Open-label randomized clinical trial of standard neoadjuvant chemotherapy with paclitaxel followed by FEC versus the combination of paclitaxel and everolimus followed by FEC in women with triple receptor-negative breast cancer†.

BACKGROUND: Everolimus synergistically enhances taxane-induced cytotoxicity in breast cancer cells in vitro and in vivo in addition to demonstrating a direct antiproliferative activity. We aim to determine pharmacodynamics changes and response of adding everolimus to standard neoadjuvant chemotherapy in triple-negative breast cancer (TNBC). PATIENTS AND METHODS: Phase II study in patients with primary TNBC randomized to T-FEC (paclitaxel 80 mg/m(2) i.v. weekly for 12 weeks, followed by 5-fluorouracil 500 mg/m(2), epirubicin 100 mg/m(2), and cyclophosphamide 500 mg/m(2) every 3 weeks for four cycles) versus TR-FEC (paclitaxel 80 mg/m(2) i.v. and everolimus 30 mg PO weekly for 12 weeks, followed by FEC). Tumor samples were collected to assess molecular changes in the PI3K/AKT/mTOR pathway, at baseline, 48 h, 12 weeks, and at surgery by reverse phase protein arrays (RPPA). Clinical end points included 12-week clinical response rate (12-week RR), pathological complete response (pCR), and toxicity. RESULTS: Sixty-two patients were registered, and 50 were randomized, 27 received T-FEC, and 23 received TR-FEC. Median age was 48 (range 31-75). There was downregulation of the mTOR pathway at 48 h in the TR-FEC arm. Twelve-week RR by ultrasound were 29.6% versus 47.8%, (P = 0.075), and pCR were 25.9% versus 30.4% (P = 0.76) for T-FEC and TR-FEC, respectively. mTOR downregulation at 48 h did not correlate with 12-week RR in the TR-FEC group (P = 0.58). Main NCI grade 3/4 toxicities included anemia, neutropenia, rash/desquamation, and vomiting in both arms. There was one case of grade 3 pneumonitis in the TR-FEC arm. No grade 3/4 stomatitis occurred. CONCLUSION: The addition of everolimus to paclitaxel was well tolerated. Everolimus downregulated mTOR signaling but downregulation of mTOR at 48 h did not correlate with 12-week RR in the TR-FEC group. CLINICAL TRIAL NUMBER: NCT00499603.

Addition of GM-CSF to trastuzumab stabilises disease in trastuzumab-resistant HER2+ metastatic breast cancer patients.

BACKGROUND: One of the proposed mechanisms of trastuzumab-induced regression of human epidermal growth factor receptor 2-positive (HER2+) tumours includes facilitation of antibody-dependent cell-mediated cytotoxicity (ADCC). Granulocyte-macrophage colony-stimulating factor (GM-CSF) mediates ADCC. We presented our pilot study of adding GM-CSF to trastuzumab in patients with trastuzumab-resistant HER2+ metastatic breast cancer. METHODS: Patients with HER2+ metastatic breast cancer that progressed after trastuzumab +/- chemotherapy were continued on trastuzumab 2 mg kg(-1) intravenous weekly and GM-CSF 250 µg m(-2) subcutaneous daily. Patients were assessed for response every 8 weeks. Treatment was continued until disease progression or intolerable toxicity. RESULTS: Seventeen patients were evaluable (median age 48 years, range 27-75 years). The median number of metastatic sites was 2 (range 1-3); the most common site was the liver (n=10). The median number of prior regimens for metastatic disease was 2 (range 1-5). No objective disease response was observed, but five patients (29%) had stable disease for a median duration of 15.8 (range 10-53.9) weeks. The most common adverse event was rash at the injection site. No grade 4 or irreversible adverse event was seen. CONCLUSION: The addition of GM-CSF to trastuzumab alone had a modest clinical benefit and acceptable safety profile in heavily pretreated patients with trastuzumab-resistant HER2+ metastatic breast cancer.

Cribriform degeneration (cri): a new recessive neurological mutation in the mouse.

The mutation cribriform degeneration (cri) occurred in the DBA/2J strain; it is in linkage group VIII, 31 recombination units from b. Homozygotes show severe vacuolar degeneration in white and gray matter of the spinal cord and brainstem, normocytic anemia at birth which decreases in severity with age, and abnormalities of electrolyte distribution.

Imatinib mesylate (Gleevec) in advanced breast cancer-expressing C-Kit or PDGFR-beta: clinical activity and biological correlations.

BACKGROUND: Novel molecular therapies for metastatic breast cancer (MBC) are necessary to improve the dismal prognosis of this condition. Imatinib mesylate (Gleevec) inhibits several protein tyrosine kinases, including platelet-derived growth factor receptor (PDGFR) and c-kit, which are preferentially expressed in tumor cells. We tested the activity of imatinib mesylate in MBC with overexpression of PDGFR or c-kit. Additionally, we sought to determine the biological correlates and immunomodulatory effects. PATIENTS AND METHODS: Thirteen patients were treated with Imatinib administered orally at 400 mg p.o. b.i.d. (800 mg/day), until disease progression. All patients demonstrated PDGFR-beta overexpression and none showed c-kit expression. RESULTS: No objective responses were observed among the 13 patients treated in an intention-to-treat analysis. All patients experienced disease progression, with a median time to progression of 1.2 months. Twelve patients have died, and the median overall survival was 7.7 months. No patient had a serious adverse event. Imatinib therapy had no effect on the plasma levels of the angiogenesis-related cytokines, vascular endothelial growth factor, PDGF, b-fibroblast growth factor, and E-selectin. Immune studies showed imatinib inhibits interferon-gamma production by TCR-activated CD4(+) T cells. CONCLUSION: Imatinib as a single agent has no clinical activity in PDGFR-overexpressing MBC and has potential immunosuppressive effects.

Hormone receptor status and pathologic response of HER2-positive breast cancer treated with neoadjuvant chemotherapy and trastuzumab.

BACKGROUND: The aim of this study was to compare the extent of pathologic response in patients with HER2-positive (HER2+) breast cancer treated with standard neoadjuvant chemotherapy, with or without trastuzumab (H), according to hormone receptor (HR) status. PATIENTS AND METHODS: We included 199 patients with HER2+ breast cancer from three successive cohorts of neo-adjuvant chemotherapy on the basis of paclitaxel (Taxol) (P) administered weekly (w) or three weekly (3-w), followed by 5-fluorouracil (F), doxorubicin (A) or epirubicin (E), and cyclophosphamide (C). Residual cancer burden (RCB) was determined from pathologic review of the primary tumor and lymph nodes and was classified as pathologic complete response (pCR) or minimal (RCB-I), moderate (RCB-II), or extensive (RCB-III) residual disease. RESULTS: In HR-positive (HR+) cancers, a higher rate of pathologic response (pCR/RCB-I) was observed with concurrent H + 3-wP/FEC (73%) than with 3-wP/FEC (34%, P = 0.002) or wP/FAC (47%; P = 0.02) chemotherapy alone. In HR-negative (HR-) cancers, there were no significant differences in the rate of pathologic response (pCR/RCB-I) from 3-wP/FAC (50%), wP/FAC (68%), or concurrent H + 3-wP/FEC (72%). CONCLUSIONS: Patients with HR+/HER2+ breast cancer obtained significant benefit from addition of trastuzumab to P/FEC chemotherapy; pathologic response rate was similar to that seen in HR-/HER2+ breast cancers.

Epidermis is the site of action of tabby (Ta) in the mouse.

The site of action of the sex-linked tabby (Ta) locus was analyzed by the technique of dermal-epidermal recombination grafting. Skin components from normal and tabby 14-day embryos were separated, recombined and grown 21 days in testes of histocompatible mice. Grafts of the combinations normal epidermis-normal dermis and normal epidermis-tabby dermis produced predominantly zig-zag hairs. Grafts of the combination tabby epidermis-normal dermis and tabby epidermis-tabby dermis produced hairs with a morphology similar to hairs found in tabby mice. We conclude from these results that the tabby locus acts within the epidermis, and has no effect on the dermis.

The T6 translocation in the mouse: its use in trisomy mapping, centromere localization, and cytological identification of linkage group 3.

The occurrence of hairless piebald mice trisomic for the chromosome segments of the T6M chromosome has shown that the LG III loci hr and s are not located on T6M. The T6 breakpoint in LG III is therefore in the position hr-s-T6. T6M must carry the gene Fkl, which is located on the far side of the T6 breakpoint from hr in LG III.-T6 reduces recombination in the hr-s region.-Trisomy for the chromosome segments of the T6M chromosome appears to severely reduce viability.-The gene hr has been shown to lie between the centromere and the T6 breakpoint. The order of loci in LG III is therefore: centromere-hr-s-T6.-Equations are given for the relation between the frequency of adjacent-2 segregation and the frequency of recovery of complementation zygotes for the case in which the translocation heterozygote can form either quadrivalent or univalent-trivalent configurations at meiosis.-Linkage Group III is carried on chromosome 14. LG VI is the other linkage group involved in T6, and is carried on chromosome 15.

Depilated (dep), a mutant gene that affects the coat of the mouse and acts in the epidermis.

Depilated is a recessive mutation on Chromosome 4 in the position b-1.93+/-0.51-dep-3.45+/-0.68.-Pt. It causes severe abnormalities of hair structure. The site of action of dep was investigated by the method of dermal-epidermal recombination. Skins from 14-day mutant and normal mouse embryos were separated into dermal and epidermal components, recombined, and grown in histocompatible mouse testes for 20 days. The recombinations made were +/+ epidermis with +/+ dermis, +/+ epidermis with dep/dep dermis, dep/dep epidermis with +/+ dermis and dep/dep epidermis with dep/dep dermis. Grafts that contained mutant epidermis as one of the components produced hairs that were similar to those found in depilated mice. There was no observable effect of the dermis on hair types produced in this experiment.

Monoclonal antibody therapy for solid tumors.

Monoclonal antibody therapy for solid tumors has many theoretical attractions and a long history. Until recently, with the approval and widespread use of rituximab (Rituxan) and trastuzumab (Herceptin), monoclonal antibody therapy for tumors had not had significant success. This article reviews basic theories behind antibody development and their clinical implementation as treatment for solid tumors. Medline was searched for articles over the past 15 years dealing with laboratory and clinical applications of antibody therapy for solid tumors. In addition, American Society of Clinical Oncology (ASCO) abstracts from the past 3 years were reviewed to complement the Medline search. This article focuses on treatment for common solid tumors, including breast, colon and lung cancers.

Influence of exposure period on in vivo hippocampal glutamate and GABA release in rats chronically exposed to lead.

Previous work has demonstrated that continual exposure to 0.2% lead (Pb) beginning at birth diminishes depolarization-induced hippocampal glutamate (GLU) and GABA release in vivo. The present study sought to extend these findings by examining Pb-induced changes as a function of exposure period. Rats were continually exposed to 0.2% Pb in the drinking water beginning at conception (Gestational-Life, GL) or two weeks after weaning (Wean-Life, WL), while exposure in a third group was begun at conception but terminated at weaning (Gestational-Wean, GW). Hippocampal transmitter release was induced in adult animals by perfusion of 150 mM K+ in the presence of Ca+2 (total release) through a microdialysis probe in one test session, followed by perfusion through a contralateral probe in the absence of Ca+2 (Ca+2-independent release) in the second session. Decreases in total GLU and GABA release were observed in the GL and WL groups compared to controls over the first 20-min after initiation of high K+, decrements that could be attributed to exposure-induced reductions in Ca+2-dependent release. The pattern of Pb-induced changes in the GL group is similar to that observed previously in a group continuously exposed from birth, indicating that gestational exposure did not further enhance the impact of Pb beginning at birth when exposure in both groups extends into adulthood. Similar responses were also found in the WL group, indicating that exposure during early development is not a requirement to induce changes in GLU and GABA release. Pb-induced decreases in response were also seen in the GW group: a decrease in Ca+2-dependent GLU release was observed, while decrements in total and Ca+2-dependent GABA release were similar to those in the GL and WL groups. Thus, exposure limited to early development is also sufficient to produce deficits in evoked transmitter release. In addition, the exposure-induced decreases in GLU responses correspond to Pb-induced impairments in long-term potentiation (LTP) observed in similarly exposed groups (Gilbert et al., 1999), providing further evidence that Pb effects on GLU release are a critical factor in the alterations found in LTP.

The role of transportation in the persuasiveness of public narratives.

Transportation was proposed as a mechanism whereby narratives can affect beliefs. Defined as absorption into a story, transportation entails imagery, affect, and attentional focus. A transportation scale was developed and validated. Experiment 1 (N = 97) demonstrated that extent of transportation augmented story-consistent beliefs and favorable evaluations of protagonists. Experiment 2 (N = 69) showed that highly transported readers found fewer false notes in a story than less-transported readers. Experiments 3 (N = 274) and 4 (N = 258) again replicated the effects of transportation on beliefs and evaluations; in the latter study, transportation was directly manipulated by using processing instructions. Reduced transportation led to reduced story-consistent beliefs and evaluations. The studies also showed that transportation and corresponding beliefs were generally unaffected by labeling a story as fact or as fiction.

The psychology of the unthinkable: taboo trade-offs, forbidden base rates, and heretical counterfactuals.

Five studies explored cognitive, affective, and behavioral responses to proscribed forms of social cognition. Experiments 1 and 2 revealed that people responded to taboo trade-offs that monetized sacred values with moral outrage and cleansing. Experiments 3 and 4 revealed that racial egalitarians were least likely to use, and angriest at those who did use, race-tainted base rates and that egalitarians who inadvertently used such base rates tried to reaffirm their fair-mindedness. Experiment 5 revealed that Christian fundamentalists were most likely to reject heretical counterfactuals that applied everyday causal schemata to Biblical narratives and to engage in moral cleansing after merely contemplating such possibilities. Although the results fit the sacred-value-protection model (SVPM) better than rival formulations, the SVPM must draw on cross-cultural taxonomies of relational schemata to specify normative boundaries on thought.

Preoperative evaluation and preparation of the pediatric patient.

A successful anesthetic is built on the foundation of the preoperative evaluation and preparation, six features of which will be discussed: (1) content and timing of the anesthesiologist's preoperative evaluation; (2) value of preoperative laboratory testing; (3) psychological effects of hospitalization and surgery; (4) approaches to psychological preparation; (5) pharmacological premedication (except for drugs designed to sedate or reduce anxiety, reviewed in the article by Bennie and McNiece); and (6) preoperative feeding schedules.

Fictional narratives change beliefs: replications of Prentice, Gerrig, and Bailis (1997) with mixed corroboration.

We report three exact replications of experiments aimed at iluminating how fictional narratives influence beliefs (Prentice, Gerrig, & Bailis, 1997). Students read fictional stories that contained weak, unsupported assertions and which took place either at their home school or at an away school. Prentice et al. found that students were influenced to accept the assertions, even those blatantly false, but that this effect on beliefs was limited to the away-school setting. We questioned the limiting of the narrative effect to remote settings. Our studies consistently reproduced the first finding, heightened acceptance of statements occurring in the conversations of narrative protagonists, but we failed to reproduce the moderating effect of school location. In an attempt to understand these discrepancies, we measured likely moderating factors such as readers' need for cognition and their extent of scrutiny of the narratives.

Rat hippocampal NMDA receptor binding as a function of chronic lead exposure level.

Chronic developmental lead (Pb) exposure is known to impair cognitive ability in children and young animals. These findings have led to research examining exposure effects on long-term potentiation (LTP), a model of synaptic plasticity, and on NMDA receptor function. This study determined the changes occurring in hippocampal 3H-MK-801 binding as a function of exposure level for comparison to changes in LTP previously reported from this laboratory. Dams were exposed to 0.1%, 0.2%, 0.5% and 1.0% Pb in the drinking water beginning at parturition, and male offspring were weaned to the same solutions as their dams and maintained on these regimens until assessment as adults. A crude membrane fraction was prepared from hippocampal tissue, and Scatchard analysis conducted in the presence of saturating concentrations of glutamate and glycine. NMDA receptor density was elevated as a result of Pb exposure with significant increases in the 0.2% (38%) and 0.5% (30%) groups compared to control group values. No changes were observed in the 0.1% and 1.0% animals, thus constituting a biphasic dose-effect relationship. These findings are an approximate reflection of analogous relationships reported for hippocampal LTP and glutamate release, suggesting that the diminished glutamate release is one cause of the receptor up-regulation. However, since increases in receptor number were uncovered, it is unlikely that changes in NMDA receptor density constitute a primary mechanism whereby Pb impairs hippocampal LTP.

Use of Project MOHAVE perfluorocarbon tracer data to evaluate source and receptor models.

Project MOHAVE was a major monitoring, modeling, and data analysis study whose objectives included the estimation of the contributions of the Mohave Power Project (MPP) and other sources to visibility impairment in the southwestern United States, in particular at Grand Canyon National Park. A major element of Project MOHAVE was the release of perfluorocarbon tracers at MPP and other locations during 50-day summer and 30-day winter intensive study periods. Tracer data (from about 30 locations) were sequestered until several source and receptor models were used to predict tracer concentrations. None of the models was successful in predicting the tracer concentrations; squared correlation coefficients between predicted and measured tracer were all less than 0.2, and most were less than 0.1.

Evaluation of wind fields used in Grand Canyon Visibility Transport Commission analyses.

The Grand Canyon Visibility Transport Commission (GCVTC) was established by the U.S. Congress to assess the potential impacts of projected growth on atmospheric visibility at Grand Canyon National Park and to make recommendations to the U.S. Environmental Protection Agency on what measures could be taken to avoid such adverse impacts. A critical input to the assessment tool used by the commission was three-dimensional model-derived wind fields used to transport the emissions. This paper describes the evaluation of the wind fields used at various stages in the assessment. Wind fields evaluated included those obtained from the Colorado State University Regional Atmospheric Modeling System (RAMS), the National Meteorological Center's Nested Grid Model (NGM), and the National Oceanic and Atmospheric Administration's Atmospheric Transport and Dispersion (ATAD) trajectory model. The model-derived wind fields were evaluated at multiple vertical levels at several locations in the southwestern United States by determining differences between model predicted winds and winds that were measured using radiosonde and radar wind profiler data. Model-derived winds were also evaluated by determining the percent of time that they were within acceptable differences from measured winds. All models had difficulties, generally meeting the acceptable criteria for less than 50% of the predictions. The RAMS model had a persistent bias toward southwesterly winds at the expense of other directions, especially failing to represent channeling by north-south mountain ranges in the lower levels. The NGM model exhibited a substantial bias in the summer months by extending northwesterly winds in the eastern Pacific Ocean well inland, in contrast to the observed southwesterlies at inland locations. The simpler ATAD trajectory model performed somewhat better than the other models, probably because of its use of more upper air sites. The results of the evaluation indicated that these wind fields could not be used to reliably predict source-receptor impacts on a particular day; thus, seasonally averaged impacts were used in the GCVTC assessment.

Middle- and Neighborhood-Scale Variations of PM10 Source Contributions in Las Vegas, Nevada.

The Las Vegas Valley PM10 Study was conducted during 1995 to determine the contributions to PM10 aerosol from fugitive dust, motor vehicle exhaust, residential wood combustion, and secondary aerosol sources. Twenty-four-hr PM10 samples were collected at two neighborhood-scale sites every sixth day for 13 months. Five week-long intensive studies were conducted over a middle-scale sub-region at 29 locations that contained many construction projects emitting fugitive dust. The study found that the zone of influence around individual emitters was less than 1 km. Most of the sampling sites in residential and commercial areas yielded equivalent PM10 concentrations in the neighborhood region, even though they were more distant from each other than they were from the nearby construction sources. Based on chemical mass balance (CMB) receptor modeling, fugitive dust accounted for 80-90% of the PM10, and motor vehicle exhaust accounted for 3-9% of the PM10 in the Las Vegas Valley.