Antimicrobial exposure is associated with decreased survival in triple-negative breast cancer.

Antimicrobial exposure during curative-intent treatment of triple-negative breast cancer (TNBC) may lead to gut microbiome dysbiosis, decreased circulating and tumor-infiltrating lymphocytes, and inferior outcomes. Here, we investigate the association of antimicrobial exposure and peripheral lymphocyte count during TNBC treatment with survival, using integrated electronic medical record and California Cancer Registry data in the Oncoshare database. Of 772 women with stage I-III TNBC treated with and without standard cytotoxic chemotherapy - prior to the immune checkpoint inhibitor era - most (654, 85%) used antimicrobials. Applying multivariate analyses, we show that each additional total or unique monthly antimicrobial prescription is associated with inferior overall and breast cancer-specific survival. This antimicrobial-mortality association is independent of changes in neutrophil count, is unrelated to disease severity, and is sustained through year three following diagnosis, suggesting antimicrobial exposure negatively impacts TNBC survival. These results may inform mechanistic studies and antimicrobial prescribing decisions in TNBC and other hormone receptor-independent cancers.

Treatment and Monitoring Variability in US Metastatic Breast Cancer Care.

PURPOSE: Treatment and monitoring options for patients with metastatic breast cancer (MBC) are increasing, but little is known about variability in care. We sought to improve understanding of MBC care and its correlates by analyzing real-world claims data using a search engine with a novel query language to enable temporal electronic phenotyping. METHODS: Using the Advanced Cohort Engine, we identified 6,180 women who met criteria for having estrogen receptor-positive, human epidermal growth factor receptor 2-negative MBC from IBM MarketScan US insurance claims (2007-2014). We characterized treatment, monitoring, and hospice usage, along with clinical and nonclinical factors affecting care. RESULTS: We observed wide variability in treatment modality and monitoring across patients and geography. Most women received first-recorded therapy with endocrine (67%) versus chemotherapy, underwent more computed tomography (CT) (76%) than positron emission tomography-CT, and were monitored using tumor markers (58%). Nearly half (46%) met criteria for aggressive disease, which were associated with receiving chemotherapy first, monitoring primarily with CT, and more frequent imaging. Older age was associated with endocrine therapy first, less frequent imaging, and less use of tumor markers. After controlling for clinical factors, care strategies varied significantly by nonclinical factors (median regional income with first-recorded therapy and imaging type, geographic region with these and with imaging frequency and use of tumor markers; P < .0001). CONCLUSION: Variability in US MBC care is explained by patient and disease factors and by nonclinical factors such as geographic region, suggesting that treatment decisions are influenced by local practice patterns and/or resources. A search engine designed to express complex electronic phenotypes from longitudinal patient records enables the identification of variability in patient care, helping to define disparities and areas for improvement.

Magnetic resonance image features identify glioblastoma phenotypic subtypes with distinct molecular pathway activities.

Glioblastoma (GBM) is the most common and highly lethal primary malignant brain tumor in adults. There is a dire need for easily accessible, noninvasive biomarkers that can delineate underlying molecular activities and predict response to therapy. To this end, we sought to identify subtypes of GBM, differentiated solely by quantitative magnetic resonance (MR) imaging features, that could be used for better management of GBM patients. Quantitative image features capturing the shape, texture, and edge sharpness of each lesion were extracted from MR images of 121 single-institution patients with de novo, solitary, unilateral GBM. Three distinct phenotypic "clusters" emerged in the development cohort using consensus clustering with 10,000 iterations on these image features. These three clusters--pre-multifocal, spherical, and rim-enhancing, names reflecting their image features--were validated in an independent cohort consisting of 144 multi-institution patients with similar tumor characteristics from The Cancer Genome Atlas (TCGA). Each cluster mapped to a unique set of molecular signaling pathways using pathway activity estimates derived from the analysis of TCGA tumor copy number and gene expression data with the PARADIGM (Pathway Recognition Algorithm Using Data Integration on Genomic Models) algorithm. Distinct pathways, such as c-Kit and FOXA, were enriched in each cluster, indicating differential molecular activities as determined by the image features. Each cluster also demonstrated differential probabilities of survival, indicating prognostic importance. Our imaging method offers a noninvasive approach to stratify GBM patients and also provides unique sets of molecular signatures to inform targeted therapy and personalized treatment of GBM.

Do plasma biomarkers of coagulation and fibrinolysis differ between patients who have experienced an acute myocardial infarction versus stable exertional angina?

BACKGROUND: Circulating concentrations of proteins associated with coagulation and fibrinolysis may differ between individuals with coronary artery disease (CAD) who develop an acute myocardial infarction (AMI) rather than stable exertional angina. METHODS: We compared plasma concentrations of fibrinogen, d-dimer, tissue-type plasminogen activator, and plasminogen activator inhibitor-1 (PAI-1) between patients whose first clinical manifestation of CAD was an AMI (n = 198) rather than stable exertional angina (n = 199). We also compared plasma concentrations of these proteins between patients with symptomatic CAD (either AMI or stable angina; n = 397) and healthy, control subjects (n = 197) to confirm the sensitivity of these assays to detect epidemiologic associations. RESULTS: At a median of 15 weeks after presentation, patients with AMI had slightly higher d-dimer concentrations than patients with stable angina (P = .057), but were not significantly different in other markers. By contrast, fibrinogen, d-dimer, and tissue-type plasminogen activator were significantly higher (P < .001) and PAI-1 lower in patients with CAD than in healthy control subjects. After statistical adjustment for clinical covariates, cardiac risk factors, medications, and other confounders, fibrinogen, d-dimer, and PAI-1 remained significantly associated with CAD. CONCLUSION: Selected plasma markers of coagulation and fibrinolysis did not distinguish patients presenting with AMI from those with stable exertional angina.

Association of polymorphisms in platelet and hemostasis system genes with acute myocardial infarction.

BACKGROUND: Genetic polymorphisms may affect the balance between coagulation and fibrinolysis and thereby affect individual vulnerability to acute myocardial infarction (MI) among patients with underlying coronary atherosclerosis. METHODS: We enrolled 1375 patients with an initial clinical presentation of coronary disease. We genotyped 49 single nucleotide polymorphisms (SNPs) in 9 coagulation system genes and compared patients who had an initial acute MI with patients who presented with stable exertional angina. RESULTS: An SNP in CD36 (rs3211956) was significantly (P = .04) more common among patients who presented with acute MI (minor allele frequency 10.5%) than patients with stable exertional angina (minor allele frequency 8.0%). This association became marginally significant, however, after adjustment for conventional cardiac risk factors in an additive genetic model (odds ratio 1.34, CI 1.00-1.88, P = .053). An SNP in ITGB3 (Leu59Pro, rs5918) was slightly, but not significantly (P = .083), more common among patients with acute MI (minor allele frequency 14.5%) than among patients with stable exertional angina (minor allele frequency 12.0%). Two linked SNPs in THBD (Ala473Val, rs1042579; and rs3176123) were slightly, but not significantly (P = .079 and 0.052, respectively), less common among patients with acute MI (minor allele frequency 16.1%) than among patients with stable exertional angina (18.7% and 19.0%, respectively). CONCLUSIONS: Four SNPs in platelet glycoprotein and hemostatic genes were nominally associated with acute MI rather than stable exertional angina as the initial clinical presentation of coronary artery disease. These findings are suggestive but require independent confirmation in larger studies.

Racial disparities in risk factors for thrombosis.

PURPOSE OF REVIEW: Until recently, the paucity of characterization of the epidemiology of venous thromboembolism among non-Caucasians has contributed to the misconception that race or ethnicity does not modify disease presentation. This review will describe the previously poorly documented magnitude of venous thromboembolism disease burden among four racial cohorts, by defining disease incidence and associated morbidity/mortality from available literature data. RECENT FINDINGS: Emerging data suggest that African-Americans possess the highest burden of venous thromboembolism, and Asians the lowest, compared with the Caucasian population. In both racial groups, however, the inheritable thrombophilic risk factors prevalent in Caucasians (factor V Leiden, Prothrombin G20210A) are distinctly rare. The presence of yet undetermined modifiers of disease, conferring susceptibility or resistance to venous thromboembolism among these racial groups, is suspected and requires further investigation. SUMMARY: Racial disparity in thrombotic disorders exists in the divergent patterns of disease incidence among different racial/ethnic cohorts, yet the genetic determinants of disease and modifiers of risk remain obscure. Further research focused on delineating the underlying etiologies of venous thromboembolism across different racial/ethnic groups promises to be a productive and much needed area of exploration.

Complete remission in advanced blastic NK-cell lymphoma/leukemia in elderly patients using the hyper-CVAD regimen.

Although its cell of origin is still controversial, the blastic NK-cell leukemia/lymphoma clearly represents a distinct type of hematopoietic neoplasm that is particularly clinically aggressive when it occurs in elderly patients as a disseminated, multi-organ disease. Consistently effective treatments have not been developed for this malignancy. The present report describes two elderly patients with widespread blastic NK-cell leukemia/lymphoma involving the skin, bone marrow, peripheral blood, lymph nodes, and viscera. In both cases the malignant cells were CD56+, CD2+, and terminal deoxynucleotidyl transferase (TdT) positive with no detectable T-cell receptor (TCR) gamma chain gene rearrangement. The cells also exhibited a low CD45 expression and strong CD99 (mic-2) expression, as seen in immature lymphoid malignancies. The above findings support the precursor NK-cell, rather than mature NK- or non-NK-cell, origin of the malignant cells. It is noteworthy that the two patients achieved complete responses to treatment with hyper-CVAD (fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone) alternating with high-dose methotrexate/cytarabine, a regimen currently utilized in acute lymphoblastic leukemia and high-grade lymphoma. The complete remission (CR) was sustained for 24 months in one patient who received four cycles (eight courses) of the treatment. It lasted 9 months in the second patient, who received only two cycles (four courses). If similar results are obtained with future patients, a randomized study comparing the hyper-CVAD regimen to other therapeutic strategies may be warranted.