The search for clarity regarding "clinically meaningful outcomes" in Alzheimer disease clinical trials: CLARITY-AD and Beyond.

CLARITY-AD is an 18-month, double-blinded, placebo-controlled, phase 3 trial which examined the safety and efficacy of the anti-amyloid agent, lecanemab, in mild cognitive impairment and mild dementia due to Alzheimer disease (AD). Lecanemab effectively reduced mean brain amyloid burden and was associated with statistically significant favorable effects, reflected by moderately less decline in the primary and secondary clinical outcomes, at 18 months compared to placebo. However, there is controversy within the AD community regarding the clinical significance of these results and whether they translate into clinically meaningful and tangible benefits on cognition or daily functions.We here review the primary and secondary clinical outcomes of CLARITY-AD and present our interpretation of the potential clinical meaningfulness of the group-level differences in study outcomes in the context of the 18-month study duration. We propose that the validation of stage-appropriate group-level thresholds for clinical meaningfulness of AD trial outcomes in biologically confirmed cohorts will allow objective interpretation of trial results and guide clinical decision-making. Further, in accordance with FDA guidance which emphasizes patient-focused drug development, the contextualization of AD clinical trial outcomes can be facilitated by supplementary individual-level data analyses which measure the risk of disease progression or summarize intraindividual change, using prespecified thresholds of clinically meaningful change, in each of the study groups over the trial period. The concepts of "time-saved" and "time-based" slowing in disease progression can be used to communicate clinical outcomes associated with emerging disease-modifying AD therapies to various stakeholders. We also describe several factors that need to be considered when evaluating outcomes of emerging AD therapies, including disease stage, the neuropathologic complexity of AD, time-based effects of disease-modifying therapies, and the possible influence of individual factors on treatment response and/or risk for adverse events. The consideration of these factors in the design and reporting of future trials of emerging AD therapies will guide clinicians regarding their appropriateness for use in various patient populations.Finally, we emphasize that data from clinical cohorts with longer durations of treatment and follow-up, including extension studies and patient registries, is needed to evaluate the long-term safety and efficacy of lecanemab in early symptomatic AD.

Outcomes of responders to PD-1/PD-L1 inhibitors who discontinue therapy after sustained disease control.

BACKGROUND: PD-1/PD-L1 immune checkpoint inhibitors (ICIs) are widely used in the treatment of metastatic malignancies. Judiciously balancing disease control (DC) against development of immune-related adverse events (irAE) remains a crucial aspect of treatment. The effect of treatment discontinuation after sustained disease control (SDC) is unknown. The purpose of this analysis was to evaluate outcomes of responders to ICI who discontinue treatment after a minimum of 12 months (SDC). METHODS: We retrospectively reviewed the database of the University of New Mexico Comprehensive Cancer Center (UNMCCC) between 2014 and 2021 and identified patients who had received ICI. Patients with metastatic solid tumors who had stopped ICI therapy after achieving SDC [stable disease, partial response, complete response (SD, PR, CR)] were selected and outcomes reviewed from their electronic health records. RESULTS: We identified 204 patients who were treated with ICI for various solid cancers. Forty-four patients (21.6%) met the criteria, of whom 35 with follow-up data were included in the final analysis; including 11 melanoma, 5 non-small cell lung, 4 head & neck, 8 renal, 4 urothelial, 1 anal, 1 Merkel cell carcinoma, and 1 liposarcoma. Patients were divided into two groups: those who stopped ICI due to an irAE [irAE group, n = 14, median treatment time (MTT), 16.6 mo] and those who stopped due to other reasons (eg completion of 2 years of therapy, n = 20, non-cancer related surgery, n = 1) (non-irAE group, n = 21, MTT, 23.7 mo). Among the irAE group, the most common irAE included pneumonitis, rash, transaminitis, and fatigue. As of data cutoff date, 9 of 14 (64%) patients continued to show SDC. Only 5 of 14 (36%) patients in this group experienced progression of disease (PD), with 1 of 2 patients achieving DC (median follow-up of 19.2 mo after last dose of treatment, range 3-50.2 mo). Among the non-irAE group, 13 of 21 (62%) continued to have SDC. Eight of 21 (38%) experienced PD after stopping treatment, 7 of whom received ICI rechallenge, with 2 of 7 achieving DC (median follow-up of 22.2 mo, range 3.6-54.8 mo). At a median follow-up of 21.3 mo from stopping ICI therapy (range, 3-54.8 mo), 10 patients (71%) from the irAE group and 13 (61.9%) from the non-irAE group are in DC and have not experienced PD. CONCLUSIONS: We demonstrate that 22 (66%) patients experienced SDC, regardless of cancer type or development of irAE. After including patients who were re-challenged with ICI due to PD, 25 (71%) remain in DC. Future prospective malignancy-specific trials are warranted to evaluate optimal treatment duration.

Humanized Patient-derived Xenograft Models of Disseminated Ovarian Cancer Recapitulate Key Aspects of the Tumor Immune Environment within the Peritoneal Cavity.

The importance of the immune microenvironment in ovarian cancer progression, metastasis, and response to therapies has become increasingly clear, especially with the new emphasis on immunotherapies. To leverage the power of patient-derived xenograft (PDX) models within a humanized immune microenvironment, three ovarian cancer PDXs were grown in humanized NBSGW (huNBSGW) mice engrafted with human CD34+ cord blood-derived hematopoietic stem cells. Analysis of cytokine levels in the ascites fluid and identification of infiltrating immune cells in the tumors demonstrated that these humanized PDX (huPDX) established an immune tumor microenvironment similar to what has been reported for patients with ovarian cancer. The lack of human myeloid cell differentiation has been a major setback for humanized mouse models, but our analysis shows that PDX engraftment increases the human myeloid population in the peripheral blood. Analysis of cytokines within the ascites fluid of huPDX revealed high levels of human M-CSF, a key myeloid differentiation factor as well as other elevated cytokines that have previously been identified in ovarian cancer patient ascites fluid including those involved in immune cell differentiation and recruitment. Human tumor-associated macrophages and tumor-infiltrating lymphocytes were detected within the tumors of humanized mice, demonstrating immune cell recruitment to tumors. Comparison of the three huPDX revealed certain differences in cytokine signatures and in the extent of immune cell recruitment. Our studies show that huNBSGW PDX models reconstitute important aspects of the ovarian cancer immune tumor microenvironment, which may recommend these models for preclinical therapeutic trials. Significance: huPDX models are ideal preclinical models for testing novel therapies. They reflect the genetic heterogeneity of the patient population, enhance human myeloid differentiation, and recruit immune cells to the tumor microenvironment.

Albuminuria, cognition, and MRI biomarkers of cerebrovascular disease in American Indians of the Zuni Pueblo.

Background: Elevated urine albumin to creatinine ratio (UACR) is associated with cerebrovascular disease and cognitive impairment in older adults, though few studies have evaluated these relationships in midlife. This is particularly important to assess in American Indian populations, which are disproportionately impacted by diabetes and kidney disease. Additionally, evidence suggests that biomarkers may perform differently in underrepresented groups, thus, it is crucial to validate biomarkers in this unique population. Methods: Twenty-five participants from the Zuni Pueblo underwent neuropsychological assessment and an MRI that included fluid attenuated inversion recovery (FLAIR) and diffusion imaging to calculate recently developed MRI markers of cerebrovascular small vessel disease (Peak width of Skeletonized Mean Diffusivity (PSMD), mean free-water fraction (mFW), white matter hyperintensity (WMH)). Results: Regression analyses indicated no significant associations between UACR, MRI biomarkers and cognitive outcomes. Analyses of covariance indicated that the Zuni Indian cohort exhibited reduced white matter damage relative to an existing cohort of older adults with vascular cognitive impairment when accounting for age, sex, and education. Slower processing speed was associated with greater white matter disease across all measures examined. Conclusions: Our pilot study validated the use of MRI biomarkers of cerebrovascular disease in this unique cohort of American Indians.

Colorectal Cancer Survival Trends in the United States From 1992 to 2018 Differ Among Persons From Five Racial and Ethnic Groups According to Stage at Diagnosis: A SEER-Based Study.

INTRODUCTION: Survival following colorectal cancer (CRC) has improved in the US since 1975, but there is limited information on stage-specific survival trends among racial and ethnic subgroups. OBJECTIVES: The purpose of this study was to estimate and compare trends in 1- and 5-year CRC cause-specific survival in the United States by both stage and race/ethnicity. METHODS: We performed a retrospective cohort study of individuals diagnosed with CRC using the 1992-2018 Surveillance, Epidemiology and End Results (SEER) database. We estimated and compared time trends in 1- and 5-year survival for CRC stage by race/ethnicity. RESULTS: Data from 399 220 individuals diagnosed with CRC were available. There were significant differences in stage-specific 1-year survival trends by race and ethnicity. Differences were most notable for distant stage CRC: survival probabilities increased most consistently for non-Hispanic American Indian/Alaska Native (AIAN) and Black (NHB) persons, but their trend lines were lower than those of Hispanic, and non-Hispanic Asian/Pacific Islander (API) and White (NHW) persons, whose initially greater gains appear to be slowing. Although the data do not support significant racial/ethnic differences in 5-year CRC survival trends by stage, AIAN and NHB persons have the lowest average survival probabilities for multiple CRC stages, and no racial/ethnic group has 5-year survival probabilities above 20% for distant-stage CRC. CONCLUSION: Although there has been an overall improvement in adjusted CRC-specific survival probabilities since 1992, AIAN and NHB persons continue to experience worse prognosis than those of other races/ethnicities. This highlights the importance of reinvigorating efforts to understand the causes of mortality in CRC, including those which may differ according to an individual's race or ethnicity.

Association between Quality of Life and Physical Functioning in a Gardening Intervention for Cancer Survivors.

Purpose: To examine potential factors associated with maintaining or improving self-reported physical function (PF) among older cancer survivors participating in a gardening intervention impacted by the Coronavirus 2019 (COVID-19) pandemic. Methods: Thirty cancer survivors completed a home-based gardening intervention to encourage a healthier diet and a more active lifestyle. Device-based measures of physical activity (PA) and surveys to evaluate quality of life (QOL; PROMIS-57 questionnaire) were administered at baseline, mid-intervention (6 months), and post-intervention (9 months). Results: Depression, fatigue, and sleeplessness at baseline were significantly associated with worse average PF scores across follow-up (2.3 to 4.9 points lower for every decrease of 5 points in the QOL score; p-values < 0.02). Worsening of these QOL domains during the intervention was also associated with an additional decrease of 2.1 to 2.9 points in PF over follow-up (p values < 0.01). Better social participation and PA at baseline were significantly associated with better average PF scores during the intervention (2.8 to 5.2 points higher for every 5-point increase in social participation or 30 min more of PA; p values < 0.05). Every 5-point increase in pain at baseline, or increases in pain during the intervention, was associated with decreases of 4.9 and 3.0 points, respectively, in PF. Conclusions: Worse QOL scores before and during the intervention were significantly associated with worse PF over follow-up. Encouraging social participation and PA through interventions such as home-based gardening may improve long-term health among older cancer survivors.

The Otago Exercise Program compared to falls prevention education in Zuni elders: a randomized controlled trial.

BACKGROUND: When a Zuni elder sustains a fall-related injury, the closest tribal skilled nursing facility is 100 miles from the Pueblo and no physical therapy services are available. Thus, fall prevention strategies as a primary intervention to avert injurious falls and preserve aging in place are needed. The objective of the study is to compare the effectiveness of a community health representative (CHR)-delivered, culturally-adapted Otago Exercise Program (OEP) fall prevention program compared to the standard of care education-based fall risk management. METHODS: "Standing Strong in Tribal Communities: Assessing Elder Falls Disparity" is mixed-methods research with a randomized controlled trial. The CHRs will be trained to deliver the culturally-adapted OEP trial and offer advantages of speaking "Shiwi" (Zuni tribal language) and understanding Zuni traditions, family structures, and elders' preferences for receiving health information. Focus groups will be conducted to assure all materials are culturally appropriate, and adapted. A physical therapist will train CHRs to screen elders for falls risk and to deliver the OEP to the intervention group and education to the control group. Up to 400 Zuni elders will be screened by the CHRs for falls risk and 200 elders will be enrolled into the study (1:1 random allocation by household). The intervention is 6 months with measurements at baseline, 3, 6 and 12 months. The primary outcome is improved strength and balance (timed up and go, sit to stand and 4 stage balance test), secondary outcomes include falls incidence, self-efficacy using Attitudes to Falls-Related Interventions Scale, Medical Outcomes Study Short Form 12 (SF-12v2) and Self-Efficacy for Managing Daily Activities. DISCUSSION: Fall prevention for Zuni elders was identified as a tribal priority and this trial is built upon longstanding collaborations between the investigative team, Zuni tribal leaders, and multiple tribal health programs. Delivery by the CHRs make this model more acceptable, and thus, more sustainable long term. This study has the potential to change best practice for elder care in tribal and rural areas with limited access to physical therapist-delivered fall prevention interventions and aligns with tribal goals to avert fall-related injury, reduce healthcare disparity, and preserve elder's independence. TRIAL REGISTRATION: NCT04876729.

Mammographic Variation Measures, Breast Density, and Breast Cancer Risk.

OBJECTIVE. Our previous work showed that variation measures, which represent breast architecture derived from mammograms, were significantly associated with breast cancer. For replication purposes, we examined the association of three variation measures (variation [V], which is measured in the image domain, and P1 and p1 [a normalized version of P1], which are derived from restricted regions in the Fourier domain) with breast cancer risk in an independent population. We also compared these measures to volumetric density measures (volumetric percent density [VPD] and dense volume [DV]) from a commercial product. MATERIALS AND METHODS. We examined 514 patients with breast cancer and 1377 control patients from a screening practice who were matched for age, date of examination, mammography unit, facility, and state of residence. Spearman rank-order correlation was used to evaluate the monotonic association between measures. Breast cancer associations were estimated using conditional logistic regression, after adjustment for age and body mass index. Odds ratios were calculated per SD increment in mammographic measure. RESULTS. These variation measures were strongly correlated with VPD (correlation, 0.68-0.80) but not with DV (correlation, 0.31-0.48). Similar to previous findings, all variation measures were significantly associated with breast cancer (odds ratio per SD: 1.30 [95% CI, 1.16-1.46] for V, 1.55 [95% CI, 1.35-1.77] for P1, and 1.51 [95% CI, 1.33-1.72] for p1). Associations of volumetric density measures with breast cancer were similar (odds ratio per SD: 1.54 [95% CI, 1.33-1.78] for VPD and 1.34 [95% CI, 1.20-1.50] for DV). When DV was included with each variation measure in the same model, all measures retained significance. CONCLUSION. Variation measures were significantly associated with breast cancer risk (comparable to the volumetric density measures) but were independent of the DV.

Association of Daily Alcohol Intake, Volumetric Breast Density, and Breast Cancer Risk.

High alcohol intake and breast density increase breast cancer (BC) risk, but their interrelationship is unknown. We examined whether volumetric density modifies and/or mediates the alcohol-BC association. BC cases (n = 2233) diagnosed from 2006 to 2013 in the San Francisco Bay area had screening mammograms 6 or more months before diagnosis; controls (n = 4562) were matched on age, mammogram date, race or ethnicity, facility, and mammography machine. Logistic regression was used to estimate alcohol-BC associations adjusted for age, body mass index, and menopause; interaction terms assessed modification. Percent mediation was quantified as the ratio of log (odds ratios [ORs]) from models with and without density measures. Alcohol consumption was associated with increased BC risk (2-sided P trend = .004), as were volumetric percent density (OR = 1.45 per SD, 95% confidence interval [CI] = 1.36 to 1.56) and dense volume (OR = 1.30, 95% CI = 1.24 to 1.37). Breast density did not modify the alcohol-BC association (2-sided P > .10 for all). Dense volume mediated 25.0% (95% CI = 5.5% to 44.4%) of the alcohol-BC association (2-sided P = .01), suggesting alcohol may partially increase BC risk by increasing fibroglandular tissue.

Remote Assessment of Functional Mobility and Strength in Older Cancer Survivors: Protocol for a Validity and Reliability Study.

BACKGROUND: Older cancer survivors, faced with both age- and treatment-related morbidity, are at increased and premature risk for physical function limitations. Physical performance is an important predictor of disability, quality of life, and premature mortality, and thus is considered an important target of interventions designed to prevent, delay, or attenuate the physical functional decline. Currently, low-cost, valid, and reliable methods to remotely assess physical performance tests that are self-administered by older adults in the home-setting do not exist, thus limiting the reach, scalability, and dissemination of interventions. OBJECTIVE: This paper will describe the rationale and design for a study to evaluate the accuracy, reliability, safety, and acceptability of videoconferencing and self-administered tests of functional mobility and strength by older cancer survivors in their own homes. METHODS: To enable remote assessment, participants receive a toolkit and instructions for setting up their test course and communicating with the investigator. Two standard gerontologic performance tests are being evaluated: the Timed Up and Go test and the 30-second chair stand test. Phase 1 of the study evaluates proof-of-concept that older cancer survivors (age ≥60 years) can follow the testing protocol and use a tablet PC to communicate with the study investigator. Phase 2 evaluates the criterion validity of videoconference compared to direct observation of the two physical performance tests. Phase 3 evaluates reliability by enrolling 5-10 participants who agree to repeat the remote assessment (without direct observation). Phase 4 enrolls 5-10 new study participants to complete the remote assessment test protocol. Feedback from participants in each phase is used to refine the test protocol and instructions. RESULTS: Enrollment began in December 2019. Ten participants completed the Phase 1 proof-of-concept. The study was paused in mid-March 2020 due to the COVID-19 pandemic. The study is expected to be completed by the end of 2020. CONCLUSIONS: This validity and reliability study will provide important information on the acceptability and safety of using videoconferencing to remotely assess two tests of functional mobility and strength, self-administered by older adults in their homes. Videoconferencing has the potential to expand the reach, scalability, and dissemination of interventions to older cancer survivors, and potentially other older adults, especially in rural areas. TRIAL REGISTRATION: ClinicalTrials.gov NCT04339959; https://clinicaltrials.gov/ct2/show/NCT04339959. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/20834.

American Indian chronic Renal insufficiency cohort study (AI-CRIC study).

BACKGROUND: Chronic kidney disease (CKD) is an increasing epidemic globally that is associated with adverse health outcomes including end stage kidney disease (ESKD), cardiovascular disease (CVD), and death. American Indians (AIs) have a higher prevalence of CKD than most other racial/ethnic groups, due in part to a high prevalence of type 2 diabetes. Other genetic and environmental factors not yet identified may also contribute to the disproportionate burden of CKD in AIs. METHOD: We will establish 3 clinical centers to recruit AIs from the Southwest United States (US) to expand the Chronic Renal Insufficiency Cohort (CRIC) study. We will follow the current CRIC protocol for kidney and cardiovascular measures and outcomes, which include ambulatory monitoring of kidney function and the use of mobile health technologies for CVD sub-phenotyping, and compare the outcomes in AIs with those in other racial/ethnic groups in CRIC. DISCUSSION: AI-CRIC will identify the role of various risk factors for rapid loss of kidney function among AIs of the Southwest US. In addition, to better understand the natural history of CKD and CVD in this high-risk population, we will identify unique risk factors for CKD and CVD progression in AIs. We will also compare event rates and risk factors for kidney and cardiovascular events in AIs with the other populations represented in CRIC.

Analysis of shared heritability in common disorders of the brain.

Disorders of the brain can exhibit considerable epidemiological comorbidity and often share symptoms, provoking debate about their etiologic overlap. We quantified the genetic sharing of 25 brain disorders from genome-wide association studies of 265,218 patients and 784,643 control participants and assessed their relationship to 17 phenotypes from 1,191,588 individuals. Psychiatric disorders share common variant risk, whereas neurological disorders appear more distinct from one another and from the psychiatric disorders. We also identified significant sharing between disorders and a number of brain phenotypes, including cognitive measures. Further, we conducted simulations to explore how statistical power, diagnostic misclassification, and phenotypic heterogeneity affect genetic correlations. These results highlight the importance of common genetic variation as a risk factor for brain disorders and the value of heritability-based methods in understanding their etiology.

Assessment of the Clinical Relevance of BRCA2 Missense Variants by Functional and Computational Approaches.

Many variants of uncertain significance (VUS) have been identified in BRCA2 through clinical genetic testing. VUS pose a significant clinical challenge because the contribution of these variants to cancer risk has not been determined. We conducted a comprehensive assessment of VUS in the BRCA2 C-terminal DNA binding domain (DBD) by using a validated functional assay of BRCA2 homologous recombination (HR) DNA-repair activity and defined a classifier of variant pathogenicity. Among 139 variants evaluated, 54 had ?99% probability of pathogenicity, and 73 had ?95% probability of neutrality. Functional assay results were compared with predictions of variant pathogenicity from the Align-GVGD protein-sequence-based prediction algorithm, which has been used for variant classification. Relative to the HR assay, Align-GVGD significantly (p < 0.05) over-predicted pathogenic variants. We subsequently combined functional and Align-GVGD prediction results in a Bayesian hierarchical model (VarCall) to estimate the overall probability of pathogenicity for each VUS. In addition, to predict the effects of all other BRCA2 DBD variants and to prioritize variants for functional studies, we used the endoPhenotype-Optimized Sequence Ensemble (ePOSE) algorithm to train classifiers for BRCA2 variants by using data from the HR functional assay. Together, the results show that systematic functional assays in combination with in silico predictors of pathogenicity provide robust tools for clinical annotation of BRCA2 VUS.

Association between mammographic breast density and histologic features of benign breast disease.

BACKGROUND: Over 40% of women undergoing breast screening have mammographically dense breasts. Elevated mammographic breast density (MBD) is an established breast cancer risk factor and is known to mask tumors within the dense tissue. However, the association of MBD with high risk benign breast disease (BBD) is unknown. METHOD: We analyzed data for 3400 women diagnosed with pathologically confirmed BBD in the Mayo Clinic BBD cohort from 1985-2001, with a clinical MBD measure (either parenchymal pattern (PP) or Breast Imaging Reporting and Data Systems (BI-RADS) density) and expert pathology review. Risk factor information was collected from medical records and questionnaires. MBD was dichotomized as dense (PP classification P2 or DY, or BI-RADS classification c or d) or non-dense (PP classification N1 or P1, or BI-RADS classification a or b). Associations of clinical and histologic characteristics with MBD were examined using logistic regression analysis to estimate odds ratios (ORs) with 95% confidence intervals (CIs). RESULTS: Of 3400 women in the study, 2163 (64%) had dense breasts. Adjusting for age and body mass index (BMI), there were positive associations of dense breasts with use of hormone therapy (HT), lack of lobular involution, presence of atypical lobular hyperplasia (ALH), histologic fibrosis, columnar cell hyperplasia/flat epithelia atypia (CCH/FEA), sclerosing adenosis (SA), cyst, usual ductal hyperplasia, and calcifications. In fully adjusted multivariate models, HT (1.3, 95% CI 1.1-1.5), ALH (1.5, 95% CI 1.0-2.2), lack of lobular involution (OR 1.6, 95% CI 1.2-2.1, compared to complete involution), fibrosis (OR 2.2, 95% CI 1.9-2.6) and CCH/FEA (OR 1.3, 95% CI 1.0-1.6) remained significantly associated with high MBD. CONCLUSION: Our findings support an association between high risk BBD and high MBD, suggesting that risks associated with the latter may act early in breast carcinogenesis.

Association of Elevated Amyloid Levels With Cognition and Biomarkers in Cognitively Normal People From the Community.

IMPORTANCE: The role of amyloid in the progression of Alzheimer disease (AD) pathophysiology is of central interest to the design of randomized clinical trials. The presence of amyloid has become a prerequisite for enrollment in several secondary prevention trials for AD, yet the precise effect of elevated amyloid levels on subsequent clinical and biomarker events is less certain. OBJECTIVE: To explore the effect of elevated amyloid levels on subsequent changes in cognition and biomarkers. DESIGN, SETTING, AND PARTICIPANTS: A total of 564 cognitively normal individuals (median age, 78 years) from the Mayo Clinic Study of Aging, a population-based longitudinal study in Olmsted County, Minnesota, with serial cognitive data were selected for this study. The data used in this study were collected from January 12, 2006, to January 9, 2014. Individuals included in this study had undergone magnetic resonance imaging, fluorodeoxyglucose positron emission tomography (FDG-PET), and Pittsburgh Compound B (PiB) PET at baseline were not cognitively impaired at baseline and had at least 1 clinical follow-up. A subset of 286 individuals also underwent serial imaging. Elevated amyloid level was defined as a standardized uptake value ratio of greater than 1.5 on PiB PET. Associations with baseline amyloid status and baseline and longitudinal change in clinical and imaging measures were evaluated after adjusting for age and hippocampal volume. APOE4 effects were also evaluated. MAIN OUTCOMES AND MEASURES: Cognitive measures of memory, language, attention/executive function, visuospatial skills, PiB levels, hippocampal and ventricular volumes, and FDG-PET measures. RESULTS: At baseline, 179 (31.7%) individuals with elevated amyloid levels had poorer cognition in all domains measured, reduced hippocampal volume, and greater FDG-PET hypometabolism. Elevated amyloid levels at baseline were associated with a greater rate of cognitive decline in all domains (0.04 to 0.09 z score units per year) except language and a greater rate of amyloid accumulation (1.6% per year), hippocampal atrophy (30 mm3 per year), and ventricular enlargement (565 mm3 per year). Elevated amyloid levels were also associated with an increased risk of mild cognitive impairment (hazard ratio, 2.9; 95% CI, 1.7-5.0, and hazard ratio, 1.6; 95% CI, 0.9-2.8, for PiB+ APOE4 carriers and PiB+ noncarriers, respectively, compared with PiB- noncarriers). These associations were largely independent of APOE4. CONCLUSIONS AND RELEVANCE: In persons selected from a population-based study, elevated amyloid levels at baseline were associated with worse cognition and imaging biomarkers at baseline and with greater clinical decline and neurodegeneration. These results have implications for the design of randomized clinical trials for AD.

Assessing associations between the AURKA-HMMR-TPX2-TUBG1 functional module and breast cancer risk in BRCA1/2 mutation carriers.

While interplay between BRCA1 and AURKA-RHAMM-TPX2-TUBG1 regulates mammary epithelial polarization, common genetic variation in HMMR (gene product RHAMM) may be associated with risk of breast cancer in BRCA1 mutation carriers. Following on these observations, we further assessed the link between the AURKA-HMMR-TPX2-TUBG1 functional module and risk of breast cancer in BRCA1 or BRCA2 mutation carriers. Forty-one single nucleotide polymorphisms (SNPs) were genotyped in 15,252 BRCA1 and 8,211 BRCA2 mutation carriers and subsequently analyzed using a retrospective likelihood approach. The association of HMMR rs299290 with breast cancer risk in BRCA1 mutation carriers was confirmed: per-allele hazard ratio (HR) = 1.10, 95% confidence interval (CI) 1.04-1.15, p = 1.9 x 10(-4) (false discovery rate (FDR)-adjusted p = 0.043). Variation in CSTF1, located next to AURKA, was also found to be associated with breast cancer risk in BRCA2 mutation carriers: rs2426618 per-allele HR = 1.10, 95% CI 1.03-1.16, p = 0.005 (FDR-adjusted p = 0.045). Assessment of pairwise interactions provided suggestions (FDR-adjusted pinteraction values > 0.05) for deviations from the multiplicative model for rs299290 and CSTF1 rs6064391, and rs299290 and TUBG1 rs11649877 in both BRCA1 and BRCA2 mutation carriers. Following these suggestions, the expression of HMMR and AURKA or TUBG1 in sporadic breast tumors was found to potentially interact, influencing patients' survival. Together, the results of this study support the hypothesis of a causative link between altered function of AURKA-HMMR-TPX2-TUBG1 and breast carcinogenesis in BRCA1/2 mutation carriers.

Prediction of breast cancer risk based on profiling with common genetic variants.

BACKGROUND: Data for multiple common susceptibility alleles for breast cancer may be combined to identify women at different levels of breast cancer risk. Such stratification could guide preventive and screening strategies. However, empirical evidence for genetic risk stratification is lacking. METHODS: We investigated the value of using 77 breast cancer-associated single nucleotide polymorphisms (SNPs) for risk stratification, in a study of 33 673 breast cancer cases and 33 381 control women of European origin. We tested all possible pair-wise multiplicative interactions and constructed a 77-SNP polygenic risk score (PRS) for breast cancer overall and by estrogen receptor (ER) status. Absolute risks of breast cancer by PRS were derived from relative risk estimates and UK incidence and mortality rates. RESULTS: There was no strong evidence for departure from a multiplicative model for any SNP pair. Women in the highest 1% of the PRS had a three-fold increased risk of developing breast cancer compared with women in the middle quintile (odds ratio [OR] = 3.36, 95% confidence interval [CI] = 2.95 to 3.83). The ORs for ER-positive and ER-negative disease were 3.73 (95% CI = 3.24 to 4.30) and 2.80 (95% CI = 2.26 to 3.46), respectively. Lifetime risk of breast cancer for women in the lowest and highest quintiles of the PRS were 5.2% and 16.6% for a woman without family history, and 8.6% and 24.4% for a woman with a first-degree family history of breast cancer. CONCLUSIONS: The PRS stratifies breast cancer risk in women both with and without a family history of breast cancer. The observed level of risk discrimination could inform targeted screening and prevention strategies. Further discrimination may be achievable through combining the PRS with lifestyle/environmental factors, although these were not considered in this report.

Candidate pathway-based genetic association study of platinum and platinum-taxane related toxicity in a cohort of primary lung cancer patients.

BACKGROUND: Chemotherapy-induced peripheral neuropathy (CIPN) is a common toxicity secondary to chemotherapy. Genetic factors may be important in predisposing patients to this adverse effect. PATIENTS AND METHODS: We studied 950 primary lung cancer patients, who received platinum or platinum-combination drug chemotherapy and who had DNA available for study. We analyzed epidemiological risk factors in 279 CIPN patients and 456 non-CIPN patients and genetic risk factors in 141 CIPN patients and 259 non-CIPN patients. The risk factors studied included demographic, diagnostic, and treatment data, as well as 174 tag SNPs (single nucleotide polymorphisms) across 43 candidate genes in the glutathione, cell cycle, DNA repair, cell signaling, and apoptosis pathways. RESULTS: Patients who had diabetes mellitus were more likely to have CIPN (p=0.0002). Other epidemiologic risk factors associated with CIPN included number of cycles (p=0.0004) and type of concurrent chemotherapy (p<0.001). SNPs most associated with CIPN were in glutathione peroxidase 7 (GPX7) gene (p values 0.0015 and 0.0028, unadjusted and adjusted) and in ATP-binding cassette sub-family C member 4 (ABCC4) gene (p values 0.037 and 0.006, unadjusted and adjusted). We also found other suggestive associations in methyl-o-guanine-methyl-transferase (MGMT) and glutathione-S-transferase (GST) isoforms. CONCLUSIONS: Epidemiological and genetic risk factors associated with CIPN in this cohort, included the type of chemotherapy drug, intensity of chemotherapy treatment, and genes known to be associated with chemotherapy resistance. These findings suggest that differentiating between cytotoxic and neurotoxic mechanisms of chemotherapy drugs is challenging but represents an important step toward individualized therapy and improving quality of life for patients.

Age-specific population frequencies of cerebral ß-amyloidosis and neurodegeneration among people with normal cognitive function aged 50-89 years: a cross-sectional study.

BACKGROUND: As preclinical Alzheimer's disease becomes a target for therapeutic intervention, the overlap between imaging abnormalities associated with typical ageing and those associated with Alzheimer's disease needs to be recognised. We aimed to characterise how typical ageing and preclinical Alzheimer's disease overlap in terms of ß-amyloidosis and neurodegeneration. METHODS: We measured age-specific frequencies of amyloidosis and neurodegeneration in individuals with normal cognitive function aged 50-89 years. Potential participants were randomly selected from the Olmsted County (MN, USA) population-based study of cognitive ageing and invited to participate in cognitive and imaging assessments. To be eligible for inclusion, individuals must have been judged clinically to have no cognitive impairment and have undergone amyloid PET, (18)F-fluorodeoxyglucose ((18)F-FDG) PET, and MRI. Imaging results were obtained from March 28, 2006, to Dec 3, 2013. Amyloid status (positive [A(+)] or negative [A(-)]) was determined by amyloid PET with (11)C Pittsburgh compound B. Neurodegeneration status (positive [N(+)] or negative [N(-)]) was determined by an Alzheimer's disease signature (18)F-FDG PET or hippocampal volume on MRI. We determined age-specific frequencies of the four groups (amyloid negative and neurodegeneration negative [A(-)N(-)], amyloid positive and neurodegeneration negative [A(+)N(-)], amyloid negative and neurodegeneration positive [A(-)N(+)], or amyloid positive and neurodegeneration positive [A(+)N(+)]) cross-sectionally using multinomial regression models. We also investigated associations of group frequencies with APOE ɛ4 status (assessed with DNA extracted from blood) and sex by including these covariates in the multinomial models. FINDINGS: The study population consisted of 985 eligible participants. The population frequency of A(-)N(-) was 100% (n=985) at age 50 years and fell to 17% (95% CI 11-24) by age 89 years. The frequency of A(+)N(-) increased to 28% (24-32) at age 74 years, then decreased to 17% (11-25) by age 89 years. The frequency of A(-)N(+) increased from age 60 years, reaching 24% (16-34) by age 89 years. The frequency of A(+)N(+) increased from age 65 years, reaching 42% (31-52) by age 89 years. The results from our multinomial models suggest that A(+)N(-) and A(+)N(+) were more frequent in APOE ɛ4 carriers than in non-carriers and that A(+)N(+) was more, and A(+)N(-) less frequent in men than in women. INTERPRETATION: Accumulation of amyloid and neurodegeneration are nearly inevitable by old age, but many people are able to maintain normal cognitive function despite these imaging abnormalities. Changes in the frequency of amyloidosis and neurodegeneration with age, which seem to be modified by APOE ɛ4 and sex, suggest that pathophysiological sequences might differ between individuals. FUNDING: US National Institute on Aging and Alexander Family Professorship of Alzheimer's Disease Research.

Baseline neuropsychiatric symptoms and the risk of incident mild cognitive impairment: a population-based study.

OBJECTIVE: The authors conducted a prospective cohort study to estimate the risk of incident mild cognitive impairment in cognitively normal elderly (aged ≥70 years) individuals with or without neuropsychiatric symptoms at baseline. The research was conducted in the setting of the population-based Mayo Clinic Study of Aging. METHOD: A classification of normal cognitive aging, mild cognitive impairment, and dementia was adjudicated by an expert consensus panel based on published criteria. Hazard ratios and 95% confidence intervals were computed using Cox proportional hazards model, with age as a time scale. Baseline Neuropsychiatric Inventory Questionnaire data were available for 1,587 cognitively normal persons who underwent at least one follow-up visit. RESULTS: The cohort was followed to incident mild cognitive impairment (N=365) or censoring variables (N=179) for a median of 5 years. Agitation (hazard ratio=3.06, 95% CI=1.89-4.93), apathy (hazard ratio=2.26, 95% CI=1.49-3.41), anxiety (hazard ratio=1.87, 95% CI=1.28-2.73), irritability (hazard ratio=1.84, 95% CI=1.31-2.58), and depression (hazard ratio=1.63, 95% CI=1.23-2.16), observed initially, increased risk for later mild cognitive impairment. Delusion and hallucination did not. A secondary analysis, limited in significance by the small number of study participants, showed that euphoria, disinhibition, and nighttime behaviors were significant predictors of nonamnestic mild cognitive impairment but not amnestic mild cognitive impairment. By contrast, depression predicted amnestic mild cognitive impairment (hazard ratio=1.74, 95% CI=1.22-2.47) but not nonamnestic mild cognitive impairment. CONCLUSIONS: An increased incidence of mild cognitive impairment was observed in community-dwelling elderly adults who had nonpsychotic psychiatric symptoms at baseline. These baseline psychiatric symptoms were of similar or greater magnitude as biomarkers (genetic and structural MRI) in increasing the risk of incident mild cognitive impairment.