Citations

Abstract PURPOSE We investigated the long term impact of SRS and WBRT in two large prospective phase III trials. METHODS Patients with 1–4 BMs +/- resection were randomized to SRS or WBRT. Cognitive deterioration was a drop of >1 standard deviation from baseline in >2/6 cognitive measures (CM). Quality of life (QOL) scores were scored 0–100 point scale. CM and QOL scores were modeled using baseline adjusted Linear Mixed Models (LMM) with uncorrelated random intercept for subject and random slopes for time. Differences in trend over time between groups and the effect of >2 cognitive scores with >2 SD change from baseline were assessed. RESULTS 88 patients were included with median follow up of 24 months. We observed decreasing CM over time (SRS: 4/6; WBRT: 5/6). Mean CM was significantly higher in SRS for Total recall and Delayed Recall at 3, 6, 9, 12 months. More patients in WBRT arm declined 1 SD in >1 and >2 CM at the 3, 6, 9, and 12 months. A 1 SD decline in >3 CM at 1 year was 21% SRS vs 47% WBRT (p=0.02). SRS had fewer patients with a 2 SD decline in >1 CM at every time point. SRS had fewer patients with a 2 SD decline at >2 and >3 CM. WBRT had lower QOL at 3 months, but switched to SRS having lower QOL at 24 months for PWB, EWB, FWB, FactG, BR, and FactBR (p<0.05). A 2 SD decline in cognition decreased mean FWB by 6.4 units (95% CI: -11, -1.75; p=0.007) and decreased QOL by 5.1 units (95% CI: -7.7, -2.5; p<0.001). CONCLUSIONS We report the first pooled prospective study demonstrating the long term outcomes of patients with BMs after cranial radiation. WBRT was associated with worse cognitive outcomes. Impaired cognition is associated with worse QOL.

Abstract Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous entity of B-cell lymphoma. Cell-of-origin (COO) classification of DLBCL is required in routine practice by the World Health Organization classification for biological and therapeutic insights. Genetic subtypes uncovered recently are based on distinct genetic alterations in DLBCL, which are different from the COO subtypes defined by gene expression signatures of normal B cells retained in DLBCL. We hypothesize that classifiers incorporating both genome-wide gene-expression and pathogenetic variables can improve the therapeutic significance of DLBCL classification. To develop such refined classifiers, we performed targeted RNA sequencing (RNA-Seq) with a commercially available next-generation sequencing (NGS) platform in a large cohort of 418 DLBCLs. Genetic and transcriptional data obtained by RNA-Seq in a single run were explored by state-of-the-art artificial intelligence (AI) to develop a NGS-COO classifier for COO assignment and NGS survival models for clinical outcome prediction. The NGS-COO model built through applying AI in the training set was robust, showing high concordance with COO classification by either Affymetrix GeneChip microarray or the NanoString Lymph2Cx assay in 2 validation sets. Although the NGS-COO model was not trained for clinical outcome, the activated B-cell–like compared with the germinal-center B-cell–like subtype had significantly poorer survival. The NGS survival models stratified 30% high-risk patients in the validation set with poor survival as in the training set. These results demonstrate that targeted RNA-Seq coupled with AI deep learning techniques provides reproducible, efficient, and affordable assays for clinical application. The clinical grade assays and NGS models integrating both genetic and transcriptional factors developed in this study may eventually support precision medicine in DLBCL.

Importance: Septoplasty is one of the most commonly performed operations in the head and neck. However, the reasons for septoplasty failure and the additional stress of performing a chondrotomy on the septal cartilage are not well understood. Design, Setting, and Participants: A finite element model of the nasal septum was created using a microcomputed tomography scan of the nasoseptal complex that was reconstructed into a three-dimensional model in silico. Testing included four common chondrotomy designs: traditional L-strut, double-cornered chondrotomy (DCC), curved L-strut, and the C-curve. Tip displacement was applied in a vector parallel to the caudal strut to simulate nasal tip palpation. Main Outcomes and Measures: With finite element analysis, the maximum principal stress (MPS), von Mises stress (VMS), harvested cartilage volume, and surface area were recorded. Results: The highest MPS for the L-strut, DCC, curved L-strut, and C-curve was identified at the corner of the chondrotomy. The MPS at the corner of the chondrotomy was reduced 44% when comparing the C-curve with the traditional L-strut. The VMS patterns showed compressive stress along the caudal septum in all models, but at the corner, the stresses were highest in the chondrotomies designed with sharp-angled corners. The VMS showed a 76% decrease when comparing the C-curve with the traditional L-strut. The stress across the anterior septal angle is also higher in models with sharp-angled corners. Cartilage harvest volumetric and surface area assessments did not show meaningful differences between shapes. Conclusions and Relevance: The highest area of stress is near the transition of the dorsal to caudal septum in all models. Stresses are relatively higher in chondrotomy shapes that contain sharp-angled corners. The relative reduction in MPS and VMS utilizing a C-curve instead of an L-strut may decrease the likelihood that the septum will deform or fail in this region. The volume and surface area of the C-curve are similar to that of the L-strut technique. Avoiding sharp-angled corners reduces the stresses at the corner of the chondrotomy and across the anterior septal angle. Using a C-curve may be an improved septoplasty design.

Abstract Structural grey matter covariance networks provide an individual quantification of morphological patterns in the brain. The network integrity is disrupted in sporadic Alzheimer’s disease, and network properties show associations with the level of amyloid pathology and cognitive decline. Therefore, these network properties might be disease progression markers. However, it remains unclear when and how grey matter network integrity changes with disease progression. We investigated these questions in autosomal dominant Alzheimer’s disease mutation carriers, whose conserved age at dementia onset allows individual staging based upon their estimated years to symptom onset. From the Dominantly Inherited Alzheimer Network observational cohort, we selected T1-weighted MRI scans from 269 mutation carriers and 170 non-carriers (mean age 38 ± 15 years, mean estimated years to symptom onset −9 ± 11), of whom 237 had longitudinal scans with a mean follow-up of 3.0 years. Single-subject grey matter networks were extracted, and we calculated for each individual the network properties which describe the network topology, including the size, clustering, path length and small worldness. We determined at which time point mutation carriers and non-carriers diverged for global and regional grey matter network metrics, both cross-sectionally and for rate of change over time. Based on cross-sectional data, the earliest difference was observed in normalized path length, which was decreased for mutation carriers in the precuneus area at 13 years and on a global level 12 years before estimated symptom onset. Based on longitudinal data, we found the earliest difference between groups on a global level 6 years before symptom onset, with a greater rate of decline of network size for mutation carriers. We further compared grey matter network small worldness with established biomarkers for Alzheimer disease (i.e. amyloid accumulation, cortical thickness, brain metabolism and cognitive function). We found that greater amyloid accumulation at baseline was associated with faster decline of small worldness over time, and decline in grey matter network measures over time was accompanied by decline in brain metabolism, cortical thinning and cognitive decline. In summary, network measures decline in autosomal dominant Alzheimer’s disease, which is alike sporadic Alzheimer’s disease, and the properties show decline over time prior to estimated symptom onset. These data suggest that single-subject networks properties obtained from structural MRI scans form an additional non-invasive tool for understanding the substrate of cognitive decline and measuring progression from preclinical to severe clinical stages of Alzheimer’s disease.

Abstract Background We report the analysis involving patients treated on the initial CODEL design. Methods Adults (>18) with newly diagnosed 1p/19q World Health Organization (WHO) grade III oligodendroglioma were randomized to radiotherapy (RT; 5940 centigray ) alone (arm A); RT with concomitant and adjuvant temozolomide (TMZ) (arm B); or TMZ alone (arm C). Primary endpoint was overall survival (OS), arm A versus B. Secondary comparisons were performed for OS and progression-free survival (PFS), comparing pooled RT arms versus TMZ-alone arm. Results Thirty-six patients were randomized equally. At median follow-up of 7.5 years, 83.3% (10/12) TMZ-alone patients progressed, versus 37.5% (9/24) on the RT arms. PFS was significantly shorter in TMZ-alone patients compared with RT patients (hazard ratio [HR] = 3.12; 95% CI: 1.26, 7.69; P = 0.014). Death from disease progression occurred in 3/12 (25%) of TMZ-alone patients and 4/24 (16.7%) on the RT arms. OS did not statistically differ between arms (comparison underpowered). After adjustment for isocitrate dehydrogenase (IDH) status (mutated/wildtype) in a Cox regression model utilizing IDH and RT treatment status as covariables (arm C vs pooled arms A + B), PFS remained shorter for patients not receiving RT (HR = 3.33; 95% CI: 1.31, 8.45; P = 0.011), but not OS ((HR = 2.78; 95% CI: 0.58, 13.22, P = 0.20). Grade 3+ adverse events occurred in 25%, 42%, and 33% of patients (arms A, B, and C). There were no differences between arms in neurocognitive decline comparing baseline to 3 months. Conclusions TMZ-alone patients experienced significantly shorter PFS than patients treated on the RT arms. The ongoing CODEL trial has been redesigned to compare RT + PCV versus RT + TMZ.

Introduction: Infants in neonatal intensive care units require painful and noxious stimuli as part of their care. Judicious use of analgesic medications, including opioids, is necessary. However, these medications have long- and short-term side effects, including potential neurotoxicity. This quality improvement project’s primary aim was to decrease opioid exposure by 33% in the first 14 days of life for infants less than 1,250 g at birth within 12 months. Methods: A multidisciplinary care team used Define, Measure, Analyze, Improve, Control methodology to identify root causes of the quality gap including: (1) inconsistent reporting of objective pain scales; (2) variable provider prescribing patterns; and (3) variable provider bedside assessment of pain. These root causes were addressed by two interventions: (1) standardized reporting of the premature infant pain profile scores and (2) implementation of an analgesia management pathway. Results: Mean opioid exposure, measured in morphine equivalents, in infants less than 1,250 g at birth during their first 14 days of life decreased from 0.64 mg/kg/d (95% confidence interval 0.41–0.87) at baseline to 0.08 mg/kg/d (95% confidence interval 0.03–0.13) during the postintervention period (P < 0.001). There was no statistical difference in rates of days to full feedings, unintentional extubations, or central line removals between epochs. Conclusions: Following the implementation of consistent pain score reporting and an analgesia management pathway, opioid exposure in the first 14 days of life for infants less than 1,250 g was significantly reduced by 88%, exceeding the project aim.