Performance of plasma p-tau217 for the detection of amyloid-ß positivity in a memory clinic cohort using an electrochemiluminescence immunoassay.

BACKGROUND: Plasma p-tau217 has emerged as the most promising blood-based marker (BBM) for the detection of Alzheimer Disease (AD) pathology, yet few studies have evaluated plasma p-tau217 performance in memory clinic settings. We examined the performance of plasma p-tau217 for the detection of AD using a high-sensitivity immunoassay in individuals undergoing diagnostic lumbar puncture (LP). METHODS: Paired plasma and cerebrospinal fluid (CSF) samples were analysed from the TIMC-BRAiN cohort. Amyloid (Aß) and Tau (T) pathology were classified based on established cut-offs for CSF Aß42 and CSF p-tau181 respectively. High-sensitivity electrochemiluminescence (ECL) immunoassays were performed on paired plasma/CSF samples for p-tau217, p-tau181, Glial Fibrillary Acidic Protein (GFAP), Neurofilament Light (NfL) and total tau (t-tau). Biomarker performance was evaluated using Receiver-Operating Curve (ROC) and Area-Under-the-Curve (AUC) analysis. RESULTS: Of 108 participants (age: 69 ± 6.5 years; 54.6% female) with paired samples obtained at time of LP, 64.8% (n = 70/108) had Aß pathology detected (35 with Mild Cognitive Impairment and 35 with mild dementia). Plasma p-tau217 was over three-fold higher in Aß + (12.4 pg/mL; 7.3-19.2 pg/mL) vs. Aß- participants (3.7 pg/mL; 2.8-4.1 pg/mL; Mann-Whitney U = 230, p < 0.001). Plasma p-tau217 exhibited excellent performance for the detection of Aß pathology (AUC: 0.91; 95% Confidence Interval [95% CI]: 0.86-0.97)-greater than for T pathology (AUC: 0.83; 95% CI: 0.75-0.90; z = 1.75, p = 0.04). Plasma p-tau217 outperformed plasma p-tau181 for the detection of Aß pathology (z = 3.24, p < 0.001). Of the other BBMs, only plasma GFAP significantly differed by Aß status which significantly correlated with plasma p-tau217 in Aß + (but not in Aß-) individuals. Application of a two-point threshold at 95% and 97.5% sensitivities & specificities may have enabled avoidance of LP in 58-68% of cases. CONCLUSIONS: Plasma p-tau217 measured using a high-sensitivity ECL immunoassay demonstrated excellent performance for detection of Aß pathology in a real-world memory clinic cohort. Moving forward, clinical use of plasma p-tau217 to detect AD pathology may substantially reduce need for confirmatory diagnostic testing for AD pathology with diagnostic LP in specialist memory services.

Treatment patterns for patients with BRCA1/2-positive metastatic castration-resistant prostate cancer.

BACKGROUND: Patients with BRCA-positive metastatic castration-resistant prostate cancer (mCRPC) have an aggressive disease course. This study aimed to describe real-world treatment patterns among patients with BRCA-positive mCRPC. MATERIALS AND METHODS: De-identified electronic health record data from the Flatiron Health-Foundation Medicine Inc. Metastatic Prostate Cancer Clinico-Genomic Database (January 01, 2011 to June 30, 2022) were used to select patients with BRCA-positive mCRPC initiating first-line (1L) therapy with an oncologist-defined advanced line of therapy (LOT) or androgen deprivation therapy (ADT) monotherapy. Treatment sequences and reasons for censoring were described in 1L, and among patients who initiated a second-line (2L) therapy. RESULTS: A total of 98 treated patients with BRCA-positive mCRPC were identified. The top 3 treatment regimens in 1L, overall, were ADT monotherapy (19%), enzalutamide (14%), and olaparib (13%). The main reason for censoring patients with ADT monotherapy was death (52.6%). Among 79 patients treated with an advanced LOT in 1L, 43.0% (n = 34) did not initiate a 2L therapy, of which, 29.4% died. In patients who initiated a 2L (n = 45), the most common 1L to 2L treatment sequence was olaparib to docetaxel (11.1%). The most prescribed 2L therapies were docetaxel (22.2%), olaparib (20.0%), abiraterone acetate (13.3%), and enzalutamide (11.1%). From 1L initiation, the median time-to-next-treatment was 6.2 months. CONCLUSION: Among patients with BRCA-positive mCRPC, ADT monotherapy, enzalutamide, and olaparib were most commonly used. Prognosis of BRCA-positive patients was poor, with most patients failing initial therapy resulting in a switch to a new therapy or death. These findings highlight the need for earlier and more effective treatments for patients with BRCA-positive mCRPC.

Real-world economic burden associated with disease progression from metastatic castration-sensitive to castration-resistant prostate cancer on treatment in the United States.

BACKGROUND: The advent of next-generation imaging will likely reduce nonmetastatic prostate cancer (PC) prevalence and increase identification of metastatic prostate cancer cases, resulting in two predominant advanced stages in the metastatic setting. There is a need to characterize changes in health care resource utilization (HRU) and costs when metastatic castration-sensitive PC (mCSPC) progresses to metastatic castration-resistant PC (mCRPC) to identify value drivers from current and new treatments. OBJECTIVE: To describe treatment patterns, HRU, and total health care costs among patients with mCSPC, before and after progression to mCRPC. METHODS: Clinical data from the Flatiron Metastatic PC Core Registry (January 1, 2013, to December 1, 2021) and linked claims from Komodo Health (January 1, 2014, to December 1, 2021) were used to identify patients with progression from mCSPC to mCRPC (date of progression was the index date) and subsequently initiated first-line mCRPC therapy on/after January 1, 2017. Treatment patterns and all-cause/PC-related HRU and health care costs were described per-patient-per-month (PPPM), separately for no more than 12 months pre-index (mCSPC disease state) and post-index (mCRPC disease state). Costs (payer's perspective) included those for services/procedures from medical claims and costs from pharmacy claims. Continuous HRU and costs were compared between the mCSPC and mCRPC disease states using Wilcoxon signed rank tests. RESULTS: Among 296 patients with mCSPC progressing to mCRPC (median age 69.0 years, 60.5% White, 15.9% Black), use of systemic therapies with androgen deprivation therapy increased dramatically from 35.1% in the mCSPC disease state to 92.9% in the mCRPC disease state, and use of androgen deprivation therapy monotherapy decreased from 25.7% to 2.4%, respectively. Although 39.2% received none of these therapies in the mCSPC disease state, this proportion decreased to 4.7% after transition to mCRPC. The mean number of days with PC-related outpatient visits increased from 1.57 to 2.16 PPPM in the mCSPC and mCRPC disease states (P < 0.001). From the mCSPC to mCRPC disease states, mean all-cause total health care costs PPPM increased from $4,424 (medical costs: $2,846) to $9,717 (medical costs: $4,654), and mean PC-related total health care costs PPPM increased from $2,859 (medical costs: $1,626) to $8,012 (medical costs: $3,285; all P < 0.001). CONCLUSIONS: In this real-world study of patients with disease progression from mCSPC to mCRPC in US clinical practice, nearly 2-in-3 patients did not receive treatment with additional systemic therapies before progression to castration resistance. Post-progression, mean PC-related total costs increased nearly 3-fold, with a more than 2-fold increase in PC-related medical costs. Use of additional systemic therapies may delay the time and cost associated with disease progression to castration resistance.

Comparison of Real-World On-Label Treatment Persistence in Patients with Psoriatic Arthritis Receiving Guselkumab Versus Subcutaneous Tumor Necrosis Factor Inhibitors.

BACKGROUND: Treatment persistence among patients with psoriatic arthritis (PsA) is essential for achieving optimal treatment outcomes. Guselkumab, a fully human interleukin-23p19-subunit inhibitor, was approved by the United States (US) Food and Drug Administration for the treatment of active PsA in July 2020, with a dosing regimen of 100 mg at week 0, week 4, then every 8 weeks. In the Phase 3 DISCOVER-1 and DISCOVER-2 studies of patients with active PsA, 94% of guselkumab-randomized patients completed treatment through 1 year and 90% did so through 2 years (DISCOVER-2). Real-world evidence is needed to compare treatment persistence while following US prescribing guidelines (i.e., on-label persistence) for guselkumab versus subcutaneous (SC) tumor necrosis factor inhibitors (TNFis). METHODS: Adults with PsA receiving guselkumab or their first SC TNFi (i.e., adalimumab, certolizumab pegol, etanercept, or golimumab) between 14 July 2020 and 31 March 2022 were identified in the IQVIA PharMetrics® Plus database (first claim defined the treatment start date [index date]). Baseline characteristics and biologic use (biologic-naïve/biologic-experienced) were assessed during the 12-month period preceding the index date. Baseline characteristics were balanced between cohorts using propensity-score weighting based on the standardized mortality ratio approach. The follow-up period spanned from the index date until the earlier of the end of continuous insurance eligibility or end of data availability. On-label persistence, defined as the absence of treatment discontinuation (based on a gap of 112 days for guselkumab or 56 days for SC TNFi) or any dose escalation/reduction during follow-up, was assessed in the weighted treatment cohorts using Kaplan-Meier (KM) curves. A Cox proportional hazards model, further adjusted for baseline biologic use, was used to compare on-label persistence between the weighted cohorts. RESULTS: The guselkumab cohort included 526 patients (mean age 49.8 years; 61.2% female) and the SC TNFi cohort included 1953 patients (mean age: 48.5 years; 60.2% female). After weighting, baseline characteristics were well balanced with a mean follow-up of 12.3-12.4 months across cohorts; 51.5% of patients in the guselkumab cohort and 16.7% in the SC TNFi cohort received biologics in the 12-month baseline period. Respective rates of treatment persistence at 3, 6, 9, and 12 months were 91.2%, 84.1%, 75.9%, and 71.5% for the guselkumab cohort versus 77.3%, 61.6%, 50.0%, and 43.7% for the SC TNFi cohort (all log-rank p < 0.001). At 12 months, patients in the guselkumab cohort were 3.0 times more likely than patients in the SC TNFi cohort to remain persistent on treatment (p < 0.001). Median time to discontinuation was not reached for the guselkumab cohort and was 8.9 months for the SC TNFi cohort. CONCLUSION: This real-world study employing US commercial health-plan claims data to assess on-label treatment persistence in PsA demonstrated that, at 12 months, guselkumab was associated with a 3 times greater likelihood of persistence compared with SC TNFi.

Discrete Relationships between Spatiotemporal Gait Characteristics and Domain-Specific Neuropsychological Performance in Midlife.

Midlife risk factors such as type 2 diabetes mellitus (T2DM) confer a significantly increased risk of cognitive impairment in later life with executive function, memory, and attention domains often affected first. Spatiotemporal gait characteristics are emerging as important integrative biomarkers of neurocognitive function and of later dementia risk. We examined 24 spatiotemporal gait parameters across five domains of gait previously linked to cognitive function on usual-pace, maximal-pace, and cognitive dual-task gait conditions in 102 middle-aged adults with (57.5 ± 8.0 years; 40% female) and without (57.0 ± 8.3 years; 62.1% female) T2DM. Neurocognitive function was measured using a neuropsychological assessment battery. T2DM was associated with significant changes in gait phases and rhythm domains at usual pace, and greater gait variability observed during maximal pace and dual tasks. In the overall cohort, both the gait pace and rhythm domains were associated with memory and executive function during usual pace. At maximal pace, gait pace parameters were associated with reaction time and delayed memory. During the cognitive dual task, associations between gait variability and both delayed memory/executive function were observed. Associations persisted following covariate adjustment and did not differ by T2DM status. Principal components analysis identified a consistent association of slower gait pace (step/stride length) and increased gait variability during maximal-pace walking with poorer memory and executive function performance. These data support the use of spatiotemporal gait as an integrative biomarker of neurocognitive function in otherwise healthy middle-aged individuals and reveal discrete associations between both differing gait tasks and gait domains with domain-specific neuropsychological performance. Employing both maximal-pace and dual-task paradigms may be important in cognitively unimpaired populations with risk factors for later cognitive decline-with the aim of identifying individuals who may benefit from potential preventative interventions.

The quality of pharmacist-led community warfarin management across 2 provinces in Canada: A cross-sectional observational study.

Background: Guidelines for anticoagulation management services recommend personnel be specially trained in warfarin management and suggest using tools such as decision-support software. To date, there have been no Canadian studies documenting the quality of warfarin management using a similar guideline recommended approach. Methods: A cross-sectional, retrospective observational study was conducted to measure the quality of pharmacist-led warfarin management using point-of-care international normalized ratio (INR) testing and decision-support software in various ambulatory settings in Canada. Settings included 4 family health teams in Ontario and 40 community pharmacies across Nova Scotia. Quality was measured using time in therapeutic range (TTR) and was reported in 3 manners: mean TTR, median TTR and time-weighted mean TTR. Results: The primary outcome included 963 patients. The combined mean and median TTR for the 2019 Ontario family health teams and Nova Scotia pharmacies was 74.2% and 77.3% (interquartile range 64%-87.9%), respectively. The time-weighted mean TTR was 76.3%. Discussion: To the best of our knowledge, the TTR achieved by this model of care is the highest reported in Canadian general practice. Since Thrombosis Canada defines good-quality warfarin management as a TTR of 60% or greater, and many studies have reported an association between higher TTR values and lower rates of thrombosis and hemorrhage, this model of care may have significant benefits for patients. Conclusion: This study demonstrates the high quality of anticoagulation management provided by specially trained pharmacists using point-of-care INR testing and decision-support software. These results support expanded access to this service for all Canadians. Can Pharm J (Ott) 2024;157:xx-xx.

Frailty in an Adult Acute Hospital Population: Predictors, Prevalence, and Outcomes.

Frailty is common among older hospital inpatients. While studies describe frailty prevalence in acute hospitals, it is usually based upon retrospective hospital-coded data or brief screening on admission rather than comprehensive geriatric assessment (CGA). Further, little is known about differences between pre-admission and current frailty status. Given this, we investigated the prevalence of pre-frailty and frailty among adult inpatients in a large university hospital after CGA. Of the 410 inpatients available, 398 were included in the study, with a median age of 70 years; 56% were male. The median length of stay (LOS) at review was 8 days. The point prevalence of frailty was 30% versus 14% for pre-frailty. The median Clinical Frailty Scale score pre-admission was 3/9, which was significantly lower than at review, which was 4/9 (p < 0.001). After adjusting for age and sex, frailty was associated with greater odds of prolonged LOS (odds ratio [OR] 1.7, p = 0.045), one-year mortality (OR 2.1, p = 0.006), and one-year institutionalisation (OR 9, p < 0.001) but not re-admission. Frailty was most prevalent on medical and orthopaedic wards. In conclusion, CGA is an important risk assessment for hospitalised patients. Frailty was highly prevalent and associated with poor healthcare outcomes. Frailty status appears to worsen significantly during admission, likely reflecting acute illness, and it may not reflect a patient's true frailty level. The development of frailty clinical care pathways is recommended in order to address the poor prognosis associated with a diagnosis of frailty in this setting.

Impact of Frailty on Healthcare Outcomes after Cardioembolic Ischaemic Stroke Due to Atrial Fibrillation.

Stroke due to atrial fibrillation (AF) is more common in older adults. Frailty is associated with AF. As little is known about the impact of frailty on cardioembolic stroke, we examined its association with important healthcare outcomes including mortality and functional outcome in stroke with AF. Data were collected from patients presenting consecutively to a regional university hospital to assess pre-admission frailty using the Clinical Frailty Scale (CFS) and function with the Modified Rankin Scale (mRS). Stroke severity was assessed on the National Institute of Health Stroke Scale (NIHSS). In total, 113 patients presenting between August 2014 and July 2016 were identified with cardioembolic stroke, median age 80 years; 60% were male. Their median NIHSS score was 6. The median pre-admission CFS score was 3; 26.5% scored ≥5/9, indicating frailty. The median pre-admission mRS scores increased significantly from 1 to 3 at discharge (p < 0.001). Frailty was associated with worse mRS scores at discharge, odds ratio 1.5, (p = 0.03). While no patients with frailty were suitable to avail of early supported discharge, 10% of those without frailty were (p = 0.02). There was no significant difference in 30-day mortality. Frailty is prevalent among patients with cardioembolic stroke due to AF and was associated with poorer functional outcomes. Although the numbers were small, these data suggest that brief frailty assessments are useful to risk-stratify patients with acute cardioembolic stroke. Frailty status on admission with stroke due to AF can help identify those more likely to have poorer outcomes, to benefit from intervention, to require prolonged rehabilitation, and to avail of ESD.

A Comparison Between In-Person and Virtual Communication Skills OSCE for Medical Students.

Objectives: This study investigates the effectiveness of a virtual format of an advanced communication skills observed structured clinical examination (OSCE) for senior medical students in comparison to an in-person format. The study also examines the emotional support students experience in the virtual setting. Our analysis was based on quantitative data collected through objective checklists and post-OSCE survey results. Methods: The virtual OSCE was a revision of an earlier in-person formative advanced communication skills OSCE for fourth-year medical students. Student performances were assessed by self and peers using objective checklists-the modified Master Interview Rating Scale (mMIRS) and Communication Behavior Checklist (CBC). The mMIRS measured interview process such as avoiding jargon and demonstrating empathy. The CBC examined interview content which included tasks specific to the content of the case. The OSCE was followed by a faculty-led debrief and quantitative survey. The virtual OSCE was conducted in 2021, and the results of the checklists and survey were compared with those collected from two earlier in-person OSCEs. Results: Eighty-three students participated in the virtual OSCE. There was no difference in mMIRS scores between the virtual and in-person OSCE. Overall CBC scores were lower in the virtual OSCE compared to in-person (p < 0.05). Sixty-seven out of 83 (80.7%) students completed the post-OSCE survey. There were no differences between the virtual and in-person OSCE in terms of educational value, whether the OSCE would change the way participants talk to patients, and preparedness to have serious conversations with patients. All respondents somewhat or strongly agreed with feeling emotionally supported during the virtual OSCE. Conclusion: The virtual format was a suitable alternative to an in-person, formative, advanced communication skills OSCE for medical students. The virtual OSCE was educationally effective and was met with student satisfaction and a sense of emotional support. Future virtual iterations must ensure adequate instruction on interview content.

New horizons in the diagnosis and management of Alzheimer's Disease in older adults.

Alzheimer's Disease (ad) is the most common cause of dementia, and in addition to cognitive decline, it directly contributes to physical frailty, falls, incontinence, institutionalisation and polypharmacy in older adults. Increasing availability of clinically validated biomarkers including cerebrospinal fluid and positron emission tomography to assess both amyloid and tau pathology has led to a reconceptualisation of ad as a clinical-biological diagnosis, rather than one based purely on clinical phenotype. However, co-pathology is frequent in older adults which influence the accuracy of biomarker interpretation. Importantly, some older adults with positive amyloid or tau pathological biomarkers may never experience cognitive impairment or dementia. These strides towards achieving an accurate clinical-biological diagnosis are occurring alongside recent positive phase 3 trial results reporting statistically significant effects of anti-amyloid Disease-Modifying Therapies (DMTs) on disease severity in early ad. However, the real-world clinical benefit of these DMTs is not clear and concerns remain regarding how trial results will translate to real-world clinical populations, potential adverse effects (including amyloid-related imaging abnormalities), which can be severe and healthcare systems readiness to afford and deliver potential DMTs to appropriate populations. Here, we review recent advances in both clinical-biological diagnostic classification and future treatment in older adults living with ad. Advocating for access to both more accurate clinical-biological diagnosis and potential DMTs must be done so in a holistic and gerontologically attuned fashion, with geriatricians advocating for enhanced multi-component and multi-disciplinary care for all older adults with ad. This includes those across the ad severity spectrum including older adults potentially ineligible for emerging DMTs.

Cost of genetic testing, delayed care, and suboptimal treatment associated with polymerase chain reaction versus next-generation sequencing biomarker testing for genomic alterations in metastatic non-small cell lung cancer.

AIMS: To assess US payers' per-patient cost of testing associated with next-generation sequencing (NGS) versus polymerase chain reaction (PCR) biomarker testing strategies among patients with metastatic non-small cell lung cancer (mNSCLC), including costs of testing, delayed care, and suboptimal treatment initiation. METHODS: A decision tree model considered biomarker testing for genomic alterations using either NGS, sequential PCR testing, or hotspot panel PCR testing. Literature-based model inputs included time-to-test results, costs for testing/medical care, costs of delaying care, costs of immunotherapy [IO]/chemotherapy [CTX] initiation prior to receiving test results, and costs of suboptimal treatment initiation after test results (i.e. costs of first-line IO/CTX in patients with actionable mutations that were undetected by PCR that would have been identified with NGS). The proportion of patients testing positive for a targetable alteration, time to appropriate therapy initiation, and per-patient costs were estimated for NGS and PCR strategies combined. RESULTS: In a modeled cohort of 1,000,000 members (25% Medicare, 75% commercial), an estimated 1,119 had mNSCLC and received testing. The proportion of patients testing positive for a targetable alteration was 45.9% for NGS and 40.0% for PCR testing. Mean per-patient costs were lowest for NGS ($8,866) compared to PCR ($18,246), with lower delayed care costs of $1,301 for NGS compared to $3,228 for PCR, and lower costs of IO/CTX initiation prior to receiving test results (NGS: $2,298; PCR:$5,991). Cost savings, reaching $10,496,220 at the 1,000,000-member plan level, were driven by more rapid treatment with appropriate therapy for patients tested with NGS (2.1 weeks) compared to PCR strategies (5.2 weeks). LIMITATIONS: Model inputs/assumptions were based on published literature or expert opinion. CONCLUSIONS: NGS testing was associated with greater cost savings versus PCR, driven by more rapid results, shorter time to appropriate therapy initiation, and minimized use of inappropriate therapies while awaiting and after test results.

Characterizing the real-world economic burden of metastatic castration-sensitive prostate cancer in the United States.

AIMS: To describe healthcare resource utilization (HRU) and costs of patients with metastatic castration-sensitive prostate cancer (mCSPC). METHODS: Linked data from Flatiron Metastatic PC Core Registry and Komodo's Healthcare Map were evaluated (01/2016-12/2021). Patients with chart-confirmed diagnoses for metastatic PC without confirmed castration resistance in Flatiron who initiated androgen deprivation therapy (ADT) monotherapy or advanced therapy for mCSPC in 2017 or later (index date) with a corresponding pharmacy or medical claim in Komodo Health were included. Advanced therapies considered were androgen-receptor signaling inhibitors, chemotherapies, estrogens, immunotherapies, poly ADP-ribose polymerase inhibitors, and radiopharmaceuticals. Patients with <12 months of continuous insurance eligibility before index were excluded. Per-patient-per-month (PPPM) all-cause and PC-related HRU and costs (medical and pharmacy; from a payer's perspective in 2022 $USD) were described in the 12-month baseline period and follow-up period (from the index date to castration resistance, end of continuous insurance eligibility, end of data availability, or death). RESULTS: Of 871 patients included (mean age: 70.6 years), 52% initiated ADT monotherapy as their index treatment without documented advanced therapy use. During baseline, 31% of patients had a PC-related inpatient admission and 94% had a PC-related outpatient visit; mean all-cause costs were $2551 PPPM and PC-related costs were $839 PPPM with $787 PPPM attributable to medical costs. Patients had a mean follow-up of 15 months, during which 38% had a PC-related inpatient admission and 98% had a PC-related outpatient visit; mean all-cause costs were $5950 PPPM with PC-related total costs of $4363 PPPM, including medical costs of $2012 PPPM. LIMITATIONS: All analyses were descriptive; statistical testing was not performed. Treatment effectiveness and clinical outcomes were not assessed. CONCLUSION: This real-world study demonstrated a significant economic burden in mCSPC patients, and a propensity to use ADT monotherapy in clinical practice despite the availability and guideline recommendations of advanced life-prolonging therapies.

Real-world economic burden of metastatic castration-resistant prostate cancer before and after first-line therapy initiation.

AIMS: To describe healthcare costs of patients with metastatic castration-resistant prostate cancer (mCRPC) initiating first-line (1 L) therapies from a US payer perspective. METHODS: Patients initiating a Flatiron oncologist-defined 1 L mCRPC therapy (index date) on or after mCRPC diagnosis were identified from linked electronic medical records/claims data from the Flatiron Metastatic Prostate Cancer (PC) Core Registry and Komodo's Healthcare Map. Patients were excluded if they initiated a clinical trial drug in 1 L, had <12 months of insurance eligibility prior to index, or no claims in Komodo's Healthcare Map for the Flatiron oncologist-defined index therapy. All-cause and PC-related total costs per-patient-per-month (PPPM), including costs for services and procedures from medical claims (i.e. medical costs) and costs from pharmacy claims (i.e. pharmacy costs), were described in the 12-month baseline period before 1 L therapy initiation (including the baseline pre- and post- mCRPC progression periods) and during 1 L therapy (follow-up). RESULTS: Among 459 patients with mCRPC (mean age 70 years, 57% White, 16% Black, 45% commercially-insured, 43% Medicare Advantage-insured, and 12% Medicaid-insured), average baseline all-cause total costs (PPPM) were $4,576 ($4,166 pre-mCRPC progression, $8,278 post-mCRPC progression). Average baseline PC-related total costs were $2,935 ($2,537 pre-mCRPC progression, $6,661 post-mCRPC progression). During an average 1 L duration of 8.5 months, mean total costs were $13,746 (all-cause) and $12,061 (PC-related) PPPM. The cost increase following 1 L therapy initiation was driven by higher PC-related outpatient and pharmacy costs. PC-related medical costs PPPM increased from $1,504 during baseline to $5,585 following 1 L mCRPC therapy initiation. LIMITATIONS: All analyses were descriptive; statistical testing was not performed. CONCLUSION: Incremental costs of progression to mCRPC are significant, with the majority of costs driven by higher PC-related costs. Using contemporary data, this study highlights the importance of utilizing effective therapies that slow progression and reduce healthcare resource demands despite the initial investment in treatment costs.

Long-term antipsychotic use, orthostatic hypotension and falls in older adults with Alzheimer's disease.

PURPOSE: Antipsychotic use in Alzheimer disease (AD) is associated with adverse events and mortality. Whilst postulated to cause/exacerbate orthostatic hypotension (OH), the exact relationship between antipsychotic use and OH has never been explored in AD-a group who are particularly vulnerable to neuro-cardiovascular instability and adverse effects of medication on orthostatic blood pressure (BP) behaviour. METHODS: We analysed longitudinal data from an 18-month trial of Nilvadipine in mild-moderate AD. We assessed the effect of long-term antipsychotic use (for the entire 18-month study duration) on orthostatic BP phenotypes measured on eight occasions, in addition to the relationship between antipsychotic use, BP phenotypes and incident falls. RESULTS: Of 509 older adults with AD (aged 72.9 ± 8.3 years, 61.9% female), 10.6% (n = 54) were prescribed a long-term antipsychotic. Over 18 months, long-term antipsychotic use was associated with a greater likelihood of experiencing sit-to-stand OH (ssOH) (OR: 1.21; 1.05-1.38, p = 0.009) which persisted on covariate adjustment. Following adjustment for important clinical confounders, both antipsychotic use (IRR: 1.80, 1.11-2.92, p = 0.018) and ssOH (IRR: 1.44, 1.00-2.06, p = 0.048) were associated with a greater risk of falls/syncope over 18 months in older adults with mild-moderate AD. CONCLUSION: Even in mild-to-moderate AD, long-term antipsychotic use was associated with ssOH. Both antipsychotic use and ssOH were associated with a greater risk of incident falls/syncope over 18 months. Further attention to optimal prescribing interventions in this cohort is warranted and may involve screening older adults with AD prescribed antipsychotics for both orthostatic symptoms and falls.

Time to next treatment in patients with chronic lymphocytic leukemia initiating first-line ibrutinib or acalabrutinib.

Aim: To investigate real-world time to next treatment in patients with chronic lymphocytic leukemia initiating first-line (1L) ibrutinib or acalabrutinib. Materials & methods: US specialty pharmacy electronic medical records (21/11/2018-30/4/2022) were used; patients initiated 1L on/after 21/11/2019 (acalabrutinib approval). Results: Among 710 patients receiving ibrutinib, 5.9% initiated next treatment (mean time to initiation = 9.2 months); among 373 patients receiving acalabrutinib, 7.5% initiated next treatment (mean time to initiation = 5.9 months). Adjusting for baseline characteristics, acalabrutinib-treated patients were 89% more likely to initiate next treatment (hazard ratio = 1.89; p = 0.016). Conclusion: This study addresses a need for real-world comparative effectiveness between 1L ibrutinib and acalabrutinib and shows that next treatment (a clinically meaningful measure for real-world progression) occurred less frequently with 1L ibrutinib.

Ibrutinib and acalabrutinib are oral medications taken once-daily and twice-daily, respectively. They are recommended as initial treatment for chronic lymphocytic leukemia (CLL). The goal of this study was to compare the efficacy of these treatments as initial treatment for CLL. To meet this goal, real-world US specialty pharmacy electronic medical records between 11/21/2018­4/30/2022 were used. Patients treated with ibrutinib or acalabrutinib as initial treatment for CLL were studied. Treatment had to be started on or after the date of acalabrutinib approval for CLL (11/21/2019). Time to next treatment was used to estimate real-world disease progression. It was defined as the time from the initiation of initial treatment with ibrutinib or acalabrutinib to the initiation of a next treatment. Study results showed that patients were observed for a median of up to 1.5 years. Over this period, next treatment was more likely for acalabrutinib (7.5%) compared with ibrutinib (5.9%). After adjusting for differences in patient characteristics, next treatment was 89% more likely with acalabrutinib than ibrutinib. This study addresses a need to compare the effectiveness of initial treatment with ibrutinib and acalabrutinib in the real-world. It helps better contextualize results from clinical trial data and shows that next treatment occurred less frequently with ibrutinib.

The CDK4/6 inhibitor revolution - a game-changing era for breast cancer treatment.

Cyclin-dependent kinase (CDK) 4/6 inhibition in combination with endocrine therapy is the standard-of-care treatment for patients with advanced-stage hormone receptor-positive, HER2 non-amplified (HR+HER2-) breast cancer. These agents can also be administered as adjuvant therapy to patients with higher-risk early stage disease. Nonetheless, the clinical success of these agents has created several challenges, such as how to address acquired resistance, identifying which patients are most likely to benefit from therapy prior to treatment, and understanding the optimal timing of administration and sequencing of these agents. In this Review, we describe the rationale for targeting CDK4/6 in patients with breast cancer, including a summary of updated clinical evidence and how this should inform clinical practice. We also discuss ongoing research efforts that are attempting to address the various challenges created by the widespread implementation of these agents.

Protocol for the Tallaght University Hospital Institute for Memory and Cognition-Biobank for Research in Ageing and Neurodegeneration.

INTRODUCTION: Alzheimer's disease and other dementias affect >50 million individuals globally and are characterised by broad clinical and biological heterogeneity. Cohort and biobank studies have played a critical role in advancing the understanding of disease pathophysiology and in identifying novel diagnostic and treatment approaches. However, further discovery and validation cohorts are required to clarify the real-world utility of new biomarkers, facilitate research into the development of novel therapies and advance our understanding of the clinical heterogeneity and pathobiology of neurodegenerative diseases. METHODS AND ANALYSIS: The Tallaght University Hospital Institute for Memory and Cognition Biobank for Research in Ageing and Neurodegeneration (TIMC-BRAiN) will recruit 1000 individuals over 5 years. Participants, who are undergoing diagnostic workup in the TIMC Memory Assessment and Support Service (TIMC-MASS), will opt to donate clinical data and biological samples to a biobank. All participants will complete a detailed clinical, neuropsychological and dementia severity assessment (including Addenbrooke's Cognitive Assessment, Repeatable Battery for Assessment of Neuropsychological Status, Clinical Dementia Rating Scale). Participants undergoing venepuncture/lumbar puncture as part of the clinical workup will be offered the opportunity to donate additional blood (serum/plasma/whole blood) and cerebrospinal fluid samples for longitudinal storage in the TIMC-BRAiN biobank. Participants are followed at 18-month intervals for repeat clinical and cognitive assessments. Anonymised clinical data and biological samples will be stored securely in a central repository and used to facilitate future studies concerned with advancing the diagnosis and treatment of neurodegenerative diseases. ETHICS AND DISSEMINATION: Ethical approval has been granted by the St. James's Hospital/Tallaght University Hospital Joint Research Ethics Committee (Project ID: 2159), which operates in compliance with the European Communities (Clinical Trials on Medicinal Products for Human Use) Regulations 2004 and ICH Good Clinical Practice Guidelines. Findings using TIMC-BRAiN will be published in a timely and open-access fashion.

Real-World Comparison of First-Line Treatment Adherence Between Single-Agent Ibrutinib and Acalabrutinib in Patients with Chronic Lymphocytic Leukemia.

Purpose: Increased dosing frequency adversely affects treatment adherence and outcomes in chronic diseases; however, such data related to treatment adherence is lacking in chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). This study compared adherence between patients treated with ibrutinib (once-daily) versus acalabrutinib (twice-daily) as first-line (1L) therapy for CLL/SLL. Patients and Methods: Specialty pharmacy electronic medical records were used to identify adults with CLL/SLL initiating 1L ibrutinib or acalabrutinib between 01/01/2018 and 11/30/2020. Adherence was measured by the proportion of days covered (PDC) and medication possession ratio (MPR) and was compared between cohorts using odds ratios (ORs) obtained from logistic regression models adjusted for baseline characteristics. Results: Between 01/01/2018 and 11/30/2020, 1374 and 140 patients initiated ibrutinib and acalabrutinib, respectively. Based on PDC/MPR ≥80%, patients treated with once-daily ibrutinib were more likely to be adherent than those treated with twice-daily acalabrutinib (OR ranges: PDC: 1.04-1.76; MPR: 1.03-1.58). At 6 months, patients on ibrutinib had a 58-76% higher likelihood of staying adherent compared to patients on acalabrutinib (PDC: 75.9% for ibrutinib vs 63.6% for acalabrutinib, OR: 1.76, P=0.008; MPR: 76.8% vs 66.9%, OR: 1.58, P=0.036) with a similar trend noted for the entire line of treatment (LOT) (PDC: 53.0% vs 41.4%, OR: 1.53, P=0.021; MPR: 58.7% vs 47.1%, OR: 1.50, P=0.027). Conclusion: In this real-world analysis, CLL/SLL patients initiating 1L once-daily ibrutinib had >50% higher treatment adherence than those initiating twice-daily acalabrutinib during their LOT. Given the importance of sustained adherence for disease control in CLL/SLL, dosing frequency may be an important consideration for patients and physicians.

Systemic Therapy for Metastatic Triple Negative Breast Cancer: Current Treatments and Future Directions.

Until recently, despite its heterogenous biology, metastatic triple negative breast cancer (TNBC) was treated as a single entity, with successive lines of palliative chemotherapy being the only systemic option. Significant gene expression studies have demonstrated the diversity of TNBC, but effective differential targeting of the four main (Basal-like 1 and 2, mesenchymal and luminal androgen receptor) molecular sub-types has largely eluded researchers. The introduction of immunotherapy, currently useful only for patients with PD-L1 positive cancers, led to the stratification of first-line therapy using this immunohistochemical biomarker. Germline BRCA gene mutations can also be targeted with PARP inhibitors in both the adjuvant and metastatic settings. In contrast, the benefit of the anti-Trop-2 antibody-drug conjugate (ADC) Sacituzumab govitecan (SG) does not appear confined to patients with tumours expressing high levels of Trop-2, leading to its potential utility for any patient with an estrogen receptor (ER)-negative, HER2-negative advanced breast cancer (ABC). Most recently, low levels of HER2 expression, detected in up to 60% of TNBC, predicts benefit from the potent HER2-directed antibody-drug conjugate trastuzumab deruxtecan (T-DXd), defining an additional treatment option for this sub-group. Regrettably, despite recent advances, the median survival of TNBC continues to lag far behind the approximately 5 years now expected for patients with ER-positive or HER2-positive breast cancers. We review the data supporting immunotherapy, ADCs, and targeted agents in subgroups of patients with TNBC, and current clinical trials that may pave the way to further advances in this challenging disease.