Should All Patients With Stage IE Gastric Mucosa-Associated Lymphoid Tissue Lymphoma Receive Antibiotic Eradication Therapy for Helicobacter pylori?

PURPOSE: H. pylori eradication therapy (HPE) can lead to tumor regression in H. pylori-positive (HPP) gastric mucosa-associated lymphoid tissue (MALT) lymphoma. However, some patients do not have detectable H. pylori (HP) infection (H. pylori-negative [HPN]) and the guidelines differ in their initial approach to HPN patients. The National Comprehensive Cancer Network (NCCN) recommends proceeding to radiation therapy, whereas European Society for Medical Oncology suggests HPE for every patient, even those who are HPN. To address this issue, we evaluated the effectiveness of HPE in limited-stage gastric MALT lymphoma. MATERIALS AND METHODS: We retrospectively reviewed patients newly diagnosed with stage IE gastric MALT lymphoma between January 2002 and December 2022. The primary outcome was the complete remission (CR) rate defined as no macroscopic findings of lymphoma and negative gastric biopsy at the follow-up gastric endoscopy. RESULTS: Fifty-two patients were reviewed, and HP infection was detected in 19 (36.5%) patients-14 by immunostaining, three by serology, and one each by stool antigen and urea breath test. All 19 HPP and eight of the 33 HPN patients received HPE treatment. The CR rate was 63% (12/19) in HPP patients and 13% (1/8) in HPN patients (P = .033). After a median follow-up of 89.7 months, only two of the 12 HPP patients achieving CR have relapsed; the one HPN patient who received HPE remains in CR at 12+ months. CONCLUSION: For limited-stage HPP gastric MALT lymphoma, HPE is an effective and durable first-line treatment and should be used. For HPN patients, the CR rate with HPE is very low in our experience and is thus in support of the NCCN guideline.

Drivers of antimicrobial resistance within the communities of Nepal from One Health perspective: a scoping review.

Background: A major driver of antimicrobial resistance (AMR) is the inappropriate use of antimicrobials. At the community level, people are often engaged in behaviors that drive AMR within human, animal, and environmental (One Health) impacts. This scoping review consolidates research to determine (a) the community's knowledge, attitudes, and practices around AMR; (b) existing community-based interventions; and (c) barriers and enablers to addressing AMR in Nepal. Methods: This scoping review follows the Joanna Briggs Institute scoping review methodology. Literature indexed in PubMed, Scopus, CINAHL, Global Index Medicus, HINARI-SUMMON, Embase (Ovid), Global Health (Ovid), CAB Abstracts (Ovid), Web of Science, and Google Scholar between January 2000 and January 2023 were reviewed for inclusion. Articles were included in the review if they considered the issues of AMR at the community level in Nepal; this excluded clinical and laboratory-based studies. A total of 47 studies met these criteria, were extracted, and analyzed to consolidate the key themes. Results: A total of 31 (66%) articles exclusively included human health; five (11%) concentrated only on animal health; no studies solely focused on environmental aspects of AMR; and the remaining studies jointly presented human, animal, and environmental aspects. Findings revealed inadequate knowledge accompanied by inappropriate practice in both the human and animal health sectors. Four community interventions improved knowledge and practices on the appropriate use of antimicrobials among community people. However, various social and economic factors were found as barriers to the appropriate use of antimicrobials in the community. Conclusion: Community engagement and One Health approaches could be key tools to improve awareness of AMR and promote behavioral change related to AM use in communities, as current studies have revealed inadequate knowledge alongside inappropriate practices shared in both human and animal health sectors. Systematic review registration: DOI: 10.17605/OSF.IO/FV326.

Factors contributing to high performance of sows in free farrowing systems.

BACKGROUND: Pressure to abolish farrowing crates is increasing, and producers are faced with decisions about which alternative system to adopt. For sow welfare, well designed free farrowing systems without close confinement are considered optimal but producers have concerns about increased piglet mortality, particularly crushing by the sow. Reporting accurate performance figures from commercial farms newly operating such systems could inform the transition process. This study investigated performance on three commercial farms operating four different zero-confinement systems, three of which were newly installed. A total of 3212 litters from 2920 sows were followed from farrowing to weaning over a three-year period with key performance indicators (KPIs) recorded. Mixed Models (LMMs, GLMMs) determined the influence of different factors (e.g. farrowing system, sow parity, management aspects) and litter characteristics on performance, including levels and causes of piglet mortality. RESULTS: Piglet mortality was significantly influenced by farm/system. Live-born mortality ranged from 10.3 to 20.6% with stillbirths ranging from 2.5 to 5.9%. A larger litter size and higher parity resulted in higher levels of mortality regardless of system. In all systems, crushing was the main cause of piglet mortality (59%), but 31% of sows did not crush any piglets, whilst 26% crushed only one piglet and the remaining sows (43%) crushed two or more piglets. System significantly influenced crushing as a percentage of all deaths, with the system with the smallest spatial footprint (m2) compared to the other systems, recording the highest levels of crushing. Time from the start of the study influenced mortality, with significant reductions in crushing mortality (by ~ 4%) over the course of the three-year study. There was a highly significant effect of length of time (days) between moving sows into the farrowing accommodation and sows farrowing on piglet mortality (P < 0.001). The less time between sows moving in and farrowing, the higher the levels of piglet mortality, with ~ 3% increase in total mortality every five days. System effects were highly significant after adjusting for parity, litter size, and days pre-farrowing. CONCLUSION: These results from commercial farms demonstrate that even sows that have not been specifically selected for free farrowing are able, in many cases, to perform well in these zero-confinement systems, but that a period of adaptation is to be expected for overall farm performance. There are performance differences between the farms/systems which can be attributed to individual farm/system characteristics (e.g. pen design and management, staff expertise, pig genotypes, etc.). Higher parity sows and those producing very large litters provide a greater challenge to piglet mortality in these free farrowing systems (just as they do in crate systems). Management significantly influences performance, and ensuring sows have plenty of time to acclimatise between moving in to farrowing accommodation and giving birth is a critical aspect of improving piglet survival.

POU6F2, a risk factor for glaucoma, myopia and dyslexia, labels specific populations of retinal ganglion cells.

Pou6f2 is a genetic connection between central corneal thickness (CCT) in the mouse and a risk factor for developing primary open-angle glaucoma. POU6F2 is also a risk factor for several conditions in humans, including glaucoma, myopia, and dyslexia. Recent findings demonstrate that POU6F2-positive retinal ganglion cells (RGCs) comprise a number of RGC subtypes in the mouse, some of which also co-stain for Cdh6 and Hoxd10. These POU6F2-positive RGCs appear to be novel of ON-OFF directionally selective ganglion cells (ooDSGCs) that do not co-stain with CART or SATB2 (typical ooDSGCs markers). These POU6F2-positive cells are sensitive to damage caused by elevated intraocular pressure. In the DBA/2J mouse glaucoma model, heavily-labeled POU6F2 RGCs decrease by 73% at 8 months of age compared to only 22% loss of total RGCs (labeled with RBPMS). Additionally, Pou6f2-/- mice suffer a significant loss of acuity and spatial contrast sensitivity along with an 11.4% loss of total RGCs. In the rhesus macaque retina, POU6F2 labels the large parasol ganglion cells that form the magnocellular (M) pathway. The association of POU6F2 with the M-pathway may reveal in part its role in human glaucoma, myopia, and dyslexia.

Cytogenetic and pathologic characterization of MYC-rearranged B-cell lymphomas in pediatric and young adult patients.

MYC-rearranged B-cell lymphoma (BCL) in the pediatric/young adult (YA) age group differs substantially in disease composition from adult cohorts. However, data regarding the partner genes, concurrent rearrangements, and ultimate diagnoses in these patients is scarce compared to that in adult cohorts. We aimed to characterize the spectrum of MYC-rearranged (MYC-R) mature, aggressive BCL in the pediatric/YA population. A retrospective study of morphologic, immunophenotypic, and fluorescence in situ hybridization (FISH) results of patients age ≤ 30 years with suspected Burkitt lymphoma (BL), diffuse large B-cell lymphoma (DLBCL) or high-grade B-cell lymphoma (HGBCL), and a MYC-R by FISH between 2013-2022 was performed. Two-hundred fifty-eight cases (129 (50%) pediatric (< 18 years) and 129 (50%) YA (18-30 years)) were included. Most MYC-R BCL in pediatric (89%) and YA (66%) cases were BL. While double-hit (DH) cytogenetics (MYC with BCL2 and/or BCL6-R, HGBCL-DH) was rare in the pediatric population (2/129, 2%), HGBCL-DH increased with age and was identified in 17/129 (13%) of YA cases. Most HGBCL-DH had MYC and BCL6-R, while BCL2-R were rare in both groups (3/258, 1%). MYC-R without an IG partner was more common in the YA group (14/116 (12%) vs 2/128 (2%), p = 0.001). The pediatric to YA transition is characterized by decreasing frequency in BL and increasing genetic heterogeneity of MYC-R BCL, with emergence of DH-BCL with MYC and BCL6-R. FISH to evaluate for BCL2 and BCL6 rearrangements is likely not warranted in the pediatric population but should continue to be applied in YA BCL.

Follicular lymphoma B cells exhibit heterogeneous transcriptional states with associated somatic alterations and tumor microenvironments.

Follicular lymphoma (FL) is an indolent non-Hodgkin lymphoma of germinal center origin, which presents with significant biologic and clinical heterogeneity. Using RNA-seq on B cells sorted from 87 FL biopsies, combined with machine-learning approaches, we identify 3 transcriptional states that divide the biological ontology of FL B cells into inflamed, proliferative, and chromatin-modifying states, with relationship to prior GC B cell phenotypes. When integrated with whole-exome sequencing and immune profiling, we find that each state was associated with a combination of mutations in chromatin modifiers, copy-number alterations to TNFAIP3, and T follicular helper cells (Tfh) cell interactions, or primarily by a microenvironment rich in activated T cells. Altogether, these data define FL B cell transcriptional states across a large cohort of patients, contribute to our understanding of FL heterogeneity at the tumor cell level, and provide a foundation for guiding therapeutic intervention.

Grant funding among underrepresented minority and women urologists at academic institutions.

INTRODUCTION: Grant funding to Urology has decreased over the last decade. Documented lack of gender and race diversity at the faculty level raises concerns for funding disparities. This study sought to characterize disparities based upon race and gender in National Institutes of Health (NIH) funding data to Urologic faculty. METHODS AND MATERIALS: Data from 145 ACGME accredited Urology residency programs incorporating faculty gender and underrepresented in medicine (URiM) status was utilized. The NIH Research Portfolio Online Report Tool was queried between 1985 and 2023 for grants related to current Urology faculty. URiM status, gender, years of practice, academic rank, and Doximity residency program rank were factors in multivariable analysis. RESULTS: A total of 2,131 faculty were included. Three hundred one Urologists received 793 urologic grants for a total of $993,919,052 in funding. By race, grants were awarded to: White 72.9%, Asian 21.8%, Hispanic 3.0%, Black 2.1%. Men received 708 grants (89.3%) worth $917,083,475 total. Women received 85 grants (10.7%) worth $76,835,577 total. Likelihood of being awarded a grant was significantly associated with non-URiM status (p < 0.001) and men (p < 0.0001). On multivariable analysis, Doximity rank (p < 0.001) and academic rank (p < 0.001) were significant predictors of receiving a grant; male gender, URiM status, and years of practice were not. Academic rank was also a significant predictor of number of grants received (p = 0.04) and total funding (p = 0.04); years of practice, Doximity rank, URiM status, and gender were not. CONCLUSIONS: NIH grants were more likely awarded to higher ranked faculty from higher Doximity ranked institutions with no differences based on URiM status or gender.

Exploring community insights on antimicrobial resistance in Nepal: a formative qualitative study.

BACKGROUND: Antimicrobial resistance (AMR) is the process by which microbes evolve mechanisms to survive the medicines designed to destroy them i.e. antimicrobials (AMs). Despite being a natural process, AMR is being hastened by the abuse of AMs. In context of Nepal, there is limited information on drivers of AMR and barriers in addressing it from a community perspective. This study explores the local language and terminology used around AMs in the community, commonly used AMs and reasons for their usage, how these AMs are sourced, and the perceived barriers to addressing AMR via One Health approach. METHODS: A phenomenological study design was utilized with applied qualitative research theoretically framed as pragmatism. Twelve in-depth interviews and informal discussions with a One Health focus, were purposively conducted with wide range of stakeholders and community resident of Kapilvastu municipality of Nepal during April 2022. The acquired data was analyzed manually via a thematic framework approach. The study obtained ethical approval from ethical review board of Nepal Health Research Council and University of Leeds. RESULTS: Nepali and Awadhi languages does not have specific words for AMs or AMR, which is understandable by the community people. Rather, community use full explanatory sentences. People use AMs but have incomplete knowledge about them and they have their own local words for these medicines. The knowledge and usage of AMs across human and animal health is impacted by socio-structural factors, limited Government regulation, inadequate supply of AMs in local government health facilities and the presence of various unregulated health providers that co-exist within the health system. Novel ideas such as the use of visual and smart technology, for instance mobile phones and social media exposure, can enable access to information about AMs and AMR. CONCLUSION: This study shows that terminology that is understandable by the community referring to AMs and AMR in Nepali and Awadhi languages does not exist, but full explanatory sentences and colloquial names are used. Despite regular utilisation, communities have incomplete knowledge regarding AMs. Since, knowledge alone cannot improve behaviour, behavioural interventions are required to address AMR via community engagement to co-produce their own solutions. TRIAL REGISTRATION: Not applicable.

Moraxella ovis and Moraxella bovoculi lipooligosaccharide biosynthesis genes, and structural characterisation of oligosaccharide from M. ovis 354T.

Moraxella ovis is a Gram-negative bacterium isolated from sheep conjunctivitis cases and is a rare isolate of infectious bovine keratoconjunctivitis (IBK). This species is closely related to M. bovoculi, another species which can also be isolated from IBK, or cattle upper respiratory tract (URT). Prior to molecular identification techniques, M. bovoculi was frequently misclassified as M. ovis. We previously described the structure of two oligosaccharides (lipooligosaccharide-derived, minor and major glycoforms) from M. bovoculi 237T (type strain, also ATCC BAA-1259T). Here, we have identified the genetic loci for lipooligosaccharide synthesis in M. ovis 354T (NCTC11227) and compared it with M. bovoculi 237T. We identified genes encoding the known glycosyltransferases Lgt6 and Lgt3 in M.ovis. These genes are conserved in Moraxella spp., including M bovoculi. We identified three further putative OS biosynthesis genes that are restricted to M. ovis and M. bovoculi. These encode enzymes predicted to function as GDP-mannose synthases, namely a mannosyltransferase and a glycosyltransferase. Adding insight into the genetic relatedness of M.ovis and M. bovoculi, the M. ovis genes have higher similarity to those in M. bovoculi genotype 2 (nasopharyngeal isolates from asymptomatic cattle), than to M. bovoculi genotype 1 (isolates from eyes of IBK-affected cattle). Sequence analysis confirmed that the predicted mannosyltransferase in M. bovoculi 237T is interrupted by a C>T polymorphism. This mutation is not present in other M. bovoculi strains sequenced to date. We isolated and characterised LOS-derived oligosaccharide from M. ovis 354T. GLC-MS and NMR spectroscopy data revealed a heptasaccharide structure with three ß-D-Glcp residues attached as branches to the central 3,4,6-α-D-Glcp, with subsequent attachment to Kdo. This inner core arrangement is consistent with the action of Lgt6 and Lgt3 glycosyltransferases. Two α-D-Manp residues are linearly attached to the 4-linked ß-D-Glcp, consistent with the presence of the two identified glycosyltransferases. This oligosaccharide structure is consistent with the previously reported minor glycoform isolated from M. bovoculi 237T.

Immune Checkpoint Inhibitor-Induced Pure Red Cell Aplasia: A Review of 2 Cases in Metastatic Melanoma.

BACKGROUND Immunotherapy is a novel treatment offering an alternative to traditional chemotherapeutic agents for different malignancies. Hematologic adverse reactions (HARs) related to immune checkpoint inhibitors (ICIs) are uncommon. Pure red cell aplasia (PRCA) is a rare hematologic complication of ICI therapy in metastatic melanoma with significant mortality risk despite treatment with steroids or immunosuppressive therapy. For unexplained acute anemia after exclusion of other causes, performing bone marrow biopsy is imperative to diagnose PRCA and rule out involvement of bone marrow by primary tumor. HARs can occur during ICI therapy or even after ICI therapy is stopped. ICI rechallenge, even after the development of HARs, is considered in some patients with good response to treatment of HARs from ICIs. Recurrence of HARs with the same or different type of reaction is seen in some patients. CASE REPORT Two cases of ICI-induced PRCA were confirmed on bone marrow biopsy after dual ICI treatment with nivolumab and ipilimumab in metastatic melanoma. In case 2, PRCA was successfully treated with steroids and later rechallenged with single-agent nivolumab, causing mild ICI-induced immune thrombocytopenia, which did not require treatment with steroids. CONCLUSIONS It is crucial to increase clinician awareness of the possibility of PRCA development not only during treatment with ICI but also after finishing treatment with ICI; there is high mortality associated with missing an opportunity to diagnose and treat PRCA on time with favorable results. ICI rechallenge can be considered in patients who showed response to immunotherapy, especially those with limited alternative therapeutic options.

Addressing antimicrobial resistance through community engagement: a framework for developing contextually relevant and impactful behaviour change interventions.

Background: Community engagement (CE) interventions often explore and promote behaviour change around a specific challenge. Suggestions for behaviour change should be co-produced in partnership with the community. To facilitate this, it is essential that the intervention includes key content that unpacks the challenge of interest via multiple sources of knowledge. However, where community lived experience and academic evidence appear misaligned, tensions can appear within the co-production dynamic of CE. This is specifically so within the context of antimicrobial resistance (AMR) where ideal behaviours are often superseded by what is practical or possible in a particular community context. Methods: Here we describe a framework for the equitable development of contextually appropriate, clearly evidenced behavioural objectives for CE interventions. This framework explores different sources of knowledge on AMR, including the potentially competing views of different stakeholders. Findings: The framework allows key content on AMR to be selected based upon academic evidence, contextual appropriateness and fit to the chosen CE approach. A case study of the framework in action exemplifies how the framework is applicable to a range of contexts, CE approaches and One Health topics beyond just AMR. Conclusions: Within CE interventions, academic evidence is crucial to develop well-informed key content. However, this formative work should also involve community members, ensuring that their contextual knowledge is valued. The type of CE approach also needs careful consideration because methodological constraints may limit the breadth and depth of information that can be delivered within an intervention, and thus the scope of key content.

NCCN Guidelines® Insights: B-Cell Lymphomas, Version 6.2023.

Novel targeted therapies (small molecule inhibitors, antibody-drug conjugates, and CD19-directed therapies) have changed the treatment landscape of relapsed/refractory B-cell lymphomas. Bruton's tyrosine kinase (BTK) inhibitors continue to evolve in the management of mantle cell lymphoma (MCL), in both the relapsed/refractory and the frontline setting. Anti-CD19 CAR T-cell therapies are now effective and approved treatment options for relapsed/refractory follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), and MCL. Bispecific T-cell engagers represent a novel immunotherapeutic approach for relapsed FL and DLBCL after multiple lines of therapies, including prior CAR T-cell therapy. These NCCN Guideline Insights highlight the significant updates to the NCCN Guidelines for B-Cell Lymphomas for the treatment of FL, DLBCL, and MCL.

Co-designing community-based interventions to tackle antimicrobial resistance (AMR): what to include and why.

Antimicrobial resistance (AMR) is a social and biological problem. Although resistance to antimicrobials is a natural phenomenon, many human behaviors are increasing the pressure on microbes to develop resistance which is resulting in many commonly used treatments becoming ineffective. These behaviors include unregulated use of antimicrobial medicines, pesticides and agricultural chemicals, the disposal of heavy metals and other pollutants into the environment, and human-induced climatic change. Addressing AMR thus calls for changes in the behaviors which drive resistance. Community engagement for antimicrobial resistance (CE4AMR) is an international and interdisciplinary network focused on tackling behavioural drivers of AMR at community level. Since 2019 this network has worked within Low-Middle Income Countries (LMICs), predominantly within Southeast Asia, to tackle behavioral drivers of AMR can be mitigated through bottom-up solutions championed by local people. This commentary presents seven Key Concepts identified from across the CE4AMR portfolio as integral to tackling AMR. We suggest it be used to guide future interventions aimed at addressing AMR via social, participatory, and behavior-change approaches.

Follicular lymphoma and diffuse large B-cell lymphoma with BCL2 and IRF4 rearrangements in adult patients.

Follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL) with concurrent BCL2 and IRF4 rearrangements are rare. It is unclear whether such cases should be classified as large B- cell lymphoma with IRF4 rearrangement or FL/DLBCL-not otherwise specified. We identified 5 adult patients (FL, N = 3 and FL/DLBCL, N = 2) with concurrent BCL2 and IRF4 rearrangements. The median age at presentation was 77 years, and three patients presented with advanced stage disease. Both nodal and extranodal sites were involved and involvement was not limited to head and neck region. With a median follow-up of 18 months, 1 patient died and 4 patients were alive, including 3 who received chemotherapy and 1 who was observed. The neoplasms were histologically heterogeneous, including grade 2 and 3 FL and DLBCL. Four cases coexpressed CD10, BCL6, BCL2 and MUM1/IRF4. The Ki67 labelling index ranged from 20% to 95%. In 4 patients, the percentage of cells with BCL2 rearrangement was equal to or slightly greater than the cells harboring IRF4 rearrangement. Two cases underwent next generation sequencing tailored for lymphoid neoplasms. Both lacked mutations involving IRF4 and NF-kB pathway genes that are frequently detected in large B-cell lymphoma with IRF4 rearrangement, and one case showed DLBCL-EZH2 type mutations, including KMT2D and BCL2 mutations, similar to 2 previously reported DLBCL with BCL2 and IRF4 rearrangements. Adults with FL and FL/DLBCL with BCL2 and IRF4 rearrangements display clinicopathologic and mutational features more akin to FL and DLBCL and should not be characterized as large B-cell lymphoma with IRF4 rearrangement.

Post-Prandial Cognitive and Blood Pressure Effects of a DHA-Rich Omega-3 Powder in Middle-Aged Males: A Pilot Study.

The use of omega-3 polyunsaturated fatty acid (ω-3 PUFA) supplements is increasingly common among middle-aged and older adults. Users of ω-3 PUFA supplements often report using such supplements to support cognitive health, despite mixed findings reported within the ω-3 PUFA literature. To date, very few studies have explored cognitive effects in distinctly middle-aged (40 to 60 years) adults, and none have examined the acute effects (in the hours following a single dose) on cognitive performance. The current study evaluated whether a single dose of ω-3 PUFA (4020 mg docosahexaenoic acid and 720 mg eicosapentaenoic acid) influences cognitive performance and cardiovascular function in middle-aged males. Cognitive performance and cardiovascular function were assessed before and 3.5-4 h after consumption of a high dose of ω-3 PUFA (DHA + EPA) or placebo, incorporated into a standardized meal (i.e., single serve of Greek yogurt). In this study of middle-aged males, no significant differential treatment effects were observed for cognitive performance. However, a significant reduction in aortic systolic blood pressure (pre-dose to post-dose) was apparent following consumption of the ω-3 PUFA (DHA + EPA) treatment (mean difference = -4.11 mmHg, p = 0.004) but not placebo (mean difference = -1.39 mmHg, p = 0.122). Future replication in a sample comprising females, as well as patients with hypertension, is merited.

Exploring the potential for children to act on antimicrobial resistance in Nepal: Valuable insights from secondary analysis of qualitative data.

This study explores the perceived roles of children in antimicrobial resistance (AMR) in two sites across Nepal. AMR is a global challenge and underpinned by many complex behavioural drivers including how antimicrobial medicines are sourced and used. Because of this social dynamic, several research groups are using community engagement (CE) approaches to understand AMR at community level. However, most data negate the importance of children in behaviours linked to, and potentially driving AMR. In this study, authors apply secondary analysis methods to 10 transcripts representing the views of 23 adults engaged in an AMR-focused film-making project. By focusing on participants' reference to children, we reveal that antimicrobial usage and adherence to health providers' messages can be influenced by the age of the patient. Secondly that children are involved in some of the behaviours which are known to drive antimicrobial resistance such as purchasing over-the-counter antibiotic drugs. Finally, community members discuss that, with careful creation of resources, AMR could be meaningfully presented in educational settings with a view to children acting as agents of change around AMR-driving behaviours. Findings suggest that age-inclusive community engagement projects could be effective in tackling AMR at community level in Nepal and other low resource settings.

Multiomic Analysis Identifies a High-Risk Metabolic and TME Depleted Signature that Predicts Early Clinical Failure in DLBCL.

PURPOSE: 60-70% of newly diagnosed diffuse large B-cell lymphoma (DLBCL) patients avoid events within 24 months of diagnosis (EFS24) and the remainder have poor outcomes. Recent genetic and molecular classification of DLBCL has advanced our knowledge of disease biology, yet were not designed to predict early events and guide anticipatory selection of novel therapies. To address this unmet need, we used an integrative multiomic approach to identify a signature at diagnosis that will identify DLBCL at high risk of early clinical failure. PATIENTS AND METHODS: Tumor biopsies from 444 newly diagnosed DLBCL were analyzed by WES and RNAseq. A combination of weighted gene correlation network analysis and differential gene expression analysis followed by integration with clinical and genomic data was used to identify a multiomic signature associated with high risk of early clinical failure. RESULTS: Current DLBCL classifiers are unable to discriminate cases who fail EFS24. We identified a high risk RNA signature that had a hazard ratio (HR, 18.46 [95% CI 6.51-52.31] P < .001) in a univariate model, which did not attenuate after adjustment for age, IPI and COO (HR, 20.8 [95% CI, 7.14-61.09] P < .001). Further analysis revealed the signature was associated with metabolic reprogramming and a depleted immune microenvironment. Finally, WES data was integrated into the signature and we found that inclusion of ARID1A mutations resulted in identification of 45% of cases with an early clinical failure which was validated in external DLBCL cohorts. CONCLUSION: This novel and integrative approach is the first to identify a signature at diagnosis that will identify DLBCL at high risk for early clinical failure and may have significant implications for design of therapeutic options.