Anti-VEGF therapy as adjuvant therapy: clouds on the horizon?

Anti-angiogenic therapies have demonstrated their value in the setting of advanced cancer, and are being explored for use in micrometastatic disease. Recent preclinical studies suggest that adjuvant anti-vascular endothelial growth factor (VEGF) therapies may increase the risk of metastasis. How concerning are these preclinical studies, and should they affect our willingness to explore anti-VEGF therapy in the adjuvant setting

A bioinformatics approach for precision medicine off-label drug drug selection among triple negative breast cancer patients

Cancer has been extensively characterized on the basis of genomics. The integration of genetic information about cancers with data on how the cancers respond to target based therapy to help to optimum cancer treatment. OBJECTIVE: The increasing usage of sequencing technology in cancer research and clinical practice has enormously advanced our understanding of cancer mechanisms. The cancer precision medicine is becoming a reality. Although off-label drug usage is a common practice in treating cancer, it suffers from the lack of knowledge base for proper cancer drug selections. This eminent need has become even more apparent considering the upcoming genomics data. METHODS: In this paper, a personalized medicine knowledge base is constructed by integrating various cancer drugs, drug-target database, and knowledge sources for the proper cancer drugs and their target selections. Based on the knowledge base, a bioinformatics approach for cancer drugs selection in precision medicine is developed. It integrates personal molecular profile data, including copy number variation, mutation, and gene expression. RESULTS: By analyzing the 85 triple negative breast cancer (TNBC) patient data in the Cancer Genome Altar, we have shown that 71.7% of the TNBC patients have FDA approved drug targets, and 51.7% of the patients have more than one drug target. Sixty-five drug targets are identified as TNBC treatment targets and 85 candidate drugs are recommended. Many existing TNBC candidate targets, such as Poly (ADP-Ribose) Polymerase 1 (PARP1), Cell division protein kinase 6 (CDK6), epidermal growth factor receptor, etc., were identified. On the other hand, we found some additional targets that are not yet fully investigated in the TNBC, such as Gamma-Glutamyl Hydrolase (GGH), Thymidylate Synthetase (TYMS), Protein Tyrosine Kinase 6 (PTK6), Topoisomerase (DNA) I, Mitochondrial (TOP1MT), Smoothened, Frizzled Class Receptor (SMO), etc. Our additional analysis of target and drug selection strategy is also fully supported by the drug screening data on TNBC cell lines in the Cancer Cell Line Encyclopedia. CONCLUSIONS: The proposed bioinformatics approach lays a foundation for cancer precision medicine. It supplies much needed knowledge base for the off-label cancer drug usage in clinics

Efficacy of Different Leuprolide Administration Schedules in Premenopausal Breast Cancer: A Retrospective Review

Background Leuprolide is a safe and effective treatment of estrogen receptor–positive premenopausal breast cancer. Data from the SOFT/TEXT trials solidified leuprolide in combination with an aromatase inhibitor as an effective hormonal treatment for premenopausal breast cancer. However, the efficacy of monthly leuprolide depot compared to leuprolide depot every 3 months in combination with an aromatase inhibitor in this patient population is unclear. Patients and Methods In this single center retrospective study, 201 patients were enrolled between January 1, 2015, and October 1, 2016; 100 were included in the 7.5 mg leuprolide monthly injection plus aromatase inhibitor group and 101 in the 22.5 mg leuprolide injection every 3 months plus aromatase inhibitor group. The primary end point was the proportion of patients who experienced ovarian ablation, defined as an estradiol concentration less than 40 pg/mL and a follicle-stimulating hormone concentration of 23 to 116 mU/mL after 3 months of treatment. Significance threshold was P < .05 (2 sided). Secondary end points included disease-free survival and overall survival at 1-year follow-up, as well as adverse events reported during treatment. Results All patients in the monthly leuprolide arm experienced ovarian ablation compared to 100 (99%) of 101 patients in the arm treated every 3 months ( P = 1). The disease-free survival rate at 1 year was 95% in the monthly leuprolide arm and 97% in the arm treated every 3 months ( P = .75). The overall survival rate at 1 year was 100% in the monthly leuprolide arm and 99% in the arm treated every 3 months ( P = 1). The most common treatment-related adverse events between the 2 groups were musculoskeletal pain, hot flashes, fatigue, and insomnia. Conclusion Leuprolide acetate depot administered every 3 months is as efficacious and tolerable as a monthly injection in combination with an aromatase inhibitor for premenopausal patients with hormone receptor–positive breast cancer

Incremental Prognostic Value of Echocardiographic Strain and Its Association with Mortality in Cancer Patients

Background Left ventricular global longitudinal systolic strain (GLS) has been shown to be superior to ejection fraction in detecting subclinical dysfunction in patients with cancer and predicting mortality in patients with cardiovascular disease. Cancer-related fatigue is common in the later stages of neoplastic malignancies and may be indicative of nonovert heart failure. The aim of this study was to determine whether reduced strain by echocardiography was associated with all-cause mortality in a cancer cohort. Methods In this retrospective study, 120 patients with cancer undergoing or scheduled to undergo chemotherapy and with normal ejection fractions (>50%) underwent assessments of GLS. GLS was derived by averaging all speckle-tracking strain segments of the left ventricle. Results Over an average follow-up period of 21.6 ± 13.9 months, 57 of 120 patients died. Univariate predictors of all-cause mortality (P < .10) were Eastern Cooperative Oncology Group performance status, male sex, hematologic malignancy, β-blocker use, and GLS. Multivariate analysis of all significant univariate variables showed that Eastern Cooperative Oncology Group performance status (hazard ratio, 2.12; 95% confidence interval, 1.54–2.92; P < .001), male sex (hazard ratio, 1.93; 95% confidence interval, 1.14–3.27; P = .014), and GLS (hazard ratio, 0.89; 95% confidence interval, 0.81–0.97; P = .012) were significantly and independently associated with mortality. Stepwise analysis of the multivariate associations showed an increase in the global χ2 value after adding GLS (P = .011) to significant clinical variables. Conclusions Eastern Cooperative Oncology Group performance status, male sex, and GLS were significantly associated with all-cause mortality in patients with cancer with normal ejection fractions receiving chemotherapy. Adding GLS to significant clinical variables provided incremental prognostic information

Analytical Validation of Variants to Aid in Genotype-Guided Therapy for Oncology

The Clinical Laboratory Improvement Amendments (CLIA) of 1988 requires that pharmacogenetic genotyping methods need to be established according to technical standards and laboratory practice guidelines before testing can be offered to patients. Testing methods for variants in ABCB1, CBR3, COMT, CYP3A7, C8ORF34, FCGR2A, FCGR3A, HAS3, NT5C2, NUDT15, SBF2, SEMA3C, SLC16A5, SLC28A3, SOD2, TLR4, and TPMT were validated in a CLIA-accredited laboratory. As no known reference materials were available, DNA samples that were from Coriell Cell Repositories (Camden, NJ) were used for the analytical validation studies. Pharmacogenetic testing methods developed here were shown to be accurate and 100% analytically sensitive and specific. Other CLIA-accredited laboratories interested in offering pharmacogenetic testing for these genetic variants, related to genotype-guided therapy for oncology, could use these publicly available samples as reference materials when developing and validating new genetic tests or refining current assays

Neutrino Halos in Clusters of Galaxies and their Weak Lensing Signature

We study whether non-linear gravitational effects of relic neutrinos on the development of clustering and large-scale structure may be observable by weak gravitational lensing. We compute the density profile of relic massive neutrinos in a spherical model of a cluster of galaxies, for several neutrino mass schemes and cluster masses. Relic neutrinos add a small perturbation to the mass profile, making it more extended in the outer parts. In principle, this non-linear neutrino perturbation is detectable in an all-sky weak lensing survey such as EUCLID by averaging the shear profile of a large fraction of the visible massive clusters in the universe, or from its signature in the general weak lensing power spectrum or its cross-spectrum with galaxies. However, correctly modeling the distribution of mass in baryons and cold dark matter and suppressing any systematic errors to the accuracy required for detecting this neutrino perturbation is severely challenging.Comment: 13 pages, 11 figures. Submitted to JCA

Pilot trial of paclitaxel-trastuzumab adjuvant therapy for early stage breast cancer: a trial of the ECOG-ACRIN cancer research group (E2198)

BACKGROUND: Blockade of human epidermal growth factor receptor type 2 (HER2) has dramatically improved outcome for patients with HER2-positive breast cancer. Trastuzumab, an anti-HER2 monoclonal antibody, has previously demonstrated improvement in overall survival (OS) in patients with metastatic and early stage HER2-positive breast cancer. However, trastuzumab can cause congestive heart failure (CHF) with an increased frequency for patients who have also received an anthracycline. The current trial was designed to evaluate the impact of the duration of trastuzumab on CHF. METHODS: E2198 included 227 eligible women with histologically confirmed stage II or IIIA HER2-positive breast cancer. The patients were randomised to receive 12 weeks of paclitaxel and trastuzumab followed by four cycles of doxorubicin and cyclophosphamide (abbreviated Arm) or the aforementioned treatment with additional 1 year of trastuzumab (conventional Arm). The primary end point was to evaluate the safety of this variable duration of trastuzumab therapy, particularly cardiac toxicity defined as CHF or left ventricular ejection fraction decrease >10%. Secondary end points included disease-free survival (DFS) and OS. RESULTS: Compared with 12-week treatment with trastuzumab, 1 year of trastuzumab-based therapy did not increase the frequency or severity of cardiac toxicity: three patients on the abbreviated Arm and four on the conventional Arm experienced CHF. The 5-year DFS was 76% and 73% for the abbreviated and conventional Arms, respectively, with a hazard ratio (HR) of 1.3 (95% CI: 0.8-2.1; P=0.3). There was also no statistically significance difference in OS (HR, 1.4; P=0.3). CONCLUSIONS: Compared with 12 weeks of treatment, 1 year of treatment with trastuzumab did not significantly increase the risk of cardiac toxicity. Although not powered for efficacy comparisons, the longer duration of trastuzumab therapy did not demonstrate a signal for marked superiority

Non-parametric strong lens inversion of SDSS J1004+4112

In this article we study the well-known strong lensing system SDSS J1004+4112. Not only does it host a large-separation lensed quasar with measured time-delay information, but several other lensed galaxies have been identified as well. A previously developed strong lens inversion procedure that is designed to handle a wide variety of constraints, is applied to this lensing system and compared to results reported in other works. Without the inclusion of a tentative central image of one of the galaxies as a constraint, we find that the model recovered by the other constraints indeed predicts an image at that location. An inversion which includes the central image provides tighter constraints on the shape of the central part of the mass map. The resulting model also predicts a central image of a second galaxy where indeed an object is visible in the available ACS images. We find masses of 2.5x10^13 M_O and 6.1x10^13 M_O within a radius of 60 kpc and 110 kpc respectively, confirming the results from other authors. The resulting mass map is compatible with an elliptical generalization of a projected NFW profile, with r_s = 58_{-13}^{+21} arcsec and c_vir = 3.91 +/- 0.74. The orientation of the elliptical NFW profile follows closely the orientation of the central cluster galaxy and the overall distribution of cluster members.Comment: 11 pages, accepted for publication in MNRA

Phase II Study of Celecoxib and Docetaxel in Non-small Cell Lung Cancer (NSCLC) Patients with Progression after Platinum-Based Therapy

IntroductionTo evaluate the efficacy and toxicity of the combination of celecoxib and docetaxel in patients with advanced non-small cell lung cancer after failure of platinum-based therapy.MethodsPatients with relapsed non-small cell lung cancer received celecoxib 400 mg orally twice daily beginning 7 days before the first cycle of docetaxel and the celecoxib was continued with no interruption. Docetaxel 75 mg/m2 was administered intravenously on a 21-day cycle. The primary end point of the study was the 6-month survival rate.ResultsTwenty-four patients were enrolled and twenty patients were treated (median age 60, M:F 16:8). Most patients had a baseline performance status of 1. The objective response rate was 10% (95% confidence interval [CI], 0–25%) and the 6-month survival rate was 59% (95% CI 37–80%). Median survival time was 6.9 months (95% CI, 2.8–15.2 months) and the 1- and 2-year survival rates were 36% (95% CI, 15–57%) and 1% (95% CI, 0–10%), respectively. The most frequent grade ≥3 adverse events were neutropenia (58%) and neutropenic fever (21%) which resulted in early closure of the trial.ConclusionsThe addition of celecoxib to docetaxel did not seem to improve the response rate and survival compared with docetaxel alone. The combination demonstrated considerable neutropenia and complications from febrile neutropenia that suggests celecoxib may enhance the marrow toxicity of docetaxel

Adiposity, Physical Function, and Their Associations With Insulin Resistance, Inflammation, and Adipokines in CKD

Rationale & Objectives: Adiposity and physical fitness levels are major drivers of cardiometabolic risk, but these relationships have not been well-characterized in chronic kidney disease (CKD). We examined the associations of visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), intrahepatic fat, and physical function with inflammation, insulin resistance, and adipokine levels in patients with CKD. Study Design: Prospective cohort study. Setting & Participants: Participants with stages 3-5 CKD not receiving maintenance dialysis, followed up at one of 8 clinical sites in the Chronic Renal Insufficiency Cohort (CRIC) Study, and who underwent magnetic resonance imaging of the abdomen at an annual CRIC Study visit (n = 419). Predictors: VAT volume, SAT volume, intrahepatic fat, body mass index, waist circumference, and time taken to complete the 400-m walk test (physical function). Outcomes: Markers of inflammation (interleukin 1β [IL-1β], IL-6, tumor necrosis factor receptor 1 [TNFR1], and TNFR2), insulin resistance (homeostasis model assessment of insulin resistance), and adipokine levels (adiponectin, total and high molecular weight, resistin, and leptin). Analytical Approach: Multivariable linear regression of VAT and SAT volume, intrahepatic fat, and physical function with individual markers (log-transformed values), adjusting for relevant covariates. Results: Mean age of the study population was 64.3 years; 41% were women, and mean estimated glomerular filtration rate was 53.2 ± 14.6 (SD) mL/min/1.73 m2. More than 85% were overweight or obese, and 40% had diabetes. Higher VAT volume, SAT volume, and liver proton density fat fraction were associated with lower levels of total and high-molecular-weight adiponectin, higher levels of leptin and insulin resistance, and lower high-density lipoprotein cholesterol and higher serum triglyceride levels. A slower 400-m walk time was associated only with higher levels of leptin, total adiponectin, plasma IL-6, and TNFR1 and did not modify the associations between fat measures and cardiometabolic risk factors. Limitations: Lack of longitudinal data and dietary details. Conclusions: Various measures of adiposity are associated with cardiometabolic risk factors. Physical function was also associated with the cardiometabolic risk factors studied and does not modify associations between fat measures and cardiometabolic risk factors. Longitudinal studies of the relationship between body fat and aerobic fitness with cardiovascular and kidney disease progression are warranted