Citations

248 Background: Hypofractionated prostate cancer radiation has showed similar results in several prior phase III studies (PCG GU 003, PACE-B, and Hypo PC RT). However, prospective phase II-III clinical trial data testing 5 tx after prostatectomy is scarce. Methods: Between 2018 and 2019, 41 patients were treated after postprostatectomy for high risk features. 5 patients were treated adjuvantly, 36 for salvage including 8 with oligometastatic disease. Indications for adjuvant RT included a PSA < 0.2 and +margins, SVI, or EPE. Salvage RT was offered for PSA ≥0.2. Oligometastatic RT for patients with ≤5 RT targets. Staging included C11 PET for all cases. Total dose to the prostate bed was 30-32 Gy in 5tx QOD with IMRT, conebeam IGRT, and MRI registration. All salvage patients received ADT for 6 months and oligometastatic patients for 18 months. Dose to the metastatic sites was 30 in 5tx QOD. Of the 41 patients 8 also received SBRT to the sites of oligometastatic disease. We looked at clinical outcomes defining biochemical failure as a PSA > 0.2 after treatment, baseline adjusted CTC AE V5.0, baseline adjusted patient reported toxicities (PRO CTC AE), QOL (EPIC, PROMIS), and AUA was used for all cases. Results: Median follow up was 23 months (range 10-37). Pre-RT T stage was T2-T3b, with 47% being T3a-b; Pre RT Median PSA of 0.4 (range < 0.1-1.9); Median GS 8 (6-9); and (+) margins in 48.8%. Sites of oligometastatic disease radiated included the LN and bone. Treatment related AE were grade 0-1 in all cases, except for one patient with G2 GU incontinence. Overall QOL remained high during follow including Promis 10 overall, mental, and physical scores; urinary bother, irritative/obstructive, and AUA scores; bowel overall, bowel bother, and bowel function scores; and overall sexual, sexual function, and sexual bother scores remained at baseline levels during follow up. Only hormonal overall, hormonal function, and hormonal bother had lower scores at 3 months that recovered by 12 months in patients treated with ADT for 6 months and by 24 months in patients treated with ADT for 18 months. A total of 3 clinical failure have been seen; 2 patients with regional failures alone; and one with axial skeleton bony failures for 93% clinical control at median follow up of 23 months. All 3 patients with clinical failure were salvaged successfully with SBRT and all patients remain disease free at last follow up. A total 5 patients with raising PSAs alone have been seen. All patients have been re-staged with C11 PET. No failures in the prostate bed or previously radiated sites have been seen. Conclusions: Toxicity for RT over 5tx is lower than expected with only one case of grade 2 urinary incontinence. QOL scores remained high during follow up, minor changes in hormonal scores were seen during ADT, but recovered after. 30-32 Gy over 5 tx provided 100% control in radiated targets and metastatic sites. Clinical trial information: NCT03570827.

AbstractObjectiveInfants with focal‐onset epilepsy are an understudied population, requiring additional evaluation for clinical assessment and prognostication. Our goal was to characterize the etiology and natural history of infantile‐onset focal epilepsy.MethodsWe retrospectively identified all infants (0–24 months) with onset of focal epilepsy while resident in Olmsted County, Minnesota, between 1980 and 2018, using the Rochester Epidemiology Project Database. We assessed the impact of etiology on both seizure and neurodevelopmental outcome, and mortality.ResultsOf 686 children with epilepsy onset <18 years, 125 (18.2%) presented with focal‐onset seizures in infancy. Median follow‐up for this group was 10.9 years (interquartile range [IQR] 6.2, 19.3). Etiology was identified in 65.6% (structural N = 62, genetic N = 13, both structural and genetic N = 3, metabolic N = 4). Of 107 patients followed >2 years, 38 (35.5%) developed drug‐resistant epilepsy (DRE). DRE was more likely with younger age at onset, known etiology, and presence of epileptic spasms. Sixty‐eight (63.0% of those with follow‐up) were developmentally delayed at last follow‐up, and known etiology, DRE, and presence of epileptic spasms were significantly associated with delay (p < .001 for all). Fifteen patients (12.0%) died at a median age of 7.1 years (IQR 1.7, 21.7), but only one death was seizure related (suspected sudden unexpected death in epilepsy [SUDEP]). Of 20 infants with normal development at onset and no known etiology with >2 years follow‐up, none developed DRE, all were seizure‐free at last follow‐up (95% off antiseizure medications [ASMs]), and all remained developmentally normal.SignificanceInfantile‐onset focal epilepsy accounts for 18% of all epilepsy in childhood, is frequently due to known etiologies, and has a high rate of DRE. However, developmentally normal infants without a known cause appear to have a very favorable course.

Introduction: Development of new intraventricular hemorrhage (IVH) within 24 hours of presentation or expansion of 1mL or more independently predicts poor outcome. Current methods for IVH volume estimation lack sufficient precision to detect this level of change. The best method of quantification with manual/semi-automated segmentation remain clinically impractical. We aimed to train and validate a convolutional neural network (CNN) to autonomously segment and quantify IVH volume in acute intracerebral hemorrhage (ICH) patients. Methods: Imaging data for training and validation was obtained from 3 international multicenter studies. IVH volumes were assessed using CNN, IVH Score (IVHS), Original Graeb Score (oGS), Modified Graeb Score (mGS), and manual segmentation using ITK-SNAP. Agreement between CNN volume and IVHS estimated volume compared to manual segmentation was assessed using intraclass correlation coefficient (ICC) and Bland-Altman charts. Accuracy of CNN segmentation was compared to manual segmentation with Dice similarity coefficient (DSC). Accuracy of hematoma expansion detection was assessed using receiver operating characteristic curves. Results: A total of 172 patients and 311 CT scans were included. Intra-rater reliability was significantly greater for CNN versus IVHS method (ICC 0.99 [95%CI 0.99 - 1.00] vs 0.76 [95%CI 0.66 - 0.83]). Accuracy of CNN segmentation was satisfactory (DSC 0.76 [95%CI 0.75 - 0.78]). Accuracy of hematoma expansion detection was substantially greater in CNN (AUC 0.91 [95%CI 0.85 - 0.97]) versus IVHS, oGS and mGS. Conclusion: Our results demonstrate that a fully automated CNN algorithm is capable of segmenting IVH volumes on multi-center data with higher intra-rater reliability and satisfactory accuracy over the current methods of IVH volume measurement tools. The algorithm has proven to be capable of detecting hematoma expansion with substantially greater accuracy over existing methods of IVH measurement.

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.