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Several reports of concurrent MYC , BCL2 , BCL6 , and CCND1 rearrangements in high-grade B-cell lymphoma (HGBL) have been recently described. Herein, we aimed to delineate the scope of this entity through a review of HGBL with a "quadruple-hit" genetic profile identified at our institution. We performed a retrospective review (2015-2023) at our institution of B-cell lymphoma (BCL) cases that were evaluated with concurrent MYC , BCL2 , and BCL6 break-apart and IGH::MYC and IGH::CCND1 dual-color dual-fusion fluorescence in situ hybridization studies. Of 203 cases meeting inclusion criteria, 2 (1%) with a quadruple-hit genetic profile were identified. Case 1 represented a 59-year-old female with widespread lymphadenopathy and a diagnosis of HGBL who exhibited primary refractoriness to dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (DA-EPOCH-R) chemotherapy. Case 2 represented a 58-year-old male with mediastinal and abdominal lymphadenopathy and a diagnosis of large BCL who died from disease after 1 cycle of DA-EPOCH-R chemotherapy. Similarly, a literature review of 7 previously reported cases of HGBL with a quadruple-hit profile also demonstrated aggressive disease behavior. Our study adds 2 new cases to the rarely encountered quadruple-hit HGBL, and a brief meta-analysis of the 9 available cases indicates aggressive disease behavior conferred by this constellation of genetic events. [ABSTRACT FROM AUTHOR] more...

Objectives Fluorescence in situ hybridization (FISH) for plasma cell neoplasms (PCNs) requires plasma cell (PC) identification or purification strategies to optimize results. We compared the efficacy of cytoplasmic immunoglobulin FISH (cIg-FISH) and fluorescence-activated cell sorting FISH (FACS-FISH) in a clinical laboratory setting. Methods The FISH analysis results of 14,855 samples from individuals with a suspected PCN subjected to cytogenetic evaluation between 2019 and 2022 with cIg-FISH (n = 6917) or FACS-FISH (n = 7938) testing were analyzed. Results Fluorescence-activated cell sorting–FISH increased the detection rate of abnormalities in comparison with cIg-FISH, with abnormal results documented in 54% vs 50% of cases, respectively (P <.001). It improved the detection of IGH::CCND1 (P <.001), IGH::MAF (P <.001), IGH::MAFB (P <.001), other IGH rearrangements (P <.001), and gains/amplifications of 1q (P <.001), whereas the detection rates of IGH::FGFR3 fusions (P =.3), loss of 17p (P =.3), and other abnormalities, including hyperdiploidy (P =.5), were similar. Insufficient PC yield for FISH analysis was decreased between cIg-FISH and FACS-FISH (22% and 3% respectively, P <.001). Flow cytometry allowed establishment of ploidy status in 91% of cases. In addition, FACS-FISH decreased analysis times, workload efforts, and operating costs. Conclusions Fluorescence-activated cell sorting–FISH is an efficient PC purification strategy that affords significant improvement in diagnostic yield and decreases workflow requirements in comparison with cIg-FISH. [ABSTRACT FROM AUTHOR] more...

Several recurrent disease-initiating genetic abnormalities define biologically, clinically, and prognostically distinct subsets of disease in B-lymphoblastic leukemia (B-ALL) [[1]]. Coexistence of ETV6/RUNX1 and MLL aberrations in B-cell precursor acute lymphoblastic leukemia discloses a small subclass of BCP-ALL. (D) Metaphase nucleus illustrating derivative chromosomes 9 (black dashed arrow) and 11 (full black arrow) with a KMT2A:MLLT3 fusion and an uninvolved chromosome 11 (white arrow) with metaphase FISH. [Extracted from the article] more...

Primary cytogenetic abnormalities in B-lymphoblastic leukemia (B-ALL) define subgroups of disease with distinct clinical implications. These subgroups are largely mutually exclusive and only rarely observed in conjunction. We describe a three-year-old female presenting with de novo B-ALL in whom dual color, dual fusion fluorescence in situ hybridization (D-FISH) evaluation suggested concurrent ETV6::RUNX1 and KMT2A::MLLT3 rearrangements. Chromosomal microarray analysis (CMA) indicated that the breakpoint within KMT2A was located outside the typical region described in KMT2A leukemogenic translocations. Owing to the unexpected identification of concurrent ETV6::RUNX1 and KMT2A translocations by D-FISH and the suspicious findings on CMA, research-based whole genome sequencing (WGS) was performed. While this analysis confirmed the ETV6::RUNX1 fusion, WGS revealed the apparent KMT2A::MLLT3 fusion detected by D-FISH resulted from a juxtaposition of the 3′ portion of KMT2A (from intron 1) to an intergenic region on chromosome 9 located 460 Kb upstream of MLLT3. The WGS results indicate the apparent KMT2A::MLLT3 rearrangement would not result in an oncogenic chimeric fusion protein, and the characteristic KMT2A::MLLT3 dual fusion identified by D-FISH testing represented a false-positive FISH result. WGS thus more precisely resolved the genomic abnormalities in this B-ALL clone in comparison to chromosomes, FISH and chromosomal microarray and enabled accurate risk stratification. This case illustrates the importance of careful interpretation of atypical cases with aberrant genomic results, comprehensively considering expected fusion product structure, assay design and integrating results in their entirety. WGS may provide a means for resolution of atypical results by standard investigation modalities. [ABSTRACT FROM AUTHOR] more...

Genomic profiling of tumor provides valuable diagnostic, prognostic and therapeutic information. However, as clinical sequencing often relies on tumor-only approaches, factors such as infiltration from cells of hematopoietic lineage may confound accurate inference of variants present in tumor. We sought to investigate the frequency of a hallmark mutation in myeloid malignancies, JAK2 V617F, in solid tumor samples subjected to genetic testing at our institution and whether these underlie coexistence of a hematologic malignancy. We tested 6571 tumor samples between 2018 and 2021 that were investigated with targeted sequencing analysis. Of these, 5 (0.07%) harbored a JAK2 V617F mutation, a frequency comparable to that reported in the cBioPortal database (74/76639, 0.1%). These included three cases of melanoma, one cutaneous squamous cell carcinoma and one colorectal adenocarcinoma occurring in patients aged 51 to 93 years. No case showed evidence of overt superimposed hematologic malignancy, yet scattered CD45-positive hematopoietic cells were documented. Four cases (80%) harbored additional BRAF, CDNK2A, TP53 and PTEN tumor-specific mutations. JAK2 V617F mutations tended to be present at lower allele frequencies than other mutations (respective means 0.09 and 0.29). Two cases with available clinical information were previously known for hematologic malignancies (polycythemia vera and systemic mastocytosis with associated polycythemia vera). Our study emphasizes the importance of maintaining vigilance to sources of misleading results with tumor-only testing such as potential for misattribution of variants from infiltrating leukocytes. Importantly, detection of JAK2 V617F mutations may indicate a concurrent myeloproliferative neoplasm and inclusion of this disclaimer in the report should be considered. [ABSTRACT FROM AUTHOR] more...

This paper presents a new category of decision-support tools that builds on today''s Geographic Information Systems (gis) and On-Line Analytical Processing (olap) technologies to facilitate Geographic Knowledge Discovery (gkd). This new category, named Spatial olap (solap), has been an R&D topic for about 5 years in a few university labs and is now being implemented by early adopters in different fields, including public health where it provides numerous advantages. In this paper, we present an example of a solap application in the field of environmental health: the ICEM-SE project. After having presented this example, we describe the design of this system and explain how it provides fast and easy access to the detailed and aggregated data that are needed for gkd and decision-making in public health. The solap concept is also described and a comparison is made with traditional gis applications. [Copyright &y& Elsevier] more...

This study investigated attachment security and behavior in 34 physically disabled infants and 26 non-disabled infants by using convergent, categorical (secure, avoidant and ambivalent) and continuous (Attachment Behavior Q-Set) measures of the relationship, based on the same set of home observations. Proportions of attachment classifications were not different for disabled and non-disabled infants, but insecure infants in the disabled group scored consistently lower on the AQS security score than non-disabled insecure infants. This result suggests that while proportions of attachment classifications may not vary as a function of infant status, insecure disabled infants are more insecure than insecure non-disabled infants. An analysis of 5 behavioral dimensions of the AQS showed that secure infants emitted the same kinds of attachment behaviors without regard for infant status. Insecure disabled infants, however, showed lower levels of secure base behavior and physical contact with mother than their non-disabled counterparts, and showed a marginal tendency to fuss more as well. Discussion focuses on the potential benefits of using convergent, categorical and continuous measures of attachment in the study of both typical and atypical groups of infants. [ABSTRACT FROM AUTHOR] more...