A national service for delivering CD19 CAR-Tin large B-cell lymphoma - The UK real-world experience.

CD19 CAR-T have emerged as a new standard treatment for relapsed/refractory (r/r) large B-cell lymphoma (LBCL). CAR-T real-world (RW) outcomes published to date suggest significant variability across countries. We provide results of a large national cohort of patients intended to be treated with CAR-T in the UK. Consecutive patients with r/r LBCL approved for CAR-T by the National CAR-T Clinical Panel between December 2018 and November 2020 across all UK CAR-T centres were included. 404/432 patients were approved [292 axicabtagene ciloleucel (axi-cel), 112 tisagenlecleucel (tisa-cel)], 300 (74%) received the cells. 110/300 (38.3%) patients achieved complete remission (CR) at 6 months (m). The overall response rate was 77% (52% CR) for axi-cel, 57% (44% CR) for tisa-cel. The 12-month progression-free survival was 41.8% (axi-cel) and 27.4% (tisa-cel). Median overall survival for the intention-to-treat population was 10.5 m, 16.2 m for infused patients. The incidence of grade ≥3 cytokine release syndrome and neurotoxicity were 7.6%/19.6% for axi-cel and 7.9%/3.9% for tisa-cel. This prospective RW population of CAR-T eligible patients offers important insights into the clinical benefit of CD19 CAR-T in LBCL in daily practice. Our results confirm long-term efficacy in patients receiving treatment similar to the pivotal trials, but highlight the significance of early CAR-T failure.

Recommendations to encourage participation of individuals from diverse backgrounds in psychiatric genetic studies.

We present innovative research practices in psychiatric genetic studies to ensure representation of individuals from diverse ancestry, sex assigned at birth, gender identity, age, body shape and size, and socioeconomic backgrounds. Due to histories of inappropriate and harmful practices against marginalized groups in both psychiatry and genetics, people of certain identities may be hesitant to participate in research studies. Yet their participation is essential to ensure diverse representation, as it is incorrect to assume that the same genetic and environmental factors influence the risk for various psychiatric disorders across all demographic groups. We present approaches developed as part of the Eating Disorders Genetics Initiative (EDGI), a study that required tailored approaches to recruit diverse populations across many countries. Considerations include research priorities and design, recruitment and study branding, transparency, and community investment and ownership. Ensuring representation in participants is costly and funders need to provide adequate support to achieve diversity in recruitment in prime awards, not just as supplemental afterthoughts. The need for diverse samples in genetic studies is critical to minimize the risk of perpetuating health disparities in psychiatry and other health research. Although the EDGI strategies were designed specifically to attract and enroll individuals with eating disorders, our approach is broadly applicable across psychiatry and other fields.

PPA2-associated sudden cardiac death: extending the clinical and allelic spectrum in 20 new families.

PURPOSE: Biallelic hypomorphic variants in PPA2, encoding the mitochondrial inorganic pyrophosphatase 2 protein, have been recently identified in individuals presenting with sudden cardiac death, occasionally triggered by alcohol intake or a viral infection. Here we report 20 new families harboring PPA2 variants. METHODS: Synthesis of clinical and molecular data concerning 34 individuals harboring five previously reported PPA2 variants and 12 novel variants, 11 of which were functionally characterized. RESULTS: Among the 34 individuals, only 6 remain alive. Twenty-three died before the age of 2 years while five died between 14 and 16 years. Within these 28 cases, 15 died of sudden cardiac arrest and 13 of acute heart failure. One case was diagnosed prenatally with cardiomyopathy. Four teenagers drank alcohol before sudden cardiac arrest. Progressive neurological signs were observed in 2/6 surviving individuals. For 11 variants, recombinant PPA2 enzyme activities were significantly decreased and sensitive to temperature, compared to wild-type PPA2 enzyme activity. CONCLUSION: We expand the clinical and mutational spectrum associated with PPA2 dysfunction. Heart failure and sudden cardiac arrest occur at various ages with inter- and intrafamilial phenotypic variability, and presentation can include progressive neurological disease. Alcohol intake can trigger cardiac arrest and should be strictly avoided.

The Eating Disorders Genetics Initiative (EDGI): study protocol.

BACKGROUND: The Eating Disorders Genetics Initiative (EDGI) is an international investigation exploring the role of genes and environment in anorexia nervosa, bulimia nervosa, and binge-eating disorder. METHODS: A total of 14,500 individuals with eating disorders and 1500 controls will be included from the United States (US), Australia (AU), New Zealand (NZ), and Denmark (DK). In the US, AU, and NZ, participants will complete comprehensive online phenotyping and will submit a saliva sample for genotyping. In DK, individuals with eating disorders will be identified by the National Patient Register, and genotyping will occur using bloodspots archived from birth. A genome-wide association study will be conducted within EDGI and via meta-analysis with other data from the Eating Disorders Working Group of the Psychiatric Genomics Consortium (PGC-ED). DISCUSSION: EDGI represents the largest genetic study of eating disorders ever to be conducted and is designed to rapidly advance the study of the genetics of the three major eating disorders (anorexia nervosa, bulimia nervosa, and binge-eating disorder). We will explicate the genetic architecture of eating disorders relative to each other and to other psychiatric and metabolic disorders and traits. Our goal is for EDGI to deliver "actionable" findings that can be transformed into clinically meaningful insights. TRIAL REGISTRATION: EDGI is a registered clinical trial: clinicaltrials.gov NCT04378101 .

Sudden Cardiac Death Due to Deficiency of the Mitochondrial Inorganic Pyrophosphatase PPA2.

We have used whole-exome sequencing in ten individuals from four unrelated pedigrees to identify biallelic missense mutations in the nuclear-encoded mitochondrial inorganic pyrophosphatase (PPA2) that are associated with mitochondrial disease. These individuals show a range of severity, indicating that PPA2 mutations may cause a spectrum of mitochondrial disease phenotypes. Severe symptoms include seizures, lactic acidosis, cardiac arrhythmia, and death within days of birth. In the index family, presentation was milder and manifested as cardiac fibrosis and an exquisite sensitivity to alcohol, leading to sudden arrhythmic cardiac death in the second decade of life. Comparison of normal and mutant PPA2-containing mitochondria from fibroblasts showed that the activity of inorganic pyrophosphatase was significantly reduced in affected individuals. Recombinant PPA2 enzymes modeling hypomorphic missense mutations had decreased activity that correlated with disease severity. These findings confirm the pathogenicity of PPA2 mutations and suggest that PPA2 is a cardiomyopathy-associated protein, which has a greater physiological importance in mitochondrial function than previously recognized.

Mutation screening using formalin-fixed paraffin-embedded tissues: a stratified approach according to DNA quality.

DNA samples from formalin-fixed paraffin-embedded tissues are highly degraded with variable quality, and this imposes a big challenge for targeted sequencing due to false positives, largely caused by PCR errors and cytosine deamination. To eliminate false positives, a common practice is to validate the detected variants by Sanger sequencing or perform targeted sequencing in duplicate. Technically, PCR errors could be removed by molecular barcoding of template DNA prior to amplification as in the HaloPlexHS design. Nonetheless, it is uncertain to what extent variants detected using this approach should be further validated. Here, we addressed this question by correlating variant reproducibility with DNA quality using HaloPlexHS target enrichment and Illumina HiSeq4000, together with an in-house validated variant calling algorithm. The overall sequencing coverage, as shown by analyses of 70 genes in 266 cases of large B-cell lymphoma, was excellent (98%) in DNA samples amenable for PCR of ≥400 bp, but suboptimal (92%) and poor (80%) in those amenable for PCR of 300 bp and 200 bp respectively. By mutation analysis in duplicate in 93 cases, we demonstrated that 20 alternative allele depth (AAD) was an optimal cut-off value for separating reproducible from non-reproducible variants in DNA samples amenable for PCR of ≥300 bp, with 97% sensitivity and 100% specificity. By cross validation with a previously established targeted sequencing protocol by Fluidigm-PCR and Illumina MiSeq, the HaloPlexHS protocol was shown to be highly sensitive and specific in mutation screening. To conclude, we proposed a stratified approach for mutation screening by HaloplexHS and Illumina HiSeq4000 according to DNA quality. DNA samples with good quality (≥400 bp) are amenable for mutation analysis with a single replicate, with only variants at 15-20 AAD requiring for further validation, while those with suboptimal quality (300 bp) are better analysed in duplicate with reproducible variants at >15 AAD regarded as true genetic changes.

Interspecific hybridization causes long-term phylogenetic discordance between nuclear and mitochondrial genomes in freshwater fishes.

Classification, phylogeography and the testing of evolutionary hypotheses rely on correct estimation of species phylogeny. Early molecular phylogenies often relied on mtDNA alone, which acts as a single linkage group with one history. Over the last decade, the use of multiple nuclear sequences has often revealed conflict among gene trees. This observation can be attributed to hybridization, lineage sorting, paralogy or selection. Here, we use 54 groups of fishes from 48 studies to estimate the degree of concordance between mitochondrial and nuclear gene trees in two ecological grades of fishes: marine and freshwater. We test the hypothesis that freshwater fish phylogenies should, on average, show more discordance because of their higher propensity for hybridization in the past. In keeping with this idea, concordance between mitochondrial and nuclear gene trees (as measured by proportion of components shared) is on average 50% higher in marine fishes. We discuss why this difference almost certainly results from introgression caused by greater historical hybridization among lineages in freshwater groups, and further emphasize the need to use multiple nuclear genes, and identify conflict among them, in estimation of species phylogeny.

Fluorescence Methods for Probing G-Quadruplex Structure in Single- and Double-Stranded DNA.

Interest in exploring G-quadruplex (G4) structures in nucleic acids is growing as it becomes more widely recognized that these structures have many interesting biological roles and chemical properties. Probing the G4-forming potential of DNA with dimethyl sulfate, polymerase stop assays, or nuclease digestion are three commonly used techniques that usually employ radio-isotopic labels for visualization. However, as fluorescent labeling methods have grown in popularity and versatility, many laboratories have moved away from the routine use of radio-isotopic methods. We have adapted traditional procedures for structural analysis of G4-forming DNA sequences by using fluorescent labels and capillary electrophoresis and demonstrate their application to well-studied G4 structures, including c-MYC PU27 G4. The three fluorescent assays described here allow interrogation of G4 structures in double- and single-stranded DNA substrates, using either chemical or enzymatic cleavage. When combined, these techniques can provide valuable information for the investigation of G4 topology and structure, as well as visualizing any structural effects caused by interaction of quadruplexes with the complementary C-rich DNA strand.

Fast-food exposure around schools in urban Adelaide.

OBJECTIVE: To assess whether exposure to fast-food outlets around schools differed depending on socio-economic status (SES). DESIGN: Binary logistic regression was used to investigate the presence and zero-inflated Poisson regression was used for the count (due to the excess of zeroes) of fast food within 1000 m and 15000 m road network buffers around schools. The low and middle SES tertiles were combined due to a lack of significant variation as the 'disadvantaged' group and compared with the high SES tertile as the 'advantaged' group. School SES was expressed using the 2011 Australian Bureau of Statistics, socio-economic indices for areas, index of relative socio-economic disadvantage. Fast-food data included independent takeaway food outlets and major fast-food chains. SETTING: Metropolitan Adelaide, South Australia. SUBJECTS: A total of 459 schools were geocoded to the street address and 1000 m and 1500 m road network distance buffers calculated. RESULTS: There was a 1·6 times greater risk of exposure to fast food within 1000 m (OR=1·634; 95 % 1·017, 2·625) and a 9·5 times greater risk of exposure to a fast food within 1500 m (OR=9·524; 95 % CI 3·497, 25·641) around disadvantaged schools compared with advantaged schools. CONCLUSIONS: Disadvantaged schools were exposed to more fast food, with more than twice the number of disadvantaged schools exposed to fast food. The higher exposure to fast food near more disadvantaged schools may reflect lower commercial land cost in low-SES areas, potentially creating more financially desirable investments for fast-food developers.

Best practice for embryology staffing in HFEA licensed assisted conception centres-guidance from Association of Reproductive & Clinical Scientists.

The Association of Reproductive and Clinical Scientists (ARCS) has long promoted the importance of externally accredited training and assessment of scientific staff within assisted conception centres to ensure professional registration and relevant training at all levels. This not only gives scientific staff the opportunity to empower themselves but also acts to ensure assisted conception centres maintain the highest standards of care and quality for patients whilst meeting HFEA requirements for staffing and training. It also provides assurance to patients that treatment is being delivered by highly trained and competent staff. Clinical embryology practice requires intense concentration, with increasingly complex treatment plans and options coupled with the ever-present consequences of clinical error at the forefront of practitioners' minds, exhaustion and burn out are very real risks. Overloading embryology teams is likely to lead to increased error rates and serious incidents. This guideline aims to bring the sector in line with other Clinical Science specialities to optimise patient care, increase safety, reduce risk (including the risk of legal action against centres and individuals), ensure the use of recognised job titles with appropriate levels of remuneration, and provide centres with a template to work towards for appropriate levels of scientific staffing.

Non-surgical management of recurrent Paget's disease of the vulva: A case report.

Paget's Disease of the Vulva is a relatively rare condition with a high rate of recurrence. Extensive work-up and treatment is warranted as lesions have the capacity to become invasive and can be associated with underlying malignancy. First line therapy includes surgical resection. For those that are not surgical candidates or who do not desire surgical intervention, non-surgical management options include topical therapy with imiquimod. Unfortunately, irritating side effects often results in poor treatment compliance and premature discontinuation limiting efficacy. Here we present a unique case of extensive, recurrent vulvar Paget's disease with excellent response to a combination therapy of imiquimod and Silver Sulfadiazine. To the best of our knowledge, this is the first documented case illustrating the utility of non-surgical management with combination therapy with topical imiquimod and Silver Sulfadiazine for treatment in patients who do not desire surgical intervention.

Avoidant/restrictive food intake disorder (ARFID) in New Zealand and Australia: a scoping review.

BACKGROUND: Avoidant/restrictive food intake disorder (ARFID) is an eating disorder that involves restrictive or avoidant eating behaviour not related to weight or body image concerns. It was first included in the Diagnostic and Statistical Manual of Mental Disorders-fifth edition (DSM-5) in 2013. ARFID frequently begins in childhood and can have serious psychosocial impacts and detrimental health consequences when nutritional and energy needs are persistently unmet. This systematic scoping review focuses on Australasia, synthesizing the current literature landscape on ARFID, and offering recommendations for targeted, actionable research directions for both funders and researchers. METHODS: Online databases and university thesis repositories were systematically searched for studies examining ARFID in the New Zealand or Australian population since 2013. Database search results were exported to Rayyan software, and two independent reviewers screened all identified sources, prior to extraction of key data. RESULTS: Twenty-nine studies and one thesis from 138 screened sources were eligible for inclusion. Frequent study types were treatment interventions and cross-sectional studies, with populations including individuals with ARFID, ED service populations, parents/caregivers, health professionals, and non-clinical populations. ARFID presents in a range of settings and is associated with poorer quality of life and significant functional impairment. Assessment of ARFID was varied, and no specific treatment guidelines for ARFID have been written as yet. CONCLUSION: This review calls for more accurate prevalence estimates of ARFID in children and larger-scale studies in all ages using validated measures. It emphasizes the need for education and training of healthcare professionals, and interdisciplinary collaboration. Established interventions like behaviour analytics should be considered, and more comprehensive research is needed on interventions for ARFID, including controlled trials and longitudinal studies. Urgent research is needed to improve outcomes for those affected by ARFID.

This scoping review examines all published literature on Avoidant/Restrictive Food Intake Disorder (ARFID) in the Australasian region since the disorder was first recognized in 2013. ARFID is an eating disorder marked by restrictive or avoidant eating behaviour unrelated to weight or body image concerns. The disorder can have serious psychosocial impacts and detrimental health consequences when nutritional and energy needs are persistently unmet. The review identifies the methods, participants, and key findings of the studies on ARFID and suggests targeted and actionable research goals for researchers and funders. It calls for more accurate information on how common ARFID is in children, for larger-scale studies using validated measures, and emphasizes the need for education and training of healthcare professionals, and a collaborative approach to treatment. We also underscore the need for longitudinal studies to better understand the landscape of ARFID in Australasia.

Eating disorders, disordered eating, and body image research in New Zealand: a scoping review.

BACKGROUND: The prevention and treatment of eating disorders relies on an extensive body of research that includes various foci and methodologies. This scoping review identified relevant studies of eating disorders, body image, and disordered eating with New Zealand samples; charted the methodologies, sample characteristics, and findings reported; and identified several gaps that should be addressed by further research. METHODS: Using scoping review methodology, two databases were searched for studies examining eating disorders, disordered eating, or body image with New Zealand samples. Snowball methods were further used to identify additional relevant articles that did not appear in initial searches. Two independent reviewers screened the titles and abstracts of 473 records. Full text assessment of the remaining 251 records resulted in 148 peer-reviewed articles being identified as eligible for the final review. A search of institutional databases yielded 106 Masters and Doctoral theses for assessment, with a total of 47 theses being identified as eligible for the final review. The included studies were classified by methodology, and the extracted information included the study foci, data collected, sample size, demographic information, and key findings. RESULTS: The eligible studies examined a variety of eating disorder categories including binge-eating disorder, bulimia nervosa, and anorexia nervosa, in addition to disordered eating behaviours and body image in nonclinical or community samples. Methodologies included treatment trials, secondary analysis of existing datasets, non-treatment experimental interventions, cross-sectional observation, case-control studies, qualitative and mixed-methods studies, and case studies or series. Across all of the studies, questionnaire and interview data were most commonly utilised. A wide range of sample sizes were evident, and studies often reported all-female or mostly-female participants, with minimal inclusion of males and gender minorities. There was also an underrepresentation of minority ethnicities in many studies, highlighting the need for future research to increase diversity within samples. CONCLUSION: This study provides a comprehensive and detailed overview of research into eating disorders and body image in New Zealand, while highlighting important considerations for both local and international research.

Feasibility and performance of continuous glucose monitoring in hyperglycemia after lung transplantation.

Background: Post-Transplant Diabetes Mellitus (PTDM) affects 20%-40% of lung transplant recipients within five years, impacting rejection, infection, cardiovascular events, and mortality. Continuous glucose monitoring (CGM) is used in diabetes but not well-studied in PTDM. Objective: This study assessed CGM performance in detecting hypoglycemia and hyperglycemia post-lung transplantation, compared to self-monitoring blood glucose. Methods: A prospective pilot study included 15 lung transplant patients (mean age 58.6 years; 53.3% men; 73.3% with pre-transplantation diabetes) managing hyperglycemia with insulin. Patients used a blinded CGM and self-monitored glucose for ten days. Data were categorized (% time in range, % high, % very high, % low, % very low) and compared using paired t-tests. Results: CGM showed superior hyperglycemia detection. Mean differences for "% very high", "% high", and "% high and % very high" were 7.12 (95% CI, 1.8-12.4), 11.1 (95% CI, 3.5-18.8), and 18.3 (95% CI: 7.37-29.24), respectively. No significant difference was found for "% low and % very low". All patients reported a positive CGM experience. Conclusion: CGM use post-lung transplantation seems feasible and offers advantages in detecting hyperglycemia and in optimizing glucose management. Study limitations include a small sample size, requiring larger studies to assess glycemic control, hypoglycemia detection, and transplant outcomes.

Visually evoked pain and its extinction using virtual reality in a patient with complex regional pain syndrome type II.

ABSTRACT: In this case report, we used virtual reality (VR) to explore pain evoked by only the appearance of being touched (rather than actually being touched) in a person with complex regional pain syndrome type II. Furthermore, we explored the degree to which this visually evoked pain could be extinguished by applying exposure principles in VR. In stage 1, we identified 4 specific scenarios where pain was triggered by visually simulated touch (without physical stimulation) and used these scenarios to quantify baseline sensitivity to visuotactile stimulation. In stage 2, the patient undertook a 12-week virtual exposure program, and the visual triggers were reassessed 3 weeks after the commencement and immediately upon completion of the program. At baseline, severe pain and a profound cold sensation were immediately and consistently evoked in concert with visually simulated touch. At 12-week follow-up, only one of the initially provocative visual stimuli triggered pain and only after 60 seconds of repeated stimulation. Unfortunately, the transfer of desensitisation from VR to the real world was limited. This case report describes the phenomena of visually evoked pain. Moreover, it describes the near complete extinguishing of visually evoked pain through virtual graded exposure. How improvements gained in VR might be better transferred to real-word improvements merits further investigation.

How genetic analysis may contribute to the understanding of avoidant/restrictive food intake disorder (ARFID).

Avoidant/restrictive food intake disorder (ARFID) was introduced in the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5). Unlike anorexia nervosa, ARFID is characterised by avoidant or restricted food intake that is not driven by weight or body shape-related concerns. As with other eating disorders, it is expected that ARFID will have a significant genetic risk component; however, sufficiently large-scale genetic investigations are yet to be performed in this group of patients. This narrative review considers the current literature on the diagnosis, presentation, and course of ARFID, including evidence for different presentations, and identifies fundamental questions about how ARFID might fit into the fluid landscape of other eating and mental disorders. In the absence of large ARFID GWAS, we consider genetic research on related conditions to point to possible features or mechanisms relevant to future ARFID investigations, and discuss the theoretical and clinical implications an ARFID GWAS. An argument for a collaborative approach to recruit ARFID participants for genome-wide association study is presented, as understanding the underlying genomic architecture of ARFID will be a key step in clarifying the biological mechanisms involved, and the development of interventions and treatments for this serious, and often debilitating disorder.

Avoidant/restrictive food intake disorder (ARFID) can be a severe and debilitating eating disorder, where individuals limit food intake for reasons unrelated to the weight and body image concerns observed in anorexia nervosa. Although genetics is known to play a significant role in other eating disorders such as anorexia nervosa and bulimia nervosa, only one study has investigated the genetic background of ARFID, and this was limited to those with ARFID within an autism cohort. This narrative review describes current knowledge about the clinical characteristics of ARFID and highlights current knowledge gaps, setting the scene for a discussion of how existing research findings about the genetics of related conditions might help guide genetic research about ARFID. A large genome-wide association study (GWAS) is recommended as the first step to addressing some of the fundamental biological questions around ARFID and will lay the framework for development of interventions and treatments that target ARFID at a biological level.

Medial and Lateral Patellar Instability Leading to Medial Patellofemoral Ligament and Lateral Retinaculum Reconstruction: A Case Report.

CASE: Combined medial and lateral patellar instability is exceptionally rare with only 3 reported cases to date. Here, we present the case of a 37-year-old White woman with multiple recurrent medial and lateral patellar instability. After failure of conservative care with bracing and therapy, she underwent surgical stabilization with medial and lateral allograft reconstruction. CONCLUSION: This case provides an example of the condition and successful surgical follow-up.

Improvement in pain interference and function by an allied health pain management program: Results of a randomized trial.

BACKGROUND: Chronic pain is a significant health problem worldwide and requires a biopsychosocial treatment approach. Access to traditional pain medicine specialist services is limited and innovative treatment models are required to support patients in tertiary care. The study evaluated the clinical effectiveness and safety of the Treatment Access Pathway (TAP), an allied health expanded scope model of care which included innovative group assessment and collaboration with patients to create individualized treatment plans. METHODS: One hundred and eighty-one patients referred to a tertiary level chronic pain service were randomly allocated to either the TAP or the waitlist study groups. Primary (pain interference) and secondary outcome measures were collected at recruitment and again at 6 months. Per-protocol analyses were utilized due to high participant attrition (46% across groups). RESULTS: The TAP group reported greater reductions in pain interference at 6 months than waitlist group (0.9, 95% CI: 0.2-1.6), with more than half of the TAP group (52%) reporting clinically significant improvement. In addition, statistically significant differences between the TAP and waitlist groups were observed for objective measurements of walking endurance (5.4 m, 95% CI: 1.7-9.1); and global impressions of change (1.4 unit decrease, 95% CI: 1-1.9). Nil adverse events were recorded. CONCLUSIONS: The study suggests that an expanded scope allied health model of care prioritizing patient choice and group-based interventions provides modest benefits for tertiary-referral chronic pain patients. TAP warrants further investigation as a potentially viable alternative for tertiary healthcare where traditional pain services are unavailable or have long waiting lists. SIGNIFICANCE: The study tests effectiveness and safety of an expanded scope allied health-led chronic pain program. Despite a high attrition rate, the study showed reduced pain interference and increased physical function in those who completed the protocol. The results are promising and support introduction of this model as an adjunct to existing traditional chronic pain models of care, with a particular focus on improving participant retention in the program. Additionally, the model of care can be used as a standalone chronic pain model of care where no other pain management resources are available. The study was registered on ANZCTR (Trial ID: ACTRN12617001284358).

Molecular High-Grade B-Cell Lymphoma: Defining a Poor-Risk Group That Requires Different Approaches to Therapy.

PURPOSE: Biologic heterogeneity is a feature of diffuse large B-cell lymphoma (DLBCL), and the existence of a subgroup with poor prognosis and phenotypic proximity to Burkitt lymphoma is well known. Conventional cytogenetics identifies some patients with rearrangements of MYC and BCL2 and/or BCL6 (double-hit lymphomas) who are increasingly treated with more intensive chemotherapy, but a more biologically coherent and clinically useful definition of this group is required. PATIENTS AND METHODS: We defined a molecular high-grade (MHG) group by applying a gene expression-based classifier to 928 patients with DLBCL from a clinical trial that investigated the addition of bortezomib to standard rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) therapy. The prognostic significance of MHG was compared with existing biomarkers. We performed targeted sequencing of 70 genes in 400 patients and explored molecular pathology using gene expression signature databases. Findings were validated in an independent data set. RESULTS: The MHG group comprised 83 patients (9%), with 75 in the cell-of-origin germinal center B-cell-like group. MYC rearranged and double-hit groups were strongly over-represented in MHG but comprised only one half of the total. Gene expression analysis revealed a proliferative phenotype with a relationship to centroblasts. Progression-free survival rate at 36 months after R-CHOP in the MHG group was 37% (95% CI, 24% to 55%) compared with 72% (95% CI, 68% to 77%) for others, and an analysis of treatment effects suggested a possible positive effect of bortezomib. Double-hit lymphomas lacking the MHG signature showed no evidence of worse outcome than other germinal center B-cell-like cases. CONCLUSION: MHG defines a biologically coherent high-grade B-cell lymphoma group with distinct molecular features and clinical outcomes that effectively doubles the size of the poor-prognosis, double-hit group. Patients with MHG may benefit from intensified chemotherapy or novel targeted therapies.