Bilateral Burkitt Lymphoma of the Ovaries: A Report of a Case in a Child with Williams Syndrome

A 10-year-old female with Williams Syndrome (WS) presented with a two-month history of fatigue, weight loss, and bilateral ovarian masses. Histologic, immunophenotypic, and cytogenetic studies confirmed the diagnosis of Burkitt lymphoma (BL). While there is no established association between the two disorders, this is the third case in the literature of Burkitt lymphoma in a patient with Williams Syndrome

Clonal and microclonal mutational heterogeneity in high hyperdiploid acute lymphoblastic leukemia.

High hyperdiploidy (HD), the most common cytogenetic subtype of B-cell acute lymphoblastic leukemia (B-ALL), is largely curable but significant treatment-related morbidity warrants investigating the biology and identifying novel drug targets. Targeted deep-sequencing of 538 cancer-relevant genes was performed in 57 HD-ALL patients lacking overt KRAS and NRAS hotspot mutations and lacking common B-ALL deletions to enrich for discovery of novel driver genes. One-third of patients harbored damaging mutations in epigenetic regulatory genes, including the putative novel driver DOT1L (n=4). Receptor tyrosine kinase (RTK)/Ras/MAPK signaling pathway mutations were found in two-thirds of patients, including novel mutations in ROS1, which mediates phosphorylation of the PTPN11-encoded protein SHP2. Mutations in FLT3 significantly co-occurred with DOT1L (p=0.04), suggesting functional cooperation in leukemogenesis. We detected an extraordinary level of tumor heterogeneity, with microclonal (mutant allele fraction <0.10) KRAS, NRAS, FLT3, and/or PTPN11 hotspot mutations evident in 31/57 (54.4%) patients. Multiple KRAS and NRAS codon 12 and 13 microclonal mutations significantly co-occurred within tumor samples (p=4.8x10-4), suggesting ongoing formation of and selection for Ras-activating mutations. Future work is required to investigate whether tumor microheterogeneity impacts clinical outcome and to elucidate the functional consequences of epigenetic dysregulation in HD-ALL, potentially leading to novel therapeutic approaches

Genomic characterization of pediatric B‐lymphoblastic lymphoma and B‐lymphoblastic leukemia using formalin‐fixed tissues

BackgroundRecurrent genomic changes in B‐lymphoblastic leukemia (B‐ALL) identified by genome‐wide single‐nucleotide polymorphism (SNP) microarray analysis provide important prognostic information, but gene copy number analysis of its rare lymphoma counterpart, B‐lymphoblastic lymphoma (B‐LBL), is limited by the low incidence and lack of fresh tissue for genomic testing.ProcedureWe used molecular inversion probe (MIP) technology to analyze and compare copy number alterations (CNAs) in archival formalin‐fixed paraffin‐embedded pediatric B‐LBL (n = 23) and B‐ALL (n = 55).ResultsSimilar to B‐ALL, CDKN2A/B deletions were the most common alteration identified in 6/23 (26%) B‐LBL cases. Eleven of 23 (48%) B‐LBL patients were hyperdiploid, but none showed triple trisomies (chromosomes 4, 10, and 17) characteristic of B‐ALL. IKZF1 and PAX5 deletions were observed in 13 and 17% of B‐LBL, respectively, which was similar to the reported frequency in B‐ALL. Immunoglobulin light chain lambda (IGL) locus deletions consistent with normal light chain rearrangement were observed in 5/23 (22%) B‐LBL cases, compared with only 1% in B‐ALL samples. None of the B‐LBL cases showed abnormal, isolated VPREB1 deletion adjacent to IGL locus, which we identified in 25% of B‐ALL.ConclusionsOur study demonstrates that the copy number profile of B‐LBL is distinct from B‐ALL, suggesting possible differences in pathogenesis between these closely related diseases.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/137353/1/pbc26363.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/137353/2/pbc26363_am.pd

How confident are young adult cancer survivors in managing their survivorship care? A report from the LIVESTRONG™ Survivorship Center of Excellence Network

This study examined the association between sociodemographic, cancer treatment, and care delivery factors on young adult cancer survivors’ confidence in managing their survivorship care

Spongiform Encephalopathy Following Allogeneic Cord Blood Transplant

A 6 year old boy developed a fatal, rapidly progressive encephalopathy 5 months after a matched unrelated cord blood transplant. Autopsy findings revealed spongiform changes in his brain. The clinical course of this child\u27s illness had many findings consistent with that of a transmissible spongiform encephalopathy (TSE). Pre-mortem and post-mortem studies failed to definitively determine an etiology. Spongiform encephalopathies include the TSEs and mitochondrial encephalopathies. Both should be considered in a post-hematopoietic stem cell transplant patient who develops a progressive encephalopathy when more common etiologies are not found

Prevalence of Abnormal Bone Density of Pediatric Patients Prior to Blood or Marrow Transplant

Osteoporosis and osteopenia are long-term side effects of bone marrow transplant (BMT). The purpose of this study was to determine the prevalence of bone mineral density (BMD) abnormalities in pediatric patients prior to BMT. Forty-four pediatric patients were evaluated with DEXA scans. The average Z-score was -0.37. Thirty-six percent had abnormal BMD. Sixty-seven percent of ALL patients had abnormal BMD. Patients with non-malignant diseases were significantly more likely to have abnormal BMD. Patients with ALL had more defects than solid tumor patients. Females had more defects than males. These results demonstrate BMD defects are common in children prior to BMT, especially in patients with ALL

Mobilization of PML-RARA Negative Blood Stem Cells and Salvage With Autologous Peripheral Blood Stem Cell Transplantation in Children With Relapsed Acute Promyelocyte Leukemia

Background. Relapsed acute promyleocytic leukemia (APL) is treated with re-induction chemotherapy, commonly arsenic trioxide, and stem cell transplantation (SCT). The effect of arsenic trioxide on autologous peripheral blood stem cell collection is unknown. Procedure. Five pediatric patients with relapsed APL had PML-RARA negative peripheral blood stem cells mobilized (four after arsenic trioxide) and underwent autologous SCT after cyclophosphamide (60 mg/kg x 2) and total body irradiation (TBI-fractionated 1,200 cGy) conditioning. Results. All five patients remain in molecular remission a median of 20 months post-transplant. Conclusion. Autologous SCT performed during molecular remission is a treatment option for pediatric patients with relapsed APL and may provide durable leukemia-free survival without the complications of allogeneic transplantation

Constitutive function of the Ikaros transcription factor in primary leukemia cells from pediatric newly diagnosed high-risk and relapsed B-precursor ALL patients.

We examined the constitutive function of the Ikaros (IK) transcription factor in blast cells from pediatric B-precursor acute lymphoblastic leukemia (BPL) patients using multiple assay platforms and bioinformatics tools. We found no evidence of diminished IK expression or function for primary cells from high-risk BPL patients including a Philadelphia chromosome (Ph)(+) subset. Relapse clones as well as very aggressive in vivo clonogenic leukemic B-cell precursors isolated from spleens of xenografted NOD/SCID mice that developed overt leukemia after inoculation with primary leukemic cells of patients with BPL invariably and abundantly expressed intact IK protein. These results demonstrate that a lost or diminished IK function is not a characteristic feature of leukemic cells in Ph(+) or Ph(-) high-risk BPL

IRF4 Translocation Status in Pediatric Follicular and Diffuse Large B-Cell Lymphoma Patients Enrolled in Children\u27s Oncology Group Trials

Large B-cell lymphoma with IRF4 rearrangement is a provisional entity in the 2017 World Health Organization classification. In order to characterize these lymphomas in children from the United States, IRF4 FISH and immunohistochemical stains were performed on 32 follicular lymphoma and diffuse large B-cell lymphoma (DLBCL) from Children\u27s Oncology Group studies. Two DLBCLs (6%) had IRF4 rearrangements, one involving the ileocecal valve and another involving the tonsil and cerebrospinal fluid. Both cases had strong, diffuse IRF4/MUM1 immunohistochemical staining, which may be a pathologic clue to the diagnosis. Reclassification of these cases may have prognostic and therapeutic implications

Transcript Levels of Ikaros Target Genes in Primary Leukemia Cells from Pediatric Ph^- and Ph⁺ BPL Patients.

<p>Expression levels of IK target genes were compared for primary leukemic cells from 155 pediatric Ph^-/BCR-ABL^- BPL patients and 20 Ph ⁺ /BCR-ABL ⁺ /BPL patients on the Mullighan study (GSE12995). Transcript signal values were obtained from hybridization onto the Affymetrix Human Genome U133A genechip arrays. Heat map depicts up and down regulated transcripts ranging from red to green respectively for mean centered log₁₀ transformed expression values and clustered according to average distance metric (<b>A</b>). Rank ordered difference in standard deviation units for Ph⁺ samples (N=20) compared to other samples (N=155) in the Mullighan study (GSE12995) were processed for enrichment of IK target genes <b>(B1)</b> and IK-regulated lymphoid priming genes <b>(B2)</b> using a supervised approach implemented in GSEA2.08 (Broad institute). Enrichment scores for calculated for the ranked members of the gene sets and normalized to the gene set size (NES) for which the P-value was calculated using 1000 permutations of the pre-ranked gene list and the FDR corrected for testing 2 gene sets. There was a significant enrichment of IK target genes (NES = 1.43, P = 0.046) for Ph⁺ patients that included the leading edge subset comprised of TSPAN13<i>, GSN</i>, MDFIC<i>, ITGA4, TREML2, RNF125</i>, IQGAP2, LAMC1, TES, DHRS3<i>, S100A10</i>, IL12RB1, ADD3<i>, GRAMD3, ATRNL1</i>, RUNX2<i>, MCOLN3</i>, ATP1B1, and CALCRL. Likewise, there was a significant enrichment of lymphoid priming genes (NES = 1.51, P = 0.039) for Ph⁺ patients that included the leading edge subset comprised of <i>IGJ</i>, CNN3, CD52, DNTT<i>, CSF1R</i>, SATB1<i>, LTB, PTGER2</i>, MEF2C, RUNX2 (Figure <b>1B.2</b>). There was a significant increase in the multivariate mean for 45 transcripts in the Ph⁺ subset of specimens compared to the pooled mean of the other subsets (MANOVA, F_1,173 = 11.29, P=0.001). The mean level of expression for each transcript in each BPL subset is illustrated in the heat map organized using a two-way hierarchical clustering method (average distance metric) to group expression profiles of transcripts and specimen subsets (<b>C</b>).</p