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AbstractBackgroundFrontotemporal dementia spectrum disorders (FTD) display complex neuropathological substrates and poor clinicopathological correlations, which hinders therapy development. Plasma P‐tau217 is an emerging tool to screen for Alzheimer’s disease (AD) pathology and may have diagnostic value in FTD.MethodPlasma P‐tau217 was measured cross‐sectionally by electrochemiluminescence in FTD patients referred to ALLFTD from ARTFL (n = 628, 45.7% female, median age 66 ± 12 years). P‐tau217 differences by baseline phenotype, disease severity and genotype were determined with non‐parametric tests and general linear models. Associations between P‐tau217 and measures of disease severity and neuropsychological performance were determined with linear regressions corrected for age, sex, phenotype and APOE.ResultThe sample included 33% behavioral variant FTD, 23.6% primary progressive aphasia (PPA), 28.5% atypical parkinsonism, 1.6% amnestic dementia (AmDem), 2.8% FTD/motoneuron disease, 3% mild cognitive/behavioral impairment and 7.5% healthy controls. Only 1.6% carried FTD‐causing mutations. P‐tau217 was not related to age (r = 0.034, 95%CI ‐0.03 – 0.12, p = 0.4). Compared to controls (0.18 ± 0.07 pg/mL), P‐tau217 was elevated only in AmDem (0.58 ± 0.9 pg/mL, p = 0.001) and logopenic PPA (lvPPA, 0.71 ± 0.62 pg/mL p < 0.001). P‐tau217 ≥ 0.42 pg/mL effectively discriminated AmDem and lvPPA from all other phenotypes (AUC 0.87, 95%CI 0.77 – 0.96, p = 0.001, 77% sensitivity, 92% specificity). AmDem (60%) and lvPPA (91.7%) had the highest prevalence of high (≥ 0.42 pg/mL) P‐tau217, and the highest prevalence of APOE4 (AmDem 40%, lvPPA 63.6%). APOE4 carriers (0.23 ± 0.22 pg/mL) had higher P‐tau217, than non‐carriers (0.19 ± 0.09 pg/mL), regardless of phenotype (APOE effect p = .002, APOE x phenotype, p = 0.44). P‐tau217 was associated with worse clinical severity, mood, memory and executive function, but not with worse motor symptoms or social cognition.ConclusionWhen FTD is suspected, high plasma P‐tau217 is strongly associated with amnestic dementia and logopenic PPA phenotypes. Pending completion of ongoing neuropathological, CSF and molecular neuroimaging analyses, the data support the use of plasma P‐tau217 to identify atypical AD as a cause or AD as a co‐pathology contributing to FTD clinical presentation.

AbstractBackgroundBlood neurofilament light chain (NfL) is a robust predictor of phenoconversion in familial frontotemporal lobar degeneration (fFTLD). The comparative value of CSF NfL and other CSF markers of degeneration in fFTLD remains unexplored.MethodFLTD‐causing mutation carriers were recruited through ALLFTD (n = 113, 56.6% female, mean age 48.1 ± 13 years; 29 C9orf72, 16 GRN, 34 MAPT, 34 mutation non‐carriers) and prospectively evaluated for 3 years. Baseline CSF was analyzed for NfL, phosphorylated neurofilament heavy chain (p‐NfH), tau, phosphorylated tau181 (p‐tau) and neurogranin using fit‐for‐purpose immunoassays. Mixed effect linear models, with random slopes, corrected for age, sex, genotype and total intracranial volume related CSF biomarkers to longitudinal clinical variables.ResultNfL (β = 0.64, p < 0.001), p‐NfH (β = 0.68, p < 0.001) and tau (β = 0.46, p < 0.001) correlated with age. There were no differences in biomarker concentrations by phenotype or severity, except for higher NfL and p‐NfH in full phenotype, compared to prodromal disease and asymptomatic carriers. Low neurogranin (β = ‐0.39, p < 0.001), low p‐tau (β = ‐0.33, p < 0.001) and high NfL (β = 0.42, p < 0.001) correlated with worse baseline disease severity measured by the CDR® Dementia Staging Instrument plus behavior and language domains from the National Alzheimer’s Disease Coordinating Center FTLD module sum of boxes (CDR®+NACC‐FTLDsb), and with other measures of global cognition, instrumental and daily function, and frontal and temporal brain volumes. Regardless of genotype, the predicted annualized rate of CDR®+NACC‐FTLDsb score worsenings per higher baseline CSF biomarker Log pg/mL were tau: 3.0 ± 0.2, NfL: 2.8 ± 0.2 and p‐NfH: 2.8 ± 0.2. High tau, NfL and p‐NfH also predicted worsening in other measures of global cognition and instrumental and daily function. Neurogranin and p‐tau did not predict clinical decline.ConclusionCSF tau, p‐tau, neurogranin, NfL and p‐NfH reflect important aspects of disease severity in fFTLD. In contrast to Alzheimer’s disease, low p‐tau and neurogranin are inversely related to clinical severity, which suggests a distinctive pathophysiological process and has implications for therapeutic development. CSF NfL, p‐NfH and tau have strong prognostic value in fFTLD.

AbstractBackgroundUp to 30% of frontotemporal dementia (FTD) cases are due to known pathogenic mutations (f‐FTD). Little is known about the factors that predict who will choose to learn their results. Upcoming clinical trials in f‐FTD may require disclosure prior to enrollment, even before symptom onset, and thus characterizing this sample is important. Furthermore, understanding the mood impacts of genetic disclosure may guide genetic counseling practice.MethodF‐FTD participants (n=568) from families with a known pathogenic mutation (MAPT, C9orf72, GRN) were enrolled through the ARTFL/LEFFTDS Longitudinal FTD Study (ALLFTD) and provided the opportunity for disclosure. Independent‐sample t‐tests compared demographic and psychosocial factors between participants who did and did not receive their results. In participants who were asymptomatic at baseline and follow up (n=199,177 with follow‐up), linear mixed effects modeling was used to investigate pre‐ to post‐disclosure changes in the 15‐item Geriatric Depression Scale (GDS).ResultOf participants from families with a known pathogenic genetic mutation, 47% received genetic disclosure. Of the asymptomatic subset (n=386), 36% know their mutation status. Of these asymptomatic learners, 46% received disclosure through the study, and the remainder learned their genetic status prior to study enrollment. None of the analyzed demographic or psychosocial factors (i.e., sex, age, education, having children) differed between learners and non‐learners (p’s > 0.05). In the longitudinal analysis of asymptomatic participants, learners showed a pre‐ to post‐increase of 0.31 GDS points/year (95%CI: ‐0.08, 0.69, p = 0.12), whereas non‐learners showed a slight decline (‐0.15 points/year, 95%CI: ‐0.36, 0.06, p = 0.16). This difference between slopes was statistically significant (0.46, 95%CI: 0.02, 0.89, p=0.04) but represents a small clinical effect. In asymptomatic learners, slopes did not differ based on mutation status (0.28, 95%CI: ‐0.66, 1.20, p=0.55). Conclusions were based on the estimates and full range of confidence intervals.ConclusionThe majority of asymptomatic research participants do not know their genetic status, which will be a consideration for clinical trials that require disclosure. No considered demographic factors were strongly associated with the decision to receive disclosure. The findings suggest that disclosure in asymptomatic participants has minimal impact on depressive symptoms regardless of genetic results.

AbstractBackgroundFrontotemporal lobar degeneration (FTLD) refers to a group of neurodegenerative conditions, affecting the frontal and/or temporal lobes. Ongoing research has provided insight into developing clinical trials for FTLD and key clinical measures such as structural MRI. To inform clinical trial design and optimize participation, it is imperative to explore facilitators and barriers for potential candidates.ObjectiveThe objective of this study is to explore facilitators and barriers to participating in future clinical trials for FTLD.MethodsAdvancing Research and Treatment for Frontotemporal Lobar Degeneration (ARTFL) and Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (LEFFTDS) are observational studies focused on characterizing FTLD syndromes in preparation for clinical trials. The 584 participants enrolled across 18 research sites in the United States and Canada completed a survey assessing interest in clinical trial participation.Results29% of respondents self‐reported as patients (63±10 years), 26% self‐reported as caregivers answering on behalf of patients (65±10 years), and 45% self‐reported as healthy but at risk for FTLD (48±14 years). Travel reimbursement was the most common factor reported to positively influence participation (≧66%), with the healthy but at risk group showing the strongest endorsement (83%). Cost and time involved in travel were possible barriers for about half of the patients (48%) and healthy but at risk respondents (53%). The respondents value receiving feedback on the study findings (≧80%) and being informed of their individual disease progression (≧75%). Particularly, keeping participation confidential was very important for the healthy but at risk group (62%). In regard to research assessments, most participants demonstrated a high interest in physical and neurological exams at a research center (≧87%) whereas only half were interested in doing more invasive procedures such as the lumbar puncture (≧52%). Overall, respondents showed a positive attitude and support for research participation (≧77%) and trusted that their health information would remain confidential in a clinical trial (≧53%).ConclusionsFavorable attitudes and interest towards medical research exist among participants. To optimize participation, clinical trials should allocate funding for travel and involve participants in feedback about study results and their disease progression. Alternatives to invasive assessments may increase participation.

Abstract Background Limited and conflicting findings have been reported regarding the association between social support and colorectal cancer (CRC) outcomes. We sought to assess the influences of marital status and living arrangement on survival outcomes among patients with stage III colon cancer. Patients and Methods We conducted a secondary analysis of 1082 patients with stage III colon cancer prospectively followed in the CALGB 89803 randomized adjuvant chemotherapy trial. Marital status and living arrangement were both self-reported at the time of enrollment as, respectively, married, divorced, separated, widowed, or never-married, and living alone, with a spouse or partner, with other family, in a nursing home, or other. Results Over a median follow-up of 7.6 years, divorced/separated/widowed patients experienced worse outcomes relative to those married regarding disease free-survival (DFS) (hazards ratio (HR), 1.44 (95% CI, 1.14-1.81); P =.002), recurrence-free survival (RFS) (HR, 1.35 (95% CI, 1.05-1.73); P = .02), and overall survival (OS) (HR, 1.40 (95% CI, 1.08-1.82); P =.01); outcomes were not significantly different for never-married patients. Compared to patients living with a spouse/partner, those living with other family experienced a DFS of 1.47 (95% CI, 1.02-2.11; P = .04), RFS of 1.34 (95% CI, 0.91-1.98; P = .14), and OS of 1.50 (95% CI, 1.00-2.25; P =.05); patients living alone did not experience significantly different outcomes. Conclusion Among patients with stage III colon cancer who received uniform treatment and follow-up within a nationwide randomized clinical trial, being divorced/separated/widowed and living with other family were significantly associated with greater colon cancer mortality. Interventions enhancing social support services may be clinically relevant for this patient population. Trial Registration ClinicalTrials.gov Identifier: NCT00003835

AbstractBackgroundMale hypogonadism (testosterone level < 300 ng/dl) is a clinical syndrome that results from failure of the testis to produce physiological levels of testosterone. Most marketed testosterone replacement therapy products often require multiple dose adjustment clinic visits to achieve the desired, eugonadal testosterone levels.ObjectiveTo evaluate the efficacy and safety of a novel oral testosterone undecanoate therapy for the treatment of hypogonadism.Material and methodsNinety‐five (N = 95) hypogonadal men were enrolled in this open‐label, single‐arm, multicenter study in the United States (NCT03242590). Subjects received 225 mg of oral testosterone undecanoate (TLANDO) twice a day for 24 days without dose adjustment. Primary efficacy was percentages of subjects who achieved mean 24‐h testosterone levels within the eugonadal range and secondary efficacies were evaluated based on the upper limit of lab normal range of testosterone concentration.ResultsSubjects enrolled were on average age of 56 years, with about 17% of subjects older than 65 years. The mean body mass index was 32.8 kg/m2. The baseline mean total testosterone values were below the normal range (202 ± 74 ng/dl). Post‐treatment with 450 mg testosterone undecanoate daily dose without dose adjustment, 80% of subjects (95% confidence interval of 72%–88%) achieved a testosterone Cavg in the normal range and restored testosterone levels to mean testosterone Cavg of 476 ± 184 ng/dl at steady state. Testosterone restoration was comparable to other approved testosterone replacement therapy products. TLANDO was well tolerated with no deaths, no drug‐related serious adverse events, and no hepatic adverse events.Discussion and conclusionsTLANDO restored testosterone levels to the normal range in the majority of hypogonadal males. This new oral testosterone replacement therapy can provide an option for no‐titration oral testosterone replacement therapy. This therapy has the potential to improve patient compliance in testosterone replacement therapy.

Abstract Introduction: The impact of cancer care and management beyond treatment is significantly high for cancer patients. Due to the complexities of cancer treatment, patients are heavily reliant upon ancillary support often rendered by friends and family. One significant yet unquantifiable impact of cancer on society is productivity loss of both patients and their caregivers. Non-Hodgkin lymphoma is considered largely incurable with a protracted clinical course punctuated with multiple remission and relapses, warranting repeated treatment and intensive clinical testing, which necessitates significant engagement of patients and caregivers. Many patients are members of the workforce at the age of diagnosis. Both working patients and caregivers need time for medical care, which translates to indirect economic impact due to lost productivity. The objectives of this analysis were to evaluate the productivity loss and indirect costs in patients with chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), or Waldenström macroglobulinemia (WM) and their caregivers. Methods: The MarketScan Commercial and Health and Productivity Management databases were used to identify patients with CLL, MCL, MZL, and WM (using ICD-9/ICD-10 codes) who were continuously enrolled for ≥6 months pre- and ≥1 month post-diagnosis (index date) from 1/1/2010 to 12/31/2019. The final study cohort included patients aged 18-64 who were full-time workers with eligibility of absentee, or short-/long-term disability on index date and for ≥1 month in follow-up. Those who were pregnant during the study period were excluded. Adult, full-time employed caregivers, defined as family members covered under the same health plan as the patient, and continuously enrolled ≥6 months pre- and ≥1 month post-index, were also identified. Among those with eligibility, the percentage with a claim of absentee, short- or long-term disability (patients only), and associated productivity time loss and indirect costs during follow-up were examined. Lost wages were calculated using the US Bureau of Labor Statistics 2019 report. For short- or long-term disabilities, mean daily wages were reduced to 70% of typical wages. Productivity time loss and costs were reported per-patient-per-month (PPPM) for each lymphoma. Results: The final patient cohort included 3,450 CLL, 448 MCL, 1,052 MZL and 394 WM patients; the caregiver cohort included 1,435 CLL, 171 MCL, 437 MZL and 190 WM caregivers. Among eligible patients, there were higher proportions of patients that had absentee claims (CLL, 76%; MCL, 72%; MZL, 72%; WM, 82%), followed by short-term disability (CLL, 16%; MCL, 36%; MZL, 18%; WM, 17%) and long-term disability (CLL, 3%; MCL, 10%; MZL, 3%; WM, 3%) (Figure 1A). The proportions of caregivers with absentee claims (CLL, 78%; MCL, 90%; MZL, 69%; WM, 75%) were also higher than those with short-term disability (CLL, 7%; MCL, 10%; MZL, 4%; WM, 8%) (Figure 1B). For all 4 lymphoma types, average illness-related absentee hours were higher in patients than caregivers (CLL, 9.5 vs 6.9; MCL, 44.5 vs 3.6; MZL, 17.0 vs 5.0; WM, 18.2 vs 8.1). A similar pattern was observed for short-term disability days (CLL, 6.9 vs 4.2; MCL, 10.8 vs 3.4; MZL, 7.0 vs 2.2; WM, 6.7 vs 4.8). Average PPPM indirect costs were higher for patients with long-term disability (CLL, $1,433; MCL, $1,233; MZL, $1,302; WM, $2,056) than with short-term disability (CLL, $1,203; MCL, $1,950; MZL, $1,145; WM. $1,177) or absentee claims (CLL, $365; MCL, $1,606; MZL, $612; WM, $662), except for patients with MCL (Figure 2A). Similar trends were observed among caregivers, though the indirect costs due to absenteeism and short-term disability were higher in patients than caregivers (Figure 2B). Conclusions: This real-world evidence study uncovered patients with CLL, MCL, MZL and WM and their caregivers incur substantial disease burden as shown by their productivity loss and indirect costs. Effective treatments that can offer a cure or better remission rates and shorter duration with less toxicity may not only enhance the patients and caregivers' quality of life but also reduce work loss. The availability of oral, targeted therapies has resulted in higher remission rates, durable responses, manageable toxicities and improved quality of life in trials. Future studies are needed to understand the impact of these oral, targeted therapies on patients' and caregivers' productivity. Figure 1 Figure 1. Disclosures Yang: BeiGene, Ltd.: Current Employment. Liu: BeiGene, Ltd.: Current Employment. Irwin: IBM Watson Health: Current Employment; BeiGene, Ltd.: Consultancy. Packnett: IBM Watson Health: Current Employment; BeiGene, Ltd.: Consultancy. Lew: BeiGene, Ltd.: Consultancy; IBM Watson Health: Current Employment. Noxon: BeiGene, Ltd.: Consultancy; IBM Watson Health: Current Employment. Tang: BeiGene, Ltd.: Current Employment. Chanan-Khan: BieGene, Jansen, Ascentage: Consultancy; BeiGene, Jansen, Ascentage: Honoraria; Alpha2 Pharmaceuticals: Patents & Royalties: Tabi; Cellectar: Current equity holder in publicly-traded company; Ascentage, Starton, Cellectar, NonoDev, Alpha2 Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Alpha2 Pharmaceuticals, NonoDev, Starton: Current holder of stock options in a privately-held company; Ascentage: Research Funding.

Background: Dementia with Lewy bodies (DLB) is one of the most common degenerative dementias. Clinical trials for individuals with DLB are increasing. We aimed to identify commonly used outcome measures for trials in DLB. Methods: A pragmatic literature search of PubMed and clinicaltrials.gov identified interventional studies including populations with DLB. Studies were included if they enrolled participants with DLB and met the National Institutes of Health criteria for a clinical trial. Data were collected using standardized forms. Outcome measures were categorized according to core and supportive features of DLB. Results: After de-duplication, 58 trials were identified. The most common cognitive outcome measures were the Mini Mental State Examination (n=24) and Cognitive Drug Research computerized Assessment System (n=5). The Clinician’s Assessment of Fluctuations was the most commonly used measure for fluctuations (n=4). Over half of studies used the Neuropsychiatric Inventory to assess behavioral symptoms (n=31). The Unified Parkinson’s Disease Rating Scale was frequently used for motor assessment (n=23). Conclusions and Relevance: Clinical trial outcomes used in DLB are rarely validated in this population and some lack face validity. There is a need to validate existing scales in DLB and develop DLB-specific outcome measures.

Abstract The purpose of this study is to compare the image quality of an integrating proton radiography (PR) system, composed of a monolithic scintillator and two digital cameras, using integral lateral-dose and integral depth-dose image reconstruction techniques. Monte Carlo simulations were used to obtain the energy deposition in a 3D monolithic scintillator detector (30 × 30 × 30 cm 3 poly vinyl toluene organic scintillator) to create radiographs of various phantoms—a slanted aluminum cube for spatial resolution analysis and a Las Vegas phantom for contrast analysis. The light emission of the scintillator was corrected using Birks scintillation model. We compared two integrating PR methods and the expected results from an idealized proton tracking radiography system. Four different image reconstruction methods were utilized in this study: integral scintillation light projected from the beams-eye view, depth-dose based reconstruction methods both with and without optimization, and single particle tracking PR was used for reference data. Results showed that heterogeneity artifact due to medium-interface mismatch was identified from the Las Vegas phantom simulated in air. Spatial resolution was found to be highest for single-event reconstruction. Contrast levels, ranked from best to worst, were found to correspond to particle tracking, optimized depth-dose, depth-dose, and projection-based image reconstructions. The image quality of a monolithic scintillator integrating PR system was sufficient to warrant further exploration. These results show promise for potential clinical use as radiographic techniques for visualizing internal patient anatomy during proton radiotherapy.