Performance of HER2 DAKO HercepTest and Ventana 4B5 immunohistochemical assays on detecting HER2 gene-amplification in uterine serous carcinomas.

We compared the performance of two commonly-used HER2 immunohistochemistry (IHC) assays in uterine serous carcinomas (USC), correlating with HER2 gene amplification by fluorescence in-situ hybridization (FISH). Sixty-five USCs were stained by both HercepTest™ and PATHWAY 4B5 assays. FISH was performed by HER2 IQFISH pharmDx. Consensus HER2 IHC scoring was performed, and HER2 testing results were evaluated using USC-specific criteria. Complete concordance between HercepTest and 4B5 assays was achieved in 44/65 tumors (68%). The overall HER2 IHC/FISH concordance was 94% (45/48) by HercepTest and 91% (42/46) by 4B5. All HER2 IHC 3+ cases with HercepTest (n = 6) and 4B5 (n = 4) were gene-amplified, corresponding to specificities of 100%. For cases with IHC 2+, 41% (7/17) by HercepTest and 42% (8/19) by 4B5 had HER2 gene amplification. The sensitivity for HercepTest and 4B5 were 38% and 25%, respectively, at a cut-off of IHC 3+ (P = 0.50), and were 81% and 75%, respectively, at a cut-off of IHC 2+ (P > 0.99). Among HER2 IHC 0-1+ cases, 3/42 cases by HercepTest and 4/42 cases by 4B5 showed amplified FISH results, corresponding to overall false negative rates of 19% for HercepTest and 25% for 4B5. By using USC-specific IHC scoring criteria, both HercepTest and 4B5 assays showed high specificities (100%) for HER2 gene amplification in IHC 3+ cases, high IHC/FISH concordance, and comparable sensitivity for detecting HER2 gene amplification. The notable false negative rates using IHC 2+ as a cut-off for reflexing FISH analysis may warrant consideration for performing FISH in IHC 1+ cases until more data become available.

Gagné's 9 Events of Instruction With Active Learning: Teaching Student Pharmacists How to Measure Blood Pressure.

As the scope of practice for pharmacists expands to include rendering physical assessment procedures, colleges and schools of pharmacy are increasingly incorporating various assessment skills into the curriculum. Pharmacy practice faculty are increasingly tasked with teaching and assessing learners on professional competency in entrustable professional activities and skills such as manual blood pressure measurement. Manual measurement using a sphygmomanometer and a stethoscope is considered the gold standard with regard to evaluating blood pressure. As pharmacy faculty begin to develop courses on physical assessment, a step-by-step, evidence-based andragogic/pedagogic method for designing, planning, instructing, and assessing learner proficiency is essential. The principles and techniques of active learning are frequently discussed and increasingly incorporated into the curricular and teaching philosophies of colleges and schools of pharmacy. However, the practical application of andragogic/pedagogic principles toward lesson planning and curation of active learning is infrequently discussed. In this article, we aim to illustrate a deliberate approach to designing and operationalizing active learning for auscultatory manual blood pressure measurement within the framework of Gagné's 9 events of instruction. For each design and instruction step, we propose user-friendly, high-impact operational practices derived empirically from education science, experience, and observations. Schematically, the approach described is intended to also facilitate instructor metacognition and knowledge building of applied andragogy/pedagogy through pre hoc, ad hoc, and post hoc reflection. Pragmatically, the approach accommodates active learning lesson planning, promotes transparency of teaching and learning, and is generalizable and applicable toward the instruction of various physical assessment procedures within the health professions.

Overview of current and emerging therapies for amytrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a devastating, fatal neuromuscular disease. Most patients die within 2 to 5 years of diagnosis. The disease stems from death of upper and lower motor neurons leading to degeneration of motor pathways and the paralytic effects of the disease. The economic cost of the disease is not clear, with estimates ranging from about $64,000 per year to $200,000. Two drugs, riluzole and edaravone, are currently FDA approved for the treatment of ALS, and each provides modest benefits in mortality and/or function. Recent developments in the understanding of the underlying pathophysiologic processes that contribute to ALS have led to the development of numerous investigational therapies, with several now in phase 3 trials. This article highlights the oral tyrosine kinase inhibitor masitinib; the antisense drug tofersen; the humanized monoclonal antibody C5 complement inhibitor ravulizumab-cwvz; and mesenchymal stem cell (MSC)-neurotrophic factor (NTF) cells, a proprietary platform that induces autologous bone marrow-derived MSCs to secrete high levels of NTFs.

Systematic Literature Review of Quetiapine for the Treatment of Psychosis in Patients With Parkinsonism.

OBJECTIVE: The purpose of this article was to determine the efficacy and tolerability of quetiapine compared with placebo or other interventions for psychosis in parkinsonism. METHODS: Participants with a diagnosis of parkinsonism participated in randomized controlled trials (RCTs) investigating the efficacy and tolerability of quetiapine for psychotic symptoms within a defined follow-up period. The authors conducted searches on PubMed, Cochrane Controlled Register of Trials, and EMBASE for articles published from January 1991 to October 2017. Study methodology and patient- and treatment-level data were independently extracted and summarized by using descriptive statistics. Studies underwent quality assessment for risk of bias. RESULTS: A total of 17,615 unique records were identified, and seven RCTs (total N=241) met inclusion criteria. Five RCTs were placebo controlled, and two compared quetiapine against clozapine. The mean study duration was 12 weeks, and the mean daily quetiapine dose was 103 mg per day (range, 12.5-300 mg). In four of five placebo-controlled RCTs, quetiapine failed to demonstrate significant improvement of psychosis in parkinsonism compared with placebo. In two clozapine-comparator RCTs, quetiapine was better tolerated but no more effective than clozapine. Across all RCTs, the mean completion rates for quetiapine, clozapine, and placebo were 66%, 68.5%, and 66%, respectively. Quetiapine did not significantly worsen motor function. CONCLUSIONS: The efficacy of quetiapine in RCTs for psychosis in parkinsonism is no better than that for placebo or clozapine. On the basis of novel data, clinicians should reevaluate traditional viewpoints on the benefits of quetiapine for psychosis in parkinsonism.

Standing and Supine Blood Pressure Outcomes Associated With Droxidopa and Midodrine in Patients With Neurogenic Orthostatic Hypotension: A Bayesian Meta-analysis and Mixed Treatment Comparison of Randomized Trials.

BACKGROUND: The comparative effects of droxidopa and midodrine on standing systolic blood pressure (sSBP) and risk of supine hypertension in patients with neurogenic orthostatic hypotension (NOH) are unknown. OBJECTIVE: To perform a Bayesian mixed-treatment comparison meta-analysis of droxidopa and midodrine in the treatment of NOH. METHODS: The PubMed, CENTRAL, and EMBASE databases were searched up to November 16, 2016. Study selection consisted of randomized trials comparing droxidopa or midodrine with placebo and reporting on changes in sSBP and supine hypertension events. Data were pooled to perform a comparison among interventions in a Bayesian fixed-effects model using vague priors and Markov chain Monte Carlo simulation with Gibbs sampling, calculating pooled mean changes in sSBP and risk ratios (RRs) for supine hypertension with associated 95% credible intervals (CrIs). RESULTS: Six studies (4 administering droxidopa and 2 administering midodrine) enrolling a total of 783 patients were included for analysis. The mean change from baseline in sSBP was significantly greater for both drugs when compared with placebo (droxidopa 6.2 mm Hg [95% CrI = 2.4-10] and midodrine 17 mm Hg [95% CrI = 11.4-23]). Comparative analysis revealed a significant credible difference between droxidopa and midodrine. The RR for supine hypertension was significantly greater for midodrine, but not droxidopa, when compared with placebo (droxidopa RR = 1.4 [95% CrI = 0.7-2.7] and midodrine RR = 5.1 [95% CrI = 1.6-24]). Conclusion and Relevance: In patients with NOH, both droxidopa and midodrine significantly increase sSBP, the latter to a greater extent. However, midodrine, but not droxidopa, significantly increases risk of supine hypertension.

Comparison of the Pharmacokinetics of Droxidopa After Dosing in the Fed Versus Fasted State and with 3-Times-Daily Dosing in Healthy Elderly Subjects.

BACKGROUND: Droxidopa is an oral prodrug of norepinephrine approved for the treatment of symptomatic neurogenic orthostatic hypotension. This two-part, randomized, crossover study evaluated the 24-h pharmacokinetic profile of droxidopa in 24 healthy elderly subjects. METHODS: Noncompartmental analysis was used to calculate the area under the plasma concentration-time curve (AUC), maximum plasma concentration (Cmax), time of Cmax (tmax), and elimination half-life (t½e) of droxidopa and metabolites. Droxidopa was administered in the fed (high-fat/high-calorie meal) or fasted state either as a single 300-mg dose (three 100-mg capsules) or 3 times/day (TID) (three 100-mg capsules) at 4-h intervals. RESULTS: Administration of a single droxidopa dose in the fed versus fasted state decreased mean Cmax (2057 vs 3160 ng/mL) and mean AUC (10,927 vs 13,857 h × ng/mL) and increased median tmax twofold (4.00 vs 2.00 h). Differences between the fed and fasted state for mean t½e (2.58 vs 2.68 h) were not observed. Fed versus fasted geometric mean ratios for Cmax and AUC were 66% [90% confidence interval (CI) 60.7-71.7] and 80% (90% CI 72.6-88.1), respectively. With TID dosing, similar values for Cmax were observed after each dose (range 2789-3389 ng/mL) with no return to baseline between doses. Norepinephrine Cmax was 895 pg/mL following dose 1, with no further increases upon subsequent doses; norepinephrine levels remained above baseline for 12-16 h after dose 1. CONCLUSIONS: Absorption of a single dose of droxidopa is slowed after a high-fat/high-calorie meal; for consistent effect, administer droxidopa in the same manner (with or without food). Pharmacokinetic parameters of droxidopa are similar after single and TID dosing. ClinicalTrials.gov Identifier: NCT01149629.

RimabotulinumtoxinB in sialorrhea: systematic review of clinical trials.

OBJECTIVE: The aim of this study was to examine the efficacy, safety and dosing practices of rimabotulinumtoxinB (BoNT-B) for the treatment of patients with sialorrhea based on a systematic review of clinical trials. METHODS: A systematic literature review was performed to identify randomized controlled trials and other comparative clinical studies of BoNT-B for the treatment of sialorrhea published in English between January 1999 and December 2015. Medical literature databases (PubMed, Cochrane Library, and EMBASE) were searched and a total of 41 records were identified. Of these, six primary publications that evaluated BoNT-B for the treatment of sialorrhea met criteria and were included in the final data report. SYNTHESIS: Total BoNT-B doses ranged from 1500 to 4000 units for sialorrhea. Most of the studies in sialorrhea showed statistically significant benefits of BoNT-B versus placebo (range 4-19.2 weeks). BoNT-B was generally well tolerated across the individual studies; most adverse events reported were considered unrelated to treatment. Adverse events considered potentially associated with BoNT-B included: dry mouth, change in saliva thickness, mild transient dysphagia, mild weakness of chewing and diarrhea. CONCLUSIONS: BoNT-B significantly reduces sialorrhea at doses between 1500 and 4000 units. The relatively mild dose-dependent adverse events suggest both direct and remote toxin effects.

Multicenter observational study of abobotulinumtoxinA neurotoxin in cervical dystonia: The ANCHOR-CD registry.

BACKGROUND: The ANCHOR-CD prospective observational registry study evaluated the effectiveness of abobotulinumtoxinA in adult idiopathic cervical dystonia (CD) in clinical practice. METHODS: Adults with CD were eligible. Treating physicians determined abobotulinumtoxinA dose and treatment interval. The primary endpoint was patient response rate (Toronto Western Spasmodic Torticollis Rating Scale [TWSTRS] score reduction≥25% and Patient Global Impression of Change [PGIC] score of +2 or +3 at Week 4 of Cycle 1). RESULTS: 350 patients enrolled (75% women; mean age 59±13.6years; 27.4% botulinum neurotoxin-naive) and 347 received at least 1 treatment. The median abobotulinumtoxinA dose for Cycle 1 was 500 Units. At Week 4, the responder rate was 30.6% (n=304) and the TWSTRS total score decreased 27.4% from baseline. PGIC of at least "Much improved" was documented in 43.6% of patients and maintained in Cycles 2 through 4 (43.3%, 48.9%, and 52.8%, respectively). A total of 39 adverse events (31 study drug-related) were reported in 17 patients (5%); the most common were dysphagia (n=6), muscle weakness (n=4), and neck pain (n=3). CONCLUSION: This study confirmed the beneficial effect of abobotulinumtoxinA on CD in routine clinical practice as measured by improvements in TWSTRS and PGIC. No new safety concerns were identified.

Treatment of psychotic symptoms in patients with Parkinson disease.

Persistent psychotic symptoms will develop in up to 60% of patients with Parkinson disease (PD). The initial approach to the management of PD psychosis (PDP) begins with addressing concurrent systemic conditions associated with psychotic behavior, such as delirium, medical conditions (eg, infections), psychiatric disorders (eg, major depression with psychotic symptoms, mania, schizophrenia), and substance misuse or withdrawal. A review of current medications is recommended, and medications that may trigger psychotic symptoms should be eliminated. If possible, antiparkinson medications should be reduced to the minimum therapeutic dose or discontinued in a sequential manner. Generally, dose reduction or discontinuation of anticholinergics is attempted first, followed by that of monoamine oxidase B inhibitors, amantadine, dopamine agonists, catechol-O-methyltransferase inhibitors, and lastly carbidopa/levodopa. The aim of antiparkinson medication dose reduction is to achieve a balance between improving drug-related psychotic symptoms and not significantly worsening the motor symptoms of PD. If additional measures are needed for chronic PDP treatment, the use of second-generation antipsychotics, such as clozapine, pimavanserin, or quetiapine, must be considered. The first-generation antipsychotics (eg, fluphenazine, haloperidol) are not recommended. In the patient with comorbid dementia, the addition of a cholinesterase inhibitor might also be beneficial for PDP. The choice of agent is based on patient-specific parameters, potential benefit, and side effects.

Pharmacotherapeutic management of pseudobulbar affect.

This activity will update pharmacists and other healthcare professionals on current treatments for pseudobulbar affect (PBA). Points of discussion will focus on the off-label therapies traditionally used to treat PBA, the FDA-approved combination drug product with PBA as an indication, and managed care aspects of treating PBA.

OnabotulinumtoxinA and AbobotulinumtoxinA Dose Conversion: a Systematic Literature Review.

OBJECTIVE: This systematic review was performed to elucidate dosing practices, dosing conversions, and related outcomes from randomized controlled trials that directly compared onabotulinumtoxinA (ONA) and abobotulinumtoxinA (ABO) at various dose conversion ratios for therapeutic use in movement disorders. METHODS: A systematic review of 3 medical literature databases (PubMed, the Cochrane Library, and EMBASE) was performed to identify relevant comparative clinical studies, systematic reviews, and meta-analyses published in the English language between January 1991 and January 2015. Studies that met predefined inclusion criteria were selected for formal data extraction and quality assessment. RESULTS: A total of 182 manuscripts were identified, of which 4 were included for analysis. Targeted clinical applications included neurological disorders. The studies compared ONA to ABO dose conversion ratios of 1:2.5 (n=1), 1:3 (n=2), and 1:4 (n=2). One study compared both 1:3 and 1:4 ratios. An ONA:ABO conversion factor of 1:2.5 was associated with similar efficacy and side effects. An ONA:ABO ratio of 1:3 provided similar or higher efficacy but an increased rate of adverse effects, and an ONA:ABO ratio of 1:4 was associated with higher efficacy but with an excessive rate of intolerable side effects. CONCLUSION: A dose conversion ratio of ONA to ABO between 1:2.5 and 1:3.0 provides comparable safety and efficacy for therapeutic movement disorders chemodenervation procedures.

Systematic Literature Review of AbobotulinumtoxinA in Clinical Trials for Lower Limb Spasticity.

To elucidate clinical trial efficacy, safety, and dosing practices of AbobotulinumtoxinA (ABO) treatment in adult patients with lower limb spasticity.A systematic literature review was performed to identify randomized controlled trials of ABO in the treatment of adult lower limb spasticity.Of the 295 records identified, 6 primary publications evaluated ABO for the management of lower limb spasticity of various etiologies and were evaluated. Total ABO doses ranged between 500 and 2000 U for lower limb spasticity, depending on the muscles injected. All studies in lower limb spasticity showed statistically significant reduction in muscle tone based on Modified Ashworth Scale of ABO versus placebo. Significant effects on active movement and pain were demonstrated albeit less consistently. ABO was generally well tolerated across the individual studies; most adverse events reported were considered unrelated to treatment. Treatment-related adverse events included but not limited to fatigue, local pain at injection site, hypertonia, dry mouth, weakness of the noninjected muscle, abnormal gait, and urinary tract infection.These data from 6 randomized clinical studies provide the beginnings of an evidence base for the use of ABO to reduce lower limb spasticity. Ongoing studies in this area will add to this evidence base.

Botulinum neurotoxin for the treatment of blepharospasm, cervical dystonia, adult spasticity, and headache: Payment policy perspectives.

This article is presented as a companion to the American Academy of Neurology guideline update on the use of botulinum neurotoxin (BoNT) for the treatment of blepharospasm, cervical dystonia, adult spasticity, and headache. Whereas the guideline update provides clarity on the efficacy of different BoNT-branded preparations for the 4 listed indications, this companion piece identifies ambiguities in the evidence for efficacy among various brand names for a given clinical indication, their dosing equivalencies, as well as different clinical indications. This article provides guidance and background information to reduce obstacles for third party payment, especially when uncertainties exist and levels of evidence are lower.

Systematic Literature Review of AbobotulinumtoxinA in Clinical Trials for Blepharospasm and Hemifacial Spasm.

BACKGROUND: The aim was to elucidate clinical trial efficacy, safety, and dosing practices of abobotulinumtoxinA (ABO) treatment in adult patients with blepharospasm and hemifacial spasm. To date, most literature reviews for blepharospasm and hemifacial spasm have examined the effectiveness of all botulinum neurotoxin type A products as a class. However, differences in dosing units and recommended schemes provide a clear rationale for reviewing each product separately. METHODS: A systematic literature review was performed to identify randomized controlled trials and other comparative clinical studies of ABO in the treatment of blepharospasm and hemifacial spasm published in English between January 1991 and March 2015. Medical literature databases (PubMed, Cochrane library, EMBASE) were searched. A total of five primary publications that evaluated ABO for the management of blepharospasm and hemifacial spasm were identified and summarized. RESULTS: Data included 374 subjects with blepharospasm and 172 subjects with hemifacial spasm treated with ABO. Total ABO doses ranged between 80 and 340 U for blepharospasm and 25 and 85 U for hemifacial spasm, depending on the severity of the clinical condition. All studies showed statistically significant benefits for the treatment of blepharospasm and hemifacial spasm. ABO was generally well tolerated across the individual studies. Adverse events considered to be associated with ABO treatment included: ptosis, tearing, blurred vision, double vision, dry eyes, and facial weakness. DISCUSSION: These data from 5 randomized clinical studies represents the available evidence base of ABO in blepharospasm and hemifacial spasm. Future studies in this area will add to this evidence base.

Clinical Outcomes in Patients with Parkinson's Disease Treated with a Monoamine Oxidase Type-B inhibitor: A Cross-Sectional, Cohort Study.

STUDY OBJECTIVE: To evaluate the long-term risk of developing cognitive symptoms (e.g., dementia, hallucinations), dyskinesia, falls, and freezing of gait (FoG) in patients with Parkinson's disease (PD) who received monoamine oxidase type B inhibitors (MAOB-Is) compared with patients who had never received MAOB-Is. DESIGN: Retrospective, cross-sectional, cohort study. SETTING: Academic movement disorders clinic. PATIENTS: One hundred eighty-one patients with idiopathic PD who were receiving MAOB-I therapy on a long-term basis for a minimum of 1 year (MAOB-I current-user cohort) and 121 patients with idiopathic PD who had never received MAOB-I therapy (MAOB-I never-user cohort [control group]) between January 1, 1996, and November 30, 2011. MEASUREMENTS AND MAIN RESULTS: The five study outcome variables were dementia, dyskinesia, falls, FoG, and hallucinations. Baseline and outcome data were collected from medical records. Patients in the MAOB-I current-user group were included only if absence of the specified outcomes was documented at baseline. Adjusted multiple logistic regression analyses were performed to calculate the odds ratios (ORs) for MAOB-I use versus never use on clinical outcomes. MAOB-I treatment was associated with a 44.7% reduced risk of dyskinesia (adjusted OR 0.553, 95% confidence interval 0.314-0.976, p=0.041), with the greatest risk reduction observed after 2 years of treatment. No significant association was noted with MAOB-I use and development of dementia, falls, FoG, or hallucinations. CONCLUSION: Long-term use of MAOB-I therapy was associated with reduced risk of dyskinesia in patients with PD.

Effect of exercise on motor and nonmotor symptoms of Parkinson's disease.

Background. Novel rehabilitation strategies have demonstrated potential benefits for motor and non-motor symptoms of Parkinson's disease (PD). Objective. To compare the effects of Lee Silverman Voice Therapy BIG (LSVT BIG therapy) versus a general exercise program (combined treadmill plus seated trunk and limb exercises) on motor and non-motor symptoms of PD. Methods. Eleven patients with early-mid stage PD participated in the prospective, double-blinded, randomized clinical trial. Both groups received 16 one-hour supervised training sessions over 4 weeks. Outcome measures included the Unified Parkinson's Disease Rating Scale (UPDRS), Beck Depression Inventory (BDI), Beck Anxiety Inventory (BAI) and Modified Fatigue Impact Scale (MFIS). Five patients performed general exercise and six patients performed LSVT BIG therapy. Post-intervention evaluations were conducted at weeks 4, 12 and 24. Results. The combined cohort made improvements at all follow-up evaluations with statistical significance for UPDRS total and motor, BDI, and MFIS (P < 0.05). Conclusion. This study demonstrated positive effects of general exercise and LSVT BIG therapy on motor and non-motor symptoms of patients with PD. Our results suggest that general exercise may be as effective as LSVT BIG therapy on symptoms of PD for patients not able to readily access outpatient LSVT BIG therapy.

Systematic literature review of abobotulinumtoxinA in clinical trials for adult upper limb spasticity.

OBJECTIVE: The aim of this study was to elucidate clinical trial efficacy, safety, and dosing practices of abobotulinumtoxinA (ABO) treatment in adult patients with upper limb spasticity (ULS). METHODS: A systematic literature review was performed to identify randomized controlled trials and other comparative clinical studies of ABO in the treatment of adult ULS published in English between January 1991 and January 2013. Medical literature databases (PubMed, Cochrane Library, and EMBASE) were searched, and a total of 295 records were identified. Of these, 12 primary publications that evaluated ABO for the management of ULS were included in the final data report. SYNTHESIS: Total ABO doses ranged between 500 and 1500 U for ULS. Most of the studies in ULS showed statistically significant benefits (reduction in muscle tone based on Ashworth score) of ABO vs. placebo. Statistical significance was reached for most evaluations of spasticity using the Modified Ashworth Scale. Statistically significant effects on active movement and pain were demonstrated, albeit less consistently. ABO was generally well tolerated across the individual studies; most adverse events reported were considered unrelated to treatment. Adverse events considered associated with ABO treatment included fatigue, tiredness, arm pain, skin rashes, flu-like symptoms, worsening of spasm, and weakness. CONCLUSIONS: On the basis of data extracted from 12 randomized clinical studies, a strong evidence base (9/12 studies) exists for the use of ABO to reduce ULS caused by stroke.