Publications by authors named "Dan H Moore"

103 Publications

A Ternary Mixture of Common Chemicals Perturbs Benign Human Breast Epithelial Cells More Than the Same Chemicals Do Individually.

Toxicol Sci 2018 09;165(1):131-144

California Pacific Medical Center Research Institute.

As a continuous source of hormonal stimulation, environmentally ubiquitous estrogenic chemicals, ie, xenoestrogens (XEs), are a potential risk factor for breast carcinogenesis. Given their wide distribution in the environment and the fact that bisphenol-A (BPA), methylparaben (MP), and perfluorooctanoic acid (PFOA) are uniformly detected in unselected body fluid samples, it must be assumed that humans are simultaneously exposed to these chemicals almost daily. We studied the effects of a ternary mixture of BPA, MP, and PFOA on benign breast epithelial cells at the range of concentrations observed for single chemicals in human samples. Measurements of exposure impact relevant to the breast were based on endpoints associated with "hallmarks" of cancer and "key characteristics" of carcinogens. These included modulation of total estrogen receptor (ER)α, phosphorylated ERα (pERα), total ERβ, S-phase induction, and apoptotic evasion. Data from live cell measurements were fit to a log-linear dose-response model. Concentration-dependent reduction of ERβ and apoptosis evasion was observed concurrently with the induction of ERα, pERα, and S-phase fraction, and an increased rate of cell proliferation. Beyond additive effects predicted by the sum of individual test XEs, mixture treatment demonstrated synergism for the ERβ and apoptosis suppression phenotypes (p > .001). Nonmalignant breast cells were more sensitive than commonly used breast cancer lines to XE treatment in 3 of 5 endpoints. All observations were validated with cells isolated from the normal breast tissue of 14 individuals. At relatively low concentrations, a chemical mixture has striking effects on normal cell function that are missed by evaluation of single components.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/toxsci/kfy126DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6135635PMC
September 2018

Gamma aminobutyric acid (GABA) modulators for amyotrophic lateral sclerosis/motor neuron disease.

Cochrane Database Syst Rev 2017 01 9;1:CD006049. Epub 2017 Jan 9.

Research Institute, California Pacific Medical Center, 475 Brannan St Suite 220, San Francisco, CA, USA, 94107.

Background: Imbalance of gamma aminobutyric acid (GABA) and related modulators has been implicated as an important factor in the pathogenesis of amyotrophic lateral sclerosis (ALS), which is also known as motor neuron disease (MND). In this context, the role and mechanism of action of gabapentin and baclofen have been extensively investigated, although with conflicting results. This is the first systematic review to assess clinical trials of GABA modulators for the treatment of ALS.

Objectives: To examine the efficacy of gabapentin, baclofen, or other GABA modulators in delaying the progression of ALS, and to evaluate adverse effects of these interventions

Search Methods: On 16 August 2016, we searched the Cochrane Neuromuscular Specialised Register, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, CINAHL Plus, AMED, and LILACS. In addition, we checked the bibliographies of the trials found in order to identify any other trials, and contacted trial authors to identify relevant unpublished results or additional clinical trials. On 30 August 2016, we searched two clinical trials registries.

Selection Criteria: Types of studies: double-blind randomized controlled trials (RCTs) or quasi-RCTsTypes of participants: adults with a diagnosis of probable or definite ALSTypes of interventions: gabapentin, baclofen, or other GABA modulators compared with placebo, no treatment, or each otherPrimary outcome: survival at one year from study enrollmentSecondary outcomes: individual rate of decline of maximum voluntary isometric contraction (MVIC), expressed as arm megascore; rate of decline of per cent predicted forced vital capacity (FVC); rate of decline of ALS Functional Rating Scale (ALSFRS); health-related quality of life; survival evaluated by pooling hazards; and adverse events DATA COLLECTION AND ANALYSIS: At least two review authors independently checked titles and abstracts identified by the searches. The review authors obtained and independently analyzed original individual participant data from each included study; additional review authors and the Cochrane Neuromuscular Managing Editor checked the outcome data. Two authors independently assessed the risk of bias in included studies.

Data Collection And Analysis: At least two review authors independently checked titles and abstracts identified by the searches. The review authors obtained and independently analyzed original individual participant data from each included study; additional review authors and the Cochrane Neuromuscular Managing Editor checked the outcome data. Two authors independently assessed the risk of bias in included studies.

Main Results: We identified two double-blind RCTs of gabapentin treatment in ALS for inclusion in this review. We found no eligible RCTs of baclofen or other GABA modulators. The selected studies were phase II and phase III trials, which lasted six and nine months, respectively. They were highly comparable because both were comparisons of oral gabapentin and placebo, performed by the same investigators. The trials enrolled 355 participants with ALS: 80 in the gabapentin group and 72 in the placebo group in the first (phase II) trial and 101 in the gabapentin group and 102 in the placebo group in the second (phase III) trial. Neither trial was long enough to report survival at one year, which was our primary outcome. We found little or no difference in estimated one-year survival between the treated group and the placebo group (78% versus 77%, P = 0.63 by log-rank test; high-quality evidence). We also found little or no difference in the rate of decline of MVIC expressed as arm megascore, or rate of FVC decline (high-quality evidence). One trial investigated monthly decline in the ALSFRS and quality of life measured using the 12-Item Short Form Survey (SF-12) and found little or no difference between groups (moderate-quality evidence). The trials reported similar adverse events. Complaints that were clearly elevated in those taking gabapentin, based on analyses of the combined data, were light-headedness, drowsiness, and limb swelling (high-quality evidence). Fatigue and falls occurred more frequently with gabapentin than with placebo in one trial, but when we combined the data for fatigue from both trials, there was no clear difference between the groups. We assessed the overall risk of bias in the included trials as low.

Authors' Conclusions: According to high-quality evidence, gabapentin is not effective in treating ALS. It does not extend survival, slow the rate of decline of muscle strength, respiratory function and, based on moderate-quality evidence, probably does not improve quality of life or slow monthly decline in the ALSFRS. Other GABA modulators have not been studied in randomized trials.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/14651858.CD006049.pub2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6953368PMC
January 2017

Phase I clinical trial of safety of L-serine for ALS patients.

Amyotroph Lateral Scler Frontotemporal Degener 2017 02 2;18(1-2):107-111. Epub 2016 Sep 2.

d Brain Chemistry Labs, Institute for Ethnomedicine , Jackson , Wyoming , USA.

We performed a randomized, double-blind phase I clinical trial for six months on the effects of oral L-serine in patients with ALS. The protocol called for enrollment of patients with a diagnosis of probable or definite ALS, age 18-85 years, disease duration of less than three years and forced vital capacity (FVC) ≥ 60%. Patients were randomly assigned to four different oral twice-daily dose regimens (0.5, 2.5, 7.5, or 15 g/dose). Blood, urine and CSF samples, ALS Functional Rating Scale-Revised (ALSFRS-R) scores and forced vital capacity (FVC) were obtained throughout the trial. Disease progression was compared with matched historical placebo controls from five previous ALS therapeutic trials. Of 20 patients enrolled, one withdrew before receiving study drug and two withdrew with gastro-intestinal problems. Three patients died during the trial. L-serine was generally well tolerated by the patients and L-serine did not appear to accelerate functional decline of patients as measured by slope of their ALSFRS-R scores. Based on this small study, L-serine appears to be generally safe for patients with ALS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/21678421.2016.1221971DOI Listing
February 2017

Exposure to the polyester PET precursor--terephthalic acid induces and perpetuates DNA damage-harboring non-malignant human breast cells.

Carcinogenesis 2015 Jan 19;36(1):168-76. Epub 2014 Nov 19.

California Pacific Medical Center Research Institute, 475 Brannan Street, San Francisco, CA 94107, USA

Identification of early perturbations induced in cells from non-cancerous breast tissue is critical for understanding possible breast cancer risk from chemical exposure. We have demonstrated previously that exposure to the ubiquitous xenoestrogens, bisphenol A (BPA) and methyl paraben, promotes the hallmarks of cancer in non-malignant human high-risk donor breast epithelial cells (HRBECs) isolated from several donors. Here we show that terephthalic acid (TPA), a major chemical precursor of polyethylene terephthalate (PET) containers used for the storage of food and beverages, increased the ERα: ERβ ratio in multiple HRBEC samples, suggesting an estrogenic effect. Although, like BPA and methyl paraben, TPA also promoted resistance to tamoxifen-induced apoptosis, unlike these chemicals instead of inducing an increased S-phase fraction, TPA treatment arrested cell proliferation. DNA-PK, ATM and members of the MRN complex, known to be involved in DNA damage sensor and effector proteins, were elevated indicating induction of DNA strand breaks. Early DNA damage checkpoint response, mediated through p53/p21, led to G1 arrest in TPA-exposed cells. Removal of TPA from the growth medium resulted in the rapid induction of BCL2, increasing the ratio of anti-: pro-apoptotic proteins, together with overexpression of Cyclin A/CDK2 proteins. Consequently, despite elevated p53(pSer15) and H2AX(pSer139), indicating sustained DNA damage, TPA exposed cells resumed robust growth rates seen prior to TPA exposure. The propensity for the perpetuation of DNA aberrations that activate DNA damage pathways in non-malignant breast cells justifies careful consideration of human exposure to TPA, particularly at vulnerable life stages.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/carcin/bgu234DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4291052PMC
January 2015

A post hoc analysis of subgroup outcomes and creatinine in the phase III clinical trial (EMPOWER) of dexpramipexole in ALS.

Amyotroph Lateral Scler Frontotemporal Degener 2014 Sep 15;15(5-6):406-13. Epub 2014 Aug 15.

Knopp Biosciences LLC , Pittsburgh, Pennsylvania , USA.

Our objective was to compare the phase II and phase III (EMPOWER) studies of dexpramipexole in ALS and evaluate potential EMPOWER responder subgroups and biomarkers based on significant inter-study population differences. In a post hoc analysis, we compared the baseline population characteristics of both dexpramipexole studies and analyzed EMPOWER efficacy outcomes and laboratory measures in subgroups defined by significant inter-study differences. Results showed that, compared with phase II, the proportion of El Escorial criteria (EEC) definite participants decreased (p = 0.005), riluzole use increased (p = 0.002), and mean symptom duration increased (p = 0.037) significantly in EMPOWER. Baseline creatinine (p < 0.001) and on-study creatinine change (p < 0.001) correlated significantly with ALSFRS-R in EMPOWER. In the EMPOWER subgroup defined by EEC-definite ALS, riluzole use, and < median symptom duration (15.3 months), dexpramipexole-treated participants had reduced ALSFRS-R slope decline (p = 0.015), decreased mortality (p = 0.011), and reduced creatinine loss (p = 0.003). In conclusion, significant differences existed between the phase II and EMPOWER study populations in ALS clinical trials of dexpramipexole. In a post hoc analysis of EMPOWER subgroups defined by these differences, potential clinical benefits of dexpramipexole were identified in the subgroup of riluzole-treated, short-symptom duration, EEC-definite ALS participants. Creatinine loss correlated with disease progression and was reduced in dexpramipexole-treated participants, suggesting it as a candidate biomarker.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3109/21678421.2014.943672DOI Listing
September 2014

Long-term outcomes among African-American and white women with breast cancer: what is the impact of comorbidity?

J Geriatr Oncol 2014 Jul 5;5(3):266-75. Epub 2014 Mar 5.

Department of Epidemiology and Biostatistics, University of California, San Francisco, CA, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA. Electronic address:

Objectives: We examined the association between comorbidity and long-term mortality from breast cancer and other causes among African-American and white women with breast cancer.

Methods: A total of 170 African-American and 829 white women aged 40-84years were followed for up to 28years with median follow-up of 11.3years in the Health and Functioning in Women (HFW) study. The impact of the Charlson Comorbidity Score (CCS) in the first few months following breast cancer diagnosis on the risk of mortality from breast cancer and other causes was examined using extended Cox models.

Results: Median follow-up was significantly shorter for African-American women than their white counterparts (median 8.5years vs. 12.3years). Compared to white women, African-American women had significantly fewer years of education, greater body mass index, were more likely to have functional limitations and later stage at breast cancer diagnosis, and fewer had adequate financial resources (all P<0.05). Proportionately more African-American women died of breast cancer than white women (37.1% vs. 31.4%, P=0.15). A positive and statistically significant time-varying effect of the Charlson Comorbidity Score (CCS) on other-cause mortality persisted throughout the first 5years of follow-up (P<0.001) but not for its remainder.

Conclusions: Higher CCS was associated with increased risk of other-cause mortality, but not breast cancer specific mortality; the association did not differ among African-American and white women.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jgo.2014.02.003DOI Listing
July 2014

Aberrant regulation of the BST2 (Tetherin) promoter enhances cell proliferation and apoptosis evasion in high grade breast cancer cells.

PLoS One 2013 20;8(6):e67191. Epub 2013 Jun 20.

California Pacific Medical Center Research Institute, San Francisco, California, USA.

Normal cellular phenotypes that serve an oncogenic function during tumorigenesis are potential candidates for cancer targeting drugs. Within a subset of invasive primary breast carcinoma, we observed relatively abundant expression of Tetherin, a cell surface protein encoded by the Bone Marrow Stromal Cell Antigen (BST2) known to play an inhibitory role in viral release from infected immune cells of the host. Using breast cancer cell lines derived from low and intermediate histopathologic grade invasive primary tumors that maintain growth-suppressive TGFβ signaling, we demonstrate that BST2 is negatively regulated by the TGFβ axis in epithelial cells. Binding of the transcription factor AP2 to the BST2 promoter was attenuated by inhibition of the TGFβ pathway thereby increasing BST2 expression in tumor cells. In contrast, inherent TGFβ resistance characteristic of high grade breast tumors is a key factor underlying compromised BST2 regulation, and consequently its constitutive overexpression relative to non-malignant breast epithelium, and to most low and intermediate grade cancer cells. In both 2-dimensional and 3-dimensional growth conditions, BST2-silenced tumor cells displayed an enhancement in tamoxifen or staurosporine-induced apoptotic cell death together with a reduction in the S-phase fraction compared to BST2 overexpressing counterparts. In a subset of breast cancer patients treated with pro apoptotic hormonal therapy, BST2 expression correlated with a trend for poor clinical outcome, further supporting its role in conferring an anti apoptotic phenotype. Similar to the effects of gene manipulation, declining levels of endogenous BST2 induced by the phytoalexin - resveratrol, restored apoptotic function, and curbed cell proliferation. We provide evidence for a direct approach that diminishes aberrant BST2 expression in cancer cells as an early targeting strategy to assist in surmounting resistance to pro apoptotic therapies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0067191PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3688682PMC
February 2014

Total skin-sparing mastectomy: a systematic review of oncologic outcomes and postoperative complications.

Ann Plast Surg 2013 Apr;70(4):435-7

From the *Division of Plastic and Reconstructive Surgery, Department of Surgery, †Department of Epidemiology and Biostatistics, and ‡Division of Breast Surgery, Department of Surgery, University of California, San Francisco, San Francisco, CA.

Introduction: Despite the potential aesthetic and psychological benefits of total skin-sparing mastectomy (TSSM) with preservation of the nipple-areolar complex (NAC) skin, there is still reluctance to use the technique due to concern for increased recurrence rates or higher postoperative complication rates. The rapidly expanding literature describing outcomes after TSSM enables a comprehensive review of recurrence rates and surgical complications.

Methods: Studies describing nipple-sparing or TSSM were identified from the MEDLINE and Cochrane databases. Studies that reported oncologic outcomes and/or data on postoperative complications were included.

Results: Twenty-seven studies were identified that met inclusion criteria, representing a total of 3331 mastectomies. Review of oncologic outcomes in the 10 studies (representing 1148 mastectomies) with documented mean/median follow-up of 2 years demonstrated an overall local-regional recurrence rate of 2.8%. Ischemic complications involving the NAC were reported in 24 studies (representing 3091 mastectomies), with 9.1% of cases reported to have some degree of NAC necrosis and 2.0% of cases complicated by complete necrosis leading to NAC loss. Sixteen studies (representing 2213 mastectomies) reported rates of skin flap necrosis, which occurred in 9.5% of cases. Eighty-one percent of the total cases reviewed involved expander-implant reconstruction; in the 16 studies (representing 2343 reconstructions) that reported outcomes after expander-implant reconstruction, overall expander-implant loss was 3.4%.

Conclusions: There is now a significant body of literature demonstrating low rates of early local-regional recurrence and postoperative complications after TSSM. These data support the use of TSSM techniques, which improve psychological and aesthetic outcomes without compromising therapeutic efficacy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/SAP.0b013e31827e5333DOI Listing
April 2013

Response.

Radiology 2013 Feb;266(2):685-6

View Article and Find Full Text PDF

Download full-text PDF

Source
February 2013

The Combined Assessment of Function and Survival (CAFS): a new endpoint for ALS clinical trials.

Amyotroph Lateral Scler Frontotemporal Degener 2013 Apr 17;14(3):162-8. Epub 2013 Jan 17.

Massachusetts General Hospital, Neurological Clinical Research Institute, Boston, Massachusetts 02114, USA.

Our objective was to describe a new endpoint for amyotrophic lateral sclerosis (ALS), the Combined Assessment of Function and Survival (CAFS). CAFS ranks patients' clinical outcomes based on survival time and change in the ALS Functional Rating Scale-Revised (ALSFRS-R) score. Each patient's outcome is compared to every other patient's outcome, assigned a score, and the summed scores are ranked. The mean rank score for each treatment group can then be calculated. A higher mean CAFS score indicates a better group outcome. Historically, ALS clinical trials have assessed survival and function as independent endpoints. Combined endpoints have been used in other diseases to decrease the confounding effect of mortality on analysis of functional outcomes. We explored the application of a similar approach in ALS, the CAFS endpoint, which was used as a pre-specified secondary analysis in a phase II study of dexpramipexole. Those results and some hypothetical examples based on modeling exercises are presented here. CAFS is the primary endpoint of a dexpramipexole phase III study in ALS. In conclusion, the CAFS is a robust statistical tool for ALS clinical trials and appropriately accounts for and weights mortality in the analysis of function.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3109/21678421.2012.762930DOI Listing
April 2013

Do patients use decision and communication aids as prompted when meeting with breast cancer specialists?

Health Expect 2015 Jun 7;18(3):379-91. Epub 2013 Jan 7.

Institute for Health Policy Studies, University of California, San Francisco, NC, USA.

Background: Our breast cancer clinic promotes patient use of decision and communication aids (DAs/CAs) through two mechanisms: coaching and prompting. From January through September 2010, we provided services to 462 of 1106 new visitors (42%). Of those 462 visitors, 267 (58%) received coaching. For the remainder (195 or 42%), the best we could do was prompt them to self-administer the DA and CAs.

Objective: We wanted to learn whether patients prompted to use DAs/CAs did so.

Methods: We surveyed prompted patients after their visits. We asked how much of each DA they reviewed, whether they listed questions, made notes and audio-recorded their consultations. We tallied frequencies and explored associations using logistic regression.

Results: Of the 195 prompted patients, 82 responded to surveys (42%). Nearly all (66/73 or 90%) reported reviewing some or all of the booklets and 52/73 (71%) reported viewing some or all of the DVDs. While 63/78 (81%) responded that they wrote a question list, only 14/61 (23%) said they showed it to their doctor. Two-thirds (51/77 or 66%) said someone took notes, but only 16/79 (20%) reported making audio recordings.

Discussion: More patients reported following prompts to use DAs than CAs. Few reported showing question lists to physicians or recording their visits. Our exploratory analyses surfaced associations between using CAs and race/ethnicity or education that merit further investigation.

Conclusion: Prompting patients assures better use of decision than communication aids. Clinicians may need to take a more active role to ensure patients receive adequate notes and recordings.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/hex.12042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5060785PMC
June 2015

Id-1 is a key transcriptional regulator of glioblastoma aggressiveness and a novel therapeutic target.

Cancer Res 2013 Mar 13;73(5):1559-69. Epub 2012 Dec 13.

Authors' Affiliation: California Pacific Medical Center, Research Institute, San Francisco, California.

Glioblastoma is the most common form of primary adult brain tumors. A majority of glioblastomas grow invasively into distant brain tissue, leading to tumor recurrence, which is ultimately incurable. It is, therefore, essential to discover master regulators that control glioblastoma invasiveness and target them therapeutically. We show here that the transcriptional regulator Id-1 plays a critical role in modulating the invasiveness of glioblastoma cell lines and primary glioblastoma cells. Id-1 expression levels positively correlate with glioma cell invasiveness in culture and with histopathologic grades in patient biopsies. Id-1 knockdown dramatically reduces glioblastoma cell invasion that is accompanied by profound morphologic changes and robust reduction in expression levels of "mesenchymal" markers, as well as inhibition of self-renewal potential and downregulation of glioma stem cell markers. Importantly, genetic knockdown of Id-1 leads to a significant increase in survival in an orthotopic model of human glioblastoma. Furthermore, we show that a nontoxic compound, cannabidiol, significantly downregulates Id-1 gene expression and associated glioma cell invasiveness and self-renewal. In addition, cannabidiol significantly inhibits the invasion of glioblastoma cells through an organotypic brain slice and glioma progression in vivo. Our results suggest that Id-1 regulates multiple tumor-promoting pathways in glioblastoma and that drugs targeting Id-1 represent a novel and promising strategy for improving the therapy and outcome of patients with glioblastoma.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/0008-5472.CAN-12-1943DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3594064PMC
March 2013

Creatine for amyotrophic lateral sclerosis/motor neuron disease.

Cochrane Database Syst Rev 2012 Dec 12;12:CD005225. Epub 2012 Dec 12.

Neurology, UCSF Medical Center, San Francisco, California, USA.

Background: Creatine, a naturally-occurring nitrogenous organic acid involved in adenosine triphosphate (ATP) production, has been shown to increase survival in mouse models of amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND). Results from human trials, however, have been mixed. Given conflicting results regarding the efficacy of creatine, we conducted a systematic review, which was updated in 2012.

Objectives: To systematically examine the efficacy of creatine efficacy in prolonging ALS survival and in slowing ALS disease progression.

Search Methods: We searched the Cochrane Neuromuscular Disease Group Specialized Register (16 July 2012), CENTRAL (2012, issue 7 in the Cochrane Library), MEDLINE (January 1966 to July 2012) and EMBASE (January 1980 to July 2012) for any trial involving creatine in the treatment of ALS. We also contacted experts in the field for any additional studies.

Selection Criteria: Randomized trials of treatment with creatine or placebo in patients diagnosed with ALS. Our primary outcome was tracheostomy-free survival time; secondary outcomes were ALS progression as measured by changes in ALS functional rating revised scores (ALSFRS-R) and per cent predicted forced vital capacity (FVC) over time.

Data Collection And Analysis: Two authors independently selected studies, assessed risk of bias and extracted data. We obtained and analyzed individual participant data from each study.

Main Results: We included three trials involving 386 participants randomized to either creatine 5 to 10 g per day or placebo. When we updated the searches in 2012 we found no additional trials. Creatine was reportedly well-tolerated in all three included studies, with no evidence of renal failure or serious adverse events specifically attributable to creatine. Using a pooled log-rank statistical test, we found no statistical difference in survival between the placebo and creatine groups across all three studies (Chi(2) = 0.09, P = 0.76). In addition, we found no statistical difference in ALSFRS-R slopes between the two groups across all three studies using a pooled linear mixed-effects model (slope difference of +0.03 ALSFRS-R/month in the creatine group; P = 0.76). Interestingly, there was a trend towards slightly worsened FVC slope in the creatine group (slope difference of -0.63 FVC/month in the creatine group) using a pooled linear mixed-effects model across the two studies which included FVC as an outcome, but this difference was not statistically significant (P = 0.054).

Authors' Conclusions: In patients already diagnosed with clinically probable or definite ALS, creatine at doses ranging from 5 to 10 g per day did not have a statistically significant effect on survival, ALSFRS-R progression or percent predicted FVC progression.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/14651858.CD005225.pub3DOI Listing
December 2012

Bisphenol-A-induced inactivation of the p53 axis underlying deregulation of proliferation kinetics, and cell death in non-malignant human breast epithelial cells.

Carcinogenesis 2013 Mar 7;34(3):703-12. Epub 2012 Dec 7.

California Pacific Medical Center Research Institute, 475 Brannan Street, San Francisco, CA 94107, USA.

Widespread distribution of bisphenol-A (BPA) complicates epidemiological studies of possible carcinogenic effects on the breast because there are few unexposed controls. To address this challenge, we previously developed non-cancerous human high-risk donor breast epithelial cell (HRBEC) cultures, wherein BPA exposure could be controlled experimentally. BPA consistently induced activation of the mammalian target of rapamycin (mTOR) pathway--accompanied by dose-dependent evasion of apoptosis and increased proliferation--in HRBECs from multiple donors. Here, we demonstrate key molecular changes underlying BPA-induced cellular reprogramming. In 3/3 BPA-exposed HRBEC cell lines, and in T47D breast cancer cells, proapoptotic negative regulators of the cell cycle (p53, p21(WAF1) and BAX) were markedly reduced, with concomitant increases in proliferation-initiating gene products (proliferating cell nuclear antigen, cyclins, CDKs and phosphorylated pRb). However, simultaneous exposure to BPA and the polyphenol, curcumin, partially or fully reduced the spectrum of effects associated with BPA alone, including mTOR pathway proteins (AKT1, RPS6, pRPS6 and 4EBP1). BPA exposure induced an increase in the ERα (Estrogen Receptor): ERβ ratio--an effect also reversed by curcumin (analysis of variance, P < 0.02 for all test proteins). At the functional level, concurrent curcumin exposure reduced BPA-induced apoptosis evasion and rapid growth kinetics in all cell lines to varying degrees. Moreover, BPA extended the proliferation potential of 6/6 primary finite-life HRBEC cultures--another effect reduced by curcumin. Even after removal of BPA, 1/6 samples maintained continuous growth--a hallmark of cancer. We show that BPA exposure induces aberrant expression of multiple checkpoints that regulate cell survival, proliferation and apoptosis and that such changes can be effectively ameliorated.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/carcin/bgs379DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3581603PMC
March 2013

Infrasound sensitizes human glioblastoma cells to cisplatin-induced apoptosis.

Integr Cancer Ther 2013 Nov 19;12(6):517-27. Epub 2012 Nov 19.

California Pacific Medical Center Research Institute, San Francisco, CA, USA.

The development of nontoxic agents that can selectively enhance the cytotoxicity of chemotherapy is an important aim in oncology. This study evaluates the ability of infrasound exposure to sensitize glioblastoma cells to cisplatin-induced apoptosis. The infrasound was delivered using a device designed to replicate the unique infrasound emissions measured during external Qigong treatments. Human glioblastoma cell lines harboring wild-type p53 (U87) or mutant p53 (U251, SF210, and SF188) were treated in culture with cisplatin, infrasound emissions, or the combination of the 2 agents. Induction of apoptosis was quantified after 24 hours by flow cytometry following annexin V/propidium iodide staining. Infrasound emissions alone, delivered at moderate levels (~10 mPa) with dynamic frequency content (7-13 Hz), did not induce apoptosis, yet combining infrasound with cisplatin augmented the induction of apoptosis by cisplatin in all the 4 cell lines (P < .05). Increased cellular uptake of the fluorophore calcein associated with infrasound exposure was quantified by fluorescence microscopy as well as flow cytometry, demonstrating increased cell membrane permeability. The 4 cell lines differed in the degree to which infrasound exposure increased calcein uptake, and these differences were predictive of the extent to which infrasound enhanced cisplatin-induced apoptosis. When exposed to specific frequencies, membrane permeabilization also appeared to be differentially responsive for each cell line, suggesting the potential for selective targeting of tissue types using isolated infrasonic frequencies. Additionally, the pressure amplitudes used in this study were several orders of magnitude less than those used in similar studies involving ultrasound and shock waves. The results of this study provide support for using infrasound to enhance the chemotherapeutic effects of cisplatin in a clinical setting.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/1534735412465641DOI Listing
November 2013

Regulatory T-lymphocytes mediate amyotrophic lateral sclerosis progression and survival.

EMBO Mol Med 2013 01 9;5(1):64-79. Epub 2012 Nov 9.

Department of Neurology, The Methodist Hospital Research Institute, Houston, TX, USA.

In amyotrophic lateral sclerosis (ALS) mice, regulatory T-lymphocytes (Tregs) are neuroprotective, slowing disease progression. To address whether Tregs and FoxP3, a transcription factor required for Treg function, similarly influence progression rates of ALS patients, T-lymphocytes from patients were assessed by flow cytometry. Both numbers of Tregs and their FoxP3 protein expressions were reduced in rapidly progressing ALS patients and inversely correlated with progression rates. The mRNA levels of FoxP3, TGF-β, IL4 and Gata3, a Th2 transcription factor, were reduced in rapidly progressing patients and inversely correlated with progression rates. Both FoxP3 and Gata3 were accurate indicators of progression rates. No differences in IL10, Tbx21, a Th1 transcription factor or IFN-γ expression were found between slow and rapidly progressing patients. A 3.5-year prospective study with a second larger cohort revealed that early reduced FoxP3 levels were indicative of progression rates at collection and predictive of future rapid progression and attenuated survival. Collectively, these data suggest that Tregs and Th2 lymphocytes influence disease progression rates. Importantly, early reduced FoxP3 levels could be used to identify rapidly progressing patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/emmm.201201544DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3569654PMC
January 2013

Smoking and survival after breast cancer diagnosis: a prospective observational study and systematic review.

Breast Cancer Res Treat 2012 Nov 29;136(2):521-33. Epub 2012 Sep 29.

Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA.

The association of smoking with outcomes following breast cancer prognosis is not well understood. In a cohort study called Life After Cancer Epidemiology (LACE), 2,265 women diagnosed with breast cancer were followed for a median of 12 years. We used multivariable proportional-hazards models to determine whether smoking, assessed approximately two years post-diagnosis, was associated with risk of death among these women. We also undertook a systematic review of all cohort studies to date that have examined the association between smoking and breast cancer mortality. Compared with never smokers, women who were current smokers had a twofold higher rate of dying from breast cancer [hazard ratio (HR) = 2.01, 95 % confidence interval (CI) 1.27-3.18] and an approximately fourfold higher rate of dying from competing (non-breast cancer) causes (HR = 3.84, 95 % CI 2.50-5.89). Among seven studies that met the inclusion criteria in the systematic review, three studies and our own reported significantly increased risk of breast cancer death with current smoking. We found little evidence of an association between former smoking and breast cancer mortality (HR = 1.24, 95 % CI 0.94-1.64). Consistent with findings from our prospective observational study, the systematic review of seven additional studies indicates positive association of current smoking with breast cancer mortality, but weak association with former smoking. Women who smoke following breast cancer diagnosis and treatment are at higher risk of death both from breast cancer and other causes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10549-012-2276-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3507472PMC
November 2012

Benefit of semiannual ipsilateral mammographic surveillance following breast conservation therapy.

Radiology 2012 Aug 12;264(2):371-7. Epub 2012 Jun 12.

Department of Radiology, University of California, San Francisco, San Francisco, CA 94115, USA.

Purpose: To compare cancer recurrence outcomes on the basis of compliant semiannual versus noncompliant annual ipsilateral mammographic surveillance following breast conservation therapy (BCT).

Materials And Methods: A HIPAA-compliant retrospective review was performed of post-BCT examinations from 1997 through 2008 by using a deidentified database. The Committee on Human Research did not require institutional review board approval for this study, which was considered quality assurance. Groups were classified according to compliance with institutional post-BCT protocol, which recommends semiannual mammographic examinations of the ipsilateral breast for 5 years. A compliant semiannual examination was defined as an examination with an interval of 0-9 months, although no examination had intervals less than 3 months. A noncompliant annual examination was defined as an examination with an interval of 9-18 months. Cancer recurrence outcomes were compared on the basis of the last examination interval leading to diagnosis.

Results: Initially, a total of 10 750 post-BCT examinations among 2329 asymptomatic patients were identified. Excluding initial mammographic follow-up, there were 8234 examinations. Of these, 7169 examinations were semiannual with 94 recurrences detected and 1065 examinations were annual with 15 recurrences detected. There were no differences in demographic risk factors or biopsy rates. Recurrences identified at semiannual intervals were significantly less advanced than those identified at annual intervals (stage I vs stage II, P = .04; stage 0 + stage I vs stage II, P = .03). Nonsignificant findings associated with semiannual versus annual intervals included smaller tumor size (mean, 11.7 vs 15.3 mm; P = .15) and node negativity (98% vs 91%, P = .28).

Conclusion: Results suggest that a semiannual interval is preferable for ipsilateral mammographic surveillance, allowing detection of a significantly higher proportion of cancer recurrences at an earlier stage than noncompliant annual surveillance.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1148/radiol.12111458DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3401347PMC
August 2012

Prognostic categories for amyotrophic lateral sclerosis.

Amyotroph Lateral Scler 2012 Oct 7;13(6):502-8. Epub 2012 Jun 7.

MRC Centre for Neurodegeneration Research, King's College London, Institute of Psychiatry, London, UK.

Our objective was to generate a prognostic classification method for amyotrophic lateral sclerosis (ALS) from a prognostic model built using clinical variables from a population register. We carried out a retrospective multivariate analysis of 713 patients with ALS over a 20-year period from the South-East England Amyotrophic Lateral Sclerosis (SEALS) population register. Patients were randomly allocated to 'discovery' or 'test' cohorts. A prognostic score was calculated using the discovery cohort and then used to predict survival in the test cohort. The score was used as a predictor variable to split the test cohort in four prognostic categories (good, moderate, average, poor). The accuracy of the score in predicting survival was tested by checking whether the predicted survival fell within the actual survival tertile which that patient was in. A prognostic score generated from one cohort of patients predicted survival for a second cohort of patients (r(2) = 0.72). Six variables were included in the survival model: age at onset, diagnostic delay, El Escorial category, use of riluzole, gender and site of onset. Cox regression demonstrated a strong relationship between these variables and survival (χ(2) 80.8, df 1, p < 0.0001, n = 343) in the test cohort. Kaplan-Meier analysis demonstrated a significant difference in survival between clinical categories (log rank 161.932, df 3, p < 0.001), and the prognostic score generated for the test cohort accurately predicted survival in 64% of the patients. In conclusion, it is possible to correctly classify patients into prognostic categories using clinical data easily available at time of diagnosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3109/17482968.2012.679281DOI Listing
October 2012

The effects of acellular dermal matrix in expander-implant breast reconstruction after total skin-sparing mastectomy: results of a prospective practice improvement study.

Plast Reconstr Surg 2012 Jun;129(6):901e-908e

San Francisco, Calif.; and Durham, N.C. From the Department of Surgery, Divisions of Plastic and Reconstructive Surgery and Breast Surgery, and the Department of Epidemiology and Biostatistics, University of California, San Francisco; and the Department of Surgery, Duke University Medical Center.

Background: Neither outcome after total skin-sparing mastectomy and expander-implant reconstruction using acellular dermal matrix nor a strategy for optimal acellular dermal matrix selection criteria has been well described.

Methods: Prospective review of three patient cohorts undergoing total skin-sparing mastectomy with preservation of the nipple-areola complex and immediate expander-implant reconstruction from 2006 to 2010 was performed. Cohort 1 (no acellular dermal matrix) comprised 90 cases in which acellular dermal matrix was not used. Cohort 2 (consecutive acellular dermal matrix) included the next 100 consecutive cases, which all received acellular dermal matrix. Cohort 3 (selective acellular dermal matrix) consisted of the next 260 cases, in which acellular dermal matrix was selectively used based on mastectomy skin flap thickness. Complication rates were compared using chi-square analysis.

Results: The study included 450 cases in 288 patients. Mean follow-up was 25.5 months. Infection occurred in 27.8 percent of the no-acellular dermal matrix cases, 20 percent of the consecutive cases, and 15.8 percent of the selective cases (p = 0.04). Unplanned return to the operating room was required in 23.3, 11, and 10 percent of cases, respectively (p = 0.004). Expander-implant loss occurred in 17.8, 7, and 5 percent of cases, respectively (p = 0.001). Additional analysis of the odds ratios of developing complications after postmastectomy radiation therapy demonstrated a specific protective benefit of acellular dermal matrix in irradiated patients.

Conclusions: Acellular dermal matrix use in expander-implant reconstruction after total skin-sparing mastectomy reduced major postoperative complications in this study. Maximal benefit is achieved with selected use in patients with thin mastectomy skin flaps and those receiving radiation therapy.

Clinical Question/level Of Evidence: Therapeutic, III.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/PRS.0b013e31824ec447DOI Listing
June 2012

Elevated levels of proliferating and recently migrated tumor-associated macrophages confer increased aggressiveness and worse outcomes in breast cancer.

Ann Surg Oncol 2012 Nov 24;19(12):3979-86. Epub 2012 May 24.

Department of Surgery, University of California, San Francisco, CA, USA.

Purpose: Macrophages play a major role in inflammatory processes and have been associated with poor prognosis in a variety of cancers, including breast cancer. Previously, we investigated the relationship of a subset of tumor-associated macrophages (PCNA(+) TAMs) with clinicopathologic characteristics of breast cancer. We reported that high PCNA(+) TAM counts were associated with hormone receptor (HR)-negative, high-grade tumors and early recurrence. To further understand the significance of elevated PCNA(+) TAMs and the functionality of TAMs, we examined the expression of S100A8/S100A9 with the antibody Mac387. The heterodimeric S100A8/S100A9 complex plays a role in inflammation and is increased in several cancer types.

Methods: We performed immunohistochemistry using the Mac387 antibody on 367 invasive human breast cancer cases. Results were compared to previous PCNA(+) TAM counts and were correlated with patient outcomes adjusting for HR status and histologic grade.

Results: Like PCNA(+) TAMs, high Mac387 counts were associated with HR negativity, high tumor grade, younger age, and decreased recurrence-free survival. Mac387, however, appears to identify both a subset of macrophages and a subset of tumor cells. The concordance between Mac387 and PCNA(+) TAM counts was low and cases that had both high Mac387 and high PCNA(+) TAMs counts had a stronger association with early recurrence.

Conclusions: The presence of high numbers of PCNA(+) TAMs and Mac387-positive cells in breast cancers with poor outcomes may implicate a subset of TAMs in breast cancer pathogenesis, and may ultimately serve to develop potential cellular targets for therapeutic interventions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1245/s10434-012-2415-2DOI Listing
November 2012

Prognostic impact of comorbidity among long-term breast cancer survivors: results from the LACE study.

Cancer Epidemiol Biomarkers Prev 2012 Jul 9;21(7):1115-25. Epub 2012 May 9.

Department of Epidemiology and Biostatistics and Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94107, USA.

Background: Little is known about the long-term impact of comorbidity among women with breast cancer.

Methods: We studied a prospective cohort of 2,272 women with breast cancer, who were recruited following initial breast cancer treatment. Associations of the Charlson comorbidity index (CCI) and hypertension with survival were evaluated in delayed entry Cox proportional hazards models.

Results: During a median follow-up of nine years, higher CCI scores were independently associated with an increased risk of death from all causes [HR, 1.32; 95% confidence interval (CI), 1.13-1.54] and from nonbreast cancer causes (HR, 1.55; 95% CI, 1.19-2.02), but not from breast cancer (HR, 1.14; 95% CI, 0.93-1.41). Hypertension was independently associated with an increased risk of death from all causes (HR, 1.55; 95% CI, 1.20-1.99), from nonbreast cancer causes (HR, 1.67; 95% CI, 1.10-2.54), and from breast cancer (HR, 1.47; 95% CI, 1.03-2.09), but these associations were no longer significant after adjustment for antihypertensive medication. The relationship between the CCI and overall survival was the strongest among women with stage I disease (stage I, HR, 1.65; 95% CI, 1.26-2.16 vs. stage III, HR, 0.53; 95% CI, 0.23-1.25).

Conclusion: The CCI was independently associated with lower overall and nonbreast cancer survival, but not with breast cancer-specific survival.

Impact: Comorbidity may play an important role in breast cancer outcomes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1055-9965.EPI-11-1228DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3470873PMC
July 2012

Riluzole for amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND).

Cochrane Database Syst Rev 2012 Mar 14(3):CD001447. Epub 2012 Mar 14.

Forbes Norris ALS Research Center, California PacificMedical Center, San Francisco, USA.

Background: Riluzole is approved for the treatment of amyotrophic lateral sclerosis in most countries. Questions persist about its clinical utility because of high cost and modest efficacy.

Objectives: To examine the efficacy of riluzole in prolonging survival and in delaying the use of surrogates (tracheostomy and mechanical ventilation) to sustain survival, and to assess the effect of riluzole upon functional health.

Search Methods: We searched the Cochrane Neuromuscular Disease Group Specialized Register (20 April 2011), the Cochrane Central Register of Controlled Trials (CENTRAL) (2011, Issue 2), MEDLINE (1966 to April 2011), EMBASE (1980 to May 2011) and made enquiries of authors of trials, Aventis (manufacturer of riluzole) and other experts in the field.

Selection Criteria: Types of studies: randomized controlled trials

Types Of Participants: adults with a diagnosis of amyotrophic lateral sclerosis Types of interventions: treatment with riluzole or placebo Types of outcome measures: Primary: pooled hazard ratio of tracheostomy-free survival over all time points with riluzole 100 mg. Secondary: per cent mortality with riluzole 50 mg, 100 mg and 200 mg; neurologic function, muscle strength and adverse events.

Data Collection And Analysis: One author performed data extraction and two other authors checked them. One author checked the data and entered them into the computer. The other authors verified the data entry. We obtained missing data from the trial authors whenever possible.

Main Results: The four trials examining tracheostomy-free survival included a total of 974 riluzole-treated patients and 503 placebo-treated patients. No new randomized controlled trials were found when we updated the searches for this update in 2011. The methodological quality was acceptable and three trials were easily comparable, although one trial (169 participants) included older patients in more advanced stages of amyotrophic lateral sclerosis and one (195 participants) had multiple primary endpoints. Riluzole 100 mg per day provided a benefit for the homogeneous group of patients in the first two trials (hazard ratio (HR) 0.80, 95% confidence internal (CI) 0.64 to 0.99, P= 0.042) and there was no evidence of heterogeneity (P = 0.33). When the third trial (which included older and more seriously affected patients) was added, there was evidence of heterogeneity (P < 0.0001) and the overall treatment effect was reduced but still significant (HR 0.84, 95% CI 0.698 to 0.997, P= 0.046). This represented a 9% gain in the probability of surviving one year (49% in the placebo and 58% in the riluzole group), and increased median survival from 11.8 to 14.8 months. There was a small beneficial effect on both bulbar and limb function, but not on muscle strength. A three-fold increase in serum alanine transferase was more frequent in riluzole-treated patients than controls (mean difference 2.62, 95% CI 1.59 to 4.31).

Authors' Conclusions: Riluzole 100 mg daily is reasonably safe and probably prolongs median survival by about two to three months in patients with amyotrophic lateral sclerosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/14651858.CD001447.pub3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7055506PMC
March 2012

The effects of dexpramipexole (KNS-760704) in individuals with amyotrophic lateral sclerosis.

Nat Med 2011 Nov 20;17(12):1652-6. Epub 2011 Nov 20.

Neurology Clinical Trial Unit, Massachusetts General Hospital, Boston, Massachusetts, USA.

Amyotrophic lateral sclerosis (ALS) is characterized by upper and lower motor neuron dysfunction and loss, rapidly progressive muscle weakness, wasting and death. Many factors, including mitochondrial dysfunction, may contribute to ALS pathogenesis. Riluzole, which has shown only modest benefits in a measure of survival time without demonstrated effects on muscle strength or function, is the only approved treatment for ALS. We tested the putative mitochondrial modulator dexpramipexole (KNS-760704; (6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine) in subjects with ALS in a two-part, double-blind safety and tolerability study, with a preliminary assessment of its effects on functional decline and mortality. In part 1, the effects of dexpramipexole (50, 150 or 300 mg d(-1)) versus placebo were assessed over 12 weeks. In part 2, after a 4-week, single-blind placebo washout, continuing subjects were re-randomized to dexpramipexole at 50 mg d(-1) or 300 mg d(-1) as double-blind active treatment for 24 weeks. Dexpramipexole was safe and well tolerated. Trends showing a dose-dependent attenuation of the slope of decline of the ALS Functional Rating Scale-Revised (ALSFRS-R) in part 1 and a statistically significant (P = 0.046) difference between groups in a joint rank test of change from baseline in ALSFRS-R and mortality in part 2 strongly support further testing of dexpramipexole in ALS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/nm.2579DOI Listing
November 2011

Impact of mammographic screening on the detection of good and poor prognosis breast cancers.

Breast Cancer Res Treat 2011 Dec 4;130(3):725-34. Epub 2011 Sep 4.

University California San Francisco, San Francisco, CA, USA.

We sought to compare the molecular signature of node negative cancers from two cohorts 15 years apart, to determine if there is molecular evidence of increase in low and ultralow risk cancers over time. We studied the impact of age, time period of diagnosis, and mammographic screening on biology of tumors where The Netherlands Cancer Institute 70-gene prognosis signature was generated as part of 2 validation series, one retrospective (1984-1992), Cohort 1, and one prospective (2004-2006), Cohort 2. A total of 866 patients were analyzed. Regardless of time period of diagnosis, the proportion of T1, grade 1, hormone receptor positive (HR) tumors, and good prognosis by 70-gene signature significantly increases as age increases (P < 0.01). In women aged 49-60, the time period of diagnosis significantly affects the proportion of cancers that were NKI 70-gene low risk: 40.6% (67/165) compared with 58% (119/205) for Cohorts 1 and 2, respectively. This is in contrast to the absence of a significant change for women under age 40, where 25% (17/68) and 30% (17/56) were low risk in Cohorts 1 and 2, respectively. In women aged 49-60, using an ultralow risk threshold of the 70-gene signature, 10% of tumors in Cohort 1 were ultralow risk compared with 30% for women with screen-detected cancers in Cohort 2. Older age and method of detection (screening) are associated with a higher likelihood of a biologically low risk tumor. In women over age 50, biologically low risk tumors are frequent and tools that classify risk may minimize overtreatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10549-011-1748-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5646368PMC
December 2011

Activation of the mTOR pathway by low levels of xenoestrogens in breast epithelial cells from high-risk women.

Carcinogenesis 2011 Nov 1;32(11):1724-33. Epub 2011 Sep 1.

California Pacific Medical Center, Research Institute, San Francisco, CA 94107, USA.

Breast cancer is an estrogen-driven disease. Consequently, hormone replacement therapy correlates with disease incidence. However, increasing male breast cancer rates over the past three decades implicate additional sources of estrogenic exposure including wide spread estrogen-mimicking chemicals or xenoestrogens (XEs), such as bisphenol-A (BPA). By exposing renewable, human, high-risk donor breast epithelial cells (HRBECs) to BPA at concentrations that are detectable in human blood, placenta and milk, we previously identified gene expression profile changes associated with activation of mammalian target of rapamycin (mTOR) pathway genesets likely to trigger prosurvival changes in human breast cells. We now provide functional validation of mTOR activation using pairwise comparisons of 16 independent HRBEC samples with and without BPA exposure. We demonstrate induction of key genes and proteins in the PI3K-mTOR pathway--AKT1, RPS6 and 4EBP1 and a concurrent reduction in the tumor suppressor, phosphatase and tensin homolog gene protein. Altered regulation of mTOR pathway proteins in BPA-treated HRBECs led to marked resistance to rapamycin, the defining mTOR inhibitor. Moreover, HRBECs pretreated with BPA, or the XE, methylparaben (MP), surmounted antiestrogenic effects of tamoxifen showing dose-dependent apoptosis evasion and induction of cell cycling. Overall, XEs, when tested in benign breast cells from multiple human subjects, consistently initiated specific functional changes of the kind that are attributed to malignant onset in breast tissue. Our observations demonstrate the feasibility of studying renewable human samples as surrogates and reinforce the concern that BPA and MP, at low concentrations detected in humans, can have adverse health consequences.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/carcin/bgr196DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3204351PMC
November 2011

Elevated PCNA+ tumor-associated macrophages in breast cancer are associated with early recurrence and non-Caucasian ethnicity.

Breast Cancer Res Treat 2011 Nov 30;130(2):635-44. Epub 2011 Jun 30.

University of California, San Francisco, San Francisco, CA, USA.

African American and Hispanic women develop more triple negative breast cancer at younger ages than Caucasian women. The frequently observed association between race and socioeconomic status (SES) has confounded our understanding of the outcomes disparities seen in these groups. Given the association between inflammatory cells and high-grade, triple negative tumors, we sought to investigate whether differences in the presence of these cells varies by race. We evaluated breast tumor specimens for the presence PCNA+ tumor-associated macrophages (TAMs) in consecutive cases from a county hospital serving primarily un- or under-insured patients. All patients in this cohort had elevated PCNA + TAM levels. Higher PCNA + TAM counts were associated with hormone receptor (HR) negative tumors and non-Caucasian ethnicity. Hispanic women specifically had significantly higher PCNA + TAM counts than Caucasian patients and shorter disease-free survival. These findings implicate immune function in the development of aggressive breast cancer and suggest a possible link between SES and the inflammatory response.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10549-011-1646-4DOI Listing
November 2011

Does use of the adjuvant! model influence use of adjuvant therapy through better risk communication?

J Natl Compr Canc Netw 2011 Jul;9(7):707-12

University of California San Francisco, USA.

Adjuvant! is a model that provides recurrence and mortality risk predictions for patients with breast cancer considering adjuvant therapies. Although low-risk patients who saw Adjuvant! chose adjuvant therapy less frequently, whether this was because of educational or other aspects of the decision aid is unknown. The authors explored whether Adjuvant! affects choice of therapy through increased patient knowledge. A subset of data were analyzed from a cluster randomized trial in which oncology practices in 2 major United States cities were randomly assigned to use either Adjuvant! or an informational pamphlet to educate patients. Of 405 patients, 48 were low-risk, with 28 assigned to the decision aid and 20 to the pamphlet. Among the low-risk patients, using frequency tables and Fisher exact tests, the authors explored whether Adjuvant! was associated with more accurate patient estimates of survival; whether accuracy was associated with treatment choice; and whether, after controlling for accuracy, any remaining association was seen between Adjuvant! and treatment choice. Adjuvant! was associated with more accurate estimates of baseline prognosis compared with the pamphlet (57% vs. 25%; P = .04). Patients who had more accurate estimates of baseline prognosis were less likely to choose adjuvant therapy (62% vs. 89%; P = .04). After controlling for accuracy, no statistically significant association was found between the use of Adjuvant! and adjuvant therapy (P = .59 and P = .11 for inaccurate and accurate patients, respectively). Adjuvant! seems to influence patient choice through educational rather than other means of persuasion. However, many patients held inaccurate risk perceptions after viewing Adjuvant!.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3528013PMC
http://dx.doi.org/10.6004/jnccn.2011.0061DOI Listing
July 2011

Risk-reducing salpingo-oophorectomy (RRSO) in BRCA mutation carriers: experience with a consecutive series of 111 patients using a standardized surgical-pathological protocol.

Int J Gynecol Cancer 2011 Jul;21(5):846-51

Cancer Risk Program, Department of Pathology, UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA 94115, USA.

Background: Women carriers of BRCA mutations often have occult malignancy found at the time of risk-reducing bilateral salpingo-oophorectomy (RRSO). We report outcomes in 111 consecutive BRCA-positive women who had RRSO using a rigorous surgical-pathological protocol from 1996 to 2008.

Method: We identified risk factors associated with finding an occult malignancy at RRSO with outcomes followed for a median of 61 months.

Results: A total of 111 BRCA carriers elected RRSO, 10 patients [9.1%] had 14 sites of occult neoplasia. Two patients had invasive serous fallopian tube carcinoma (TSC) only, 1 patient had invasive serous ovarian carcinoma (OSC) only, 5 patients had tubal intraepithelial carcinoma (TIC) only, and 2 patients had multifocal lesions of the ovary (OSC) and TIC. Occult ovarian carcinomas were only detected in BRCA1 patients, and all BRCA2 carcinomas involved only the fallopian tube. The odds of finding occult carcinoma is 4 times greater (odds ratio, 4.3; 95% confidence interval, 1.06-20.7) in women older than 50 than in younger ones (P=0.023). A history of invasive breast cancer was associated with a reduced risk of occult carcinoma (odds ratio, 0.2; 95% confidence interval, 0.05-0.85). In median follow-up of 5 years, recurrence rate after detection of an occult carcinoma was 10% and the risk for primary peritoneal carcinoma was less than 1%.

Conclusion: A rigorous surgical protocol with meticulous pathologic review at RRSO yielded an overall detection rate of 9.1% for occult gynecological carcinoma in BRCA mutation carriers followed by a multidisciplinary team at a single institution. Primary peritoneal carcinoma after RRSO is rare.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/IGC.0b013e31821bc7e3DOI Listing
July 2011

Impact of decision aids in a sustained implementation at a breast care center.

Patient Educ Couns 2012 Feb 12;86(2):195-204. Epub 2011 Jun 12.

Institute for Health Policy Studies, University of California, San Francisco, USA.

Objective: We examined the reach and impact of five decision aids (DAs) routinely distributed to breast cancer patients as part of a shared decision making demonstration project.

Methods: From 2005 to 2008, we surveyed patients' change in knowledge and decisional conflict (DC) before and after their review of DAs. Using bivariate tests, we identified significant predictors of change in knowledge or decisional conflict and entered significant predictors into a multivariate regression model.

Results: We distributed 1553 DAs to 1098 patients and received 549 completed surveys. The DAs were associated with increased knowledge and decreased DC. For knowledge, significant predictors of above-average change included: lower baseline knowledge and viewing the surgery decision aid. For decisional conflict, significant predictors of above-average change included: higher decisional conflict; viewing any of the early-stage cancer DAs; and Hispanic ethnicity.

Conclusions: DAs used in routine care were associated with significant knowledge gains and reductions in decisional conflict. Some subsets of patients (those reporting low baseline knowledge, high DC, or Hispanic ethnicity) may benefit more than others.

Practice Implications: Breast cancer patients benefit overall from routine distribution of DAs. Our exploratory findings may be useful in generating hypotheses to identify target populations who would most benefit from reviewing DAs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.pec.2011.05.011DOI Listing
February 2012