Vaccine and other compound development for AD has resulted in recent increased focus on mild impairment, and increased importance of diagnostic precision and discrimination among healthy elderly (HE), MCI, mild and moderate AD subjects. Amnestic MCI is related to hippocampal pathology and in memory testing is characterized by decreased benefit from cuing and additional exposure to material to be remembered; memory impairment in mild AD is characterized as impairment in savings. In a unique long term memory consolidation paradigm, the CNTB distinguished HE, MCI and AD, and mild from moderate AD. Two studies using the CNTB in AD subjects were conducted. In the first, 56 subjects were presented a selective reminding word list learning module (WLL/SR), at 0 and 24 hours; delayed free recall (WLL/DR)and delayed word recognition were measured at 2 and 24 hours; visits at 0, 6, 12 months. In the second study, a battery of CNTB modules assessing verbal and visual memory, attention/concentration, and language was administered to 54 mild and 55 moderate AD subjects. Multivariate ANOVA indicated statistically significant differences among HE, MCI, AD on most measures at most time points and visits; WLL/SR distinguished the three groups at all time points and visits: 0 and 24 hours, 0, 6, and 12 months (all ps <.005). Statistically significant differences: WLL/SR 24 minus 0 hour difference scores, number of LTM (long term memory) words, declining benefit seen longitudinally in MCI compared to HE. Statistically significant differences between mild vs moderate AD included: CNTB Summary Score, verbal and visual memory, language, and simple reaction time (all ps < .02). Additional analyses and results will be reported. The CNTB distinguishes Healthy Elderly, MCI, and AD, and mild from moderate AD. Enhanced precision in discrimination among these groups has the potential to accelerate AD compound development.
TPS485 Background: HCC is a leading cause of cancer-related deaths worldwide. LEN is now a first-line treatment option for patients with uHCC, based on the REFLECT study in which LEN was established as noninferior to sorafenib (SOR) for overall survival (OS); LEN also demonstrated statistically significant and clinically meaningful improvements in progression-free survival, time-to-progression, and objective response rate vs SOR. The safety profile of LEN was consistent with its known side-effect profile. This postauthorization safety study aims to better characterize the safety of LEN, including hepatotoxicity, in real-life conditions in a Western population. Methods: This prospective, open-label, observational study (NCT04763408) will enroll patients with advanced or uHCC in routine clinical practice whom the treating physician has decided to treat with LEN (n = 500) or SOR (n = 500) according to the product labels. Enrollment is planned for 60 sites across Europe, Australia, USA, and Russia. The primary endpoint is the safety of LEN (hepatic-related toxicity and overall safety profile with regard to serious adverse events, grade ≥3 adverse events, and dose modifications and discontinuations due to adverse events). Secondary endpoints include treatment patterns (duration of treatment, incidence of dose interruptions and dose reductions, relative dose intensity, and subsequent treatments) and OS with LEN. Similar efficacy and safety data will be collected with SOR as an internal control for the population. Additionally, associations will be explored between patients’ baseline characteristics and treatment decisions as well as clinical and safety outcomes. Visits will be scheduled according to routine practice. Patients will be followed from initiation of treatment until the end of observation (whichever occurs first: withdrawal of consent, loss to follow-up, death, or end of the study [ie, 6 months after the last patient is enrolled]). Safety will be collected from initiation of LEN or SOR until the earlier of: 28 days after LEN/SOR discontinuation or the end of observation for patients who did not discontinue. Patients will be followed for survival and subsequent anticancer treatments until the end of observation, irrespective of length of treatment. Clinical trial information: NCT04763408.
Specific neuropsychological test batteries may be more sensitive to cognitive decline in early Alzheimer's Disease (AD) than general cognition measures like ADAS-cog or CAMCOG. Establishing clinically meaningful change using the most sensitive measures of cognition across the spectrum of dementia severity will aid the evaluation of new interventions. This study examined the ability of the ADAS-cog (total), the CAMCOG (total score and learning memory), Hopkins Verbal Learning Test- delayed recall (HVLT-DR) and the CANTAB computerized cognition battery (Paired Associates Learning[PAL], choice reaction time[CRT] and spatial working memory [SWM]) to discriminate among healthy elderly (HE, n = 31), amnestic mild cognitive impairment (aMCI, n = 20) and mild to moderate Alzheimer's Disease (AD, n = 19) and to detect change in cognitive function over 1 year. In addition to the cognitive tests, functional status (ADCS-ADL) and self-reported memory impairment (EMQ) were assessed at baseline, 6 months and 1 year. CAMCOG total, CANTAB PAL, and HVLT-DR discriminated among HE, aMCI, and AD. CAMCOG learning memory did not discriminate between HE and MCI and CANTAB SWM did not discriminate between MCI and AD. ADCS-ADL scores showed a non-significant trend toward functional decline among AD and aMCI subjects but not among HE. Both Camcog total score and ADAS-cog indicated significant cognitive decline over 1 year among AD subjects but not among MCI subjects. HE and aMCI showed significant learning effects on the PAL total errors at 1 year. Neither HVLT-DR nor SWM showed decline at 1 year for HE or aMCI. AD subjects showed no change in PAL, HVLT DR or SWM at 1 year. Floor effects were observed for HVLT DR and PAL among AD subjects. Measures of episodic memory, like PAL and HVLT-DR may be better suited to screening for cognitive impairment than evaluating treatment outcomes in aMCI over a 1 year period. Longer follow-up may be required to detect progression of cognitive decline in aMCI.
Multinational AD clinical trials require cross-cultural adaptation to ensure that cognitive endpoints, known to be sensitive to age, gender and education, measure equivalent concepts across cultures. The multidimensionality of cognition makes adaptation particularly challenging. Evaluation of psychometric properties and comparison of patient performance across countries can be used to assess the adequacy of culturally adapted scales. The objective of this analysis is to assess the measurement characteristics of commonly used cognitive endpoints in a cohort of mild-to-moderate (M2M) AD in China and to compare them to published data from a US cohort of similar patients. An observational study enrolled subjects with mild-to-moderate AD at 13 sites in China. Subjects had a diagnosis of probable AD; cognitive and functional decline ≥1year, Mini-Mental State Examination (MMSE) score ≥15 and ≤26, > a 6th grade reading level and if treated, pharmacologically stable. All cognitive tests were administered by raters trained and certified prior to study start. The performance of subjects in this study is compared to that of AD subjects from the United States AD Neuroimaging Initiative (US-ADNI) cohort. The US cohort was generally older; more educated and had milder disease according to the MMSE and CDR. Subjects in China made more overall errors on the ADAS-cog but performance on recall, recognition, digit span and fluency was not different between the two cohorts. Performance on trail-making (TMT) was markedly worse in the China cohort. Conceptual equivalence in cognitive measures should not be assumed based on translations alone. Comparing performance characteristics to similar populations across languages may provide further insight into tests' cross-cultural equivalence. The inconsistency of performance across cognitive tests in this analysis suggests that further exploration of conceptual and cultural equivalence of some cognition tests, namely the ADAS-cog recall and recognition and Trails A and B, may be warranted.
Abstract Background: Triple negative breast cancer is defined by lack of expression of ER/PR (immunohistochemistry expression <1%) and absence of HER2 gene amplification. However, data regarding endocrine therapy benefit in patients with low levels (1-10%) of ER/PR expression are lacking. Furthermore, gene expression studies show tremendous similarities between HER2 negative tumors with low and negative ER/PR status. Accordingly, the 2020 ASCO/CAP guideline designates that ER expression of 1-10% be reported as a distinct “ER low positive” category. Utilizing data from a prospective registry, the aim of this study was to determine the impact of low versus negative ER/PR status on clinico-pathologic characteristics and survival outcomes in patients with HER2 negative breast cancers. Methods: 516 subjects with stage I-III HER2 negative breast cancer and ER/PR IHC ≤10% were enrolled in an IRB-approved multisite prospective registry between 2011 and 2019. Demographic, clinical, pathologic, and treatment information was collected, and patients were followed for recurrence and survival. Patients were categorized according to ER/PR expression into two groups: TNBC (ER and PR <1%) and Low-ER (ER and/or PR 1-10%). Recurrence free survival (RFS) and overall survival (OS) were estimated according to the Kaplan-Meier method and compared among groups by log-rank test, followed by Cox regression analysis. Results: TNBC and Low-ER groups comprised 451/516 (87.4%) and 65/516 (12.6%) patients, respectively. Demographic, clinical, pathologic, and treatment characteristics of the two groups are described in Table 1. Median follow-up was 39 months. Three-year RFS was 82% for both TNBC and Low-ER groups (p=0.70). Three-year OS was 88% and 83% for TNBC and Low-ER groups, respectively (p=0.63). Twenty percent of patients in the Low-ER group received adjuvant endocrine therapy, and endocrine therapy use did not impact outcomes in the Low-ER group (RFS: p=0.32; OS: p=0.88). On multivariate analysis, T stage, nodal status, and age significantly impacted RFS (T stage 3/4 vs 1/2, HR=2.7, p<0.001; nodal status positive vs negative, HR=2.4, p<0.001; age above vs below median, HR=1.8, p=0.006) and OS (T stage 3/4 vs 1/2, HR=3.6, p<0.001; nodal status positive vs negative, HR=2.8, p<0.001; age above vs below median, HR=1.026, p=0.01). For patients who received neoadjuvant chemotherapy, achievement of pathological complete response (pCR) was associated with superior RFS (3-year RFS of 95% and 67% in those with and without pCR, respectively, HR=0.18, p<0.001). Conclusions: Patients with TNBC and Low-ER HER2 negative breast cancer present with similar clinico-pathologic characteristics, including prevalence of germline BRCA1/2 mutation. Prognosis and rate of pCR (with neo-adjuvant chemotherapy) in patients with Low-ER HER2 negative breast cancer is similar to those with TNBC. The role and efficacy of adjuvant endocrine therapy in patients with Low-ER breast cancer is unclear. These findings support consideration for inclusion of patients with Low-ER disease along with TNBC for future clinical trial eligibility and planning. Table 1. Demographic, clinical, pathologic, and treatment characteristicsCharacteristics - N (%)All N=516TNBC (ER & PR <1%) n=451Low-ER (ER or PR 1-10%) n=65pAge at diagnosis, years - median (range)53 (23-97)54 (23-97)51 (28-76)0.61RaceWhite386 (75%)335 (74%)51 (79%)0.69Black101 (20%)89 (20%)12 (19%)Asian8 (2%)8 (2%)0 (0%)Menopausal statusPre214 (42%)181 (41%)33 (51%)0.25Post295 (58%)263 (59%)32 (49%)Histological gradeI2 (0.4%)2 (0.4%)0 (0%)0.82II86 (17%)76 (17%)10 (15%)III428 (83%)373 (83%)55 (85%)T stageT1-2446 (87%)388 (87%)58 (89%)0.56T3-467 (13%)60 (13%)7 (11%)N statusPositive177 (34%)158 (35%)19 (29%)0.36Negative339 (66%)293 (65%)46 (71%)TNM stageI179 (35%)150 (33%)29 (44%)0.10II263 (51%)232 (52%)31 (48%)III74 (14%)69 (15%)5 (8%)Germline BRCA1/2 mutationYes70 (14%)64 (14%)6 (9%)0.53No357 (69%)309 (69%)48 (74%)Unknown89 (17%)78 (17%)11 (17%)ChemotherapyNeoadjuvant357 (69%)318 (71%)39 (60%)0.23Adjuvant147 (29%)123 (27%)24 (37%)None12 (2%)10 (2%)2 (3%)Surgery typeMastectomy308 (60%)275 (61%)33 (51%)0.10Lumpectomy205 (40%)173 (39%)32 (49%)Adjuvant endocrine therapyYes20 (4%)7 (2%)13 (20%)<0.001No496 (96%)444 (98%)52 (80%)pCR (in patients with neoadjuvant chemotherapy, n=357)176 (49%)157 (49%)19 (49%)0.94 Citation Format: Rachel Yoder, Bruce F Kimler, Joshua M Staley, Kelsey Schwensen, Yen Y Wang, Karissa Finke, Anne O'Dea, Lauren Nye, Manana Elia, Gregory Crane, Richard McKittrick, Robert Pluenneke, Sheshadri Madhusudhana, Larry Beck, Roberto Rodriguez, Anuj Shrestha, Larry Corum, Mark Marsico, Andrew K Godwin, Qamar Khan, Priyanka Sharma. Impact of low versus negative estrogen/progesterone receptor status on clinico-pathologic characteristics and survival outcomes in HER2 negative breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS6-04.
AD endpoints are translated and culturally adapted for multiregional trials with the intent of preserving their cognitive and functional concepts. However, data supporting performance of AD endpoints across countries and cultures are sparse. To examine the potential influence of culture on the measurement of cognition and function, we evaluated regional variability in the ADAS-Cog and the ADCS-ADL using baseline data from a global trial of subjects with mild-to-moderate AD. Mild-to-moderate AD subjects (n=2,221) were recruited from 21 countries for a double-blind, placebo-controlled randomized clinical trial. Countries were grouped into one of six geographic regions. To assess ADAS-Cog and ADCS-ADL item scores across regions, data were stratified according to disease severity (mild, MMSE= 21-26; moderate, MMSE= 15-20). To present the data graphically, standardized z-scores were calculated within each stratum. These standardized z-scores were then pooled across disease severity and re-standardized. ADAS-Cog: The largest absolute z-scores were observed in the Middle East, South America and the Far East, primarily in the Commands, Praxis, and Naming items. The Middle East and South American z-scores indicate subjects tended to perform worse than the overall study population mean, while Far East and Oceania performed better than average. Absolute z-scores for North America and the European Union were the smallest, though this observation may be due, in part, to the sample sizes of these regions comprising a large proportion of the total on which the standardized scores were based. ADCS-ADL: The Middle East and South American z-scores were consistently lower than the mean (suggesting more functional impairment) in basic activities and activities related to communication and engagement. Oceania z-scores were consistently larger than average indicating reduced functional impairment. Assuming no true underlying interaction between geographic region and cognitive and functional performance, these data suggest there may be residual variance in the measurement of cognition and function related to cultural differences across regions. Future evaluation of the psychometric characteristics of the endpoints by region may provide further insight into the influence of cultural variability on measurement error.
Leveraging real-world data to better understand health care utilization patterns prior to and after incident AD diagnosis may help inform the clinical management of the disease. Medical and pharmacy claims data from a large, geographically diverse, commercial, US Medicare Advantage health plan, for the period 2009–2014, were used to identify cases of newly diagnosed AD. The following beneficiaries were eligible for inclusion in the analysis: aged ≥65 with medical and prescription drug coverage, a claims history of either ≥2 AD diagnostic codes or one diagnosis code and a prescription fill for a medication indicated to treat AD, and ≥24 months of continuous coverage in the health plan prior to and after a diagnosis. Descriptive statistics were used to estimate mean monthly health care utilization and total health plan costs in the two years prior to incident AD diagnosis. A control cohort of elderly individuals without any dementia type was constructed using a 1:1 exact match for age, gender, and geographic region. A cohort of 4,039 beneficiaries was identified for inclusion in the analysis, 72% of whom were female. Health care utilization and monthly Medicare expenditures trended upward approximately 6–12 months prior to the diagnosis, with a clear peak in the 30 days immediately prior to the incident diagnosis (i.e. index month). Increases in the mean number of monthly outpatient visits (80%), emergency room visits (502%), inpatient stays (829%) and medication use (22%) were observed in the index month, compared to the 12 months prior to index. Mean per-person expenditures were greater among the AD cohort relative to controls in the index month ($1,446 v $376) and in the 12 months prior to index ($3,993 v $3,449).
Few long-term studies reporting incidence and behavioral data for Chlamydia trachomatis (CT) infection in the general population have been published. Such studies are important to understand risk factors associated with infection and to develop screening recommendations.A fixed prospective 4-year cohort study of 898 sexually active Norwegian women, aged 16 to 23 years at study start, was conducted to assess incidence, repeat infection, and risk factors associated with genital CT infection. Participants were interviewed at study start and at 6-month intervals thereafter for behavioral characteristics. The women were tested for CT infection at 12-month intervals beginning at study start. Risk factors were assessed using Fisher exact test and conditional logistic regression. Person-time was estimated in survival analyses and incidence of CT infection was reported as events per 100 woman-years.Median duration of observation was 48.0 months (range 10-74) whereas 4.4 specimens were collected per woman (range 2-5). Of the 836 women eligible for the analysis, 19 (2.2%) had a prevalent infection at baseline. The 4-year cumulative incidence of CT infection was 7.7 (95% CI: 6.7-8.7) with annual incidences ranging from 1.2 to 2.9 per 100 woman-years. The 2-year cumulative incidence of repeat CT infection was 11.2 (95% CI: 9.3-13.1) per 100 woman-years. In multivariate analyses, factors associated with incident CT infection were young age (< or =24 years) and number of new partners over the last 12 months prior being tested.The annual incidences observed for women 24 years or younger with 1 or more new partners over the last 12 months support recommendations for annual testing for CT in this age group in Norway.
There is a need for novel domain-specific cognitive outcome measures for clinical trials in the preclinical stages of Alzheimer's disease (AD) as this is where treatment is thought to be most effective in delaying cognitive and functional decline. Traditionally the MMSE and ADAS-Cog are used to determine efficacy of drugs for AD, but these measures are not sensitive enough for use in the preclinical stages of the disease. A longitudinal, observational, exploratory study was conducted to determine the sensitivity to change of a battery of cognitive tests versus change in functional and subjective memory rating scales. Functional change, assumed to be a valid marker of progression of neurocognitive disorders such as AD, was used to identify the most sensitive cognitive correlates of decline. 30 healthy elderly, 20 MCI and 17 AD participants from the OPTIMA cohort who fit eligibility criteria for the study were assessed on the ADAS-Cog, CANTAB tests of episodic and spatial working memory (SWM) and reaction time (RTI) and on the OPTIMA neuropsychological test battery. Subjects or study partners (for AD participants) completed the ADCS-ADL (Activities of daily living) and Everyday Memory Questionnaire (EMQ) for functional and subjective memory assessment. These tests were repeated 3 times at 6 monthly intervals. Spearman's correlations between cognitive and clinical change score measures showed that for AD patients, the ADCS-ADL, particularly instrumental ADL, correlated with CANTAB reaction time measures (P <0.05) and with ADAS-cog total score and recognition errors. In MCI, the ADCS-ADL (basic ADL) was associated with CANTAB RTI scores and a trend with Hopkins Verbal Learning Test (HVLT) discrimination index (r = 0.45, P = 0.067); while the Symbol Digits Modalities Test (SDMT) and ADAS-cog total score correlated with the ADCS-ADL total score and instrumental ADL scores. EMQ subscores were associated with various memory measures on the HVLT, the SDMT, total CAMCOG score and CANTAB SWM. The significance of these findings in relation to the sensitivity of cognitive measures to change over time and relevance to RCTs will be reported.
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