years for lung cancer. Analysis of the mutational spectrum showed a predominance of G:C-->A:T transitions at CpG sites, suggesting an endogenous formation, eg, by deamination of 5-methylcytosine, rather than a causation by environmental mutagenic carcinogens. The location of mutations within the p53 gene was found to be similar to that of somatic mutations in sporadic tumors. There is no evidence of an organ or target cell specificity of p53 germline mutations; the occasional familial clustering of certain tumor types is more likely to reflect the genetic background of the respective kindred or the additional influence of environmental and nongenetic host factors.

Tubular adenoma of the choroid plexus: evidence for glandular differentiation of the neuroepithelium.

A case of tubular adenoma arising in the right ventricular choroid plexus of a 4-month-old boy is described. A basic pattern of neoplastic glandular epithelium and lack of papillary architecture distinguished this tumor from a papilloma. Coexpression of S -100 protein, transthyretin and cytokeratin identified the neoplastic cells as being of choroid plexus origin. Immunohistochemical detection of MIB-1 showed a proliferation rate (16%) similar to adenomas in more conventional locations, but not encountered in benign brain tumors. In situ detection of DNA-derived oligonucleosomal fragments by TUNEL analysis, on the other hand, detected apoptotic activity in 5-8% of tumor cells. The indolent course of the disease in the present case, thus, might suggest a compensatory elimination of proliferating cells by apoptosis. This possibly points to mechanisms of neoplastic transformation different from those involved in choroid plexus papillomas.

Infrequent alterations of the p15, p16, CDK4 and cyclin D1 genes in non-astrocytic human brain tumors.

While several genetic alterations associated with the evolution of the astrocytomas have been identified, the molecular basis of non-astrocytic brain tumors has remained largely unknown. In this study, p15, p16, CDK4 and cyclin D1 genes were analyzed in 69 nonastrocytic human brain tumors, including 17 oligodendrogliomas, 16 medulloblastomas/primitive neuroectodermal tumors (PNETs), 14 ependymomas and 22 meningiomas. Southern blot analysis of DNA from frozen samples showed no homozygous deletions in p15 or p16 genes in any of these tumors. No mobility shift was found by PCR-single-strand conformation polymorphism (PCR-SSCP) analysis in exons 1 and 2 of the p15 gene and exons 1 and 2 of the p16 genes, except for one oligodendroglioma. Direct sequencing of DNA from this tumor showed a G --> A transition at nucleotide 436 (codon 140) in exon 2 of the p16 gene, which is a common polymorphism. Southern blot analyses revealed no amplification of CDK4 and cyclin D1 genes in any of the neoplasms analyzed. In contrast to astrocytic brain tumors, which show frequent loss of the p16 gene and amplification of the CDK4 gene, alteration of these genes appears to be rare in other neoplasms of the human nervous system.

Intratemporal facial nerve perineurioma.

Forty-two cases of perineurioma have been reported in the literature. This report adds the first intratemporal facial nerve perineurioma to the literature and reviews the others. Unlike schwannoma and neurofibroma, the histological features of perineurioma demonstrate onion bulb-like structures with a strong positive immunoreactivity for epithelial membrane antigen. The clinical history of gradual facial nerve paresis was 15 years in the case presentation and the clinical diagnosis of tumor was overlooked.