Ponatinib dose-ranging study in chronic-phase chronic myeloid leukemia: a randomized, open-label phase 2 clinical trial.

In PACE (Ponatinib Ph+ ALL and CML Evaluation), a phase 2 trial of ponatinib that included patients with chronic-phase chronic myeloid leukemia (CP-CML) resistant to multiple prior tyrosine kinase inhibitors (TKIs), ponatinib showed deep and durable responses, but arterial occlusive events (AOEs) emerged as notable adverse events. Post hoc analyses indicated that AOEs are dose dependent. We assessed the benefit/risk ratio across 3 ponatinib starting doses in the first prospective study to evaluate a novel, response-based, dose-reduction strategy for TKI treatment. Adults with CP-CML resistant to or intolerant of at least 2 prior BCR-ABL1 TKIs or with a BCR-ABL1 T315I mutation were randomly assigned 1:1:1 to 3 cohorts receiving ponatinib 45, 30, or 15 mg once daily. In patients who received 45 or 30 mg daily the dose was reduced to 15 mg upon response (BCR-ABL1IS transcript levels ≤1%). The primary end point was response at 12 months. From August 2015 through May 2019, 283 patients were randomly assigned to the cohorts: 282 (94 per dose group) received treatment (data cutoff, 31 May 2020). The primary end point (98.3% confidence interval) was achieved in 44.1% (31.7-57.0) in the 45-mg cohort, 29.0% (18.4-41.6) in the 30-mg cohort, and 23.1% (13.4-35.3) in the 15-mg cohort. Independently confirmed grade 3 or above treatment-emergent AOEs occurred in 5, 5, and 3 patients in the 45-, 30-, and 15-mg cohorts, respectively. All cohorts showed benefit in this highly resistant CP-CML population. Optimal benefit/risk outcomes occurred with the 45-mg starting dose, which was decreased to 15 mg upon achievement of a response. This trial is registered on www.clinicaltrials.gov as NCT02467270.

Cerebrospinal fluid neurofilament concentration reflects disease severity in frontotemporal degeneration.

OBJECTIVE: Cerebrospinal fluid (CSF) neurofilament light chain (NfL) concentration is elevated in neurological disorders, including frontotemporal degeneration (FTD). We investigated the clinical correlates of elevated CSF NfL levels in FTD. METHODS: CSF NfL, amyloid-ß1-42 (Aß42), tau, and phosphorylated tau concentrations were compared in 47 normal controls (NC), 8 asymptomatic gene carriers (NC2) of FTD-causing mutations, and 79 FTD (45 behavioral variant frontotemporal dementia [bvFTD], 18 progressive nonfluent aphasia [PNFA], 16 semantic dementia [SD]), 22 progressive supranuclear palsy, 50 Alzheimer disease, 6 Parkinson disease, and 17 corticobasal syndrome patients. Correlations between CSF analyte levels were performed with neuropsychological measures and the Clinical Dementia Rating scale sum of boxes (CDRsb). Voxel-based morphometry of structural magnetic resonance images determined the relationship between brain volume and CSF NfL. RESULTS: Mean CSF NfL concentrations were higher in bvFTD, SD, and PNFA than other groups. NfL in NC2 was similar to NC. CSF NfL, but not other CSF measures, correlated with CDRsb and neuropsychological measures in FTD, but not in other diagnostic groups. Analyses in 2 independent FTD cohorts and a group of autopsy-verified or biomarker-enriched cases confirmed the larger group analysis. In FTD, gray and white matter volume negatively correlated with CSF NfL concentration, such that individuals with the highest NfL levels exhibited the most atrophy. INTERPRETATION: CSF NfL is elevated in symptomatic FTD and correlates with disease severity. This measurement may be a useful surrogate endpoint of disease severity in FTD clinical trials. Longitudinal studies of CSF NfL in FTD are warranted.

Divergent CSF τ alterations in two common tauopathies: Alzheimer's disease and progressive supranuclear palsy.

BACKGROUND: Elevated CSF τ is considered a biomarker of neuronal injury in newly developed Alzheimer's disease (AD) and mild cognitive impairment (MCI) criteria. However, previous studies have failed to detect alterations of τ species in other primary tauopathies. We assessed CSF τ protein abnormalities in AD, a tauopathy with prominent Aß pathology, and progressive supranuclear palsy (PSP), a primary tauopathy characterised by deposition of four microtubule-binding repeat (4R) τ with minimal Aß pathology. METHODS: 26 normal control (NC), 37 AD, and 24 patients with PSP participated in the study. AD and PSP were matched for severity using the clinical dementia rating sum of boxes (CDR-sb) scores. The INNO BIA AlzBio3 multiplex immunoassay was used to measure CSF Aß, total τ, and ptau181. Additional, novel ELISAs targeting different N-terminal and central τ epitopes were developed to examine CSF τ components and to investigate interactions between diagnostic group, demographics and genetic variables. RESULTS: PSP had lower CSF N-terminal and C-terminal τ concentrations than NC and AD measured with the novel τ ELISAs and the standard AlzBio3 τ and ptau assays. AD had higher total τ and ptau levels than NC and PSP. There was a gender by diagnosis interaction in AD and PSP for most τ species, with lower concentrations for male compared to female patients. CONCLUSIONS: CSF τ fragment concentrations are different in PSP compared with AD despite the presence of severe τ pathology and neuronal injury in both disorders. CSF τ concentration likely reflects multiple factors in addition to the degree of neuronal injury.

Retrospective analysis of arterial occlusive events in the PACE trial by an independent adjudication committee.

BACKGROUND: The phase 2 PACE (Ponatinib Ph+ ALL and CML Evaluation) trial of ponatinib showed robust long-term benefit in relapsed Philadelphia chromosome-positive (Ph+) leukemia; arterial occlusive events (AOEs) occurred in ≥ 25% of patients based on investigator reporting. However, AOE rates vary depending on the definitions and reporting approach used. METHODS: To better understand clinically relevant AOEs with ponatinib, an independent cardiovascular adjudication committee reviewed 5-year AOE data from the PACE trial according to a charter-defined process and standardized event definitions. RESULTS: A total of 449 patients with chronic myeloid leukemia (CML) or Ph+ acute lymphoblastic leukemia (ALL) received ponatinib (median age 59 y; 47% female; 93% ≥ 2 prior tyrosine kinase inhibitors (TKIs); median follow-up, 37.3 months). The adjudicated AOE rate (17%) was lower than the non-adjudicated rate (i.e., rate before adjudication; 25%). The only adjudicated AOE in > 2% of patients was peripheral arterial occlusive disease (4%). Exposure-adjusted incidence of newly occurring adjudicated AOEs decreased over time. Patients with multiple baseline cardiovascular risk factors had higher adjudicated AOE rates than those without risk factors. CONCLUSIONS: This independent adjudication study identified lower AOE rates than previously reported, suggesting earlier overestimation that may inaccurately reflect AOE risk with ponatinib. This trial was registered under ClinicalTrials.gov identifier NCT01207440 on September 23, 2010 ( https://clinicaltrials.gov/ct2/show/NCT01207440 ).

The factor structure of The Fear Survey Schedule for Children--II in Trinidadian children and adolescents.

Part of understanding normal and abnormal fear in children and adolescents is having knowledge of how they acquire fears and of how fears change across development. One way to examine the relative contributions of heredity and environment to the experience of fear is to study fear across cultures. The Fear Survey Schedule for Children-II (FSSC-II; Gullone, E., & King, N. J. (1992). Psychometric evaluation of a revised fear survey schedule for children and adolescents. Journal of Child Psychology and Psychiatry, 33, 987-998) is one measure that has some evidence for cross-cultural validity. The present analysis examined the factor structure of the FSSC-II scores of 884 Trinidadian children and adolescents. Factor consistency across age, sex, and nationality (Trinidadian and American) was examined by calculating the coefficients of congruence for each pair of conceptually similar factors. Results indicated a five-factor structure for the overall sample. Although the solution was conceptually similar to those reported in other studies that used versions of the FSSC, the obtained structure was not congruent across age, sex, or nationality.

Physostigmine and hyoscine improves protection against the lethal and incapacitating effects of nerve agent poisoning in the guinea-pig.

This study is drawn from a work programme aimed at developing improved medical counter measures for nerve agent poisoning. Guinea-pigs were administered pyridostigmine (5.1 microg/h) or physostigmine (4.7 microg/h) and hyoscine (1.94 microg/h) for 6 days via a subcutaneously implanted mini osmotic pump. Pyridostigmine inhibited red cell acetylcholinesterase (AChE) by 44.2 +/- 2.7% and plasma cholinesterase (ChE) by 29.9 +/- 1.8%. Physostigmine and hyoscine inhibited red cell AChE by 18.7 +/- 3.7% and plasma ChE by 44.1 +/- 3.1%. On day 6, animals were challenged with a lethal dose of tabun (GA; 125 microg/kg), sarin (GB; 51.2 microg/kg), soman (GD; 31.2 microg/kg), GF (50 microg/kg) or VX (11.25 microg/kg) administered by the subcutaneous route. Animals were closely observed for signs of poisoning. The time to the onset of signs of poisoning was similar for all the agents except for VX, which showed a delay compared to the other agents. Following pretreatment with either pyridostigmine or physostigmine and hyoscine most animals survived for 2-3 h following nerve agent administration. In contrast, only physostigmine and hyoscine prevented or reduced the duration of the signs of incapacitation and the temperature drop produced by all the agents. Pyridostigmine-pretreated animals showed little or no recovery from incapacitation prior to death. Physostigmine and hyoscine pretreatment provided statistically (P < 0.05) better protection against GB, GD and VX lethality (24 h) than pyridostigmine pretreatment and better protection against GA and GF lethality.

Identification and Preclinical Pharmacology of the γ-Secretase Modulator BMS-869780.

Alzheimer's disease is the most prevalent cause of dementia and is associated with accumulation of amyloid-ß peptide (Aß), particularly the 42-amino acid Aß1-42, in the brain. Aß1-42 levels can be decreased by γ-secretase modulators (GSM), which are small molecules that modulate γ-secretase, an enzyme essential for Aß production. BMS-869780 is a potent GSM that decreased Aß1-42 and Aß1-40 and increased Aß1-37 and Aß1-38, without inhibiting overall levels of Aß peptides or other APP processing intermediates. BMS-869780 also did not inhibit Notch processing by γ-secretase and lowered brain Aß1-42 without evidence of Notch-related side effects in rats. Human pharmacokinetic (PK) parameters were predicted through allometric scaling of PK in rat, dog, and monkey and were combined with the rat pharmacodynamic (PD) parameters to predict the relationship between BMS-869780 dose, exposure and Aß1-42 levels in human. Off-target and safety margins were then based on comparisons to the predicted exposure required for robust Aß1-42 lowering. Because of insufficient safety predictions and the relatively high predicted human daily dose of 700 mg, further evaluation of BMS-869780 as a potential clinical candidate was discontinued. Nevertheless, BMS-869780 demonstrates the potential of the GSM approach for robust lowering of brain Aß1-42 without Notch-related side effects.

Surgical-office-based versus radiology-referral-based breast ultrasonography: a comparison of efficiency, cost, and patient satisfaction.

BACKGROUND: The differences in efficiency, cost of care, and patient satisfaction between surgical-office-based (SB) breast ultrasonography by the surgeon and radiology-referral-based (RB) ultrasonography by the radiologist in the workup of lumps and imaging abnormalities have not been computed. STUDY DESIGN: Charts of 61 consecutive patients requiring breast ultrasonography at the Comprehensive Breast Center from October through December 2005 were evaluated. The SB ultrasonography approach was compared with the RB approach. Matching variables were patient age, presenting complaint, Gail risk score, ultrasonography findings, interventional procedure, and histopathology reports. Outcomes variables were efficiency (time from presentation and establishment of diagnosis), cost of care, and patient satisfaction. RESULTS: Twenty-nine patients had RB and 32 had SB breast ultrasonography. The RB and SB groups were similar in age, Gail risk, and ultrasonography findings. Median time to establish diagnosis in the RB group was 23 days, versus 1 day in the SB group (p < 0.0001). Median cost of care in the RB versus SB group was $659.00 versus $369.50 (p = 0.253), and net revenue generated was $85.00 versus $195.00 (p = 0.005), respectively. Forty-nine of 61 (80.3%) patients responded to the satisfaction survey. Forty-seven of 49 (96%) patients expect the diagnosis to be established within 48 hours. Twenty-eight of 28 (100%) patients in the SB group regarded their imaging study to be efficient, versus 5 of 21 patients in the RB group (p = 0.005); 16 of 21 in the RB group versus 26 of 28 in the SB group thought they adequately understood the ultrasonography findings at the time of study (p = 0.051). Twenty-four (86%) SB patients versus 14 (67%) RB patients rated overall experience as excellent (p = 0.055). CONCLUSIONS: SB breast ultrasonography is an efficient, cost-effective, and patient-friendly approach to breast problems.