Metformin plus chemotherapy versus chemotherapy alone in the first-line treatment of HER2-negative metastatic breast cancer. The MYME randomized, phase 2 clinical trial.

PURPOSE: To investigate the efficacy of metformin (M) plus chemotherapy versus chemotherapy alone in metastatic breast cancer (MBC). METHODS: Non-diabetic women with HER2-negative MBC were randomized to receive non-pegylated liposomal doxorubicin (NPLD) 60 mg/m2 + cyclophosphamide (C) 600 mg/m2 × 8 cycles Q21 days plus M 2000 mg/day (arm A) versus NPLD/C (arm B). The primary endpoint was progression-free survival (PFS). RESULTS: One-hundred-twenty-two patients were evaluable for PFS. At a median follow-up of 39.6 months (interquartile range [IQR] 24.6-50.7 months), 112 PFS events and 71 deaths have been registered. Median PFS was 9.4 months (95% CI 7.8-10.4) in arm A and 9.9 (95% CI 7.4-11.5) in arm B (P = 0.651). In patients with HOMA index < 2.5, median PFS was 10.4 months (95% CI 9.6-11.7) versus 8.5 (95% CI 5.8-9.7) in those with HOMA index ≥ 2.5 (P = 0.034). Grade 3/4 neutropenia was the most common toxicity, occurring in 54.4% of arm A patients and 72.3% of the arm B group (P = 0.019). M induced diarrhea (G2) was observed in 8.8% of patients in Arm A. The effect of M was similar in patients with HOMA index < 2.5 and ≥ 2.5, for PFS and OS. CONCLUSIONS: The MYME trial failed to provide evidence in support of an anticancer activity of M in combination with first line CT in MBC. A significantly shorter PFS was observed in insulin-resistant patients (HOMA ≥ 2.5). Noteworthy, M had a significant effect on CT induced severe neutropenia. Further development of M in combination with CT in the setting of MBC is not warranted.

Nine weeks versus 1 year adjuvant trastuzumab in combination with chemotherapy: final results of the phase III randomized Short-HER study‡.

Background: Chemotherapy plus 1-year trastuzumab is the standard adjuvant treatment of HER2-positive breast cancer. The efficacy of less extended trastuzumab exposure is under investigation. The short-HER study was aimed to assess the non-inferiority of 9 weeks versus 1 year of adjuvant trastuzumab combined with chemotherapy. Patients and methods: HER2-positive breast cancer patients with node-positive or, if node negative, with at least one risk factor (pT>2 cm, G3, lympho-vascular invasion, Ki-67 > 20%, age ≤35 years, or hormone receptor negativity) were randomly assigned to receive sequential anthracycline-taxane combinations plus 1-year trastuzumab (arm A, long) or plus 9 weeks trastuzumab (arm B, short). This study was designed as a non-inferiority trial with disease-free survival (DFS) as primary end point. A DFS hazard ratio (HR) <1.29 was chosen as the non-inferiority margin. Analyses according to the frequentist and Bayesian approach were planned. Secondary end points included 2-year failure rate and cardiac safety. Results: A total of 1254 patients from 82 centers were randomized (arm A, long: n = 627; arm B, short: n = 626). Five-year DFS is 88% in the long and 85% in the short arm. The HR is 1.13 (90% CI 0.89-1.42), with the upper limit of the CI crossing the non-inferiority margin. According to the Bayesian analysis, the probability that the short arm is non-inferior to the long one is 80%. The 5-year overall survival (OS) is 95.2% in the long and 95.0% in the short arm (HR 1.07, 90% CI 0.74-1.56). Cardiac events are significantly lower in the short arm (risk-ratio 0.33, 95% CI 0.22-0.50, P < 0.0001). Conclusions: This study failed to show the non-inferiority of a shorter trastuzumab administration. One-year trastuzumab remains the standard. However, a 9-week administration decreases the risk of severe cardiac toxicity and can be an option for patients with cardiac events during treatment and for those with a low risk of relapse. Trial Registration: EUDRACT number: 2007-004326-25; NCI ClinicalTrials.gov number: NCT00629278.

Genetic evidence for a novel familial Alzheimer's disease locus on chromosome 14.

Familial Alzheimer's disease (FAD) has been shown to be genetically heterogeneous, with a very small proportion of early onset pedigrees being associated with mutations in the amyloid precursor protein (APP) gene on chromosome 21, and some late onset pedigrees showing associations with markers on chromosome 19. We now provide evidence for a major early onset FAD locus on the long arm of chromosome 14 near the markers D14S43 and D14S53 (multipoint lod score z = 23.4) and suggest that the inheritance of FAD may be more complex than had initially been suspected.

Immunosuppressive activity of 13-cis-retinoic acid and prevention of experimental autoimmune encephalomyelitis in rats.

Some activities of retinoids on cellular and humoral immunity have been described, but the available data are conflicting or obtained at concentrations that are toxic in vivo. In this study, we demonstrate that 13-cis-retinoic acid (13-cRA), a retinoid well tolerated in human therapy, can suppress T cell-mediated immunity in rats. Treatment with pharmacological concentrations of 13-cRA prevented active as well as passive transfer experimental autoimmune encephalomyelitis (EAE) and suppressed lymphocyte responsiveness to T cell mitogens, suggesting that the drug activity included suppression of an effector T cell response. In addition, mitogen- and antigen-induced lymphocyte proliferation was inhibited in vitro in the presence of concentrations of 13-cRA equivalent to or less than those achieved in vivo, further suggesting that the prevention of EAE was due to a suppressive activity on T cell-mediated immunity. The immunosuppressive activity of 13-cRA included suppression of interleukin 2, whose production was inhibited in splenocytes. These data indicate that, in an in vivo mammalian system, 13-cRA exerts a suppressive activity on T cell-mediated immunity intensive enough to suppress an ongoing immune response, and that this effect can be achieved at nontoxic concentrations that may also be attained in human therapy.

Risk factors and genetic background for Alzheimer's disease.

Analytic epidemiology has contributed significantly to the generation and testing of hypotheses of the causes of AD. Several case-control studies have indicated risk factors related to the genetic hypothesis, such as: the presence of cases of either AD or Down's syndrome in other family members and the advanced age of the mother at subject's birth. In this respect recent molecular biology studies on DNA from patients affected by the familial form of AD, have demonstrated a genetic polymorphism localized on chromosome 21. On the same chromosome, the gene coding for beta-amyloid has been also recently localized. Immune, viral and toxic factors, thought to cause AD, have been also investigated in case-control studies, none of them has been found consistently associated with the disease, with the only exception of the head trauma. On the other hand most case-control studies have been carried out in younger cases and no large studies are yet available for late onset patients.

The etiology of Alzheimer's disease: an epidemiologic point of view.

Putative risk factors for Alzheimer's disease, other than familial aggregation, are: Down's syndrome among relatives, late maternal age, head injury, viral agents, toxic exposures, and immune factors. Current epidemiologic and genetic data are inconclusive, but indicate etiologic heterogeneity. We suggest to investigate separately: autosomal dominant, familial, and sporadic cases.

Interrater reliability in assessing functional systems and disability on the Kurtzke scale in multiple sclerosis.

Interexaminer agreement in the use of quantitative scales for the evaluation of neurological deficits is essential to the reliability of clinical data from cooperative studies on multiple sclerosis. In this study, four neurologists, arranged into six pairs, examined 24 patients with definite multiple sclerosis and assessed each functional system and disability on the Kurtzke scale. As expressed by the kappa index, interobserver agreement was rather low, ranging from 30% to 50%. Sensory and mental functions turned out to be the most variable. The kappa indexes reached values above 85%, when raters who differed by no more than one point were considered as agreeing. A point difference on the scale of, at most, two units seemed to be a reliable index of clinical change. Moreover, these results pointed to the necessity for a specific training program for raters and for periodic control of interobserver variability in multicenter surveys.

The cardiovascular outcome of patients with motor impairment and extensive leukoaraiosis.

BACKGROUND AND METHODS: The long-term outcome of patients with motor impairment and extensive leukoaraiosis on computed tomographic scan is unknown. We studied the incidence of stroke, myocardial infarction, and death in 31 such patients (cases) and in 68 neurologic patients without leukoaraiosis (controls). The patients in both groups had a routine neurologic and cardiovascular assessment and were followed up for 51.9 +/- 20.1 (mean +/- SD) months (cases) and 49.5 +/- 18.6 months (controls). RESULTS: The 6-year risk of cumulative stroke, as determined by life table analysis, was 49% among cases and 16% among controls (hazard ratio, 3.0; 95% confidence interval, 1.2 to 7.5). The risk of stroke or myocardial infarction was 69% vs 36% (hazard ratio, 2.9; 95% confidence interval, 1.4 to 6.2). The stroke risk remained significantly increased among cases after adjustment for age, sex, and any conventional vascular risk factor, while it was reduced (hazard ratio, 2.5; 95% confidence interval, 0.8 to 7.4) after adjustment for history of lacunar stroke was corrected for and was almost halved (hazard ratio, 1.6; 95% confidence interval, 0.5 to 4.6) after adjustment for the presence of lacunar infarction images on computed tomographic scan. CONCLUSIONS: Patients with motor impairment and extensive leukoaraiosis have a very poor cardiovascular outcome. Lacunar infarction might be the major determinant of the outcome in these patients.

Cognitive impairment in early-onset multiple sclerosis. Pattern, predictors, and impact on everyday life in a 4-year follow-up.

OBJECTIVES: To assess the evolution of cognitive dysfunction in early-onset multiple sclerosis, to identify clinical predictors of mental decline, and to determine its impact on a patient's everyday life. DESIGN: The cognitive performance of 50 patients with multiple sclerosis on a neuropsychological battery was compared with that of 70 control subjects initially and again after a 4-year interval. Clinical predictors of cognitive impairment and its effect on daily life were analyzed by stepwise linear regression. SETTING: The research clinic of a university department of neurology. PARTICIPANTS: A consecutive sample of 50 inpatients and outpatients with multiple sclerosis (mean disease duration, 1.58 years) and 70 demographically matched healthy control subjects selected from the patients' relatives and friends. MAIN OUTCOME MEASURES: Mean psychometric test scores of both groups at the initial and follow-up testing. Regression coefficients measuring the relationship between clinical parameters and cognitive capacity and between mental decline and performance of common tasks measured by the Environmental and the Incapacity Status scales. RESULTS: Multiple sclerosis-related deficits in verbal memory and abstract reasoning on initial testing remained more or less stable on the retest, at which time linguistic disturbances on the Set and Token tests also emerged. A patient's initial disability level predicted decreased performance on only four of 13 cognitive variables, and disease duration did so on only two. Extent of intellectual decline on initial testing, initial disability level, and progressive course were independent determinants of handicap in a patient's work and social activities. CONCLUSIONS: Cognitive and neurological deficits appear not to develop in parallel. Yet cognitive dysfunction proves to be a predictor of handicap in everyday life, even in patients in the incipient phase of multiple sclerosis.

Alzheimer skin fibroblasts show increased susceptibility to free radicals.

We have studied the response to toxic oxygen metabolites of fibroblasts derived from skin biopsies of 5 patients with familial (FAD) and 4 with sporadic (AD) Alzheimer's disease compared with those derived from 4 normal controls. Fibroblasts were damaged by the generation of oxygen metabolites during the enzymatic oxidation of acetaldehyde by 50 munits of xanthine-oxidase (Xo). To quantify cell damage we measured lactate dehydrogenase (LDH) activity in the culture medium and cell viability in fibroblast cultures. We found a significant increase in LDH activity in the FAD vs. controls and also in the AD vs. controls.

Choline acetyltransferase (ChAT) activity differs in right and left human temporal lobes.

Choline acetyltransferase (ChAT) activity was studied in different areas and in sequential sections of the cortical layers in the first temporal gyrus of left and right hemispheres of four human brains. The ChAT activity values obtained in all the samples from left hemisphere were significantly higher than in the right hemisphere. Furthermore, the study of ChAT activity in the cortical layers in Brodmann area 22 shows a greater left prevalence of enzymatic activity in cortical layers II and IV. The biochemical data seem to suggest a possible morphologic and/or functional difference between the two hemispheres.

Origin of the distinction between Alzheimer's disease and senile dementia: how history can clarify nosology.

Since the beginning of the century, psychiatrists and neurologists have been arguing about the identity of presenile (Alzheimer's disease) and senile dementia. History reveals that the distinction was originally based on anecdotal clinical observations and that competition among universities was one of the underlying determinants. The personal opinion of Kraepelin played a major role. Given his widespread reputation and authority, he generated a dogma difficult to change. Reports based on large clinicopathologic series have shown that the pathologies of presenile and senile dementia are not qualitatively different. Although the controversy continues, many have come to regard Alzheimer's disease and senile dementia as part of the same spectrum of disease, independent of the age of onset.

Long-term safety of azathioprine therapy in multiple sclerosis.

We compared the frequency of malignancies in 207 multiple sclerosis patients (mean age 35.75 years, SD 10.60) who took 2.0 mg/kg azathioprine daily (mean duration 4.16 years; SD 2.38) and in 247 nontreated patients (mean age 35.44 years; SD 11.94). Five malignancies were diagnosed in the azathioprine group compared with seven in the control group. The age-adjusted occurrence rate was 3.62/1,000 person-years (95% CI, 1.17 to 8.43) in the treated and 4.24/1,000 person-years (95% CI, 1.70 to 8.73) in the nontreated group; the age-adjusted relative risk of developing a tumor was 0.85.

Lack of efficacy of phosphatidylcholine in ataxias.

We gave phosphatidylcholine orally at a daily dosage of 9 grams for 4 years to 20 subjects with Friedreich's ataxia (FA) and 24 with olivopontocerebellar atrophy (OPCA). There was no clinical improvement during the follow-up compared with 12 ataxic patients (six FA and six OPCA) who did not receive any treatment. A 6-month trial at a double dose did not have any significant effect. This study indicates that phosphatidylcholine does not change the natural course of ataxias.

Dementia is a major predictor of death among the Italian elderly. ILSA Working Group. Italian Longitudinal Study on Aging.

BACKGROUND: Neurologic diseases are rarely listed on death certificates because death is more often attributed to cardiovascular and pneumonic events occurring during terminal stages. OBJECTIVE: To evaluate the effect of major age-associated neurologic and non-neurologic diseases on survival in a cohort of Italian elderly. METHODS: A population-based multicenter survey, carried out in eight Italian municipalities, with a sample of 5,632 individuals aged 65 to 84 years. The entire sample was screened for all the diseases under study, and all individuals were interviewed about risk factors. Those who screened positive underwent clinical assessments by specialists. Two years after the baseline survey, the study population was followed up to determine the vital status either directly from the individuals or from proxy respondents. A copy of the death certificate was obtained for each individual who had died. The risk of dying (mortality risk ratio [MRR]) was calculated using the Cox proportional hazards model in which we included all the diseases under study, age, gender, and years of education. RESULTS: At follow-up (mean duration 26.7 +/- 5.4 months) 444 individuals had died. The Cox proportional hazards model selected the following as significant predictors of death: age (for year of age MRR = 1.12; 95% confidence interval [CI], 1.08 to 1.15), male gender (MRR = 1.72; 95% CI, 1.27 to 2.34), institutionalization (MRR = 4.17; 95% CI, 2.20 to 7.94), dementia (MRR = 3.61; 95% CI, 2.55 to 5.11), neoplasm (MRR = 2.01; 95% CI, 1.20 to 3.38), heart failure (MRR = 1.87; 95% CI, 1.27 to 2.76), and diabetes (MRR = 1.62; 95% CI, 1.12 to 2.34). CONCLUSIONS: These data provide further evidence on the malignancy of dementia, which proved the major predictor of death in the elderly, with an MRR higher than neoplastic diseases and other severe age-associated conditions.

Prevalence of clinically diagnosed Alzheimer's disease and other dementing disorders: a door-to-door survey in Appignano, Macerata Province, Italy.

The purpose of this study was to investigate the prevalence of dementia in an Italian population using a door-to-door 2-phase design. As part of a social and health survey, we administered the Hodkinson abbreviated mental test to all persons over age 59 residing in the Commune of Appignano on January 1, 1987 (N = 778). We then investigated all subjects scoring 7 or less on the cognitive test following a standardized diagnostic protocol. We found 48 patients affected by dementia, yielding a crude prevalence ratio (cases per 100 population over age 59) of 6.2; prevalence ratios were 2.6 for Alzheimer's disease, 2.2 for multi-infarct dementia, 0.8 for mixed dementia, 0.4 for secondary dementia, and 0.3 for unspecified dementia. Age- and sex-specific prevalence ratios increased steeply with age and were consistently higher in women for Alzheimer's disease and in men for dementia of all types and multi-infarct dementia. Alzheimer's disease was slightly more frequent than multi-infarct dementia; however, the most common type of dementia varied across age groups. Most cases of Alzheimer's disease were sporadic and had a late age of onset. Comparison with other populations suggests that dementia of all types is as frequent in Appignano as elsewhere, and that Alzheimer's disease might be more frequent in rural than in urban populations.

Risk factors for clinically diagnosed Alzheimer's disease: a case-control study of an Italian population.

We conducted a case-control study of 116 patients with the clinical diagnosis of Alzheimer's disease (AD) in seven Italian centers. One hundred sixteen hospital controls and 97 population controls were matched by age, sex, and region of residence to the cases. A structured questionnaire was administered to the next-of-kin of cases and controls by trained interviewers to identify possible risk factors. Genetic, viral, toxic, immunologic, medical, surgical, and personality factors were investigated. Dementia among first- or second-degree relatives and advanced age of the mother at subject's birth (age over 40) were associated with AD. Head trauma was more frequent in cases than in either hospital or population controls, but the differences were not significant. Our data did not confirm the previously reported association with antecedent thyroid disease or family history of Down's syndrome.

Estrogen-replacement therapy and Alzheimer's disease in the Italian Longitudinal Study on Aging.

OBJECTIVE: To study the association of estrogen-replacement therapy and other estrogen-related variables with Alzheimer's disease in postmenopausal women. BACKGROUND: Postmenopausal estrogen use has been reported to lower the risk of Alzheimer's disease. DESIGN: A population-based, multicenter survey was carried out in eight Italian municipalities. The sample of 2,816 women, aged 65 to 84 years, was randomly selected from the population register of each municipality and stratified in 5-year age groups. All women were screened using the Mini-Mental State Examination and interviewed concerning risk factors. Those who screened positive underwent a clinical assessment. Dementia syndrome was diagnosed according to DSM-III-R criteria, and Alzheimer's disease was diagnosed according to NINCDS-ADRDA criteria for possible and probable Alzheimer's disease. RESULTS: The estimated prevalence of postmenopausal estrogen use adjusted to the 1991 Italian female population was 12.3%. The frequency of estrogen use was higher among nonpatients compared with Alzheimer's disease patients (odds ratio, 0.24; 95% confidence interval, 0.07 to 0.77). The inverse association between estrogen therapy and Alzheimer's disease remained significant after adjustment for age, education, age at menarche, age at menopause, smoking and alcohol habits, body weight at the age of 50 years, and number of children (odds ratio, 0.28; 95% confidence interval, 0.08 to 0.98). CONCLUSIONS: Our data from a population-based study support the hypothesis that estrogen-replacement therapy is associated with a reduced prevalence of Alzheimer's disease in postmenopausal women. Prospective clinical trials are required to enable women and their physicians to weigh risks and benefits of estrogen-replacement therapy for the prevention of dementia.