Citations

Abstract Richter’s syndrome (RS) arising from chronic lymphocytic leukemia (CLL) is a striking example of an aggressive malignant histology that emerges from indolent cancer. RS is a major barrier to disease control in CLL and is associated with poor clinical outcomes and limited survival. The genetic basis of RS is poorly understood, and its relationship to the antecedent CLL remains incompletely characterized. To study RS, we performed whole-exome sequencing (WES) on samples collected from 52 patients with RS of diffuse large B cell lymphoma (DLBCL) histology. For this genomic characterization, samples from 42 patients were analyzed as ‘trios’ (matched germline, CLL and RS tissue DNA) and those from 10 as ‘duos’ (matched CLL and RS DNA). Beyond addressing contamination of CLL DNA in the germline sample, we developed methods for discriminating between the RS and CLL clones which often coexist in the same samples. The discovery cohort revealed that RS and CLL were clonally-related in 45/52 (87%) cases based on WES analysis, with a distinct RS clone emerging from a CLL subclone. The remaining 13% were determined to be clonally unrelated. RS clones presented ~3x higher rates of additional mutations than the ancestral CLL clones from which they developed. We identified novel RS somatic driver mutations (in IRF2BP2, SRSF1, B2M, DNMT3A and others), a high rate of copy number variations with recurrent deletions (e.g., del(17p) [TP53], del(13q14.3), del(7q36), and del(15q13.11) [MGA], del(9p21.3) [CDKN2A/B], del(16q12.2)), focal amplifications (amp(7q21.2) [CDK6], amp(8q24.2) [RECQL4, MYC], amp(13q31.2) [ERCC5], and frequent whole genome duplication. To further investigate RS and CLL clonal evolution, we performed single-cell RNA-sequencing on biopsies at the time of RS diagnosis in 5 individuals with clonally related transformation. Using our novel tool, CNVSingle, we inferred allele specific single-cell copy number alterations, yielding cluster-specific copy number profiles that matched the WES results of individual subclones of the RS and CLL populations. This enabled mapping genetic clones to specific expression patterns. Finally, we devised and tested a methodology that uses cfDNA for early detection of emerging Richter’s disease and have successfully identified Richter‘s tumor DNA in the blood several months prior to the clinical diagnosis. Our study thus defines drivers, distinct molecular subtypes and evolutionary path to RS and suggests strategies for its improved detection. Citation Format: Erin M. Parry, Ignaty Leshchiner, Romain Guièze, Connor Johnson, Eugen Tausch, Sameer Parikh, Camilla Lemvigh, Conor Messer, Daniel Rosebrock, Filippo Utro, Chaya Levovitz, Kahn Rhrissorrakrai, Matthew Davids, Raquel A. Jacobs, Kara Slowik, Julien Broseus, Shanye Yin, Shuqiang Li, Geoff Fell, Ziao Lin, Binyamin A. Knisbacher, Neil Ruthen, Dimitri Livitz, Christof Schneider, Jialin Ma, Julian Hess, Laura Z. Rassenti, Thomas J. Kipps, Nitin Jain, William Wierda, Florence Cymbalista, Neil E. Kay, Kenneth J. Livak, Brian P. Danysh, Chip Stewart, Donna Neuberg, Jennifer R. Brown, Laxmi Parida, Stephan Stilgenbauer, Gad Getz, Catherine J. Wu. Evolutionary history of transformation from chronic lymphocytic leukemia to Richter’s syndrome [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4007.

This study explored the ability to identify causal relationships between diseases and imaging findings from their co-occurrences in radiology reports. A natural language processing (NLP) system with negative-expression filtering detected positive mentions of 16,912 disorders, interventions, and imaging findings in 1,702,462 consecutive radiology reports; the 55,564 causal relations defined by the Radiology Gamuts Ontology (RGO) served as reference standard. Conditions were considered to co-occur if they were present in reports from the same patient. The ϕ and κ statistics both achieved AUC0.70, P<0.001 in identifying causal relationships from pairwise co-occurrence data. Analysis of radiology reports can identify a large proportion of known causal associations among diseases and imaging findings. Automated approaches hold promise to identify causal relationships among diseases and imaging findings from their co-occurrence in text-based radiology reports.

Systemic racism is embedded in healthcare settings and is linked to high maternal mortality rates for Black women in US Society. Doulas, or birth support workers, are uniquely positioned to advocate for women of color going through the birthing process, but little is understood on how doulas come to terms with race, racism, and whiteness in maternal healthcare settings. Using qualitative in-depth interviews with 11 doulas in northeast Florida, this research study found that doulas’ advocacy for maternal justice leads to an intersection with racial justice through their support of minority women clients. Doulas shared stories of racial injustice when they compared their white and Black client experiences, leading to shifting strategies to address racism in maternal healthcare settings. Doulas also grappled with their connection to whiteness through their own identities and interaction with white and minority clients. Many doulas shared a need for anti-racism training and recruitment of Black doulas to meet the needs of women of color going through the birthing process.

Abstract Background Children with inflammatory bowel disease [IBD] are disproportionally affected by recurrent Clostridioides difficile infection [rCDI]. Although faecal microbiota transplantation [FMT] has been used with good efficacy in adults with IBD, little is known about outcomes associated with FMT in paediatric IBD. Methods We performed a retrospective review of FMT at 20 paediatric centres in the USA from March 2012 to March 2020. Children with and without IBD were compared with determined differences in the efficacy of FMT for rCDI. In addition, children with IBD with and without a successful outcome were compared with determined predictors of success. Safety data and IBD-specific outcomes were obtained. Results A total of 396 paediatric patients, including 148 with IBD, were included. Children with IBD were no less likely to have a successful first FMT then the non-IBD affected cohort [76% vs 81%, p = 0.17]. Among children with IBD, patients were more likely to have a successful FMT if they received FMT with fresh stool [p = 0.03], were without diarrhoea prior to FMT [p = 0.03], or had a shorter time from rCDI diagnosis until FMT [p = 0.04]. Children with a failed FMT were more likely to have clinically active IBD post-FMT [p = 0.002] and 19 [13%] patients had an IBD-related hospitalisation in the 3-month follow-up. Conclusions Based on the findings from this large US multicentre cohort, the efficacy of FMT for the treatment of rCDI did not differ in children with IBD. Failed FMT among children with IBD was possibly related to the presence of clinically active IBD.

INTRODUCTION: Significant variability between colonoscopy operators contributes to postcolonoscopy colorectal cancers (CRCs). We aimed to estimate postcolonoscopy colorectal neoplasia (CRN) detection by multi-target stool DNA (mt-sDNA), which has not previously been studied for this purpose. METHODS: In a retrospective cohort of patients with +mt-sDNA and completed follow-up colonoscopy, positive predictive value (PPV) for endpoints of any CRN, advanced adenoma, right-sided neoplasia, sessile serrated polyps (SSP), and CRC were stratified by the time since previous colonoscopy (0–9, 10, and ≥11 years). mt-sDNA PPV at ≤9 years from previous average-risk screening colonoscopy was used to estimate CRN missed at previous screening colonoscopy. RESULTS: Among the 850 studied patients with +mt-sDNA after a previous negative screening colonoscopy, any CRN was found in 535 (PPV 63%). Among 107 average-risk patients having +mt-sDNA ≤9 years after last negative colonoscopy, any CRN was found in 67 (PPV 63%), advanced neoplasia in 16 (PPV 15%), right-sided CRN in 48 (PPV 46%), and SSP in 20 (PPV 19%). These rates were similar to those in 47 additional average risk persons with previous incomplete colonoscopy and in an additional 68 persons at increased CRC risk. One CRC (stage I) was found in an average risk patient who was mt-sDNA positive 6 years after negative screening colonoscopy. DISCUSSION: The high PPV of mt-sDNA 0–9 years after a negative screening colonoscopy suggests that lesions were likely missed on previous examination or may have arisen de novo . mt-sDNA as an interval test after negative screening colonoscopy warrants further study.

Background Persistent post-traumatic headache most commonly has symptoms that overlap those of migraine. In some cases, it can be clinically difficult to differentiate persistent post-traumatic headache with a migraine phenotype from migraine. The objective of this study was to develop a classification model based on questionnaire data and structural neuroimaging data that distinguishes individuals with migraine from those with persistent post-traumatic headache. Methods Questionnaires assessing headache characteristics, sensory hypersensitivities, cognitive functioning, and mood, as well as T1-weighted magnetic resonance imaging and diffusion tensor data from 34 patients with migraine and 48 patients with persistent post-traumatic headache attributed to mild traumatic brain injury were included for analysis. The majority of patients with persistent post-traumatic headache had a migraine/probable migraine phenotype (77%). A machine-learning leave-one-out cross-validation algorithm determined the average accuracy for distinguishing individual migraine patients from individual patients with persistent post-traumatic headache. Results Based on questionnaire data alone, the average classification accuracy for determining whether an individual person had migraine or persistent post-traumatic headache was 71.9%. Adding imaging data features to the model improved the classification accuracy to 78%, including an average accuracy of 97.1% for identifying individual migraine patients and an average accuracy of 64.6% for identifying individual patients with persistent post-traumatic headache. The most important clinical features that contributed to the classification accuracy included questions related to anxiety and decision making. Cortical brain features and fibertract data from the following regions or tracts most contributed to the classification accuracy: Bilateral superior temporal, inferior parietal and posterior cingulate; right lateral occipital, uncinate, and superior longitudinal fasciculus. A post-hoc analysis showed that compared to incorrectly classified persistent post-traumatic headache patients, those who were correctly classified as having persistent post-traumatic headache had more severe physical, autonomic, anxiety and depression symptoms, were more likely to have post-traumatic stress disorder, and were more likely to have had mild traumatic brain injury attributed to blasts. Discussion A classification model that included a combination of questionnaire data and structural imaging parameters classified individual patients as having migraine versus persistent post-traumatic headache with good accuracy. The most important clinical measures that contributed to the classification accuracy included questions on mood. Regional brain structures and fibertracts that play roles in pain processing and pain integration were important brain features that contributed to the classification accuracy. The lower classification accuracy for patients with persistent post-traumatic headache compared to migraine may be related to greater heterogeneity of patients in the persistent post-traumatic headache cohort regarding their traumatic brain injury mechanisms, and physical, emotional, and cognitive symptoms.