Providing access to risk prediction tools via the HL7 XML-formatted risk web service

Background: Cancer risk prediction tools provide valuable information to clinicians but remain computationally challenging. Many clinics find that Ca Gene or Hughes Risk Apps fit their needs for easy- and ready-to-use software to obtain cancer risks; however, these resources may not fit all clinics’ needs. The Hughes Risk Apps Group and Bayes Mendel Lab therefore developed a web service, called “Risk Service", which may be integrated into any client software to quickly obtain standardized and up-to-date risk predictions for Bayes Mendel tools (BRCAPRO, MMRpro, PancPRO, and MelaPRO), the Tyrer-Cuzick IBIS Breast Cancer Risk Evaluation Tool, and the Colorectal Cancer Risk Assessment Tool. Findings: Software clients that can convert their local structured data into the HL7 XML-formatted family and clinical patient history (Pedigree model) may integrate with the Risk Service. The Risk Service uses Apache Tomcat and Apache Axis2 technologies to provide an all Java web service. The software client sends HL7 XML information containing anonymized family and clinical history to a Dana-Farber Cancer Institute (DFCI) server where it is parsed, interpreted, and processed by multiple risk tools. The Risk Service then formats the results into an HL7 style message and returns the risk predictions to the originating software client. Upon consent, users may allow DFCI to maintain the data for future research. The Risk Service implementation is exemplified through Hughes Risk Apps. Conclusions: The Risk Service broadens the availability of valuable, up-to-date cancer risk tools and allows clinics and researchers to integrate risk prediction tools into their own software interface designed for their needs. Each software package can collect risk data using its own interface, and display the results using its own interface, while using a central, up-to-date risk calculator. This allows users to choose from multiple interfaces while always getting the latest risk calculations. Consenting users contribute their data for future research, thus building a rich multi-center resource

Phase I Clinical Trials in Acute Myeloid Leukemia: 23-Year Experience From Cancer Therapy Evaluation Program of the National Cancer Institute

Therapy for acute myeloid leukemia (AML) has largely remained unchanged, and outcomes are unsatisfactory. We sought to analyze outcomes of AML patients enrolled in phase I studies to determine whether overall response rates (ORR) and mortality rates have changed over time

Integrated genomic analyses identify ARID1A and ARID1B alterations in the childhood cancer neuroblastoma

Neuroblastomas are tumors of peripheral sympathetic neurons and are the most common solid tumor in children. To determine the genetic basis for neuroblastoma we performed whole-genome sequencing (6 cases), exome sequencing (16 cases), genome-wide rearrangement analyses (32 cases), and targeted analyses of specific genomic loci (40 cases) using massively parallel sequencing. On average each tumor had 19 somatic alterations in coding genes (range, 3–70). Among genes not previously known to be involved in neuroblastoma, chromosomal deletions and sequence alterations of chromatin remodeling genes, ARID1A and ARID1B, were identified in 8 of 71 tumors (11%) and were associated with early treatment failure and decreased survival. Using tumor-specific structural alterations, we developed an approach to identify rearranged DNA fragments in sera, providing personalized biomarkers for minimal residual disease detection and monitoring. These results highlight dysregulation of chromatin remodeling in pediatric tumorigenesis and provide new approaches for the management of neuroblastoma patients

Association of acute myeloid leukemias most immature phenotype with risk groups and outcomes

The precise phenotype and biology of acute myeloid leukemia stem cells remain controversial, in part because the “gold standard” immunodeficient mouse engraftment assay fails in a significant fraction of patients and identifies multiple cell-types in others. We sought to analyze the clinical utility of a novel assay for putative leukemia stem cells in a large prospective cohort. The leukemic clone’s most primitive hematopoietic cellular phenotype was prospectively identified in 109 newly-diagnosed acute myeloid leukemia patients, and analyzed against clinical risk groups and outcomes. Most (80/109) patients harbored CD34+CD38− leukemia cells. The CD34+CD38− leukemia cells in 47 of the 80 patients displayed intermediate aldehyde dehydrogenase expression, while normal CD34+CD38− hematopoietic stem cells expressed high levels of aldehyde dehydrogenase. In the other 33/80 patients, the CD34+CD38− leukemia cells exhibited high aldehyde dehydrogenase activity, and most (28/33, 85%) harbored poor-risk cytogenetics or FMS-like tyrosine kinase 3 internal tandem translocations. No CD34+ leukemia cells could be detected in 28/109 patients, including 14/21 patients with nucleophosmin-1 mutations and 6/7 acute promyelocytic leukemia patients. The patients with CD34+CD38− leukemia cells with high aldehyde dehydrogenase activity manifested a significantly lower complete remission rate, as well as poorer event-free and overall survivals. The leukemic clone’s most immature phenotype was heterogeneous with respect to CD34, CD38, and ALDH expression, but correlated with acute myeloid leukemia risk groups and outcomes. The strong clinical correlations suggest that the most immature phenotype detectable in the leukemia might serve as a biomarker for “clinically-relevant” leukemia stem cells. ClinicalTrials.gov: {"type":"clinical-trial","attrs":{"text":"NCT01349972","term_id":"NCT01349972"}}NCT01349972

Repurposing Itraconazole as a Treatment for Advanced Prostate Cancer: A Noncomparative Randomized Phase II Trial in Men With Metastatic Castration‐Resistant Prostate Cancer

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/139926/1/onco0163-sup-0001.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/139926/2/onco0163.pd

Coupled Networks of Permanent Protected Areas and Dynamic Conservation Areas for Biodiversity Conservation Under Climate Change

The complexity of climate change impacts on ecological processes necessitates flexible and adaptive conservation strategies that cross traditional disciplines. Current strategies involving protected areas are predominantly fixed in space, and may on their own be inadequate under climate change. Here, we propose a novel approach to climate adaptation that combines permanent protected areas with temporary conservation areas to create flexible networks. Previous work has tended to consider permanent and dynamic protection as separate actions, but their integration could draw on the strengths of both approaches to improve biodiversity conservation and help manage for ecological uncertainty in the coming decades. As there are often time lags in the establishment of new permanent protected areas, the inclusion of dynamic conservation areas within permanent networks could provide critical transient protection to mitigate land-use changes and biodiversity redistributions. This integrated approach may be particularly useful in highly human-modified and fragmented landscapes where areas of conservation value are limited and long-term place-based protection is unfeasible. To determine when such an approach may be feasible, we propose the use of a decision framework. Under certain scenarios, these coupled networks have the potential to increase spatio-temporal network connectivity and help maintain biodiversity and ecological processes under climate change. Implementing these networks would require multidisciplinary scientific evidence, new policies, creative funding solutions, and broader acceptance of a dynamic approach to biodiversity conservation

Association of Variants in Candidate Genes with Lipid Profiles in Women with Early Breast Cancer on Adjuvant Aromatase Inhibitor Therapy

Purpose: Aromatase inhibitors can exert unfavorable effects on lipid profiles; however, previous studies have reported inconsistent results. We describe the association of single-nucleotide polymorphisms (SNP) in candidate genes with lipid profiles in women treated with adjuvant aromatase inhibitors. Experimental design: We conducted a prospective observational study to test the associations between SNPs in candidate genes in estrogen signaling and aromatase inhibitor metabolism pathways with fasting lipid profiles during the first 3 months of aromatase inhibitor therapy in postmenopausal women with early breast cancer randomized to adjuvant letrozole or exemestane. We performed genetic association analysis and multivariable linear regressions using dominant, recessive, and additive models. Results: A total of 303 women had complete genetic and lipid data and were evaluable for analysis. In letrozole-treated patients, SNPs in CYP19A1, including rs4646, rs10046, rs700518, rs749292, rs2289106, rs3759811, and rs4775936 were significantly associated with decreases in triglycerides by 20.2 mg/dL and 39.3 mg/dL (P < 0.00053), respectively, and with variable changes in high-density lipoprotein (HDL-C) from decreases by 4.2 mg/dL to increases by 9.8 mg/dL (P < 0.00053). Conclusions: Variants in CYP19A1 are associated with decreases in triglycerides and variable changes in HDL-C in postmenopausal women on adjuvant aromatase inhibitors. Future studies are needed to validate these findings, and to identify breast cancer survivors who are at higher risk for cardiovascular disease with aromatase inhibitor therapy

Coupled networks of permanent protected areas and dynamic conservation areas for biodiversity conservation under climate change

The complexity of climate change impacts on ecological processes necessitates flexible and adaptive conservation strategies that cross traditional disciplines. Current strategies involving protected areas are predominantly fixed in space, and may on their own be inadequate under climate change. Here, we propose a novel approach to climate adaptation that combines permanent protected areas with temporary conservation areas to create flexible networks. Previous work has tended to consider permanent and dynamic protection as separate actions, but their integration could draw on the strengths of both approaches to improve biodiversity conservation and help manage for ecological uncertainty in the coming decades. As there are often time lags in the establishment of new permanent protected areas, the inclusion of dynamic conservation areas within permanent networks could provide critical transient protection to mitigate land-use changes and biodiversity redistributions. This integrated approach may be particularly useful in highly human-modified and fragmented landscapes where areas of conservation value are limited and long-term place-based protection is unfeasible. To determine when such an approach may be feasible, we propose the use of a decision framework. Under certain scenarios, these coupled networks have the potential to increase spatio-temporal network connectivity and help maintain biodiversity and ecological processes under climate change. Implementing these networks would require multidisciplinary scientific evidence, new policies, creative funding solutions, and broader acceptance of a dynamic approach to biodiversity conservation

Changes in breast density and circulating estrogens in postmenopausal women receiving adjuvant anastrozole

Factors associated with an increased risk of breast cancer include prior breast cancer, high circulating estrogens, and increased breast density. Adjuvant aromatase inhibitors are associated with a reduction in incidence of contralateral breast cancer. We conducted a prospective, single-arm, single-institution study to determine whether use of anastrozole is associated with changes in contralateral breast density and circulating estrogens. Eligible patients included postmenopausal women with hormone receptor-positive early-stage breast cancer who had completed local therapy, had an intact contralateral breast, and were recommended an aromatase inhibitor as their only systemic therapy. Participants received anastrozole 1 mg daily for 12 months on study. We assessed contralateral breast density and serum estrogens at baseline, 6, and 12 months. The primary endpoint was change in contralateral percent breast density from baseline to 12 months. Secondary endpoints included change in serum estrone sulfate from baseline to 12 months. Fifty-four patients were accrued. At 12 months, compared with baseline, there was a nonstatistically significant reduction in breast density (mean change: -16%, 95% CI: -30 to 2, P = 0.08) and a significant reduction in estrone sulfate (mean change: -93%, 95% CI: -94 to -91, P < 0.001). Eighteen women achieved 20% or greater relative reduction in contralateral percent density at 12 months compared with baseline; however, no measured patient or disease characteristics distinguished these women from the overall population. Large trials are required to provide additional data on the relationship between aromatase inhibitors and breast density and, more importantly, whether observed changes in breast density correlate with meaningful disease-specific outcomes