Gemcitabine and pemetrexed administered in rapid sequence as front-line chemotherapy for advanced non-small-cell lung cancer: a phase II clinical trial.

BACKGROUND: Previous studies of the gemcitabine-pemetrexed combination in patients with late-stage non-small-cell lung cancer (NSCLC) utilized a 90-min delay between gemcitabine and pemetrexed administration. This phase II study evaluated activity when these agents were administered in rapid succession. MATERIALS AND METHODS: Chemonaive patients with late-stage NSCLC received gemcitabine 1250 mg/m(2) on days 1 and 8, with pemetrexed 500 mg/m(2) immediately following day 8 gemcitabine every 21 days for six cycles, folic acid, B(12), and steroid prophylaxis. RESULTS: Fifty-four enrolled patients (53 treated) completed a median of four cycles. Median dose intensity was 84% (gemcitabine) and 83% (pemetrexed); 68% of patients required dose adjustments. Response was as follows: complete response, 0; partial response, 7 (13%); stable disease, 29 (54%); progressive disease, 9 (17%); and unknown/unavailable, 9 (17%). Median progression-free and overall survival was 4.6 and 12.4 months, respectively. Common grade 3 or 4 toxic effects were as follows: neutropenia (40%); fatigue and dyspnea (21% each); pneumonia (17%); febrile neutropenia and thrombocytopenia (11% each); and anemia (6%). CONCLUSIONS: The gemcitabine-pemetrexed combination is minimally active in late-stage NSCLC, with a high incidence of grade 3 or 4 toxic effects requiring frequent dose adjustments. A gemcitabine dose <1250 mg/m(2) warrants consideration for future trials exploring this doublet. Administering day 8 pemetrexed immediately after gemcitabine does not appear to negatively impact therapeutic index.

Advanced bronchioloalveolar carcinoma: a phase II trial of paclitaxel by 96-hour infusion (SWOG 9714): a Southwest Oncology Group study.

BACKGROUND: There are no published prospective trials of chemotherapy for advanced bronchioloalveolar carcinoma (BAC), a subtype of non-small-cell lung cancer for which there is no current standard therapy. This phase II study assesses the efficacy and toxicity of 96-h paclitaxel in chemotherapy-naive patients with advanced BAC. PATIENTS AND METHODS: Patients with histologically confirmed stage IIIB (with pleural effusion) or stage IV BAC were eligible. Treatment consisted of paclitaxel 35 mg/m2/24 h continuously infused over 96 h (days 1-4) every 21 days for up to six courses. RESULTS: A total of 58 eligible patients were enrolled. The objective response rate was 14% (all partial responses, 9% confirmed); 40% of patients demonstrated stable disease. The median progression-free and overall survivals were 5 and 12 months, respectively. Grade 3 or greater toxicities included neutropenia/granulocytopenia (43%), febrile neutropenia (12%), infection (22%), and stomatitis/pharyngitis (10%); there were five treatment-related deaths. CONCLUSIONS: S9714 represents the first prospective multi-institutional cooperative group trial focusing on treatment outcomes in BAC. Studies targeting this population are feasible, and while first-line paclitaxel administered as a prolonged infusion is active in this setting, toxicities limits the utility of this regimen. S9714 serves as a historical control for BAC patients against which future therapeutic approaches can be compared.

Cancer vaccines for the treatment and prevention of non small-cell lung cancer.

Cancer vaccines targeting non small-cell lung cancer (NSCLC) have been studied for decades; clinical trials, for the most part, have focused on the use of autologous and allogeneic whole-tumor cell vaccines. Recent advances in molecular biology and immunology, however, have allowed the identification of many tumor antigens involved in the generation of immunity to NSCLC. Although small-cell lung cancer (SCLC) is commonly thought of as an immunogenic tumor, it is now clear that NSCLC is also capable of eliciting an endogenous immune response in patients with the disease and, in fact, has a natural history that may make NSCLC more amenable to vaccine therapy as an adjuvant treatment strategy. This review will high-light the major components of the immune system that may potentially interact with tumor-associated proteins as well as outline the immunologic similarities and differences between SCLC and NSCLC. Tumor antigens that elicit immune responses in patients with NSCLC will be discussed. Finally, clinical trials of whole-tumor cell vaccines, both autologous and allogeneic, and tumor antigen-specific vaccines will also be discussed.

Epidemiological, clinical, and neuropathological study of apolipoprotein E genotype in Alzheimer's disease.

Our studies of the APOE genotype in AD confirm a strong association of the epsilon 4 allele with development of AD and a decreased risk associated with epsilon 2. From a clinical/neuropathological perspective, the major effects of APOE epsilon 4 are to lower the age of onset and to increase the amount of A beta deposit in the brain. Neither rate of progression nor number of neurofibrillary tangles were affected. We also carried out a longitudinal population-based assessment of the APOE genotype to determine the risk for developing cognitive impairment of someone in the general population based on APOE genotype. APOE epsilon 4 carried about 1.4-fold increased risk, and APOE epsilon 2 about 1.7-fold decreased risk. Thus, inheritance of APOE epsilon 4 is a major biological risk factor for AD, but it has limited utility as a prognostic indicator for development of dementia in an individual.

Clinical and pathological correlates of apolipoprotein E epsilon 4 in Alzheimer's disease.

Inheritance of the apolipoprotein E (apoE) epsilon 4 allele is associated with a high likelihood of developing Alzheimer's disease (AD). The pathophysiologic basis of this genetic influence is unknown. We reasoned that understanding the influence of apoE epsilon 4 on the clinical course and neuropathological features of AD may provide tests of potential mechanisms. We carried out a prospective longitudinal study to compare the age of onset, duration, and rate of progression of 359 AD patients to apoE genotype. Thirty-one of the individuals who died during the study were available for quantitative neuropathological evaluation. Statistically unbiased stereological counts of neurofibrillary tangles (NFTs) and A beta deposits were assessed in a high-order association cortex, the superior temporal sulcus. Analysis of clinical parameters compared with apoE genotype showed that the epsilon 4 allele is associated with an earlier age of onset but no change in rate of progression of dementia. Quantitative neuropathological assessment revealed that NFTs were strongly associated with clinical measures of dementia duration and severity but not with apoE genotype. A beta deposition, by contrast, was not related to clinical features but was elevated in association with apoE epsilon 4. These results indicate that apoE epsilon 4 is associated with selective clinical and neuropathological features of AD and support hypotheses that focus on an influence of apoE epsilon 4 on amyloid deposition.

Quantitative analysis of senile plaques in Alzheimer disease: observation of log-normal size distribution and molecular epidemiology of differences associated with apolipoprotein E genotype and trisomy 21 (Down syndrome).

The discovery that the epsilon 4 allele of the apolipoprotein E (apoE) gene is a putative risk factor for Alzheimer disease (AD) in the general population has highlighted the role of genetic influences in this extremely common and disabling illness. It has long been recognized that another genetic abnormality, trisomy 21 (Down syndrome), is associated with early and severe development of AD neuropathological lesions. It remains a challenge, however, to understand how these facts relate to the pathological changes in the brains of AD patients. We used computerized image analysis to examine the size distribution of one of the characteristic neuropathological lesions in AD, deposits of A beta peptide in senile plaques (SPs). Surprisingly, we find that a log-normal distribution fits the SP size distribution quite well, motivating a porous model of SP morphogenesis. We then analyzed SP size distribution curves in genotypically defined subgroups of AD patients. The data demonstrate that both apoE epsilon 4/AD and trisomy 21/AD lead to increased amyloid deposition, but by apparently different mechanisms. The size distribution curve is shifted toward larger plaques in trisomy 21/AD, probably reflecting increased A beta production. In apoE epsilon 4/AD, the size distribution is unchanged but the number of SP is increased compared to apoE epsilon 3, suggesting increased probability of SP initiation. These results demonstrate that subgroups of AD patients defined on the basis of molecular characteristics have quantitatively different neuropathological phenotypes.

Neuropathological changes in Down's syndrome hippocampal formation. Effect of age and apolipoprotein E genotype.

BACKGROUND: The neuropathological changes of Alzheimer's disease occur universally in individuals with Down's syndrome as they reach middle age and worsen with increasing age. Thus, evaluation of patients of various ages with Down's syndrome allows one to construct a life history of the development of neuropathological changes associated with Alzheimer's disease at various points in the disease process. METHODS: We have used semiquantitative scales and quantitative computerized image analysis techniques to analyze the characteristics of neurofibrillary tangle formation and A beta amyloid deposition in the hippocampal formation and inferior temporal gyrus in 36 individuals with Down's syndrome ranging in age from 4 to 73 years. RESULTS: Neurofibrillary tangles occur in a hierarchical distribution in a circumscribed set of neuronal fields, affecting the entorhinal cortex, area CA1/subiculum, then other hippocampal subfields. Although amyloid deposition occurs more evenly in a more widespread distribution, it also accumulates over the years 30 to 50. Surprisingly, examination of the patients available older than 50 years showed no trend toward continued increased deposition of amyloid. Within this group, however, individuals who had inherited the apolipoprotein E (Apo E) epsilon 4 genotype contained more than twice the amyloid burden of individuals who did not inherit the Apo E epsilon 4 genotype. COMMENT: This large series of cases confirms earlier observations that had suggested early vulnerability of entorhinal cortex and CA1/subiculum for neurofibrillary tangles and a more widespread but specific topography of A beta deposition. Moreover, it demonstrates quantitatively that the lesions increase to a certain level and then apparently reach a plateau. The level of amyloid deposition in Down's syndrome is higher than in sporadic Alzheimer's disease. Inheritance of the Apo E epsilon 4 genotype appears to be an additional (independent) risk factor for developing higher levels of amyloid accumulation.

Reduced apolipoprotein epsilon 4 allele frequency in the oldest old Alzheimer's patients and cognitively normal individuals.

Recent genetic studies show that the apolipoprotein E epsilon 4 allele (ApoE-epsilon 4) is a risk factor for Alzheimer's disease (AD). If ApoE-epsilon 4 individuals develop AD as they get older, we would expect a decrease in ApoE-epsilon 4 allele frequency with increasing age. We found a marked decline in ApoE-epsilon 4 allele frequency with advancing age in both AD and cognitively normal controls (p < 0.003), although in all age groups the ApoE-epsilon 4 allele was overrepresented (p < 0.0001). Nonetheless, a few cognitively normal nonagenarians were ApoE-epsilon 4 positive. Thus, our data support two new conclusions: (1) the ApoE-epsilon 4 associated risk for AD is age-dependent, probably due to censoring by the earlier development of AD in ApoE-epsilon 4 individuals, and (2) despite the ApoE-epsilon 4 associated risk for AD, it is possible to reach extreme old age with normal cognition.

Frequency of the apolipoprotein E epsilon 2 allele is diminished in sporadic Alzheimer disease.

Recent data have demonstrated genetic disequilibrium between inheritance of the apolipoprotein E (apoE) epsilon 4 allele and increased risk of Alzheimer disease. We tested the idea that inheritance of other allelic variations of apoE might also increase or decrease the risk of developing Alzheimer disease. We studied apoE genotypes in a large clinic based population of Alzheimer disease patients and age-compatible, tested control individuals. We confirm the genetic disequilibrium between apoE epsilon 4 and Alzheimer disease and now report that inheritance of apoE epsilon 2, another common variant of the apolipoprotein E gene, is negatively associated with risk of developing Alzheimer disease.

Effects of excitotoxic lesions of the septum and vertical limb nucleus of the diagonal band of Broca on conditional visual discrimination: relationship between performance and choline acetyltransferase activity in the cingulate cortex.

Four experiments examined the role of the cholinergic projections from the septum and vertical limb nucleus of the diagonal band of Broca (VDB) in acquisition and performance of a conditional visual discrimination. In experiments 1-3, excitotoxic lesions were made of the septum and VDB in rats using quisqualic acid, which resulted in significant reductions in ChAT activity in the hippocampus and cingulate cortex, but with no effects on cortical monoamines. In experiment 1, there were significant impairments in acquisition of the conditional discrimination, which did not result from motivational impairments. Experiment 2 repeated these results with lesion parameters, which produced variable effects on hippocampal and cingulate ChAT activity. Those rats with reductions in predominantly cingulate ChAT were most impaired in acquisition, but those with predominantly hippocampal reductions were relatively unimpaired. Experiment 3 showed that quisquate-induced lesions of the VDB, but not of the more caudal VDB and horizontal limb nucleus of the diagonal band, produced deficits, and a model incorporating the results of experiments 1-3 showed a highly significant correlation between errors of commission and cingulate cortical ChAT activity (r = -0.82, p < 0.001). Experiment 4 used the excitotoxin AMPA to lesion the VDB in rats pretrained on a modified form of the conditional discrimination task. In one subgroup of rats this excitotoxin produced profound and regionally selective reductions in ChAT activity. This subgroup was also impaired in relearning the discrimination to criterion. Again, there was a significant inverse relationship between the number of errors of commission made in relearning the discrimination and cingulate ChAT activity (r = -0.94, p < 0.001). These experiments suggest that excitotoxic lesions of the septum/VDB produce deficits in conditional discrimination learning and performance, and that the integrity of the projection to the cingulate cortex is more crucial than that to the hippocampus in this effect. Moreover, there is a close relationship between discrimination performance and cholinergic function in the cingulate cortex. In conjunction with other results, these data suggest that different aspects of cognition and memory are modulated by cholinergic activity in different cortical regions.

Conditioned release of neurotransmitters as measured by microdialysis.

The purpose of this research was to measure conditioned release of neurotransmitters in vivo and to study their role as neuromodulators in neural circuits controlling food intake. 1. Extracellular serotonin (5HT) was measured in the hypothalamus during (a) injection of the anorectic drug d-fenfluramine, (b) a normal meal and (c) during the taste of a flavor that previously had been paired with nausea. All these situations increased 5HT, suggesting it plays a role in suppression of food intake. 2. Extracellular dopamine (DA) in the nucleus accumbens (NAC) was released (a) during eating and (b) by a conditioned taste associated with intragastric infusion of carbohydrate, but (c) DA decreased in response to a taste that had been paired with nausea. Thus some DA projections to the NAC may modulate circuits that reinforce eating safe food. Drugs that release DA mimic, in part, this safe food effect.(ABSTRACT TRUNCATED AT 250 WORDS)

Hypothalamic serotonin in treatments for feeding disorders and depression as studied by brain microdialysis.

Microdialysis was used to measure changes in extracellular serotonin in the hypothalamus of rats while they engaged in feeding behavior or received drug treatments used to treat feeding disorders and affective disorders in humans. Hypothalamic serotonin increased significantly relative to controls in response to (1) intraperitoneal tryptophan after food deprivation, (2) the smell of food and eating a meal, (3) a conditioned taste aversion, (4) d-fenfluramine and fluoxetine, and (5) an amphetamine challenge test after chronic low doses of lithium. In some cases, increases correlated with nonspecific behavioral arousal were seen in the hippocampus. The results suggest that diet, drug, and behavioral therapies, alone or combined, can be used to preferentially modify hypothalamic serotonin in the control of behavioral, emotional, and endocrine problems.

Effects of conditioned taste aversion on extracellular serotonin in the lateral hypothalamus and hippocampus of freely moving rats.

This study used microdialysis to monitor extracellular levels of 5-HT and its metabolite, 5-hydroxyindole acetic acid (5-HIAA) in the lateral hypothalamus (LH) and hippocampus of freely moving rats that had developed a CTA to a 2.5 mM saccharin solution (CS) following its pairing with illness induced by lithium chloride (US). Results showed that oral infusion of the saccharin CS significantly enhanced extracellular LH 5-HT in animals that had developed a taste aversion compared with control groups, including unconditioned (CS-no US) and pseudoconditioned (no CS-US) subjects. As an anatomical control, the hippocampus was identified based on previous research suggesting that it is not integrally involved in CTA learning or retrieval and that 5-HT in this brain site does not directly mediate feeding behavior but is closely correlated with arousal. In contrast with the results obtained in the LH, hippocampal 5-HT was not preferentially elevated in subjects in the CTA group but rather was increased to the same extend in both CTA and control groups after saccharin infusion. Moreover, the increase in LH 5-HT for the CTA group was nearly twice that observed in the hippocampus for any group. Acute administration of LiCl elevated extracellular 5-HT to similar levels in both sites, well above the changes observed following conditioning. 5-HIAA was unaffected in either brain site by oral infusion of saccharin solution or injection of LiCl.(ABSTRACT TRUNCATED AT 250 WORDS)

Translating Alzheimer's disease educational videotapes into Spanish.

Limited information in Spanish concerning the availability of health services results in limited access to these services for the Hispanic population. This article describes a model for producing a health education videotape in Spanish. The planning strategy, script translation, and problems encountered with non-Spanish-speaking technical production staff are discussed.

Hypothermic cardiopulmonary bypass: a comparison between alpha and pH stat regulation in the dog.

The accepted normal pH of 7.40 may not be optimal at lower temperatures. This study evaluated the effect of maintaining pH in the accepted normal range at hypothermia (group 1, pH stat) or at normothermia (group 2, alpha stat) on organ blood flow and hemodynamics in dogs. The desired pH was achieved at all temperatures by adjusting pCO2. Hypothermia to 20 degrees C was induced by high flow bypass in both groups followed by 45 min of reduced flow before rewarming. In group 1 (n = 10), pH was 7.45 +/- 0.02 at 20 degrees C and in group 2 (n = 11) it was 7.64 +/- 0.01. A greater base excess developed by the end of the low flow period in pH stat animals (-9.4 +/- 1.1 vs -2.8 +/- 0.8, P less than .001) and resulted in continued acidosis after rewarming in the pH stat group compared to those in the alpha stat group (7.32 +/- 0.03 vs 7.38 +/- 0.01, P less than .02). Expressed as a percentage of baseline, regional blood flows after rewarming for group 1 were: brain 112 +/- 8%, renal cortex 48 +/- 8% (P less than 0.005, rewarm vs baseline), renal medulla 36 +/- 9% (P less than 0.005, rewarm vs baseline), epicardium 198 +/- 40% (P less than 0.05, rewarm vs baseline), endocardium 151 +/- 25%.(ABSTRACT TRUNCATED AT 250 WORDS)