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Davidson B.L.,University of Washington | Verheijen S.,University of Amsterdam | Lensing A.W.A.,Bayer AG | Gebel M.,Bayer AG | And 4 more authors.
JAMA Internal Medicine | Year: 2014

IMPORTANCE Combined anticoagulant and aspirin therapy is associated with increased bleeding risk in patients with atrial fibrillation, but the bleeding risk of combined use of anticoagulant and nonsteroidal anti-inflammatory drugs (NSAIDs) is poorly documented. OBJECTIVE To estimate the bleeding risk of combined anticoagulant (rivaroxaban or enoxaparin-vitamin K antagonist [VKA]) and NSAID or aspirin therapy in patients with venous thromboembolism. DESIGN, SETTING, AND PARTICIPANTS Prospective analysis of observational data from the EINSTEIN deep vein thrombosis and pulmonary embolism clinical trials comparing rivaroxaban with enoxaparin-VKA treatment, trials performed in hospitals and clinics in 8246 patients enrolled from 2007 to 2009. EXPOSURE Bleeding event rates during exposure to NSAID and aspirin therapy were compared to time without exposure. MAIN OUTCOMES AND MEASURES Days of NSAID or aspirin use and nonuse, clinically relevant bleeding event and major bleeding event rates by patient-years, and hazard ratios. RESULTS During NSAID-anticoagulant concomitant treatment, clinically relevant bleeding occurred with an event rate of 37.5 per 100 patient-years vs 16.6 per 100 patient-years during anticoagulant use only (hazard ratio [HR], 1.77 [95%CI, 1.46-2.14]). Major bleeding during NSAID-anticoagulant treatment occurred with an event rate of 6.5 per 100 patient-years, compared to 2.0 per 100 patient-years during nonuse (HR, 2.37 [95%CI, 1.51-3.75]). For aspirin-anticoagulant concomitant treatment, clinically relevant bleeding occurred with an event rate of 36.6 per 100 patient-years, compared to 16.9 per 100 patient-years during aspirin nonuse (HR, 1.70 [95%CI, 1.38-2.11]). Major bleeding in aspirin-anticoagulant-treated patients occurred with an event rate of 4.8 per 100 patient-years, compared to 2.2 per 100 patient-years during aspirin nonuse (HR, 1.50 [95%CI, 0.86-2.62]). Increases in risk for clinically relevant and major bleeding were similar for rivaroxaban and enoxaparin-VKA anticoagulation regimens. CONCLUSIONS AND RELEVANCE Among patients with venous thromboembolism receiving anticoagulant therapy, concomitant use of an NSAID or aspirin is associated with an increased risk of clinically relevant and major bleeding. Copyright 2014 American Medical Association. All rights reserved.


PubMed | The Oncology Institute of Hope & Innovation, Drug Safety Navigator LLC, Heron Therapeutics Inc., EMB Statistical Solutions LLC and 8 more.
Type: Journal Article | Journal: Future oncology (London, England) | Year: 2016

APF530, extended-release granisetron, provides sustained release for 5 days for acute- and delayed-phase chemotherapy-induced nausea and vomiting (CINV). We compared efficacy and safety of APF530 versus ondansetron for delayed CINV after highly emetogenic chemotherapy (HEC), following a guideline-recommended three-drug regimen.HEC patients received APF530 500 mg subcutaneously or ondansetron 0.15 mg/kg intravenously, with dexamethasone and fosaprepitant. Primary end point was delayed-phase complete response (no emesis or rescue medication).A higher percentage of APF530 versus ondansetron patients had delayed-phase complete response (p = 0.014). APF530 was generally well tolerated; treatment-emergent adverse event incidence was similar across arms, mostly mild-to-moderate injection-site reactions.APF530 versus the standard three-drug regimen provided superior control of delayed-phase CINV following HEC. ClinicalTrials.gov : NCT02106494.


PubMed | Oncology Hematology Care, Tongji University, Center of Oncology of Poland, Clopton Clinic and 12 more.
Type: Journal Article | Journal: Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer | Year: 2016

Therapeutic antibodies to immune checkpoints show promising results. Programmed death-ligand 1 (PD-L1), an immune checkpoint ligand, blocks the cancer immunity cycle by binding the PD-L1 receptor (programmed death 1). We investigated PD-L1 protein expression and messenger RNA (mRNA) levels in SCLC.PD-L1 protein expression and mRNA levels were determined by immunohistochemistry (IHC) with SP142 and Dako 28-8 PD-L1 antibodies and in situ hybridization in primary tumor tissue microarrays in both tumor cells and tumor-infiltrating immune cells (TIICs) obtained from a limited-disease SCLC cohort of 98 patients. An additional cohort of 96 tumor specimens from patients with extensive-disease SCLC was assessed for PD-L1 protein expression in tumor cells with Dako 28-8 antibody only.The overall prevalence of PD-L1 protein expression in tumor cells was 16.5%. In the limited-disease cohort, the prevalences of PD-L1 protein expression in tumor cells with SP142 and Dako 28-8 were 14.7% and 19.4% (tumor proportion score cutoff 1%) and PD-L1 mRNA ISH expression was positive in 15.5% of tumor samples. Increased PD-L1 protein/mRNA expression was associated with the presence of more TIICs (p < 0.05). The extensive-disease cohort demonstrated a 14.9% positivity of PD-L1 protein expression in tumor cells with Dako 28-8 antibody.A subset of SCLCs is characterized by positive PD-L1 and/or mRNA expression in tumor cells. Higher PD-L1 and mRNA expression correlate with more infiltration of TIICs. The prevalence of PD-L1 in SCLC is lower than that published for NSCLC. The predictive role of PD-L1 expression in SCLC treatment remains to be established.


Andre F.,University Paris - Sud | O'Regan R.,Emory University | Ozguroglu M.,Istanbul University | Toi M.,Kyoto University | And 20 more authors.
The Lancet Oncology | Year: 2014

Background: Disease progression in patients with HER2-positive breast cancer receiving trastuzumab might be associated with activation of the PI3K/Akt/mTOR intracellular signalling pathway. We aimed to assess whether the addition of the mTOR inhibitor everolimus to trastuzumab might restore sensitivity to trastuzumab. Methods: In this randomised, double-blind, placebo-controlled, phase 3 trial, we recruited women with HER2-positive, trastuzumab-resistant, advanced breast carcinoma who had previously received taxane therapy. Eligible patients were randomly assigned (1:1) using a central patient screening and randomisation system to daily everolimus (5 mg/day) plus weekly trastuzumab (2 mg/kg) and vinorelbine (25 mg/m2) or to placebo plus trastuzumab plus vinorelbine, in 3-week cycles, stratified by previous lapatinib use. The primary endpoint was progression-free survival (PFS) by local assessment in the intention-to-treat population. We report the final analysis for PFS; overall survival follow-up is still in progress. This trial is registered with ClinicalTrials.gov, number NCT01007942. Findings: Between Oct 26, 2009, and May 23, 2012, 569 patients were randomly assigned to everolimus (n=284) or placebo (n=285). Median follow-up at the time of analysis was 20·2 months (IQR 15·0-27·1). Median PFS was 7·00 months (95% CI 6·74-8·18) with everolimus and 5·78 months (5·49-6·90) with placebo (hazard ratio 0·78 [95% CI 0·65-0·95]; p=0·0067). The most common grade 3-4 adverse events were neutropenia (204 [73%] of 280 patients in the everolimus group vs 175 [62%] of 282 patients in the placebo group), leucopenia (106 [38%] vs 82 [29%]), anaemia (53 [19%] vs 17 [6%]), febrile neutropenia (44 [16%] vs ten [4%]), stomatitis (37 [13%] vs four [1%]), and fatigue (34 [12%] vs 11 [4%]). Serious adverse events were reported in 117 (42%) patients in the everolimus group and 55 (20%) in the placebo group; two on-treatment deaths due to adverse events occurred in each group. Interpretation: The addition of everolimus to trastuzumab plus vinorelbine significantly prolongs PFS in patients with trastuzumab-resistant and taxane-pretreated, HER2-positive, advanced breast cancer. The clinical benefit should be considered in the context of the adverse event profile in this population. Funding: Novartis Pharmaceuticals Corporation. © 2014 Elsevier Ltd.


Lyons R.M.,Cancer Care Centers of South Texas | Marek B.J.,U.S. Oncology | Marek B.J.,Texas Oncology South Texas Cancer Center | Paley C.,Novartis | And 5 more authors.
Leukemia Research | Year: 2014

This 5-year, prospective registry enrolled 600 lower-risk MDS patients (pts) with transfusional iron overload. Clinical outcomes were compared between chelated and nonchelated pts. At baseline, cardiovascular comorbidities were more common in non-chelated pts, and MDS therapy was more common in chelated pts. At 24 months, chelation was associated with longer median overall survival (52.2 months vs. 104.4 months; p< .0001) and a trend toward longer leukemia-free survival and fewer cardiac events. No differences in safety were apparent between groups. Limitations of this analysis included, varying time from diagnosis and duration of chelation, and the fact that the decision to chelate may have been influenced by pt clinical status. © 2013 The Authors.


Di Bella N.,U.S. Oncology Research Inc. | Di Bella N.,Rocky Mountain Cancer Centers | Taetle R.,U.S. Oncology Research Inc. | Kolibaba K.,U.S. Oncology Research Inc. | And 14 more authors.
Blood | Year: 2010

This study evaluated the efficacy and safety of single-agent bortezomib in indolent B-cell lymphoma that had relapsed from or was refractory to rituximab. Sixty patients enrolled: 59 were treated with bortezomib 1.3 mg/m2 on days 1, 4, 8, and 11 for up to eight 21-day cycles; responders could receive 4 additional cycles; maintenance was optional. Fifty-three evaluable patients completed more than 2 cycles. The median age was 70 years, 53% female, Ann Arbor stage III-IIIE (28%) and IV (65%); 43 patients (72%) had more than 2 prior regimens; and 6 patients went on to maintenance. Overall responses are as follows: 1 complete response (1.9%), 3 unconfirmed complete response (5.7%), 3 partial response (5.7%), 34 stable disease (64.2%), and 12 progressive disease (22.6%). Median time to response = 2.2 months (range, 1.2-5.3 months); duration of response = 7.9 months (2.8-21.3 months); 1-year survival was 73% and 2-year survival was 58%; median survival = 27.7 months (range, 1.4-30.9 months); median progression-free survival = 5.1 months (range, 0.2-27.7 months), median time to progression = 5.1 months (range, 0.2-27.7 months), and median event-free survival = 1.8 months (range, 0.2-27.7 months). Treatment-related grade 3 or 4 adverse events included: thrombocytopenia (20%), fatigue (10%), neutropenia (8.5%), and neuropathy and diarrhea (6.8% each). This study demonstrates that bortezomib has modest activity against marginal zone and follicular lymphoma; it has the potential for combination with other agents in low-grade lymphomas. Maintenance therapy should be explored further. © 2010 by The American Society of Hematology.


Wilks S.T.,Cancer Care Centers of South Texas
Breast | Year: 2015

Human epidermal growth factor receptor 2 (HER2) overexpression occurs in up to 30% of breast cancers and is a marker of aggressive disease. While HER2-targeted therapies have improved outcomes in these tumors, resistance to these agents develops in a large proportion of patients. Determining molecular mechanisms underlying resistance might help improve outcomes for patients with HER2-positive disease by allowing development of strategies to overcome resistance. Activation of signaling pathways involving the phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) pathway might contribute to the development of resistance to HER2-targeted therapies. Several inhibitors of this pathway are under investigation in this disease setting and phase 3 data for everolimus in combination with trastuzumab and chemotherapy in trastuzumab-refractory, advanced disease are promising. In this review, molecular mechanisms underlying resistance to HER2-targeted therapies are considered and evidence for strategies to manage resistance is evaluated, including the use of inhibitors of the PI3K/Akt/mTOR pathway. © 2015 The Author.


Lyons R.M.,Cancer Care Centers of South Texas | Wilks S.T.,Cancer Care Centers of South Texas | Young S.,Telik | Brown G.L.,Telik
Journal of Hematology and Oncology | Year: 2011

Idiopathic chronic neutropenia (ICN) describes a heterogeneous group of hematologic diseases characterized by low circulating neutrophil levels often associated with recurrent fevers, chronic mucosal inflammation, and severe systemic infections. The severity and risk of complications, including serious infections, are inversely proportional to the absolute neutrophil count (ANC), with the greatest problems occurring in patients with an ANC of less than 0.5 × 10 9/L. This case report describes a 64-year-old female with longstanding rheumatoid arthritis who subsequently developed ICN with frequent episodes of sepsis requiring hospitalization and prolonged courses of antibiotics over a 4-year period. She was treated with granulocyte colony stimulating factors (G-CSF) but had a delayed, highly variable, and volatile response. She was enrolled in a clinical trial evaluating the oral investigational agent ezatiostat. Ezatiostat, a glutathione S-transferase P1-1 inhibitor, activates Jun kinase, promoting the growth and maturation of hematopoietic progenitor stem cells. She responded by the end of the first month of treatment with stabilization of her ANC (despite tapering and then stopping G-CSF), clearing of fever, and healing of areas of infection. This ANC response to ezatiostat treatment has now been sustained for over 8 months and continues. These results suggest potential roles for ezatiostat in the treatment of patients with ICN who are not responsive to G-CSF, as an oral therapy alternative, or as an adjunct to G-CSF, and further studies are warranted. © 2011 Lyons et al; licensee BioMed Central Ltd.


Manea P.J.,Cancer Care Centers of South Texas
Clinical Journal of Oncology Nursing | Year: 2014

Myelofibrosis (MF) is a rare myeloproliferative neoplasm of the bone marrow associated with shortened survival. The disease is characterized by splenomegaly, cytopenias, and multiple disease-related symptoms that reduce quality of life. The clinical management of MF can be challenging because of its heterogeneous presentation and disease course. Therefore, knowledge of the underlying pathology and clinical manifestations of MF is needed. Ruxolitinib, a Janus kinase (JAK) 1 and 2 inhibitor, is the first therapy to be approved by the U.S. Food and Drug Administration for intermediate- or high-risk MF. Ruxolitinib therapy offers advantages over the previous palliative treatments and has shown durable reductions in splenomegaly and disease symptoms as well as improvements in quality of life. Two-year follow-up of the phase III trials also has shown that ruxolitinib treatment was associated with a survival advantage relative to control groups. Dose-dependent thrombocytopenia and anemia are expected but manageable adverse effects caused by the targeted JAK inhibition of ruxolitinib. This review provides an overview of MF and assessment of the primary clinical disease manifestations, with a focus on ruxolitinib from the oncology nurse perspective. © Oncology Nursing Society.


PubMed | Cancer Care Centers of South Texas
Type: Journal Article | Journal: Medical physics | Year: 2016

To quantify the dosimetric impact of the tandem loading in the treatment of cervical cancer for HDR brachytherapy procedures.Ten patients were evaluated, each of whom received 5 fractions of treatment. Tandem and ovoid sets were inserted into the uterine cavity based on institutional protocols and procedures. Following insertion and stabilization, CT image sets of 1.5mm slice thickness were acquired and sent to the Oncentra V4.3 Treatment Planning System. Critical structures such as the CTV, bladder, rectum, sigmoid, and bowel were contoured and a fractional dose of 5.5Gy was prescribed to Point A for each patient. Six different treatment plans were created for each fraction using varying tandem weightings; from 0.5 to 1.4 times that of the ovoids. Surface dose evaluation of various ovoid diameters, 2.0-3.5cm, at the vaginal fornices was also investigated.Critical structures were evaluated based on varying dose and volume constraints, in particular the 2.0 cc volume recommendation cited by the gynecological GEC-ESTRO working group. Based on dose volume histogram evaluation, a reduction of dose to the critical structures was most often discovered when the tandem weighting was increased. CTV coverage showed little change as the tandem weighting was varied. Ovoid surface dose decreased by 50-65% as the tandem weighting increased.The advantage of 3D planning with HDR brachytherapy is the dose optimization for each individual treatment plan. This investigation shows that by utilizing large tandem weightings, 1.4 times greater than the ovoid, one can still achieve adequate coverage of the CTV and relatively low doses to the critical structures. In some cases, one would still have to optimize further per individual case. In addition, the ovoid surface dose was greatly decreased when large tandem weighting was utilized; especially for small ovoid diameters.

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