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PurposeBisphosphonates reduce bone metastases in postmenopausal women with early-stage breast cancer but carry the risk of bisphosphonate-related osteonecrosis of the jaw (BRONJ). We describe risk factors for BRONJ and compare BRONJ provoked by infection or trauma with spontaneous lesions, which carry a better prognosis.MethodsSWOG 0307 randomized women with stage I–III breast cancer to receive zoledronic acid (ZA), clodronate (CL), or ibandronate (IB) for 3 years, implemented BRONJ prevention guidelines, and collected information about dental health and development of BRONJ. All statistical tests were two-sided.ResultsOf 6018 women, 48 developed BRONJ. Infection was present in 21 (43.8%). Median time to BRONJ was 2.1 years for ZA, 2.0 years for IB, and 3.4 years for clodronate (p = 0.04). BRONJ was associated with bisphosphonate type (28/2231 (1.26%) for ZA, 8/2235 (0.36%) for CL, 12/1552 (0.77%) for IB), dental calculus (OR 2.03), gingivitis (OR 2.11), moderate/severe periodontal disease (OR 2.87), and periodontitis > 4 mm (OR 2.20) (p < 0.05). Of 57 lesions, BRONJ occurred spontaneously in 20 (35.1%) and was provoked by dental extraction in 20 (35.1%), periodontal disease in 14 (24.6%), denture trauma in 6 (10.5%), and dental surgery in 2 (3.5%). Spontaneous BRONJ occurred more frequently at the mylohyoid ridge. There were no differences in dental disease, infection, or bisphosphonate type between spontaneous and provoked BRONJ.ConclusionZA and worse dental health were associated with increased incidence of BRONJ, with a trend toward additive risk when combined. BRONJ incidence was lower than in similar studies, with prevention strategies likely linked to this.Clinical trial numberNCT00127205Registration dateJuly 2005

TAILORx established the role of the 21-gene predictor of genetic risk in ascertaining treatment for women with hormone-receptor–positive, human epidermal growth factor receptor 2–negative breast cancer. Clinical risk factors provided additional prognostic information for women with intermediate genetic risk.

The development of nucleoside analogues has had a major impact on cancer therapy. CS-682 is a novel, orally administered nucleoside analogue with a unique mechanism of action. CS-682 undergoes conversion to the active metabolite, CNDAC, which then leads to the inhibition of DNA polymerase and a novel \"DNA self-strand breaking mechanism.\" We conducted a Phase I study of CS-682, administered orally five days per week in patients with refractory solid tumor malignancies. Forty-eight patients were enrolled on study. The recommended phase II dose of 30 mg/m(2) given orally once daily for 5 days a week for 4 weeks followed by 2 weeks off drug, was well tolerated. The most common dose limiting toxicity was neutropenia, which occurred at the highest dose levels of CS-682. This was correlated with higher CNDAC Cmax and AUC values. No tumor responses were noted in this heavily pretreated population. However, given the ease of administration and tolerability, further investigation of this agent is warranted.

BackgroundHypertension and proteinuria are common bevacizumab-induced toxicities. No validated biomarkers are available for identifying patients at risk of these toxicities.MethodsA genome-wide association study (GWAS) meta-analysis was performed in 1039 bevacizumab-treated patients of European ancestry in four clinical trials (CALGB 40502, 40503, 80303, 90401). Grade ≥2 hypertension and proteinuria were recorded (CTCAE v.3.0). Single-nucleotide polymorphism (SNP)-toxicity associations were determined using a cause-specific Cox model adjusting for age and sex.ResultsThe most significant SNP associated with hypertension with concordant effect in three out of the four studies (p-value <0.05 for each study) was rs6770663 (A > G) in KCNAB1, with the G allele increasing the risk of hypertension (p-value = 4.16 × 10−6). The effect of the G allele was replicated in ECOG-ACRIN E5103 in 582 patients (p-value = 0.005). The meta-analysis of all five studies for rs6770663 led to p-value = 7.73 × 10−8, close to genome-wide significance. The most significant SNP associated with proteinuria was rs339947 (C > A, between DNAH5 and TRIO), with the A allele increasing the risk of proteinuria (p-value = 1.58 × 10−7).ConclusionsThe results from the largest study of bevacizumab toxicity provide new markers of drug safety for further evaluations. SNP in KCNAB1 validated in an independent dataset provides evidence toward its clinical applicability to predict bevacizumab-induced hypertension.ClinicalTrials.gov Identifier: NCT00785291 (CALGB 40502); NCT00601900 (CALGB 40503); NCT00088894 (CALGB 80303) and NCT00110214 (CALGB 90401).

Massively parallel DNA sequencing technologies provide an unprecedented ability to screen entire genomes for genetic changes associated with tumour progression. Here we describe the genomic analyses of four DNA samples from an African-American patient with basal-like breast cancer: peripheral blood, the primary tumour, a brain metastasis and a xenograft derived from the primary tumour. The metastasis contained two de novo mutations and a large deletion not present in the primary tumour, and was significantly enriched for 20 shared mutations. The xenograft retained all primary tumour mutations and displayed a mutation enrichment pattern that resembled the metastasis. Two overlapping large deletions, encompassing CTNNA1 , were present in all three tumour samples. The differential mutation frequencies and structural variation patterns in metastasis and xenograft compared with the primary tumour indicate that secondary tumours may arise from a minority of cells within the primary tumour. Cancer progression genomics With the latest DNA sequencing technologies it is now possible to screen an entire genome for the genetic changes associated with tumour progression. This approach has been used to obtain complete sequences of four DNA samples from a 44-year-old African-American patient with basal-like breast cancer: the primary tumour, peripheral blood, a brain metastasis and a first-passage xenograft derived from the primary tumour. Mutational analysis suggests that the metastasis tumour specifically selects a subset of cells from the primary tumour that contain pre-existing mutations, and also develops a small number of de novo mutations. Massively parallel DNA sequencing allows entire genomes to be screened for genetic changes associated with tumour progression. Here, the genomes of four DNA samples from a 44-year-old African-American patient with basal-like breast cancer were analysed. The samples came from peripheral blood, the primary tumour, a brain metastasis and a xenograft derived from the primary tumour. The findings indicate that cells with a distinct subset of the primary tumour mutation might be selected during metastasis and xenografting.

PurposeHER2 + breast cancer (BC) is an aggressive subtype with high rates of brain metastases (BCBM). Two-thirds of HER2 + BCBM demonstrate activation of the PI3K/mTOR pathway driving resistance to anti-HER2 therapy. This phase II study evaluated everolimus (E), a brain-permeable mTOR inhibitor, trastuzumab (T), and vinorelbine (V) in patients with HER2 + BCBM.Patients and methodsEligible patients had progressive HER2 + BCBM. The primary endpoint was intracranial response rate (RR); secondary objectives were CNS clinical benefit rate (CBR), extracranial RR, time to progression (TTP), overall survival (OS), and targeted sequencing of tumors from enrolled patients. A two-stage design distinguished intracranial RR of 5% versus 20%.Results32 patients were evaluable for toxicity, 26 for efficacy. Intracranial RR was 4% (1 PR). CNS CBR at 6 mos was 27%; at 3 mos 65%. Median intracranial TTP was 3.9 mos (95% CI 2.2–5). OS was 12.2 mos (95% CI 0.6–20.2). Grade 3–4 toxicities included neutropenia (41%), anemia (16%), and stomatitis (16%). Mutations in TP53 and PIK3CA were common in BCBM. Mutations in the PI3K/mTOR pathway were not associated with response. ERBB2 amplification was higher in BCBM compared to primary BC; ERBB2 amplification in the primary BC trended toward worse OS.ConclusionWhile intracranial RR to ETV was low in HER2 + BCBM patients, one-third achieved CNS CBR; TTP/OS was similar to historical control. No new toxicity signals were observed. Further analysis of the genomic underpinnings of BCBM to identify tractable prognostic and/or predictive biomarkers is warranted. Clinical Trial: (NCT01305941).

Comprised of twenty-nine specially commissioned essays, A Companion to Hume examines the depth of the philosophies and influence of one of history's most remarkable thinkers. Demonstrates the range of Hume's work and illuminates the ongoing debates that it has generated Organized by subject, with introductions to each section to orient the reader Explores topics such as knowledge, passion, morality, religion, economics, and politics Examines the paradoxes of Hume's thought and his legacy, covering the methods, themes, and consequences of his contributions to philosophy

Microbial forensics is a scientific discipline dedicated to analyzing evidence from a bioterrorism act, biocrime, or inadvertent microorganism or toxin release for attribution purposes. This emerging discipline seeks to offer investigators the tools and techniques to support efforts to identify the source of a biological threat agent and attribute a biothreat act to a particular person or group. Microbial forensics is still in the early stages of development and faces substantial scientific challenges to continue to build capacity. The unlawful use of biological agents poses substantial dangers to individuals, public health, the environment, the economies of nations, and global peace. It also is likely that scientific, political, and media-based controversy will surround any investigation of the alleged use of a biological agent, and can be expected to affect significantly the role that scientific information or evidence can play. For these reasons, building awareness of and capacity in microbial forensics can assist in our understanding of what may have occurred during a biothreat event, and international collaborations that engage the broader scientific and policy-making communities are likely to strengthen our microbial forensics capabilities. One goal would be to create a shared technical understanding of the possibilities - and limitations - of the scientific bases for microbial forensics analysis. Science Needs for Microbial Forensics: Developing Initial International Research Priorities , based partly on a workshop held in Zabgreb, Croatia in 2013, identifies scientific needs that must be addressed to improve the capabilities of microbial forensics to investigate infectious disease outbreaks and provide evidence of sufficient quality to support legal proceedings and the development of government policies. This report discusses issues of sampling, validation, data sharing, reference collection, research priorities, global disease monitoring, and training and education to promote international collaboration and further advance the field.

Microbial forensics is a scientific discipline dedicated to analyzing evidence from a bioterrorism act, biocrime, or inadvertent microorganism or toxin release for attribution purposes. This emerging discipline seeks to offer investigators the tools and techniques to support efforts to identify the source of a biological threat agent and attribute a biothreat act to a particular person or group. Microbial forensics is still in the early stages of development and faces substantial scientific challenges to continue to build capacity. The unlawful use of biological agents poses substantial dangers to individuals, public health, the environment, the economies of nations, and global peace. It also is likely that scientific, political, and media-based controversy will surround any investigation of the alleged use of a biological agent, and can be expected to affect significantly the role that scientific information or evidence can play. For these reasons, building awareness of and capacity in microbial forensics can assist in our understanding of what may have occurred during a biothreat event, and international collaborations that engage the broader scientific and policy-making communities are likely to strengthen our microbial forensics capabilities. One goal would be to create a shared technical understanding of the possibilities - and limitations - of the scientific bases for microbial forensics analysis. Science Needs for Microbial Forensics: Developing Initial International Research Priorities , based partly on a workshop held in Zabgreb, Croatia in 2013, identifies scientific needs that must be addressed to improve the capabilities of microbial forensics to investigate infectious disease outbreaks and provide evidence of sufficient quality to support legal proceedings and the development of government policies. This report discusses issues of sampling, validation, data sharing, reference collection, research priorities, global disease monitoring, and training and education to promote international collaboration and further advance the field.