Citations

Context.— One goal of the joint College of American Pathologists/American College of Medical Genetics and Genomics Cytogenetics Committee is to ensure the accurate detection and description of chromosomal abnormalities in both constitutional and neoplastic specimens, including hematologic neoplasms. Objective.— To report a 20-year performance summary (1999–2018) of conventional chromosome challenges focusing on hematologic neoplasms. Design.— A retrospective review was performed from 1999 through 2018 to identify karyotype challenges specifically addressing hematologic neoplasms. The overall performance of participants was examined to identify potential recurring errors of clinical significance. Results.— Of 288 total conventional chromosome challenges from 1999–2018, 87 (30.2%) were presented in the context of a hematologic neoplasm, based on the provided clinical history, specimen type, and/or chromosomal abnormalities. For these 87 hematologic neoplasm challenges, 91 individual cases were provided and graded on the basis of abnormality recognition and karyotype nomenclature (ISCN, International System for Human Cytogenomic [previously Cytogenetic] Nomenclature). Of the 91 cases, 89 (97.8%) and 87 (95.6%) exceeded the required 80% consensus for grading of abnormality recognition and correct karyotype nomenclature, respectively. The 2 cases (2 of 91; 2.2%) that failed to meet the 80% consensus for abnormality recognition had complex karyotypes. The 4 cases (4 of 91; 4.4%) that failed to meet the 80% consensus for correct karyotype nomenclature were the result of incorrect abnormality recognition (2 cases), missing brackets in the karyotype (1 case), and incorrect breakpoint designation (1 case). Conclusions.— This 20-year review demonstrates clinical cytogenetics laboratories have been and continue to be highly proficient in the detection and description of chromosomal abnormalities associated with hematologic neoplasms.

AbstractMetaphase cytogenetic abnormalities, plasma cell proliferation index (PCPro), and gain 1q by fluorescence in situ hybridization (FISH) are associated with inferior survival in newly diagnosed multiple myeloma (MM) treated with novel agents; however, their role in risk stratification is unclear in the era of the revised International Staging System (R-ISS). The objective of this study was to determine if these predictors improve risk stratification in newly diagnosed MM when accounting for R-ISS and age. We studied a retrospective cohort of 483 patients with newly diagnosed MM treated with proteasome inhibitors and/or immunomodulators. On multivariable analysis, R-ISS, age, metaphase cytogenetic abnormalities (both in aggregate and for specific abnormalities), PCPro, and FISH gain 1q were associated with inferior progression-free (PFS) and overall survival (OS). We devised a risk scoring system based on hazard ratios from multivariable analyses and assigned patients to low-, intermediate-, and high-risk groups based on their cumulative scores. The addition of metaphase cytogenetic abnormalities, PCPro, and FISH gain 1q to a risk scoring system accounting for R-ISS and age did not improve risk discrimination of Kaplan-Meier estimates for PFS or OS. Moreover, they did not improve prognostic performance when evaluated by Uno’s censoring-adjusted C-statistic. Lastly, we performed a paired analysis of metaphase cytogenetic and interphase FISH abnormalities, which revealed the former to be insensitive for the detection of prognostic chromosomal abnormalities. Ultimately, metaphase cytogenetics lack sensitivity for important chromosomal aberrations and, along with PCPro and FISH gain 1q, do not improve risk stratification in MM when accounting for R-ISS and age.

Abstract Objectives The association of bipolar disorder with early and excessive cardiovascular disease was identified over a century ago. Nonetheless, the vascular‐bipolar link remains underrecognized, particularly with regard to how this link can contribute to our understanding of pathogenesis and treatment. Methods An international group of experts completed a selective review of the literature, distilling core themes, identifying limitations and gaps in the literature, and highlighting future directions to bridge these gaps. Results The association between bipolar disorder and vascular disease is large in magnitude, consistent across studies, and independent of confounding variables where assessed. The vascular‐bipolar link is multifactorial and is difficult to study given the latency between the onset of bipolar disorder, often in adolescence or early adulthood, and subsequent vascular disease, which usually occurs decades later. As a result, studies have often focused on risk factors for vascular disease or intermediate phenotypes, such as structural and functional vascular imaging measures. There is interest in identifying the most relevant mediators of this relationship, including lifestyle (eg, smoking, diet, exercise), medications, and systemic biological mediators (eg, inflammation). Nonetheless, there is a paucity of treatment studies that deliberately engage these mediators, and thus far no treatment studies have focused on engaging vascular imaging targets. Conclusions Further research focused on the vascular‐bipolar link holds promise for gleaning insights regarding the underlying causes of bipolar disorder, identifying novel treatment approaches, and mitigating disparities in cardiovascular outcomes for people with bipolar disorder.

AbstractInfant leukemias are a rare group of neoplasms that are clinically and biologically distinct from their pediatric and adult counterparts. Unlike leukemia in older children where survival rates are generally favorable, infants with leukemia have a 5‐year event‐free survival rate of <50%. The majority of infant leukemias are characterized by KMT2A (MLL) rearrangements (~70 to 80% in acute lymphoblastic leukemia), which appear to be drivers of early leukemogenesis. In this report, we describe three cases: a 9‐month‐old female infant with B‐acute lymphoblastic leukemia (B‐ALL), an 8‐month‐old female presenting with B/myeloid mixed phenotype acute leukemia (MPAL), and a 16‐month‐old male with B‐ALL. The first case had a normal karyotype and B‐ALL FISH results consistent with an atypical KMT2A rearrangement. The second case had trisomy 10 as the sole chromosomal abnormality and a normal KMT2A FISH result. Case 3 had trisomy 8 and a t(11;15)(q23;q21), an atypical KMT2A rearrangement by FISH studies, and a focal deletion of 15q with a breakpoint within the USP8 gene by chromosomal microarray. Mate pair sequencing was performed on all three cases and identified a KMT2A‐USP2 rearrangement (cases 1 and 2) or a KMT2A‐USP8 rearrangement (case 3). These recently characterized KMT2A fusions have been described exclusively in infant and pediatric leukemia cases where the incidence varies vary according to leukemia subtype, are considered high‐risk, with a high incidence of central nervous system involvement, poor response to initial prednisone treatment, and poor event free survival. Additionally, approximately half of cases are unable to be resolved using standard cytogenetic approaches and are likely under recognized. Therefore, targeted molecular approaches are suggested in genetically unresolved infant leukemia cases to characterize these prognostically relevant clones.

Abstract Osteolineage cell‐derived extracellular vesicles (EVs) play a regulatory role in hematopoiesis and have been shown to promote the ex vivo expansion of human hematopoietic stem and progenitor cells (HSPCs). Here, we demonstrate that EVs from different human osteolineage sources do not have the same HSPC expansion promoting potential. Comparison of stimulatory and non‐stimulatory osteolineage EVs by next‐generation sequencing and mass spectrometry analyses revealed distinct microRNA and protein signatures identifying EV‐derived candidate regulators of ex vivo HSPC expansion. Accordingly, the treatment of umbilical cord blood‐derived CD34 + HSPCs with stimulatory EVs‐altered HSPC transcriptome, including genes with known roles in cell proliferation. An integrative bioinformatics approach, which connects the HSPC gene expression data with the candidate cargo in stimulatory EVs, delineated the potentially targeted biological functions and pathways during hematopoietic cell expansion and development. In conclusion, our study gives novel insights into the complex biological role of EVs in osteolineage cell‐HSPC crosstalk and promotes the utility of EVs and their cargo as therapeutic agents in regenerative medicine.

The presence of KMT2A/AFF1 rearrangement in B-lymphoblastic leukemia (B-ALL) is an independent poor prognostic factor and has been associated with higher rate of treatment failure and higher risk of linage switch under therapy. Blinatumomab has shown promising therapeutic results in refractory or relapsed B-ALL; however, it has potential risk of inducing lineage switch, especially in KMT2A/AFF1 rearranged B-ALL into acute myeloid leukemia and/or myeloid sarcoma. We report a 40-year-old female with KMT2A/AFF1-rearranged B-ALL that was refractory to conventional chemotherapy. Following administration of blinatumomab, she developed a breast mass proven to be myeloid sarcoma, in addition to bone marrow involvement by AML. Approximately six weeks after cessation of blinatumomab, a repeat bone marrow examination revealed B/myeloid MPAL.

Background: “Practice effects” (PE), or performance improvements due to prior exposure to testing, are known to confound cognitive test results, particularly when short intervals occur between two test sessions. Objective: We examined two subsamples with short or long re-test intervals from a recent clinical trial. Methods: Thirty-four non-depressed adults with mild Huntington Disease (HD) participated. Three cognitive tests were administered at screening and again at baseline, before active treatment randomization. Half the sample had a 24-hour retest interval while the other half was >6-days. Results: The two groups differed on demographic/clinical factors (age, Total Motor Score and Total Functional Capacity). After controlling for age and motor score, PE differences were found on three of the five UHDRS cognitive tests: the longer interval group showed larger PE on Symbol-Digit Modalities and Stroop color, while the rapid interval group had larger PE on Stroop interference. Controlling for screening cognitive performance yielded similar results. Conclusions: Length of interval between screening and baseline visits and level of disease severity may influence stability of UHDRS cognitive test results in clinical trials in HD.

Background: Small lymphocytic lymphoma/chronic lymphocytic leukemia (SLL/CLL) is a lymphoproliferative disorder of small mature B-cells, most commonly presenting with peripheral blood and bone marrow involvement. Tumoral lesions are variably encountered, resulting from either lymph node involvement or, less commonly, infiltration into virtually any extramedullary site. The prognostic assessment of patients with SLL/CLL relies strongly on the identification of recurrent chromosomal abnormalities, which are routinely tested by fluorescence in situ hybridization (FISH) on peripheral blood or bone marrow specimens. However, the incidence of such recurrent chromosomal abnormalities on tumoral lesions has only been studied on small series, and its concordance with peripheral blood and/or bone marrow testing remains unknown. We hereby report a large series of chromosomal abnormalities detected on tumoral SLL/CLL lesions, based on a validated FISH panel for formalin-fixed/paraffin-embedded (FFPE) biopsy sections. Methods: FISH was performed at Mayo Clinic on FFPE tissue sections from biopsies obtained from May 2014 to November 2018, as clinically indicated. Pathology reports and H&E-stained sections were reviewed and were consistent with a diagnosis of SLL/CLL in all cases. Probes were validated to detect previously described chromosomal abnormalities in SLL/CLL, including trisomy 12 (+12) and deletions of 6q23 (6q-), 11q22.3 (11q-), 13q14.3 (13q-) and 17p13.1 (17p-). Available FISH results performed on peripheral blood or bone marrow samples from these patients were also reviewed for comparison. Results: Tissue biopsies involved by SLL/CLL from 346 patients were evaluated by FISH. The majority of specimens were either lymph nodes (65%) or soft tissue masses (29%). The median age was 66.9 years (range: 36 to 91), and the male to female ratio was 2.1:1. FISH abnormalities were identified in 60% of evaluated tissue sections. The most frequently detected aberration was +12 (35%), followed by 13q- (24%), 11q- (15%), 17p- (6%) and 6q- (2%) (Figure A). In particular, the incidence of +12 was significantly higher, and the incidence of 13q- significantly lower compared to frequencies previously reported on peripheral blood or bone marrow specimens (p<0.01 for both abnormalities, in comparison to a recently published cohort of 1585 patients: Br J Haematol 2016;173:105). Most cases had 1 abnormality (55%), with fewer patients having 2 abnormalities (13%), and only 1 case showing 3 abnormalities. Of 47 patients with 2 or more chromosomal aberrations, most (72%) had 13q- in combination with either 11q- (7 cases), +12 (10 cases) or 17p- (7 cases) (Figure 1B). Of 29 patients with positive blood or bone marrow FISH results within 12 months of tissue biopsy, 7 patients (24%) had discrepant results, all of which were limited to discordant +12 and/or 13q- detection. In 14 additional patients with positive blood or bone marrow FISH results more than 12 months before or after tissue biopsy, discordant results were found in 3 cases (21%), all of which indicated gains of 17p- (2 cases) or 11q- (1 case) on the follow-up analysis. Conclusions: We hereby report the largest documented series (to the best of our knowledge) of FISH results performed on tumoral lesions of SLL/CLL. Trisomy 12 was overrepresented in tumoral lesions, as compared to the reported predominance of 13q- in leukemic involvement. Discrepant results between concurrent tumoral and leukemic FISH testing were limited to differences in +12 and 13q- in our series. We also document the acquisition of aberrancies of unfavorable prognosis (17p- and 11q-) on follow up FISH analysis in a small subset of patients, which should be taken into account when considering repeat FISH studies. Figure Disclosures Horna: MorphoSys AG: Research Funding.