Citations

This study aims to characterize the patterns of functional change experienced between 5 and 10 years after moderate-severe traumatic brain injury (TBI). The study included TBI Model Systems national database participants ( N = 372) at six sites who experienced TBI, received inpatient rehabilitation, and were followed at 5 and 10 years post-TBI. Outcome measures included self- or proxy-reported Functional Independence Measure (FIM TM ) structured interview at 5 and 10 years post-TBI and domain change indices (DCIs) at 10 years to assess subjective change over the previous 5 years. When all seven FIM and subjective DCI subscales were considered together, 69% reported improvement in at least one subscale and 41% reported decline in at least one subscale; 51% reported more domains improved than declined, and 20% reported more domains declined than improved. Age at injury, post-traumatic amnesia duration, FIM, and depression and anxiety at year 5 were associated with FIM change and DCI measures. Although most persons with moderate-severe TBI do not experience widespread change from year 5 to 10 on individual FIM subscales or perceived domain-specific subscales, the vast majority do report change in one or more domains, with more improvement than decline and more change in subjective DCI than in FIM. Clinicians and researchers should be alert to the possibility of both positive and deleterious changes many years after TBI.

Although Epstein–Barr virus (EBV) is hypothesized to be a prerequisite for multiple sclerosis (MS), up to 15% of children with a diagnosis of MS were reported to be EBV‐seronegative. When re‐evaluating 25 EBV‐seronegative children out of 189 pediatric patients with a diagnosis of clinically isolated syndrome/MS, we found anti–myelin oligodendrocyte glycoprotein (MOG) antibody in 11 of 25 (44%) EBV‐seronegative but only 9 of 164 (5.5%,p < 0.001) EBV‐seropositive patients. After critical review, MS remained a plausible diagnosis in only 4 of 14 EBV‐seronegative/MOG antibody–negative patients. In children with an MS‐like presentation, EBV seronegativity should alert clinicians to consider diagnoses other than MS, especially MOG‐antibody disease. ANN NEUROL 2021;89:1234–1239

AbstractBackground and AimThe primary aim was to validate the Pancreatitis Activity Scoring System (PASS) in a multicenter prospectively ascertained acute pancreatitis (AP) cohort. Second, we investigated the association of early PASS trajectories with disease severity and length of hospital stay (LOS).MethodsData were prospectively collected through the APPRENTICE consortium (2015–2018). AP severity was categorized based on revised Atlanta classification. Delta PASS (ΔPASS) was calculated by subtracting activity score from baseline value. PASS trajectories were compared between severity subsets. Subsequently, the cohort was subdivided into three LOS subgroups as short (S‐LOS): 2–3 days; intermediate (I‐LOS): 3–7 days; and long (L‐LOS): ≥7 days. The generalized estimating equations model was implemented to compare PASS trajectories.ResultsThere were 434 subjects analyzed including 322 (74%) mild, 86 (20%) moderately severe, and 26 (6%) severe AP. Severe AP subjects had the highest activity levels and the slowest rate of decline in activity (P = 0.039). Focusing on mild AP, L‐LOS subjects (34%) had 28 points per day slower decline; whereas, S‐LOS group (13%) showed 34 points per day sharper decrease compared with I‐LOS (53%; P < 0.001). We noticed an outlier subset with a median admission‐PASS of 466 compared with 140 in the rest. Morphine equivalent dose constituted 80% of the total PASS in the outliers (median morphine equivalent dose score = 392), compared with only 25% in normal‐range subjects (score = 33, P value < 0.001).ConclusionsThis study highlighted that PASS can quantify AP activity. Significant differences in PASS trajectories were found both in revised Atlanta classification severity and LOS groups, which can be harnessed in AP monitoring/management (ClincialTrials.gov number, NCT03075618).

Abstract BACKGROUND: Brain metastatic disease occurs in 10-30% of metastatic breast cancer cases. The incidence of brain metastases is increasing, yet overall survival remains &lt; 2 years. Treatment of brain metastases is limited with current clinical practice centered on radiation, chemotherapy and surgery. Although these treatments may prolong survival in the short term, targeting oncogenic alterations in brain metastases may deliver a more sustained clinical benefit. In this multicenter study, we comprehensively characterized DNA and RNA alterations that aberrantly drive specific oncogenic pathway activity pertinent to breast cancer brain metastases (BCBM). METHODS: RNA sequencing was performed on a cohort of patient-matched primary and resected brain metastatic tumours (45 patients; N=90 samples). Whole exome DNA sequencing (WXS) was performed for 18/45 patients (54 trios consisting of primary tumor, brain metastasis and matched normal tissue). An independent brain metastatic WXS cohort (N=21 patients) (PMID: 26410082) was also analysed resulting in a total of 39 patient samples. Recurrent somatic copy number alterations (SCNA), somatic single nucleotide variants (SNVs) and mutational signatures were identified from WXS data. Expressed gene fusions were detected computationally from RNA-Seq (N=45 cases) RESULTS: Of the 45 BCBM patients, median age at diagnosis was 51 years [25, 67], median overall survival 57 months (range 18-255) with median brain metastases free survival 34 months (range 5-216).Clinical molecular subtype of the primary tumour included 13 ER+/HER2- (29%), 16 HER2+ (35.5%) and 16 TNBC (35.5%). Regions of significant recurrent amplifications and deletions in BCBM (N=39 patients) were identified in 4q12, 10q11.21, 8p11.23, 8q23.3 and 17q12 (FDR &lt; 0.10). Recurrent expressed gene fusions identified in known cancer driver genes were associated with chromatin modification, MAPK and HER signaling pathways. Mutational signature analysis of SNVs identified signatures associated with ageing, mismatch repair and homologous recombination deficiency (HRD) mutational processes. The relative contribution of the HRD signature was significantly increased in brain metastases compared to matched primary tumour (p &lt; 0.05). Concordantly increased HRD in the brain metastatic transcriptome was confirmed in these patients by gene set variation analysis (GSVA) of homologous recombination pathway genes from KEGG database in RNA-Seq data. Moreover, in the extended BCBM RNA-Seq (N=45 patients) GSVA pathway scores were elevated in brain metastases relative to primary tumours, validating the functional significance of altered DNA repair defects in brain metastases CONCLUSIONS: Here, we report recurrent genetic drivers, supported by altered functional transcriptome, unique to brain metastasis that may have clinical implications for prognosis and treatment choice. Specifically, targeting defects in the homologous recombination repair mechanism may represent new therapeutic strategies and management opportunities for breast cancer brain metastases patients. Citation Format: Nicola S Cosgrove, Damir Varešlija, Stephen Keelan, Simon Furney, Jodi M Carter, Steven N Hart, Siddhartha Yadav, Arnold DK Hill, Steffi Oesterreich, Adrian V Lee, Fergus J Couch, Leonie Young. Homologous recombination deficiency represents a new therapeutic strategy for breast cancer brain metastases [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD13-01.

Abstract Background: It is not known whether modifiable lifestyle factors that predict survival after invasive breast cancer differ by subtype. Methods: We analyzed data for 121,435 women diagnosed with breast cancer from 67 studies in the Breast Cancer Association Consortium with 16,890 deaths (8,554 breast cancer specific) over 10 years. Cox regression was used to estimate associations between risk factors and 10-year all-cause mortality and breast cancer–specific mortality overall, by estrogen receptor (ER) status, and by intrinsic-like subtype. Results: There was no evidence of heterogeneous associations between risk factors and mortality by subtype (Padj &gt; 0.30). The strongest associations were between all-cause mortality and BMI ≥30 versus 18.5–25 kg/m2 [HR (95% confidence interval (CI), 1.19 (1.06–1.34)]; current versus never smoking [1.37 (1.27–1.47)], high versus low physical activity [0.43 (0.21–0.86)], age ≥30 years versus &lt;20 years at first pregnancy [0.79 (0.72–0.86)]; &gt;0–&lt;5 years versus ≥10 years since last full-term birth [1.31 (1.11–1.55)]; ever versus never use of oral contraceptives [0.91 (0.87–0.96)]; ever versus never use of menopausal hormone therapy, including current estrogen–progestin therapy [0.61 (0.54–0.69)]. Similar associations with breast cancer mortality were weaker; for example, 1.11 (1.02–1.21) for current versus never smoking. Conclusions: We confirm associations between modifiable lifestyle factors and 10-year all-cause mortality. There was no strong evidence that associations differed by ER status or intrinsic-like subtype. Impact: Given the large dataset and lack of evidence that associations between modifiable risk factors and 10-year mortality differed by subtype, these associations could be cautiously used in prognostication models to inform patient-centered care.

Abstract To evaluate the racial and ethnic differences in prevalence of germline pathogenic variants (PVs) and the effect of race and ethnicity on breast cancer (BC) risk among carriers, results of multigene testing of 77 900 women with BC (non-Hispanic White [NHW] = 57 003; Ashkenazi-Jewish = 4798; Black = 6722; Hispanic = 5194; and Asian = 4183) were analyzed, and the frequency of PVs in each gene were compared between BC patients (cases) and race- and ethnicity-matched gnomAD reference controls. Compared with NHWs, BRCA1 PVs were enriched in Ashkenazi-Jews and Hispanics, whereas CHEK2 PVs were statistically significantly lower in Blacks, Hispanics, and Asians (all 2-sided P &lt; .05). In case-control studies, BARD1 PVs were associated with high risks (odds ratio &gt; 4.00) of BC in Blacks, Hispanics, and Asians; ATM PVs were associated with increased risk of BC among all races and ethnicities except Asians, whereas CHEK2 and BRIP1 PVs were associated with increased risk of BC among NHWs and Hispanics only. These findings suggest a need for personalized management of BC risk in PV carriers based on race and ethnicity.