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.

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.

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.

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.

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.

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.

Identification of a BRCA2-specific modifier locus at 6p24 related to breast cancer risk.

Common genetic variants contribute to the observed variation in breast cancer risk for BRCA2 mutation carriers; those known to date have all been found through population-based genome-wide association studies (GWAS). To comprehensively identify breast cancer risk modifying loci for BRCA2 mutation carriers, we conducted a deep replication of an ongoing GWAS discovery study. Using the ranked P-values of the breast cancer associations with the imputed genotype of 1.4 M SNPs, 19,029 SNPs were selected and designed for inclusion on a custom Illumina array that included a total of 211,155 SNPs as part of a multi-consortial project. DNA samples from 3,881 breast cancer affected and 4,330 unaffected BRCA2 mutation carriers from 47 studies belonging to the Consortium of Investigators of Modifiers of BRCA1/2 were genotyped and available for analysis. We replicated previously reported breast cancer susceptibility alleles in these BRCA2 mutation carriers and for several regions (including FGFR2, MAP3K1, CDKN2A/B, and PTHLH) identified SNPs that have stronger evidence of association than those previously published. We also identified a novel susceptibility allele at 6p24 that was inversely associated with risk in BRCA2 mutation carriers (rs9348512; per allele HR = 0.85, 95% CI 0.80-0.90, P = 3.9 × 10(-8)). This SNP was not associated with breast cancer risk either in the general population or in BRCA1 mutation carriers. The locus lies within a region containing TFAP2A, which encodes a transcriptional activation protein that interacts with several tumor suppressor genes. This report identifies the first breast cancer risk locus specific to a BRCA2 mutation background. This comprehensive update of novel and previously reported breast cancer susceptibility loci contributes to the establishment of a panel of SNPs that modify breast cancer risk in BRCA2 mutation carriers. This panel may have clinical utility for women with BRCA2 mutations weighing options for medical prevention of breast cancer.

Mild cognitive impairment due to Alzheimer disease in the community.

OBJECTIVE: The newly proposed National Institute on Aging-Alzheimer's Association (NIA-AA) criteria for mild cognitive impairment (MCI) due to Alzheimer disease (AD) suggest a combination of clinical features and biomarker measures, but their performance in the community is not known. METHODS: The Mayo Clinic Study of Aging (MCSA) is a population-based longitudinal study of nondemented subjects in Olmsted County, Minnesota. A sample of 154 MCI subjects from the MCSA was compared to a sample of 58 amnestic MCI subjects from the Alzheimer's Disease Neuroimaging Initiative 1 (ADNI-1) to assess the applicability of the criteria in both settings and to assess their outcomes. RESULTS: Fourteen percent of MCSA and 16% of ADNI-1 of subjects were biomarker negative. In addition, 14% of MCSA and 12% of ADNI-1 subjects had evidence for amyloid deposition only, whereas 43% of MCSA and 55% of ADNI-1 subjects had evidence for amyloid deposition plus neurodegeneration (magnetic resonance imaging atrophy, fluorodeoxyglucose positron emission tomography hypometabolism, or both). However, a considerable number of subjects had biomarkers inconsistent with the proposed AD model; for example, 29% of MCSA subjects and 17% of ADNI-1 subjects had evidence for neurodegeneration without amyloid deposition. These subjects may not be on an AD pathway. Neurodegeneration appears to be a key factor in predicting progression relative to amyloid deposition alone. INTERPRETATION: The NIA-AA criteria apply to most MCI subjects in both the community and clinical trials settings; however, a sizeable proportion of subjects had conflicting biomarkers, which may be very important and need to be explored.

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.

Evaluation of chromosome 6p22 as a breast cancer risk modifier locus in a follow-up study of BRCA2 mutation carriers.

Several common germline variants identified through genome-wide association studies of breast cancer risk in the general population have recently been shown to be associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers. When combined, these variants can identify marked differences in the absolute risk of developing breast cancer for mutation carriers, suggesting that additional modifier loci may further enhance individual risk assessment for BRCA1 and BRCA2 mutation carriers. Recently, a common variant on 6p22 (rs9393597) was found to be associated with increased breast cancer risk for BRCA2 mutation carriers [hazard ratio (HR) = 1.55, 95 % confidence interval (CI) 1.25-1.92, p = 6.0 × 10(-5)]. This observation was based on data from GWAS studies in which, despite statistical correction for multiple comparisons, the possibility of false discovery remains a concern. Here, we report on an analysis of this variant in an additional 6,165 BRCA1 and 3,900 BRCA2 mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). In this replication analysis, rs9393597 was not associated with breast cancer risk for BRCA2 mutation carriers (HR = 1.09, 95 % CI 0.96-1.24, p = 0.18). No association with ovarian cancer risk for BRCA1 or BRCA2 mutation carriers or with breast cancer risk for BRCA1 mutation carriers was observed. This follow-up study suggests that, contrary to our initial report, this variant is not associated with breast cancer risk among individuals with germline BRCA2 mutations.

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.

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.

Brain beta-amyloid measures and magnetic resonance imaging atrophy both predict time-to-progression from mild cognitive impairment to Alzheimer's disease.

Biomarkers of brain Aß amyloid deposition can be measured either by cerebrospinal fluid Aß42 or Pittsburgh compound B positron emission tomography imaging. Our objective was to evaluate the ability of Aß load and neurodegenerative atrophy on magnetic resonance imaging to predict shorter time-to-progression from mild cognitive impairment to Alzheimer's dementia and to characterize the effect of these biomarkers on the risk of progression as they become increasingly abnormal. A total of 218 subjects with mild cognitive impairment were identified from the Alzheimer's Disease Neuroimaging Initiative. The primary outcome was time-to-progression to Alzheimer's dementia. Hippocampal volumes were measured and adjusted for intracranial volume. We used a new method of pooling cerebrospinal fluid Aß42 and Pittsburgh compound B positron emission tomography measures to produce equivalent measures of brain Aß load from either source and analysed the results using multiple imputation methods. We performed our analyses in two phases. First, we grouped our subjects into those who were 'amyloid positive' (n = 165, with the assumption that Alzheimer's pathology is dominant in this group) and those who were 'amyloid negative' (n = 53). In the second phase, we included all 218 subjects with mild cognitive impairment to evaluate the biomarkers in a sample that we assumed to contain a full spectrum of expected pathologies. In a Kaplan-Meier analysis, amyloid positive subjects with mild cognitive impairment were much more likely to progress to dementia within 2 years than amyloid negative subjects with mild cognitive impairment (50 versus 19%). Among amyloid positive subjects with mild cognitive impairment only, hippocampal atrophy predicted shorter time-to-progression (P < 0.001) while Aß load did not (P = 0.44). In contrast, when all 218 subjects with mild cognitive impairment were combined (amyloid positive and negative), hippocampal atrophy and Aß load predicted shorter time-to-progression with comparable power (hazard ratio for an inter-quartile difference of 2.6 for both); however, the risk profile was linear throughout the range of hippocampal atrophy values but reached a ceiling at higher values of brain Aß load. Our results are consistent with a model of Alzheimer's disease in which Aß deposition initiates the pathological cascade but is not the direct cause of cognitive impairment as evidenced by the fact that Aß load severity is decoupled from risk of progression at high levels. In contrast, hippocampal atrophy indicates how far along the neurodegenerative path one is, and hence how close to progressing to dementia. Possible explanations for our finding that many subjects with mild cognitive impairment have intermediate levels of Aß load include: (i) individual subjects may reach an Aß load plateau at varying absolute levels; (ii) some subjects may be more biologically susceptible to Aß than others; and (iii) subjects with mild cognitive impairment with intermediate levels of Aß may represent individuals with Alzheimer's disease co-existent with other pathologies.

Language and behavior domains enhance the value of the clinical dementia rating scale.

BACKGROUND: The six domain standard Clinical Dementia Rating Scale (CDRstd) has been successful for staging patients with the clinical syndrome of probable Alzheimer's disease (AD). The CDRstd does not specifically address language dysfunction or alteration in personality and social behaviors which are prominent in behavioral variant frontotemporal dementia (bvFTD) and primary progressive aphasia (PPA). OBJECTIVE: To determine the value of adding domains of Language (LANG), and Behavior, Comportment, and Personality (BEHAV) to the CDRstd for the evaluation of patients with bvFTD and PPA. METHODS: Two new domains, LANG and BEHAV, were constructed to parallel the six domains sampled in the CDRstd. Clinical and neuropsychological test data were obtained from the National Alzheimer's Coordinating Center. The dataset contained information on 2550 probable AD, 88 vascular dementia, 281 dementia with Lewy body, 234 bvFTD, and 137 PPA patients. RESULTS: There were 76.5% of bvFTD and 99.3% of PPA patients with abnormal ratings (>0) on the LANG domain; 90.2% of bvFTD and 63.5% of PPA had abnormal ratings on the BEHAV domain. In patients with a CDRstd sum of boxes score of <4, 53.7% of bvFTD had BEHAV domain and 78.6% of PPA patients had LANG domain scores>1. Among probable AD patients, 3.7% had LANG ratings that were ≥1 and 3.8% had BEHAV ratings that were ≥1. Logistic regression analyses showed that adding either the LANG or BEHAV domains to the CDRstd sum of boxes score significantly improved the discrimination between probable AD, bvFTD, and PPA. CONCLUSIONS: The new LANG and BEHAV domains add value to the CDRstd for the characterization of the nonamnestic symptoms that are prominent in patients with bvFTD and PPA but that also occur in those with probable AD.

Transforming cerebrospinal fluid Aß42 measures into calculated Pittsburgh Compound B units of brain Aß amyloid.

BACKGROUND: Positron-emission tomography (PET) imaging of amyloid with Pittsburgh Compound B (PIB) and Aß42 levels in the cerebrospinal fluid (CSF Aß42) demonstrate a highly significant inverse correlation. Both these techniques are presumed to measure brain Aß amyloid load. The objectives of this study were to develop a method to transform CSF Aß42 measures into calculated PIB measures (PIBcalc) of Aß amyloid load, and to partially validate the method in an independent sample of subjects. METHODS: In all, 41 subjects from the Alzheimer's Disease Neuroimaging Initiative (ADNI) underwent PIB PET imaging and lumbar puncture (LP) at the same time. This sample, referred to as the "training" sample (nine cognitively normal subjects, 22 subjects with mild cognitive impairment, and 10 subjects with Alzheimer's disease), was used to develop a regression model by which CSF Aß42 (with apolipoprotein E ɛ4 carrier status as a covariate) was transformed into units of PIB PET (PIBcalc). An independent "supporting" sample of 362 ADNI subjects (105 cognitively normal subjects, 164 subjects with mild cognitive impairment, and 93 subjects with Alzheimer's disease) who underwent LP but not PIB PET imaging had their CSF Aß42 values converted to PIBcalc. These values were compared with the overall PIB PET distribution found in the ADNI subjects (n=102). RESULTS: A linear regression model demonstrates good prediction of actual PIB PET from CSF Aß42 measures obtained in the training sample (R(2)=0.77, P<.001). PIBcalc data (derived from CSF Aß42) in the supporting sample of 362 ADNI subjects who underwent LP but not PIB PET imaging demonstrate group-wise distributions that are highly consistent with the larger ADNI PIB PET distribution and with published PIB PET imaging studies. CONCLUSION: Although the precise parameters of this model are specific for the ADNI sample, we conclude that CSF Aß42 can be transformed into PIBcalc measures of Aß amyloid load. Brain Aß amyloid load can be ascertained at baseline in therapeutic or observational studies by either CSF or amyloid PET imaging and the data can be pooled using well-established multiple imputation techniques that account for the uncertainty in a CSF-based PIBcalc value.

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.

Evidence for SMAD3 as a modifier of breast cancer risk in BRCA2 mutation carriers.

INTRODUCTION: Current attempts to identify genetic modifiers of BRCA1 and BRCA2 associated risk have focused on a candidate gene approach, based on knowledge of gene functions, or the development of large genome-wide association studies. In this study, we evaluated 24 SNPs tagged to 14 candidate genes derived through a novel approach that analysed gene expression differences to prioritise candidate modifier genes for association studies. METHODS: We successfully genotyped 24 SNPs in a cohort of up to 4,724 BRCA1 and 2,693 BRCA2 female mutation carriers from 15 study groups and assessed whether these variants were associated with risk of breast cancer in BRCA1 and BRCA2 mutation carriers. RESULTS: SNPs in five of the 14 candidate genes showed evidence of association with breast cancer risk for BRCA1 or BRCA2 carriers (P < 0.05). Notably, the minor alleles of two SNPs (rs7166081 and rs3825977) in high linkage disequilibrium (r² = 0.77), located at the SMAD3 locus (15q22), were each associated with increased breast cancer risk for BRCA2 mutation carriers (relative risk = 1.25, 95% confidence interval = 1.07 to 1.45, P(trend) = 0.004; and relative risk = 1.20, 95% confidence interval = 1.03 to 1.40, P(trend) = 0.018). CONCLUSIONS: This study provides evidence that the SMAD3 gene, which encodes a key regulatory protein in the transforming growth factor beta signalling pathway and is known to interact directly with BRCA2, may contribute to increased risk of breast cancer in BRCA2 mutation carriers. This finding suggests that genes with expression associated with BRCA1 and BRCA2 mutation status are enriched for the presence of common genetic modifiers of breast cancer risk in these populations.

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.