Developmental trajectories and cooperating genomic events define molecular subtypes of BCR::ABL1-positive ALL.

ABSTRACT: Distinct diagnostic entities within BCR::ABL1-positive acute lymphoblastic leukemia (ALL) are currently defined by the International Consensus Classification of myeloid neoplasms and acute leukemias (ICC): "lymphoid only", with BCR::ABL1 observed exclusively in lymphatic precursors, vs "multilineage", where BCR::ABL1 is also present in other hematopoietic lineages. Here, we analyzed transcriptomes of 327 BCR::ABL1-positive patients with ALL (age, 2-84 years; median, 46 years) and identified 2 main gene expression clusters reproducible across 4 independent patient cohorts. Fluorescence in situ hybridization analysis of fluorescence-activated cell-sorted hematopoietic compartments showed distinct BCR::ABL1 involvement in myeloid cells for these clusters (n = 18/18 vs n = 3/16 patients; P < .001), indicating that a multilineage or lymphoid BCR::ABL1 subtype can be inferred from gene expression. Further subclusters grouped samples according to cooperating genomic events (multilineage: HBS1L deletion or monosomy 7; lymphoid: IKZF1-/- or CDKN2A/PAX5 deletions/hyperdiploidy). A novel HSB1L transcript was highly specific for BCR::ABL1 multilineage cases independent of HBS1L genomic aberrations. Treatment on current German Multicenter Study Group for Adult ALL (GMALL) protocols resulted in comparable disease-free survival (DFS) for multilineage vs lymphoid cluster patients (3-year DFS: 70% vs 61%; P = .530; n = 91). However, the IKZF1-/- enriched lymphoid subcluster was associated with inferior DFS, whereas hyperdiploid cases showed a superior outcome. Thus, gene expression clusters define underlying developmental trajectories and distinct patterns of cooperating events in BCR::ABL1-positive ALL with prognostic relevance.

Tele-Neuropsychology: From Science to Policy to Practice.

OBJECTIVE: The primary aim of this paper is to accelerate the number of randomized experimental studies of the reliability and validity in-home tele-neuropsychological testing (tele-np-t). METHOD: We conducted a critical review of the tele-neuropsychology literature. We discuss this research in the context of the United States' public and private healthcare payer systems, including the Centers for Medicare & Medicaid Services (CMS) and Current Procedural Terminology (CPT) coding system's telehealth lists, and existing disparities in healthcare access. RESULTS: The number of tele-np publications has been stagnant since the onset of the COVID-19 pandemic. There are less published experimental studies of tele-neuropsychology (tele-np), and particularly in-home tele-np-t, than other tele-np publications. There is strong foundational evidence of the acceptability, feasibility, and reliability of tele-np-t, but relatively few studies of the reliability and validity of in-home tele-np-t using randomization methodology. CONCLUSIONS: More studies of the reliability and validity of in-home tele-np-t using randomization methodology are necessary to support inclusion of tele-np-t codes on the CMS and CPT telehealth lists, and subsequently, the integration and delivery of in-home tele-np-t services across providers and institutions. These actions are needed to maintain equitable reimbursement of in-home tele-np-t services and address the widespread disparities in healthcare access.

Translocations activating IRF4 identify a subtype of germinal center-derived B-cell lymphoma affecting predominantly children and young adults.

The prognosis of germinal center-derived B-cell (GCB) lymphomas, including follicular lymphoma and diffuse large-B-cell lymphoma (DLBCL), strongly depends on age. Children have a more favorable outcome than adults. It is not known whether this is because of differences in host characteristics, treatment protocols, or tumor biology, including the presence of chromosomal alterations. By screening for novel IGH translocation partners in pediatric and adult lymphomas, we identified chromosomal translocations juxtaposing the IRF4 oncogene next to one of the immunoglobulin (IG) loci as a novel recurrent aberration in mature B-cell lymphoma. FISH revealed 20 of 427 lymphomas to carry an IG/IRF4-fusion. Those were predominantly GCB-type DLBCL or follicular lymphoma grade 3, shared strong expression of IRF4/MUM1 and BCL6, and lacked PRDM1/BLIMP1 expression and t(14;18)/BCL2 breaks. BCL6 aberrations were common. The gene expression profile of IG/IRF4-positive lymphomas differed from other subtypes of DLBCL. A classifier for IG/IRF4 positivity containing 27 genes allowed accurate prediction. IG/IRF4 positivity was associated with young age and a favorable outcome. Our results suggest IRF4 translocations to be primary alterations in a molecularly defined subset of GCB-derived lymphomas. The probability for this subtype of lymphoma significantly decreases with age, suggesting that diversity in tumor biology might contribute to the age-dependent differences in prognosis of lymphoma.

Cognitive functioning in pediatric transverse myelitis.

BACKGROUND: Transverse myelitis (TM) is an inflammatory disease of the spinal cord. In pediatric TM patients, cognitive and psychological problems have been described only anecdotally. OBJECTIVES: Study aims include describing cognitive dysfunction among a cohort of pediatric TM patients as well as qualitatively exploring the impact of depression, medication, and fatigue on cognitive functioning. METHODS: Twenty-four consecutive TM patients referred to a pediatric demyelinating diseases clinic completed neuropsychological screening. Means, standard deviations (SD), and percentages of patients performing at or below 1.0, 1.5, and 2.0 SD from the mean on tests administered are presented. RESULTS: Means were generally average across domains; however, scores ranged widely across subjects within each domain. The highest rate of deficits was observed in fine-motor speed/dexterity. Slightly higher frequencies of impairment were observed in attention and memory as compared to processing speed and verbal fluency. Results did not suggest a clear association between cognitive problems and depression or medication use but did suggest that fatigue may impact cognitive functioning. CONCLUSIONS: This study is the first to document cognitive deficits in pediatric TM and raises questions regarding our understanding of the central nervous system (CNS) injury associated with TM. Findings warrant further exploration of neuropsychological outcomes in TM to inform appropriate intervention.

The CBFA2T3/ACSF3 locus is recurrently involved in IGH chromosomal translocation t(14;16)(q32;q24) in pediatric B-cell lymphoma with germinal center phenotype.

Translocations involving immunoglobulin (IG) loci are the hallmarks of several subtypes of B-cell lymphoma. Common to these translocations is that cellular proto-oncogenes come under the influence of IG regulatory elements leading to deregulated expression. In case of a breakpoint in the IGH switch region, oncogene activation can take place on both derivative chromosomes, which means that in principle one translocation can result in concurrent activation of two genes. By fluorescence in situ hybridization (FISH), we identified a case of leukemic B-cell lymphoma in a child with an IGH break and unknown partner. Subsequent long-distance inverse PCR revealed fusion of IGH Sl in 14q32 and the 50 region of CBFA2T3 in 16q24.3, suggesting presence of the t(14;16)(q32;q24.3). Candidate oncogenes targeted through this translocation are CBFA2T3 and ACSF3, which could be activated on der(16) and der(14), respectively. FISH screening of a population-based cohort of B-cell lymphomas from a prospective trial for the treatment of lymphoma in childhood (BFM-NHL) identified additionally a follicular lymphoma Grade 3/diffuse large B-cell lymphoma with IGH-CBFA2T3/ACSF3 juxtaposition. Both lymphomas shared expression of CD10 and CD20 in the absence of TdT, suggesting a germinal center (GC) B-cell origin. Our data indicate that the CBFA2T3/ACSF3 locus is a novel recurrent oncogenic target of IGH translocations, which might contribute to the pathogenesis of pediatric GC-derived B-cell lymphoma.

Double heterozygosity for mutations in BRCA1 and BRCA2 in German breast cancer patients: implications on test strategies and clinical management.

Double heterozygosity for disease-causing BRCA1 and BRCA2 mutations is a very rare condition in most populations. Here we describe genetic and clinical data of eight female double heterozygotes (DH) for BRCA1 and BRCA2 mutations found in a cohort of 8162 German breast/ovarian cancer families and compare it with the data of their single heterozygous relatives and of the index patients of the German Consortium for Hereditary Breast and Ovarian Cancer. Furthermore, we analyze the phenotypic features of these patients with respect to age at onset of first cancer, first breast/ovarian cancer and the number of disease manifestations and compare them to that of published Caucasian female DHs and their single heterozygous female relatives. German DHs were not significantly younger at diagnosis of first breast cancer than the single heterozygous index patients of the German Consortium. However, if the data of our study were pooled with that of the literature, DHs were substantially younger at onset of first cancer (mean age 40.4 years, 95 % CI = 36.6-44.1) than their single heterozygous female relatives (mean age 51.9 years, 95 % CI = 46.8-57.0). The two groups also differed concerning the onset of first breast cancer (mean age 40.6 years, 95 % CI = 36.6-44.5 vs. 52.6, 95 % CI = 47.5-57.6). In addition, DHs had a more severe disease than their female relatives carrying a single BRCA mutation (1.4 vs. 0.6 manifestations per person). In contrast to Ashkenazi Jewish females, Caucasian DH females might develop breast cancer at an earlier age and have a more severe disease than single heterozygous BRCA mutation carriers. Therefore, DHs may benefit from more intensive surveillance programs/follow-up care and prophylactic surgery.

Deregulation of the telomerase reverse transcriptase (TERT) gene by chromosomal translocations in B-cell malignancies.

Sequence variants at the TERT-CLPTM1L locus in chromosome 5p have been recently associated with disposition for various cancers. Here we show that this locus including the gene encoding the telomerase reverse-transcriptase TERT at 5p13.33 is rarely but recurrently targeted by somatic chromosomal translocations to IGH and non-IG loci in B-cell neoplasms, including acute lymphoblastic leukemia, chronic lymphocytic leukemia, mantle cell lymphoma and splenic marginal zone lymphoma. In addition, cases with genomic amplification of TERT locus were identified. Tumors bearing chromosomal aberrations involving TERT showed higher TERT transcriptional expression and increased telomerase activity. These data suggest that deregulation of TERT gene by chromosomal abnormalities leading to increased telomerase activity might contribute to B-cell lymphomagenesis.

Deregulated expression of cytokine receptor gene, CRLF2, is involved in lymphoid transformation in B-cell precursor acute lymphoblastic leukemia.

We report 2 novel, cryptic chromosomal abnormalities in precursor B-cell acute lymphoblastic leukemia (BCP-ALL): a translocation, either t(X;14)(p22;q32) or t(Y;14)(p11;q32), in 33 patients and an interstitial deletion, either del(X)(p22.33p22.33) or del(Y)(p11.32p11.32), in 64 patients, involving the pseudoautosomal region (PAR1) of the sex chromosomes. The incidence of these abnormalities was 5% in childhood ALL (0.8% with the translocation, 4.2% with the deletion). Patients with the translocation were older (median age, 16 years), whereas the patients with the deletion were younger (median age, 4 years). The 2 abnormalities result in deregulated expression of the cytokine receptor, cytokine receptor-like factor 2, CRLF2 (also known as thymic stromal-derived lymphopoietin receptor, TSLPR). Overexpression of CRLF2 was associated with activation of the JAK-STAT pathway in cell lines and transduced primary B-cell progenitors, sustaining their proliferation and indicating a causal role of CRLF2 overexpression in lymphoid transformation. In Down syndrome (DS) ALL and 2 non-DS BCP-ALL cell lines, CRLF2 deregulation was associated with mutations of the JAK2 pseudokinase domain, suggesting oncogenic cooperation as well as highlighting a link between non-DS ALL and JAK2 mutations.

Predictors of Cognitive Performance Among Infants Treated for Brain Tumors: Findings From a Multisite, Prospective, Longitudinal Trial.

PURPOSE: Infants treated for CNS malignancies experience a significantly poorer response to treatment and are particularly at risk for neuropsychological deficits. The literature is limited and inconsistent regarding cognitive outcomes among this group. We investigated predictors of cognitive outcomes in children treated for brain tumors during infancy as part of a large, prospective, multisite, longitudinal trial. PATIENTS AND METHODS: One hundred thirty-nine infants with a newly diagnosed CNS tumor were treated with chemotherapy, with or without focal proton or photon radiation therapy (RT). Cognitive assessments were conducted at baseline, 6 months, 1 year, and then annually for 5 years. The median length of follow-up was 816 days (26.8 months). Neurocognitive testing included assessment of intellectual functioning (intellectual quotient [IQ]), parent ratings of executive functioning and emotional and behavioral functioning, and socioeconomic status. RESULTS: At baseline, IQ, parent-reported working memory, and parent-reported adaptive functioning were worse than normative expectations. Baseline cognitive difficulties were associated with younger age at diagnosis and lower socioeconomic status. Linear mixed models did not demonstrate a decline in IQ over time. There were increased parent-reported attention and executive problems over time. Increased concerns were related to supratentorial tumor location and CSF diversion. There were no differences in cognitive outcomes based on treatment exposure (chemotherapy-only v chemotherapy with RT and proton v photon focal RT). CONCLUSION: Even before adjuvant therapy, young children with brain tumors experience cognitive difficulties that can affect quality of life. Changes in cognitive functioning over time were dependent on tumor location and surgical factors rather than adjuvant therapy. These findings may serve to guide treatment planning and indicate targets for cognitive monitoring and intervention.

Genomic insights into the pathogenesis of Epstein-Barr virus-associated diffuse large B-cell lymphoma by whole-genome and targeted amplicon sequencing.

Epstein-Barr virus (EBV)-associated diffuse large B-cell lymphoma not otherwise specified (DLBCL NOS) constitute a distinct clinicopathological entity in the current World Health Organization (WHO) classification. However, its genomic features remain sparsely characterized. Here, we combine whole-genome sequencing (WGS), targeted amplicon sequencing (tNGS), and fluorescence in situ hybridization (FISH) from 47 EBV + DLBCL (NOS) cases to delineate the genomic landscape of this rare disease. Integrated WGS and tNGS analysis clearly distinguished this tumor type from EBV-negative DLBCL due to frequent mutations in ARID1A (45%), KMT2A/KMT2D (32/30%), ANKRD11 (32%), or NOTCH2 (32%). WGS uncovered structural aberrations including 6q deletions (5/8 patients), which were subsequently validated by FISH (14/32 cases). Expanding on previous reports, we identified recurrent alterations in CCR6 (15%), DAPK1 (15%), TNFRSF21 (13%), CCR7 (11%), and YY1 (6%). Lastly, functional annotation of the mutational landscape by sequential gene set enrichment and network propagation predicted an effect on the nuclear factor κB (NFκB) pathway (CSNK2A2, CARD10), IL6/JAK/STAT (SOCS1/3, STAT3), and WNT signaling (FRAT1, SFRP5) alongside aberrations in immunological processes, such as interferon response. This first comprehensive description of EBV + DLBCL (NOS) tumors substantiates the evidence of its pathobiological independence and helps stratify the molecular taxonomy of aggressive lymphomas in the effort for future therapeutic strategies.

The BCR-ABL1 kinase bypasses selection for the expression of a pre-B cell receptor in pre-B acute lymphoblastic leukemia cells.

The BCR-ABL1 kinase expressed in acute lymphoblastic leukemia (ALL) drives malignant transformation of human pre-B cells. Comparing genome-wide gene expression profiles of BCR-ABL1+ pre-B ALL and normal bone marrow pre-B cells by serial analysis of gene expression, many genes involved in pre-B cell receptor signaling are silenced in the leukemia cells. Although normal pre-B cells are selected for the expression of a functional pre-B cell receptor, BCR-ABL1+ ALL cells mostly do not harbor a productively rearranged IGH allele. In these cases, we identified traces of secondary VH gene rearrangements, which may have rendered an initially productive VH region gene nonfunctional. Even BCR-ABL1+ ALL cells harboring a functional VH region gene are unresponsive to pre-B cell receptor engagement and exhibit autonomous oscillatory Ca2+ signaling activity. Conversely, leukemia subclones surviving inhibition of BCR-ABL1 by STI571 restore responsiveness to antigen receptor engagement and differentiate into immature B cells expressing immunoglobulin light chains. BCR-ABL1 kinase activity is linked to defective pre-B cell receptor signaling and the expression of a truncated isoform of the pre-B cell receptor-associated linker molecule SLP65. Also in primary leukemia cells, truncated SLP65 is expressed before but not after treatment of the patients with STI571. We conclude that inhibition of BCR-ABL1 reconstitutes selection for leukemia cells expressing a functional (pre-) B cell receptor.

Molecular characterization of a novel chromosomal translocation t(12;14)(q23;q11.2) in T-lymphoblastic lymphoma between the T-cell receptor delta-deleting elements (TRDREC and TRAJ61) and the hypothetical gene C12orf42.

Chromosomal aberrations have diagnostic, prognostic, and therapeutic relevance in hematologic malignancies. By combining fine-tiling comparative genomic hybridization (FT-CGH) and ligation-mediated PCR (LM-PCR), we established a fast, robust approach to precisely characterize chromosomal breakpoints. Using this approach, we clarified at the molecular level novel chromosomal translocation t(12;14)(q23;q11.2) in T-lymphoblastic lymphoma. The translocation occurred during the deletional rearrangement of the T-cell receptor delta gene (TRD), which is a pivotal step in T cell differentiation toward the alpha/beta vs. the gamma/delta lineage. We found that this rearrangement disrupted the hypothetical gene C12orf42 and brought the Achaete-scute complex homolog 1 gene into proximity of the TRA enhancer, which encodes a member of the basic helix-loop-helix family of transcription factors and is overexpressed in thyroid and lung cancers.

A survey of international clinical teleneuropsychology service provision prior to and in the context of COVID-19.

Objective: Despite expansion of telecommunication strategies across health services and data supporting feasibility of videoconference-based neuropsychological assessment, relatively little is known about teleneuropsychology (TeleNP) use in practice. The current COVID-19 pandemic provides an opportunity for greater use of TeleNP and understanding of neuropsychologists' experience with this unique assessment medium.Methods: During the course of a no-cost global webinar related to practical/ethical considerations of TeleNP practice, attendees were invited to engage in a 26-question survey about their TeleNP use and related COVID-19 concerns. TeleNP practices before the COVID-19 pandemic and early on during the global outbreak were queried among survey participants, along with examination of TeleNP intentions following COVID-19.Results: Multiple countries were represented across five continents, with two-thirds of respondents being from the United States. Approximately one-fourth of respondents reported using TeleNP for clinical interview, feedback, and intervention prior to the onset of the COVID-19 pandemic, and approximately one-tenth of individuals used TeleNP for testadministration. Increased use of TeleNP for clinical interview, feedback, and intervention was reported within the first few weeks of the global COVID-19 outbreak, though the use of TeleNP for testing remained relatively unchanged. Most respondents indicated an intention for future use of TeleNP.Conclusions: Our findings suggest the use of TeleNP is increasing, although use of remote TeleNP testing is still developing. Findings also illustrate increasing use of TeleNP in the context of the COVID-19 pandemic and encourage follow-up investigation in future studies to understand the changing practices and rates of TeleNP provision over time.

Home-Based Pediatric Teleneuropsychology: A validation study.

OBJECTIVE: To evaluate home-based teleneuropsychology in a pediatric cohort to determine if assessment via in-person and home-based videoconference yield similar results. The second objective was to determine the level of satisfaction with videoconference-based assessment among participants and caregivers. METHOD: Fifty-eight participants, aged 6-20 years, were recruited through specialty programs for pediatric demyelinating disorders. Each participant was administered the same brief neuropsychological battery of common measures twice, once during an in-person session and once during a remote home-based videoconference session. Order of sessions was counterbalanced and time between assessments ranged from 1 to 50 days. It was hypothesized that results obtained through in-person vs. remote videoconference sessions would not be significantly different and that most participants and caregivers would rate the experience with teleneuropsychology as satisfactory. RESULTS: Mann-Whitney U tests showed no significant differences in results obtained in the in-person first vs. remote videoconference first sessions or the change in performance across sessions. Satisfaction ratings by participants and caregivers were largely favorable for the use of the videoconference testing format. CONCLUSIONS: The current study is the first to validate home-based teleneuropsychology and is the first to validate teleneuropsychological assessment in a pediatric sample. Future studies should replicate these findings as well as expand on sample size, diversity of populations evaluated, and the assessment tools administered. Careful consideration of ethical and practical factors should be given before providing pediatric teleneuropsychology services.

Inter Organizational Practice Committee Recommendations/Guidance for Teleneuropsychology in Response to the COVID-19 Pandemic†.

OBJECTIVE: The Inter Organizational Practice Committee convened a workgroup to provide rapid guidance about teleneuropsychology (TeleNP) in response to the COVID-19 pandemic. METHOD: A collaborative panel of experts from major professional organizations developed provisional guidance for neuropsychological practice during the pandemic. The stakeholders included the American Academy of Clinical Neuropsychology/American Board of Clinical Neuropsychology, the National Academy of Neuropsychology, Division 40 of the American Psychological Association, the American Board of Professional Neuropsychology, and the American Psychological Association Services, Inc. The group reviewed literature; collated federal, regional, and state regulations and information from insurers; and surveyed practitioners to identify best practices. RESULTS: Literature indicates that TeleNP may offer reliable and valid assessments, but clinicians need to consider limitations, develop new informed consent procedures, report modifications of standard procedures, and state limitations to diagnostic conclusions and recommendations. Specific limitations affect TeleNP assessments of older adults, younger children, individuals with limited access to technology, and individuals with other individual, cultural, and/or linguistic differences. TeleNP may be contraindicated or infeasible given specific patient characteristics, circumstances, and referral questions. Considerations for billing TeleNP services are offered with reservations that clinicians must verify procedures independently. Guidance about technical issues and "tips" for TeleNP procedures are provided. CONCLUSION: This document provides provisional guidance with links to resources and established guidelines for telepsychology. Specific recommendations extend these practices to TeleNP. These recommendations may be revised as circumstances evolve, with updates posted continuously at IOPC.online.

InterOrganizational practice committee recommendations/guidance for teleneuropsychology (TeleNP) in response to the COVID-19 pandemic.

Objective: The Inter Organizational Practice Committee (IOPC) convened a workgroup to provide rapid guidance about teleneuropsychology (TeleNP) in response to the COVID-19 pandemic.Method: A collaborative panel of experts from major professional organizations developed provisional guidance for neuropsychological practice during the pandemic. The stakeholders included the American Academy of Clinical Neuropsychology/American Board of Clinical Neuropsychology, the National Academy of Neuropsychology, Division 40 of the American Psychological Association, the American Board of Professional Neuropsychology, and the American Psychological Association Services, Inc. The group reviewed literature, collated federal, regional and state regulations and information from insurers, and surveyed practitioners to identify best practices.Results: Literature indicates that TeleNP may offer reliable and valid assessments, but clinicians need to consider limitations, develop new informed consent procedures, report modifications of standard procedures, and state limitations to diagnostic conclusions and recommendations. Specific limitations affect TeleNP assessments of older adults, younger children, individuals with limited access to technology, and individuals with other individual, cultural, and/or linguistic differences. TeleNP may be contraindicated or infeasible given specific patient characteristics, circumstances, and referral questions. Considerations for billing TeleNP services are offered with reservations that clinicians must verify procedures independently. Guidance about technical issues and "tips" for TeleNP procedures are provided.Conclusion: This document provides provisional guidance with links to resources and established guidelines for telepsychology. Specific recommendations extend these practices to TeleNP. These recommendations may be revised as circumstances evolve, with updates posted continuously at OPC.online.

GeneChip analyses point to novel pathogenetic mechanisms in mantle cell lymphoma.

The translocation t(11;14)(q13;q32) is the genetic hallmark of mantle cell lymphoma (MCL) but is not sufficient for inducing lymphomagenesis. Here we performed genome-wide 100K GeneChip Mapping in 26 t(11;14)-positive MCL and six MCL cell lines. Partial uniparental disomy (pUPD) was shown to be a recurrent chromosomal event not only in MCL cell lines but also in primary MCL. Remarkably, pUPD affected recurrent targets of deletion like 11q, 13q and 17p. Moreover, we identified 12 novel regions of recurrent gain and loss as well as 12 high-level amplifications and eight homozygously deleted regions hitherto undescribed in MCL. Interestingly, GeneChip analyses identified different genes, encoding proteins involved in microtubule dynamics, such as MAP2, MAP6 and TP53, as targets for chromosomal aberration in MCL. Further investigation, including mutation analyses, fluorescence in situ hybridisation as well as epigenetic and expression studies, revealed additional aberrations frequently affecting these genes. In total, 19 of 20 MCL cases, which were subjected to genetic and epigenetic analyses, and five of six MCL cell lines harboured at least one aberration in MAP2, MAP6 or TP53. These findings provide evidence that alterations of microtubule dynamics might be one of the critical events in MCL lymphomagenesis contributing to chromosomal instability.

A biologic definition of Burkitt's lymphoma from transcriptional and genomic profiling.

BACKGROUND: The distinction between Burkitt's lymphoma and diffuse large-B-cell lymphoma is unclear. We used transcriptional and genomic profiling to define Burkitt's lymphoma more precisely and to distinguish subgroups in other types of mature aggressive B-cell lymphomas. METHODS: We performed gene-expression profiling using Affymetrix U133A GeneChips with RNA from 220 mature aggressive B-cell lymphomas, including a core group of 8 Burkitt's lymphomas that met all World Health Organization (WHO) criteria. A molecular signature for Burkitt's lymphoma was generated, and chromosomal abnormalities were detected with interphase fluorescence in situ hybridization and array-based comparative genomic hybridization. RESULTS: We used the molecular signature for Burkitt's lymphoma to identify 44 cases: 11 had the morphologic features of diffuse large-B-cell lymphomas, 4 were unclassifiable mature aggressive B-cell lymphomas, and 29 had a classic or atypical Burkitt's morphologic appearance. Also, five did not have a detectable IG-myc Burkitt's translocation, whereas the others contained an IG-myc fusion, mostly in simple karyotypes. Of the 176 lymphomas without the molecular signature for Burkitt's lymphoma, 155 were diffuse large-B-cell lymphomas. Of these 155 cases, 21 percent had a chromosomal breakpoint at the myc locus associated with complex chromosomal changes and an unfavorable clinical course. CONCLUSIONS: Our molecular definition of Burkitt's lymphoma clarifies and extends the spectrum of the WHO criteria for Burkitt's lymphoma. In mature aggressive B-cell lymphomas without a gene signature for Burkitt's lymphoma, chromosomal breakpoints at the myc locus were associated with an adverse clinical outcome.

Identification of the gene encoding cyclin E1 (CCNE1) as a novel IGH translocation partner in t(14;19)(q32;q12) in diffuse large B-cell lymphoma.

In a subset of B-cell malignancies, the genes encoding members of the cyclin D familiy are juxtaposed to immunoglobulin loci through recurrent chromosomal translocations. Here, we identified the gene encoding cyclin E1 as novel translocation partner of the immunoglobulin heavy chain (IGH) locus involved in a t(14;19)(q32;q12) in a case of t(8;14)(q24;q32) IGH-MYC-positive leukemic diffuse large B-cell lymphoma. The translocation breakpoints were cloned and mapped to the switch region Salpha1 of IGH in 14q32 and approximately 60kb centromeric to CCNE1 in 19q12. Immunohistochemical analysis revealed overexpression of the cyclin E1 protein in this case, which to a comparable extent was observed in 3/41 independent DLBCL. These data indicate that cyclin E1 may act as a novel oncogene in B-cell lymphomagenesis.

New onset transverse myelitis diagnostic accuracy and patient experiences.

IMPORTANCE: Patients afflicted with rare diseases often have a delay in diagnosis and treatment. Understanding the prevalence and impact of delayed diagnosis in transverse myelitis could trigger directed educational initiatives to increase clinician awareness and improve care. OBJECTIVE: To determine if symptoms at onset or care provider initially approached was associated with time to diagnosis, treatment or outcome in patients with transverse myelitis. DESIGN: This was an online patient and caregiver standardized survey to collect data about the initial medical experience. Patients were recruited through social media to complete a survey about initial symptoms, care provider approached for diagnosis, first events (hospital admission, testing, sent home, etc.), first diagnosis, time to treatment and outcomes. The data was collected by an independent, non-profit patient advocacy organization (The Transverse Myelitis Association) and provided to researchers for analysis. SETTING: This was an online survey of a prevalent cohort of individuals diagnosis with transverse myelitis. PARTICIPANTS: Patients with various autoimmune disorders responded to the survey. These included patients with multiple sclerosis, neuromyelitis optica, acute disseminated encephalomyelitis and idiopathic transverse myelitis. Only data about patients, greater than a year of age, with a diagnosis of transverse myelitis were included in the study.