Citations

AbstractBackground and purposePrimary lateral sclerosis (PLS) is a neurodegenerative disorder that primarily affects the central motor system. In rare cases, clinical features of PLS may overlap with those of progressive supranuclear palsy (PSP). We investigate neuroimaging features that can help distinguish PLS with overlapping features of PSP (PLS‐PSP) from PSP.MethodsSix patients with PLS‐PSP were enrolled between 2019 and 2023. We compared their clinical and neuroimaging characteristics with 18 PSP–Richardson syndrome (PSP‐RS) patients and 20 healthy controls. Magnetic resonance imaging, 18F‐flortaucipir positron emission tomography (PET), quantitative susceptibility mapping, and diffusion tensor imaging tractography (DTI) were performed to evaluate eight brain regions of interest. Area under the receiver operating characteristic curve (AUROC) was calculated.ResultsFive of the six PLS‐PSP patients (83.3%) were male. Median age at symptom onset was 61.5 (52.5–63) years, and all had mixed features of PLS and PSP. Volumes of the pallidum, caudate, midbrain, and cerebellar dentate were smaller in PSP‐RS than PLS‐PSP, providing good discrimination (AUROC = 0.75 for all). The susceptibilities in pallidum, midbrain, and cerebellar dentate were greater in PSP‐RS compared to PLS‐PSP, providing excellent discrimination (AUROC ≥ 0.90 for all). On DTI, fractional anisotropy (FA) in the posterior limb of the internal capsule from the corticospinal tract was lower in PLS‐PSP compared to PSP‐RS (AUROC = 0.86), but FA in the superior cerebellar peduncle was lower in PSP‐RS (AUROC = 0.95). Pallidum flortaucipir PET uptake was greater in PSP‐RS compared to PLS‐PSP (AUROC = 0.74).ConclusionsRegional brain volume, tractography, and magnetic susceptibility, but not tau‐PET, are useful in distinguishing PLS‐PSP from PSP.

Importance Effects of antiamyloid agents, targeting either fibrillar or soluble monomeric amyloid peptides, on downstream biomarkers in cerebrospinal fluid (CSF) and plasma are largely unknown in dominantly inherited Alzheimer disease (DIAD). Objective To investigate longitudinal biomarker changes of synaptic dysfunction, neuroinflammation, and neurodegeneration in individuals with DIAD who are receiving antiamyloid treatment. Design, Setting, and Participants From 2012 to 2019, the Dominantly Inherited Alzheimer Network Trial Unit (DIAN-TU-001) study, a double-blind, placebo-controlled, randomized clinical trial, investigated gantenerumab and solanezumab in DIAD. Carriers of gene variants were assigned 3:1 to either drug or placebo. The present analysis was conducted from April to June 2023. DIAN-TU-001 spans 25 study sites in 7 countries. Biofluids and neuroimaging from carriers of DIAD gene variants in the gantenerumab, solanezumab, and placebo groups were analyzed. Interventions In 2016, initial dosing of gantenerumab, 225 mg (subcutaneously every 4 weeks) was increased every 8 weeks up to 1200 mg. In 2017, initial dosing of solanezumab, 400 mg (intravenously every 4 weeks) was increased up to 1600 mg every 4 weeks. Main Outcomes and Measures Longitudinal changes in CSF levels of neurogranin, soluble triggering receptor expressed on myeloid cells 2 (sTREM2), chitinase 3–like 1 protein (YKL-40), glial fibrillary acidic protein (GFAP), neurofilament light protein (NfL), and plasma levels of GFAP and NfL. Results Of 236 eligible participants screened, 43 were excluded. A total of 142 participants (mean [SD] age, 44 [10] years; 72 female [51%]) were included in the study (gantenerumab, 52 [37%]; solanezumab, 50 [35%]; placebo, 40 [28%]). Relative to placebo, gantenerumab significantly reduced CSF neurogranin level at year 4 (mean [SD] β = −242.43 [48.04] pg/mL; P < .001); reduced plasma GFAP level at year 1 (mean [SD] β = −0.02 [0.01] ng/mL; P = .02), year 2 (mean [SD] β = −0.03 [0.01] ng/mL; P = .002), and year 4 (mean [SD] β = −0.06 [0.02] ng/mL; P < .001); and increased CSF sTREM2 level at year 2 (mean [SD] β = 1.12 [0.43] ng/mL; P = .01) and year 4 (mean [SD] β = 1.06 [0.52] ng/mL; P = .04). Solanezumab significantly increased CSF NfL (log) at year 4 (mean [SD] β = 0.14 [0.06]; P = .02). Correlation analysis for rates of change found stronger correlations between CSF markers and fluid markers with Pittsburgh compound B positron emission tomography for solanezumab and placebo. Conclusions and Relevance This randomized clinical trial supports the importance of fibrillar amyloid reduction in multiple AD-related processes of neuroinflammation and neurodegeneration in CSF and plasma in DIAD. Additional studies of antiaggregated amyloid therapies in sporadic AD and DIAD are needed to determine the utility of nonamyloid biomarkers in determining disease modification. Trial Registration ClinicalTrials.gov Identifier: NCT04623242

Abstract Purpose Our objectives were to compare overall survival (OS) and pulmonary relapse between patients with metastatic Ewing sarcoma (EWS) at diagnosis who achieve rapid complete response (RCR) and those with residual pulmonary nodules after induction chemotherapy (non‐RCR). Patients and methods This retrospective cohort study included children under 20 years with metastatic EWS treated from 2007 to 2020 at 19 institutions in the Pediatric Surgical Oncology Research Collaborative. Chi‐square tests were conducted for differences among groups. Kaplan–Meier curves were generated for OS and pulmonary relapse. Results Among 148 patients with metastatic EWS at diagnosis, 61 (41.2%) achieved RCR. Five‐year OS was 71.2% for patients who achieved RCR, and 50.2% for those without RCR ( p = .04), and in multivariable regression among patients with isolated pulmonary metastases, RCR (hazards ratio [HR] 0.42; 95% confidence interval [CI]: 0.17–0.99) and whole lung irradiation (WLI) (HR 0.35; 95% CI: 0.16–0.77) were associated with improved survival. Pulmonary relapse occurred in 57 (37%) patients, including 18 (29%) in the RCR and 36 (41%) in the non‐RCR groups ( p = .14). Five‐year pulmonary relapse rates did not significantly differ based on RCR (33.0%) versus non‐RCR (47.0%, p = .13), or WLI (38.8%) versus no WLI (46.0%, p = .32). Discussion Patients with EWS who had isolated pulmonary metastases at diagnosis had improved OS if they achieved RCR and received WLI, despite having no significant differences in rates of pulmonary relapse.

Abstract Background Minimal clinically important differences (MCIDs) quantify the clinical relevance of quality of life results at the individual patient and group level. The aim of this study was to estimate the MCID for the Brief Fatigue Inventory (BFI) and the Worst and Usual Fatigue items in patients with brain or CNS cancer undergoing curative radiotherapy. Methods Data from a multi-site prospective registry was used. The MCID was calculated using distribution-based and anchor-based approaches. For the anchor-based approach, the fatigue item from the PROMIS-10 served as the anchor to determine if a patient improved, deteriorated, or had no change from baseline to end of treatment (EOT). We compared the unadjusted means on the BFI for the 3 groups to calculate the MCID. For the distribution-based approaches, we calculated the MCID as 0.5 SD of the scores and as 1.96 times the standard error of measurement. Results Three-hundred and fifty nine patients with brain or CNS tumors undergoing curative radiotherapy filled out the 9-item BFI at baseline and EOT. The MCID for the BFI was 1.33 (ranging from 0.99 to 1.70 across the approaches), 1.51 (ranging from 1.16 to 2.02) and 1.76 (ranging from 1.38 to 2.14) for the usual and worst fatigue items, respectively. Conclusions This study provides the MCID ranges for the BFI and Worst and Usual fatigue items, which will allow clinically meaningful conclusions to be drawn from BFI scores. These results can be used to select optimal treatments for patients with brain or CNS cancer or to interpret BFI scores from clinical trials.

Tubulin, one of the most abundant cytoskeletal building blocks, has numerous isotypes in metazoans encoded by different conserved genes. Whether these distinct isotypes form cell type– and context-specific microtubule structures is poorly understood. Based on a cohort of 12 patients with primary ciliary dyskinesia as well as mouse mutants, we identified and characterized variants in the TUBB4B isotype that specifically perturbed centriole and cilium biogenesis. Distinct TUBB4B variants differentially affected microtubule dynamics and cilia formation in a dominant-negative manner. Structure-function studies revealed that different TUBB4B variants disrupted distinct tubulin interfaces, thereby enabling stratification of patients into three classes of ciliopathic diseases. These findings show that specific tubulin isotypes have distinct and nonredundant subcellular functions and establish a link between tubulinopathies and ciliopathies.

Abstract There has been an increase in volume as well as an improvement in overall survival (OS) after hematopoietic cell transplantation (HCT) for hematologic disorders. It is unknown if these changes have affected racial/ethnic minorities equally. In this observational study from the Center for International Blood and Marrow Transplant Research of 79 904 autologous (auto) and 65 662 allogeneic (allo) HCTs, we examined the volume and rates of change of autoHCT and alloHCT over time and trends in OS in 4 racial/ethnic groups: non-Hispanic Whites (NHWs), non-Hispanic African Americans (NHAAs), and Hispanics across 5 2-year cohorts from 2009 to 2018. Rates of change were compared using Poisson model. Adjusted and unadjusted Cox proportional hazards models examined trends in mortality in the 4 racial/ethnic groups over 5 study time periods. The rates of increase in volume were significantly higher for Hispanics and NHAAs vs NHW for both autoHCT and alloHCT. Adjusted overall mortality after autoHCT was comparable across all racial/ethnic groups. NHAA adults (hazard ratio [HR] 1.13; 95% confidence interval [CI] 1.04-1.22; P = .004) and pediatric patients (HR 1.62; 95% CI 1.3-2.03; P < .001) had a higher risk of mortality after alloHCT than NHWs. Improvement in OS over time was seen in all 4 groups after both autoHCT and alloHCT. Our study shows the rate of change for the use of autoHCT and alloHCT is higher in NHAAs and Hispanics than in NHWs. Survival after autoHCT and alloHCT improved over time; however, NHAAs have worse OS after alloHCT, which has persisted. Continued efforts are needed to mitigate disparities for patients requiring alloHCT.

Introduction: Age ≥ 70 is used to exclude patients from cardiac transplantation. Elderly patients may be offered left ventricular assist device (LVAD) therapy as an alternative. It remains poorly defined how they respond to LVAD support. Hypothesis: Elderly patients have LVAD outcomes that are non-inferior to younger patients. Methods: Data on 1,149 continuous-flow LVAD recipients from May 2004 to May 2015 was pooled from the Mechanical Circulatory Support Research Network (MCSRN). Groups were assigned based on Age ≥ 70 (n = 163) and < 70 (n = 986). Results: Patients age ≥ 70 were more likely to be male (91%), have an ischemic cardiomyopathy (71%), atrial fibrillation (41%), hypertension (66%), diabetes (38%) and prior sternotomy (45%). Older patients also had a lower BMI and higher creatinine, 26.7 ± 0.4 v. 29.9 ± 0.5 and 1.46 ± 0.04 v. 1.35 ± 0.02, p < 0.05. The hazard ratio for mortality was highest in elderly patients in the early post-operative period and stabilized over time with no long-term differences in survival, p = 0.18, Figure 1a. Elderly patients had equivalent rates of device thrombosis and stroke, p = 0.47 and 0.44, Figures 1b-c. Survival free of gastrointestinal bleeding (GIB) at 1-year was 58% in elderly patients compared to 69% in younger patients, Figure 1d, p < 0.01. Multivariate cox regression revealed that age ≥ 70 was not a significant predictor of mortality (HR 0.93, 95% CI 0.69 - 1.25, p = 0.62), but pre-operative creatinine (HR 1.54, 95% CI 1.28 - 1.86, p < 0.01) and bilirubin (HR 1.2, 95% CI 1.03 - 1.4, p = 0.02) were. When age was considered a continuous variable, the HR was 1.2 (95% CI 1.07 - 1.3 per 10y, p < 0.01). Conclusions: Elderly patients, age ≥ 70, have equivalent long-term survival after LVAD implantation with similar rates of device thrombosis and stroke. Rates of GIB were higher in the elderly and this finding warrants caution when choosing anti-coagulation protocols in the elderly. Overall age ≥ 70 does not portend a poorer survival after LVAD implant.

Introduction: Advanced age is a risk factor for poor outcomes following left ventricular assist device (LVAD) implant. A means of identifying elderly patients with acceptable mortality risk following LVAD surgery is not currently available. The HeartMate II (HMII) Risk Score (HMRS) was recently developed and validated, providing good risk discrimination for predicting survival in patients undergoing HMII implant. Independent survival predictors in the model included age and markers of renal function, coagulopathy and nutrition. We hypothesize that the HMRS will provide utility for risk stratification of the elderly LVAD candidate. Methods: Elderly patients (age >65 years) enrolled into the HMII Destination Therapy (DT) and Bridge to Transplant trials were selected for the study (n=444). Complete data for HMRS calculation was available in 98% (n=435). Preoperative patient HMRS was calculated according to the formula: HMRS = ln(1.29)*decade of age + ln(0.71)*Albumin + ln(1.37)*Cr + ln(1.86)*INR + ln(0.52)*LVAD Center Volume >=15 + ln(0.67)*Implant after 2007. Patients were trichotimized into high (HMRS >1.0), medium (HMRS 0.50-1.0), and low (HMRS <=0.50) risk categories (as previously defined in model development) based on HMRS. The primary endpoint was survival at 1 year following LVAD implant, estimated using Kaplan-Meier methods. Results: The mean cohort age was 71±4 years and 84% (n=372) had devices implanted for DT. The table shows the HMRS along with mean±stddev values for the score's components. All between-group differences were statistically significant (Kruskal-Wallis p<0.05), although differences in age were not clinically significant. Survival based on HMRS strata is shown in the figure. Patients in the low and medium risk groups had survivals >80% at 1 year following LVAD implant. Conclusions: The HMRS can be used to identify elderly patients with survivals comparable to that of the general LVAD population.

Background: Patients (pts) with protein losing enteropathy (PLE) following the Fontan operation (op) have a reported 50% mortality at 5 years (yrs) post diagnosis. We review our clinical outcomes in this pt population. Methods: From 1997 to 2010, 42 pts (55% M) with PLE following the Fontan op were identified from clinical databases. Data were collected by retrospective chart review. Results: Mean age at PLE diagnosis was 18.9 yrs + 11 (4.7-57.9 yrs) and initial Fontan op was 10.1 yrs + 10.8 (1.8-37.6 yrs). Mean time from Fontan op to PLE diagnosis was 8.4 yrs + 14.2 (30 days-27yrs). Types of Fontan op included: atriopulmonary connection (28, 67%), lateral tunnel or intraatrial conduit (6, 14%), or extracardiac conduit (8, 19%). Mean time from diagnosis to last follow-up was 8 yrs + 6 (1-22yrs). Survival was 88% at 5 yrs. There were 11 deaths, mean age 32 yrs + 7.7 (22-47 yrs). Mean time interval from diagnosis to death was 7.5 yrs + 5.4 (1-18yrs). Causes of death include: sepsis (7), complications after Fontan conversion (1), and unknown (3). Decreased survival was seen in pts with high Fontan pressure (mean >15mmHg, p=0.04), decreased ventricular function (EF < 55%, p=0.03), and NYHA class >2 at diagnosis (p=0.04). Pts who died had higher pulmonary vascular resistance (3.8 + 1.6 WU vs 2.1 + 1.1 WU, p=0.017), lower cardiac index (1.6 L/min/m 2 + 0.4 vs 2.7 L/min/m 2 + 0.7, p<0.0001), and lower mixed venous saturation (53% versus 66%, p=0.01) compared to survivors. All factors were obtained at initial PLE diagnosis. Pts treated with medical therapy only (n=15) resulted in symptomatic improvement in 7 pts (47%), no improvement in 5 (33%), and death in 3 (20%). Pts treated with medical + surgical/interventional catheterization procedures (n=27) resulted in symptomatic improvement in 10 pts (37%), no improvement in 9 (33%), and death in 8 (30%). Treatments used more in survivors included spironolactone (21, 68%), octreotide (7, 21%), sildenafil (6, 19%), fenestration creation (15, 48%), and relief of Fontan obstruction (7, 23%). Of the 31 survivors, 17 pts remain well-controlled. Conclusions: PLE remains difficult to treat, but in the current era, survival has improved with advances in treatment. Further study is needed to understand the mechanism of disease and ideal treatment strategy.