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Bates M.,Monogram Biosciences | Sperinde J.,Monogram Biosciences | Kostler W.J.,Medical University of Vienna | Ali S.M.,Lebanon Veterans Affairs Medical Center | And 11 more authors.
Annals of Oncology | Year: 2011

Background: Patients with metastatic breast cancer (MBC) overexpressing HER2 (human epidermal growth factor receptor 2) are currently selected for treatment with trastuzumab, but not all patients respond. Patients and methods: Using a novel assay, HER2 protein expression (H2T) was measured in formalin-fixed, paraffin-embedded primary breast tumors from 98 women treated with trastuzumab-based therapy for MBC. Using subpopulation treatment effect pattern plots, the population was divided into H2T low (H2T < 13.8), H2T high (H2T ≥ 68.5), and H2T intermediate (13.8 ≤ H2T < 68.5) subgroups. Kaplan-Meier (KM) analyses were carried out comparing the groups for time to progression (TTP) and overall survival (OS). Cox multivariate analyses were carried out to identify correlates of clinical outcome. Bootstrapping analyses were carried out to test the robustness of the results. Results: TTP improved with increasing H2T until, at the highest levels of H2T, an abrupt decrease in the TTP was observed. KM analyses demonstrated that patients with H2T low tumors [median TTP 4.2 months, hazard ratio (HR) = 3.7, P < 0.0001] or H2T high tumors (median TTP 4.6 months, HR = 2.7, P = 0.008) had significantly shorter TTP than patients whose tumors were H2T intermediate (median TTP 12 months). OS analyses yielded similar results. Conclusions: MBC patients with very high levels of H2T may represent a subgroup with de novo resistance to trastuzumab. These results are preliminary and require confirmation in larger controlled clinical cohorts. © The Author 2011. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.


PubMed | Carolinas Medical Center, U.S. National Institutes of Health, Lebanon Veterans Affairs Medical Center and Walter Reed Army Institute of Research
Type: Journal Article | Journal: Military medicine | Year: 2015

Orthopedic trauma remains one of the most survivable battlefield injuries seen in modern conflicts. Translating research into practice is a critical bridge that permits surgeons to further optimize medical outcomes. Orthopedic surgeons serving in the military may treat little to no trauma in their stateside practice. In conflict zones, however, the majority of their patients will have traumatic injuries. Determining risk factors for nonevidence-based practice can help identify provider knowledge gaps, which can then be targeted before deployment. Surveys were developed which sought to identify factors contributing to continued medical education and practice, as well as scenario-based questions on military-relevant orthopedic trauma. Analysis of 188 survey respondents revealed that providers with military service and less than 10 years of practice are optimally bridging research into military-relevant orthopedic trauma practice.


Woodruff A.E.,New York University | Woodruff A.E.,Buffalo General Medical Center | Kelley A.M.,Lebanon Veterans Affairs Medical Center | Hempel C.A.,New York University | And 6 more authors.
Annals of Pharmacotherapy | Year: 2016

Background: Loop diuretics play a crucial role in symptom management in patients with fluid overload. There is a paucity of data regarding optimal diuretic dose at hospital discharge for acute decompensated heart failure (ADHF) patients requiring loop diuretics. Objective: To compare all-cause 30-day readmission in ADHF patients on chronic loop diuretics who had an increase in loop diuretic dose at discharge (relative to their preadmission dose) with patients without a change or a decrease in loop diuretic dose at discharge. Methods: This was a multicenter, retrospective cohort study. Institutional review board approval was obtained. Patients admitted with a primary discharge diagnosis of heart failure, evidence of fluid overload, and reduced ejection fraction were included. Patients were divided into 2 groups based on total daily loop diuretic dose at discharge: those discharged on an increased dose and those discharged on a dose less than or equal to their preadmission dose. Results: A total of 131 patient admissions met inclusion criteria; 50 had an increase in loop diuretic dose at discharge, and 81 were discharged with no change or a decrease in diuretic dose. Patients in the increased dose group had an all-cause 30-day readmission rate of 20% compared with 38% of patients with no change or a decrease in diuretic dose (adjusted odds ratio = 0.320; 95% CI = 0.117-0.873). Conclusion: In patients admitted for ADHF with reduced ejection fraction and evidence of fluid overload, an increase in loop diuretic dose at discharge was associated with a reduced rate of 30-day hospital readmission. © 2016, © The Author(s) 2016.


Malinowski J.M.,Wilkes University | Gehret M.M.,Lebanon Veterans Affairs Medical Center
American Journal of Health-System Pharmacy | Year: 2010

Purpose. The efficacy and safety of phytosterols for the management of dyslipidemia are reviewed. Summary. Phytosterols have been evaluated in over 40 clinical trials. The incorporation of 2 g of phytosterols daily into margarine, mayonnaise, orange juice, olive oil, low-fat milk, yogurt, and tablets is associated with significant reductions in lowdensity-lipoprotein (LDL) cholesterol from baseline over 1-12 months in adults with normal or high cholesterol, in children, and in patients with type 2 diabetes mellitus. Phytosterol dosages of 1.6-3 g daily have been shown to reduce LDL cholesterol by 4.1-15% versus placebo within the first month of therapy. One meta-analysis found mean reductions of 10-11%, but results vary. Several placebo-controlled trials found that the addition of phytosterols to statin therapy was associated with reductions of 7-20% in LDL cholesterol for up to 1.5 years. Overall, phytosterols are useful for reducing LDL cholesterol in patients who cannot reach their treatment goal by diet alone or who are taking maximum tolerated doses of statins. These products offer an alternative to statins in patients who cannot take statins or whose statin dosage is restricted because of potential drug interactions or concomitant diseases. Commonly reported adverse effects are primarily gastrointestinal in nature. Conclusion. Phytosterol therapy produces an average 10-11% reduction in LDL cholesterol concentration, but it is unknown whether this effect persists beyond two years. Phytosterol products are well tolerated and have few drug interactions, but their long-term safety has not been established. Current evidence is sufficient to recommend phytosterols for lowering LDL cholesterol in adults.


Lipton A.,Pennsylvania State University | Kostler W.J.,Medical University of Vienna | Leitzel K.,Pennsylvania State University | Ali S.M.,Pennsylvania State University | And 7 more authors.
Cancer | Year: 2010

BACKGROUND: Only a portion of breast cancer patients currently selected for trastuzumab therapy respond. METHODS: Using a novel assay (HERmark) to quantify total human epidermal growth factor receptor 2 (HER2) expression, the authors examined outcomes in 102 trastuzumab-treated metastatic breast cancer patients previously assessed as immunohistochemistry (IHC) 3+ by local but not central IHC, or fluorescence in situ hybridization (FISH) positive, and then retested by central FISH. RESULTS: Of 102 MBC patients previously scored as IHC 3+ or 2+/FISH-positive and treated with trastuzumab-containing regimens, 98 had both central FISH and HER2 total expression values. Sixty-six of 76 central FISH-positive patients (87%) had high HER2 total expression levels (concordant positive), and 19 of 22 central FISH-negative patients (86%) were HER2 total expression low (concordant negative). Fourteen percent (3 of 22) of central FISH-negative patients were HER2 total expression high (discordant HER2 total expression high), and 13% (10 of 76) of central FISH-positive patients were HER2 total expression low (discordant HER2 total expression low). The concordant positive group had a significantly longer time to progression (TTP, median = 11.3 months) compared with the concordant negative group (median TTP, 4.5 months; hazard ratio [HR] = 0.42, P <.001), and also compared with the discordant HER2 total expression low group (median TTP, 3.7 months; HR = 0.43, P =.01). The discordant HER2 total expression low group behaved similarly compared with concordant negatives (HR = 1, P =.99). In analyses restricted to central FISH-positive patients only (n = 77), Cox proportional hazards multivariate regression identified HER2 total expression as an independent predictor of TTP (HR = 0.29, P =.0015) and overall survival (HR = 0.19, P <.001). CONCLUSIONS: A subset of patients with HER2 gene amplification by FISH express low levels of HER2 protein and have reduced response to trastuzumab-containing therapy, similar to FISH-negative patients. This cohort represents a training dataset, and the observed relationships and derived cutoffs require validation in an independent cohort of trastuzumab-treated metastatic breast cancer patients. © 2010 American Cancer Society.


Lipton A.,Pennsylvania State University | Lipton A.,Lebanon Veterans Affairs Medical Center | Lipton A.,Queen's University | Lipton A.,University of Toronto | And 46 more authors.
Journal of Clinical Oncology | Year: 2011

Purpose: We investigated the association of bone-only relapse with a pretreatment marker of bone resorption: serum beta C-terminal telopeptide (B-CTx) of type I collagen. Methods: Pretreatment serum B-CTx concentrations were determined from 621 of 667 patients with primary breast cancer enrolled onto the NCIC CTG MA.14 phase III adjuvant trial of tamoxifen with or without octreotide. Recurrence-free survival (RFS) was a secondary end point; the focus here was bone-only relapse. We analyzed continuous or categorical (.71 ng/mL cut point) serum B-CTx in stepwise forward multivariate Cox regression, adjusted for trial stratification factors. We also examined B-CTx and bone relapse by pretrial chemotherapy status. Results: At median 7.9 years follow-up, 123 of 621 patients experienced recurrence; 19 (3.1%) of 621 had bone-only recurrence, and 47 (7.5%) of 621 had bone plus other sites of recurrence. Larger pathologic tumor size (P = .001) and elevated continuous and categorical serum B-CTx were associated with shorter bone-only RFS (both P = .02) when added to a model with factors significant in the main trial analyses (hazard ratio [HR], 3.43 and 3.50, respectively; 95% CI, 1.20 to 9.77 and 1.26 to 9.75, respectively). The univariate HR for B-CTx was 2.80 (95% CI, 1.05 to 7.48; P = .03). Elevated serum B-CTx was also associated with shorter bone-only RFS (P = .02) when added to a model with factors significant in the main trial analyses. Serum B-CTx level was not associated with any other type of recurrence. Serum B-CTx was not significantly different for patients who underwent pretrial chemotherapy, compared with those who did not (P=.27), nor did pretrial chemotherapy affect bone relapse (P = .48 for bone only; P = .76 for bone with other relapse). Conclusion: Higher pretreatment serum B-CTx was a significant predictor of shorter RFS for bone-only metastasis. Increased bone resorption creates an environment that promotes growth of breast cancer cells. © 2011 by American Society of Clinical Oncology.


Lipton A.,Pennsylvania State University | Goodman L.,Monogram Biosciences | Goodman L.,Biodesix | Leitzel K.,Pennsylvania State University | And 30 more authors.
Breast Cancer Research and Treatment | Year: 2013

Trastuzumab is effective in the treatment of HER2/neu over-expressing breast cancer, but not all patients benefit from it. In vitro data suggest a role for HER3 in the initiation of signaling activity involving the AKT-mTOR pathway leading to trastuzumab insensitivity. We sought to investigate the potential of HER3 alone and in the context of p95HER2 (p95), a trastuzumab resistance marker, as biomarkers of trastuzumab escape. Using the VeraTag ® assay platform, we developed a dual antibody proximity-based assay for the precise quantitation of HER3 total protein (H3T) from formalin-fixed paraffin-embedded (FFPE) breast tumors. We then measured H3T in 89 patients with metastatic breast cancer treated with trastuzumab-based therapy, and correlated the results with progression-free survival and overall survival using Kaplan-Meier and decision tree analyses that also included HER2 total (H2T) and p95 expression levels. Within the sub-population of patients that over-expressed HER2, high levels of HER3 and/or p95 protein expression were significantly associated with poor clinical outcomes on trastuzumab-based therapy. Based on quantitative H3T, p95, and H2T measurements, multiple subtypes of HER2-positive breast cancer were identified that differ in their outcome following trastuzumab therapy. These data suggest that HER3 and p95 are informative biomarkers of clinical outcomes on trastuzumab therapy, and that multiple subtypes of HER2-positive breast cancer may be defined by quantitative measurements of H3T, p95, and H2T. © 2013 The Author(s).


Vong K.S.,Southern Nevada Healthcare System | Koons K.A.,Lebanon Veterans Affairs Medical Center | Carnes P.A.,Lebanon Veterans Affairs Medical Center
American Journal of Health-System Pharmacy | Year: 2013

Purpose. The development and implementation of a nontraditional pharmacy residency program at a Veterans Affairs medical center (VAMC) are described. Summary. The nontraditional pharmacy residency program at Lebanon VAMC was designed in accordance with the ASHP accreditation standard. The residency program was structured to meet staff needs without compromising patient care or significantly affecting the pharmacy services provided. The purpose statement, intended outcomes, and learning goals and objectives of the nontraditional pharmacy residency program were formulated to be equivalent to those of a traditional one-year pharmacy residency program, enabling practicing pharmacists to obtain similar overall learning experiences. The nontraditional residency program at Lebanon VAMC spans two years. The non-traditional program structure is based on a four- to six-week residency learning experience that alternates with a comparable time in the work schedule. Each required or elective learning experience ranges from four to six weeks. Longitudinal learning experiences may extend up to two years. One pharmacist was matched and began the residency in July 2012 as the inaugural nontraditional postgraduate year 1 (PGY1) pharmacy resident at Lebanon VAMC, the second institution to implement the nontraditional program within the Veterans Health Administration. The resident is expected to complete the program in June 2014 and remain committed to the Lebanon VAMC pharmacy service for a minimum of two years thereafter. Conclusion. A nontraditional PGY1 pharmacy residency program was successfully developed and implemented for pharmacists who aspire to complete residency training and improve their clinical, leadership, and preceptorship skills.

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