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We retrospectively studied the impact of cytogenetic abnormalities in 328 consecutive newly diagnosed multiple myeloma (MM) patients. High-risk cytogenetic abnormalities (HRCAs) included del (17p), amp/gain (1q21), t(4;14), and t(14;16). We defined a standard-risk group by the absence of HRCA, an intermediate-risk group with one HRCA, and a high-risk (HiR) group with at least two HRCAs. The HiR group constituted 14.3% of patients and was associated with a median overall survival (OS) of 28.6 months and progression-free survival (PFS) of 14.0 months. Moreover, the HiR group predicted poor outcomes for OS and PFS in multivariate analyses, and bortezomib prolongation to nine cycles could not bring additional benefit to this entity, suggesting the necessity of more effective therapies for these patients. Furthermore, we confirmed the independent prognostic impact of amp 1q21 in this real-world study.

A 70-year-old male was referred to our hospital for marked thrombocytosis without anemia. The patient simultaneously presented with an MPL W515L mutation, one of the major driver mutations in essential thrombocythemia (ET), and deletion of 5q, a characteristic cytogenetic abnormality in myelodysplastic syndrome (MDS). Bone marrow examination showed a combination of both mature hyperlobulated megakaryocytes, as found in ET, and small hypolobulated megakaryocytes, typically found in MDS with del(5q). The present case is consistent with the recently proposed category of myeloid neoplasms with isolated del(5q) and an MPN driver mutation.

The prognostic value of CD56 and CD117 expression on myeloma cells is controversial. This study aims to analyze the correlation of CD56 and CD117 expression with cytogenetic abnormalities and survival. A total of 128 patients with newly diagnosed multiple myeloma (NDMM) were recruited in this single-center retrospective study. Flow cytometry and FISH tests of marrow cells were performed for all of the subjects. The statistical methods included a chi-squared test, univariate and multivariate COX regressions, and a Kaplan-Meier survival curve analysis. Regarding the cytogenetics, the incidence of IgH/FGFR3 translocation was more frequent in patients with a negative CD56 (p = 0.003). CD56 negativity was an independent adverse factor associated with a poor prognosis (p = 0.019) and indicated a shorter overall survival (OS) (p = 0.021). Patients with dual negative CD56 and CD117 trended toward a poorer OS (CD56−CD117− vs. CD56+CD117−, p = 0.011; CD56−CD117− vs. CD56+CD117+, p = 0.013). In conclusion, CD56 is a prognostic marker that independently affects OS and is associated with adverse cytogenetic abnormalities. Patients with a dual negativity of CD56 and CD117 have a worse clinical outcome.

Objective Premature ovarian insufficiency is a lack of ovarian functions in patients younger than 40 years old. Genetic causes leading to accelerated follicle depletion may result in premature ovarian insufficiency. We aimed to determine genetic etiology of nonsyndromic premature ovarian insufficiency cases from Turkey. Materials and methods We analyzed 86 nonsyndromic premature ovarian insufficiency cases and 26 matched control female participants. Participants have been investigated in cytogenetic analysis followed by FMR1 repeat size expansions and search of variants for nine premature ovarian insufficiency-associated genes. Results Four cases had a structural cytogenetic abnormality. Two cases revealed with premutation size FMR1 triplet repeat expansion. Four cases carried variants in which two were very rare in FSHR and PDPK1, and three were novel in NR5A1, PDPK1, and POF1B genes. Six novel variants have been identified in NOBOX, NR5A1, POF1B, and PDPK1 in control population assigned to be benign alterations. Conclusion Mosaicism of sex chromosomes was responsible in 4.6% and FMR1 premutation in 2.4% of premature ovarian insufficiency cases, while the association of premature ovarian insufficiency-related genes was found very subtle. Novel variants in NR5A1, PDPK1, and POF1B may necessitate further evaluation for their association with premature ovarian insufficiency via functional studies.

A 68-year-old male was diagnosed with acute promyelocytic leukemia (APL). A G-banding chromosomal analysis revealed the co-existence of two clones: one with del(20q) and t(15;17)(q22;q12) and another with del(20q) alone. During the remission of APL following treatment with all-trans-retinoic acid, del(20q) was persistently identified, indicating a diagnosis of cytogenetic abnormalities of undetermined significance (CCAUS) with isolated del(20q). Bicytopenia developed 48 months after the remission of APL. The presence of isolated del(20q) was detected in the G-banding analysis, whereas morphological dysplasia of hematopoietic cells was not confirmed. This case showed indolent progression from CCAUS after the remission of APL to clonal cytopenia of undetermined significance (CCUS). CCUS with isolated del(20q) persisted for 24 months without any finding of hematological malignancies. At the most recent follow-up, targeted capture sequencing showed the U2AF1 S34F mutation. Considerable attention needs to be paid in follow-ups for CCAUS with del(20q) after the treatment of leukemia.

Introduction Prognosis of patients with newly diagnosed multiple myeloma (MM), a third most common hematological cancer, is dependent on baseline cytogenetics. However, little is known about the prognostic significance of cytogenetic evolution (CE) at the time between the diagnosis and relapse of MM. Objectives Here, we retrospectively analyzed the prognostic impact of CE detected in a routine interphase fluorescence in situ hybridization (FISH) test in a cohort of patients with MM. Patients and methods Among 650 patients evaluated with the FISH MM panel at our center between 2014 and 2019, we identified 29 individuals with MM who had been tested twice, at the time of diagnosis and relapse. Cytogenetic evolution was defined as the acquisition or loss of at least 1 cytogenetic abnormality at relapse (FISH2) compared with the baseline test result (FISH1). Results Cytogenetic evolution was seen in 14 patients (48%), whereas 15 had stable cytogenetics. Acquired chromosome 17p deletion (del[17p]) was the most common type of CE, found in 7 patients (24%). In univariable analysis, stable cytogenetics predicted longer overall survival (median not reached vs 3.8 years; hazard ratio [HR], 0.15; P = 0.04; median follow‑up of 3.1 years) and longer overall survival after FISH2 (median not reached vs 0.8 years; HR, 0.13; P = 0.002; median follow‑up of 0.6 years). In multivariable analysis, acquired del(17p) predicted shorter progression‑free survival and the overall survival after FISH2 (HR, 9.3 and 18.8; P = 0.005 and P = 0.004, respectively). Conclusions Presence of CE and, particularly, the acquisition of new del(17p) at relapse, negatively affect the outcome of MM. Therefore, re‑evaluation of FISH at MM relapse should be included in routine clinical practice.

Multiple isodicentric Y chromosome [idic(Y)] is a cytogenetic abnormality consisting of duplicative copies of the short-arm of Y chromosome. Several mechanisms have been postulated to explain the f...

Ring chromosome 6, r(6), is an extremely rare cytogenetic abnormality with clinical heterogeneity which arises typically de novo. The phenotypes of r(6) can be highly variable, ranging from almost normal to severe malformations and neurological defects. Up to now, only 33 cases have been reported in the literature. In this 10-year follow-up study, we report a case presenting distinctive facial features, severe developmental delay, and gray matter heterotopia with r(6) and terminal deletions of 6p25.3 (115426-384174, 268 kb) and 6q26-27 (168697778-170732033, 2.03 Mb) encompassing 2 and 15 candidate genes, respectively, which were detected using G-banding karyotyping, FISH, and chromosomal microarray analysis. We also analyzed the available information on the clinical features of the reported r(6) cases in order to provide more valuable information on genotype-phenotype correlations. To the best of our knowledge, this is the first report of gray matter heterotopia manifested in a patient with r(6) in China, and the deletions of 6p and 6q in our case are the smallest with the precise size of euchromatic material loss currently known.

Key Clinical Message We report two male siblings with SDS. They have the same compound heterozygous mutations. Only one of the siblings acquired cytogenetic abnormality of i(7q) 2 years after diagnosis, became transfusion‐dependent, and underwent allogeneic hematopoietic stem cell transplantation. These cases indicate that i(7q) is associated with significant cytopenia in SDS patients.

Summary The definition of the myelodysplastic syndrome (MDS) subtype ‘MDS with isolated del(5q)’ was expanded to include cases with one additional non-chromosome 7 based cytogenetic abnormality in the 2016 revised World Health Organization classification. This study applied the revised definition to a large primary MDS cohort, and evaluated the prognostic impact of the additional cytogenetic abnormality. Seventy-two of 1067 patients (7%) met the ‘MDS with isolated del(5q)’ criteria, 11 (1%) of whom had an additional cytogenetic abnormality. There was no survival difference between patients in whom del(5q) occurred alone, compared to those with one additional cytogenetic abnormality (P = 0·52).

Flow cytometric immunophenotyping still stands on a significant position as a diagnostic tool against acute lymphoblastic leukemia (ALL). Improvement of flow cytometry (FCM) instrument and increasing availability of monoclonal antibodies and fluorochromes enable multicolor analysis and accurate diagnosis. But molecular diagnostic method also made a big progress especially in genome-wide analysis. The World Health Organization (WHO) classification of tumors of the hematopoietic and lymphoid tissues was first established in 2008, then in 2017 it was revised diagnostic criteria including morphologic, phenotypic, and more genotypic features (Wenzinger et al., Curr Hematol Malig Rep 13:275–288, 2018). Thus, such a recent progress of genomic analysis alters a role of immunophenotyping for pediatric ALL. Currently, entities of pediatric ALL are divided into subtypes by not only immunophenotyping but various cytogenetic abnormalities. Immunophenotyping may become no longer crucial but only exist to decide initial treatment until an identification of cytogenetic abnormalities in the near future. However, recently it turned out that immunophenotypic patterns indicate a specific feature according to each cytogenetic abnormality. To predict cytogenetic abnormality based on specific immunophenotype may fulfill an efficient cytogenetic diagnosis for most of known cytogenetic abnormalities. This chapter indicates the present situation of flow cytometric testing and current application for pediatric ALL, based on a new era of genomic analysis.

One of the diagnostic criteria for Acute Myeloblastic Leukemia (AML) is the presence of 20% myeloid blasts in peripheral blood or bone marrow. Some cases with recurrent cytogenetic abnormalities also fall in this category with blast cell count less than 20%. Thus, in the presence of these genetic abnormalities, the patients are classified as AML regardless of blast cell count. One of these genetic heterogeneities is t(8; 21) (q22, q22.1) which is more commonly seen in children and young adults. In this study, a 14-year-old boy is reported with a final diagnosis of AML, which was presented with fever and bicytopenia, clinically suspicious for acute leukemia. Laboratory results reported less than 20% blasts in bone marrow aspiration smears but genetic alteration t(8; 21) (q22, q22.1) was detected by molecular exams.

NUT midline carcinoma (NMC) is a very rare, highly malignant disease with a specific cytogenetic abnormality t(15;19)(q14;p13.1). This tumor can occur throughout life, unfortunately, most cases are characterized by the presence of metastases at the time of diagnosis. There are clear cytogenetic and molecular-biological criterias for diagnosis. There are no specific standards of therapy that provide effective treatment of this pathology in the world. However, the presence of a chimeric oncogene characterizing the tumor is promising in terms of targeting drug research in the framework of international cooperation. It is also necessary to collect information about this rare disease to analyze it and to identify the most effective therapy method. This article presents an analysis of the clinical case of NMC, first diagnosed in a child of 9-yearsold in the Republic of Belarus.

The phenotypic expression in DS is determined by the type of underlying cytogenetic abnormality. Almost 90-95% cases of DS are due to pure trisomy of the 21st chromosome; 6-7% is the result of mosaicism and in only 3-5% of cases it results from Robertsonian translocation (ROB). About 1/3rd cases of unbalanced Robertsonian translocation causing DS are inherited. We report a 1-year-old-boy with DS secondary to rea(21;21) ROB.

Introduction A meta-analysis of three large randomized trials has demonstrated that len maint prolongs progression free survival (PFS) and overall survival (OS) in pts with MM who have undergone ASCT. While len maint benefits pts with both high-risk and standard-risk cytogenetics, it does not appear to provide equal magnitude of benefit to patients with high-risk cytogenetics. We conducted a retrospective analysis comparing the outcomes of pts with MM who underwent ASCT at our institution and len maint compared to no maint. We further evaluated the impact of len maint on the two cytogenetic groups. Methods We performed a retrospective analysis of 1002 consecutive pts with newly diagnosed MM who underwent ASCT at The Ohio State University between 1992 through 2016. Data were collected regarding patient demographics, disease characteristics, therapy received including maint, and clinical outcomes. Pts were excluded from the analysis if they received len combination or other drug maint therapies. High-risk cytogenetics was defined as having t(4;14), t(14;16), gain 1q, or del17p. PFS and OS were estimated using Kaplan-Meier method. Log-rank test was used to compare PFS and OS between the groups and Cox proportional hazard models were used to estimate the hazard ratios (HR). Results Pt characteristics are listed in Table 1. 484 pts (53.3%) received no maint while 423 pts (46.7%) received len maint. 245 pts (24.4%) had high-risk cytogenetics while 561 pts (56%) had standard-risk cytogenetics with the remaining unknown. Both PFS and OS were significantly better in the len maint group compared to the no maint group (Figure 1). Adjusting for pts age at transplant, cytogenetic risk, pre-transplant and post-transplant disease status, and ISS staging, the superiority in PFS and OS remained statistically significant, HR=0.50 (95% CI: 0.41-0.62), p Conclusion Consistent with previously published data, our results demonstrate an improvement in outcomes in MM pts treated with len maint following ASCT compared to no maint regardless of cytogenetic risk group. Larger studies are needed to assess the individual benefit obtained with len maint with each high-risk cytogenetic abnormality. Several trials incorporating newer drugs with novel mechanisms of action are currently being done that could further optimize maint therapy and lead to better outcomes in high-risk group.

AIMS Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an aggressive neoplasm with leukaemic features and frequent skin involvement. Translocations involving the MYC locus have been recently identified as recurrent cytogenetic abnormalities in this entity. The aim of this study was to assess the clinicopathological, immunophenotypic and genetic features in MYC-rearranged BPDCN cases. METHODS AND RESULTS Pathology archives from six major institutes were queried for cases of BPDCN with 8q24 MYC translocations, and two cases were identified. A literature review identified 14 cases. Clinicopathological features, immunophenotype and cytogenetic and molecular data were reviewed. In these 16 MYC-rearranged cases, the median age at diagnosis was 70.5 years, and there was a male predominance. Whereas all cases showed marrow involvement, skin lesions (62.5%) and lymphadenopathy (50%) were variably seen. The median survival was 11 months. The median percentage of blasts in peripheral blood was 9%. All cases showed expression of CD4, with 10 of 16 being positive for CD56. HLA-DR, CD123, TCL1 and CD303 were positive in all cases tested. Cytogenetic analysis revealed a single recurrent translocation partner of MYC at 6p21 in 11 cases (69%), whereas four cases showed different MYC translocation partners (2p12, Xq24, 3p25, and 14q32). Interestingly, the group of patients with t(6;8)(p21;q24) showed an older median age at diagnosis (74 years) and a remarkably shorter median survival (3 months). CONCLUSIONS Translocations involving the 8q24 MYC locus more frequently manifest as t(6;8)(p21;q24), and, given its association with specific clinicopathological features suggesting even more aggressive behaviour, t(6;8)(p21;q24) indicate a genetically defined subgroup within BPDCN.

Translocations involving MYC are highly characteristic for Burkitt lymphoma (BL). BCL2 expression has also been found previously in about 10 to 20% of BL cases, and BCL2 translocation is a major mechanism for the deregulation of BCL2 expression in non-Hodgkin lymphomas. However, we know little about the incidence of MYC/BCL2 double-hit (DH) in BL. We examined BL cases to determine how frequently they contained BCL2 translocations in combination with MYC translocations using fluorescence in situ hybridization. We also determined the effect of BCL2 expression on clinical outcomes of BL. BCL2 translocations were detected in 3.5% (2/57 cases) of the cases, and BCL2 expression was detected in 33%. Two cases with BCL2 translocation also showed BCL2 expression. The incidence of BCL2 expression was significantly higher in patients 16 years of age and older (46%) than in patients under 16 years of age (6%). Among patients 16 years of age and older, we did not detect significant differences in overall survival with respect to BCL2 expression status. In conclusion, BCL2 translocation is a rare cytogenetic abnormality in BL, and BL probably accounts for only a small fraction of MYC/BCL2 DH lymphomas. BCL2 expression in BL is probably not associated with BCL2 translocations.

Objectives: Session 1 of the 2013 Society for Hematopathology/European Association for Hematopathology Workshop was devoted to the cases of acute myeloid leukemia (AML) with recurrent cytogenetic abnormalities. Methods: Based on World Health Organization 2008 criteria, seven specific translocations are defined as “recurrent” in AML. Of these seven, three are considered to be AML defining regardless of blast percentage. Workshop cases provided the opportunity to consider potential new AML-defining cytogenetic mutations, as well as other unique aspects of AML with cytogenetic abnormalities. Results: Most of the 38 cases submitted were acute promyelocytic leukemia (APL) with t(15;17)(q24.1;q21.1) and so-called variants (12 cases), AML with t(8;21)(q22;q22) (seven cases), AML with inv(3)(q11q26.2) (six cases), and AML with 11q23 translocations (five cases). Conclusions: This review focuses on providing updated recommendations for the rapid diagnosis of APL, discussing the types and significance of variant RARA mutations in APL-like leukemias, and refining low-blast-count (oligoblastic) AML. In addition, the significance of unique morphologic, immunophenotypic, and genetic variations in AML defined by a recurrent cytogenetic abnormality is included.

2 Abstract: The early identification of leukemia form in cancer patients can greatly increase the likelihood of recovery. Diagnostic methods that distinguish among the disease's many forms are either costly or do not exist. Amongst the existing diagnostic methods are immune- phenotype and cytogenetic abnormality, which require time to obtain results and are costly to perform due to their requirement of well equipped laboratories. Thus, there is a need for fast and cost- effective method that results in the identification of the different leukemia forms or types. Therefore, we propose the use of digital image morphological analysis of microscopic images of leukemic blood cells for the identification purpose. We present in this paper the first phase of an automated leukemia form identification system, which is the segmentation of infected cell images. The segmentation process provides two enhanced images for each blood cell; containing the cytoplasm and the nuclei regions. Unique features for each form of leukemia can then be extracted from the two images and used for identification.

Acute myeloid leukemia (AML) with t(3;5)(q25;q34), belonging to AML with myelodysplasia related changes according to WHO classification in 2008, is a subtype of AML that is particularly rare in children. NPM1/MLF1 fusion gene produced as a result of t(3;5)(q25;q34) was cloned, however, the exact mechanism of its role in leukemogenesis has not been clarified. Although this cytogenetic abnormality is regarded as an intermediate risk factor, its clinical significance is controversial until now. More cases need to be reported and investigated, therefore we present a case of AML with t(3;5)(q25;q34) in a 14-year-old girl with literature review. pISSN 2233-5250 / eISSN 2233-4580 http://dx.doi.org/10.15264/cpho.2014.21.2.149 Clin Pediatr Hematol Oncol 2014;21:149∼152

Lenalidomide (LEN) has established a new paradigm of targeted therapy in MDS. The mechanistic underpinnings of LEN efficacy are related to the synthetic lethality of this agent through its ability to bind cereblon (CRBN). LEN induces degradation of CK1α, which is encoded by the CSNK1A1 gene located on the del(5q) CDR, whereby haploinsufficient levels of this gene allow for selective toxicity to deletion mutants. Another common cytogenetic abnormality present in patients with myeloid neoplasia (MN) is -7/del(7q). To date no selective therapies exist for -7/del(7q), an urgent unfulfilled need, given the poor prognosis associated with this cytogenetic abnormality. We were interested to explore if this same notion of selective toxicity may be possible in del(7q) myeloid patients and sought to screen drugs for this focused population. From a large cohort of patients with MN (n=3,328), we found -7/del(7q) in 10% (n=316) of patients. We first identified a signature pattern of haploinsufficient genes on -7/del(7q) based on NGS. We then searched for haploinsufficient genes which, if targeted by investigational drugs, could provide a therapeutic window for selected MN subtypes in analogy to LEN in del(5q). For the purpose of our analysis, haploinsufficient expression was defined as 97) with sensitivity levels of KG-1 in the lower μM ranges. Our analysis also identified changes in death box-RNA-helicases (DDX41, DDX24,DDX54) and DNA binding proteins (CHD3), opening the possibility that MLN4924 might lead to degradation of key proteins implicated in the pathogenesis of MDS/ AML. The therapeutic index was confirmed by the absence of toxicity to normal CD34+ cells which were unresponsive to MLN4924 because they lack the expression of NEDD8-activating enzyme (NAE) (major target of MLN4924). In contrast to normal cells, NAE is highly expressed in myeloid cancer cells. In an ongoing dose-escalation study of MLN4924 plus AZA, 1 patient with -7 had stable disease after 6 cycles of therapy and 2 patients with del(7q) achieved complete and partial remissions. In sum, we propose that MN with -7/del(7q) abnormalities might represent a patient population genetically hypersensitive to synthetic lethality by neddylation inhibitors. Disclosures Hutter: MLL Munich Leukemia Laboratory: Employment. Advani:Glycomimetics: Consultancy, Research Funding; Kite Pharmaceuticals: Consultancy; Macrogenics: Research Funding; Pfizer: Honoraria, Research Funding; Amgen: Research Funding; Abbvie: Research Funding. Kelly:Novartis, Bayer, Janssen, Pharmacyclics, Celgene, Astrazeneca, Seattle Genetics: Honoraria, Speakers Bureau; Genentech, Verastem: Consultancy; Takeda: Research Funding. Saunthararajah:Novo Nordisk: Consultancy; EpiDestiny: Consultancy, Equity Ownership, Patents & Royalties. Meggendorfer:MLL Munich Leukemia Laboratory: Employment. Sekeres:Celgene: Membership on an entity's Board of Directors or advisory committees; Millenium: Membership on an entity's Board of Directors or advisory committees; Syros: Membership on an entity's Board of Directors or advisory committees. Savona:AbbVie: Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Patents & Royalties; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; Incyte Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm Therapeutics: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Selvita: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sunesis: Research Funding. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Maciejewski:Alexion: Consultancy; Novartis: Consultancy.

e19531 Background: There is uncertainty about the prognostic and predictive significance of t(11;14), long considered a standard risk cytogenetic abnormality in multiple myeloma (MM). This translocation is associated with elevated BCL-2 expression which may explain responses to venetoclax that have been reported previously. In a real-world database derived from EMR data, we sought to characterize real-world treatment patterns and outcomes from this unique MM cohort. Methods: Records for MM patients with t(11;14) diagnosed between 2000 and 2017 were identified in the COTA real-world database. Descriptive statistics were used to summarize the data. Results: 399 MM patients with t(11;14) were identified. Patient characteristics are summarized in the Table. The most frequent first-line treatments were bortezomib + dexamethasone + lenalidomide (134, 33.6%), bortezomib + cyclophosphamide + dexamethasone (69, 17.3%), and bortezomib + dexamethasone (60, 15.0%). Six (1.5%) patients received venetoclax. Response and progression-free survival data are being analyzed and will be presented at the meeting. Median overall survival was 14.3 (95% CI 10.4 – not yet reached) years. Conclusions: Real-world databases are useful in describing treatment patterns and outcomes in narrowly defined cohorts such as MM with t(11;14). The OS result reported here is unexpectedly long and will be fully explored prior to presentation. [Table: see text]

623 Background: While gain of chromosome 5q is a frequently seen cytogenetic abnormality noted to occur in patients with renal cell carcinoma (RCC), little is known about its prognostic significance. We investigated the association of gain of 5q with disease-free survival (DFS) in patients with localized (non-metastatic T1-2) RCC. Methods: All patients from UCLA with primary tumor stage T1-2 RCC who had tumor cytogenetic analysis on tumor specimen were included. Alterations in chromosome 5q was specifically reviewed in this study. Logistic regression analyses were used to assess association of gain of 5q with final histopathology, ISUP grading, and T-stage. Cox proportional hazard modeling and Kaplan-Meier analyses were used to assess the impact of gain of 5q on DFS. Recurrence was defined as any local recurrence or development of new metastasis. Results: A total of 676 patients were included in this study. Gain of 5q occurred in 108 (16%) patients and was more commonly seen in clear cell versus non-clear cell tumors (19% vs. 9%, p = .002). Gain of 5q was associated with low grade ISUP (1 or 2) of clear-cell RCC (p = 0.011). On survival analysis, there was a 67% decreased risk of RCC recurrence for patients with gain of 5q (HR = 0.33, p = 0.018). The 5- and 10-year risk of recurrence was 2% vs. 16% and 14% vs. 28% for patients with and without gain of 5q, respectively (p = 0.013). In multivariable Cox analysis, the gain of 5q was an independent prognostic factor (p = .026 with ISUP grade and p = .025 with T-stage). These findings were confirmed among clear-cell RCC subgroup. Conclusions: Gain of chromosome 5q is an independent prognostic factor associated with decreased risk of recurrence in patients with localized T1-2 renal cell carcinoma. Identifying patients with a gain of 5q will improve the stratification of the risk of recurrence, could allow to adapt the follow-up protocols and avoid adjuvant treatment.

626 Background: Several tumor-suppressor genes have been mapped to chromosome 10q, including PTEN. While loss of 10q is a frequently seen cytogenetic abnormality noted to occur in patients with renal cell carcinoma (RCC), little is known about its prognostic significance. We investigated the association of loss of 10q with pathological features and disease-free survival (DFS) in patients with localized RCC. Methods: All patients from UCLA with primary localized RCC who had tumor cytogenetic analysis were included. Alterations in chromosome 10q was specifically reviewed for this study. Logistic regression analyses were used to assess association of loss of 10q with ISUP grading, and T-stage. Cox proportional hazard modeling and Kaplan-Meier analyses were used to assess the impact of loss of 10q on DFS and OS. Recurrence was defined as any local recurrence or development of new metastasis after surgery. Results: A total of 886 patients were included in this study. Loss of 10q occurred in 68 (7.7%) patients and was more commonly seen in chromophobe subtype (24% vs. 6% in non-chromophobe RCC, p < .0001). Loss of 10q was associated with greater tumor size (mean 6.3 vs 5.1 cm, OR = 1.085 [1.024-1.150], p = .008), T3-stage (37% vs 23%, OR = 1.99 [1.17-3.39], p = .011), and ISUP 3-4 (61% vs 37%, OR = 2.64 [1.58-4.40], p < .0001). On survival analysis, after a mean follow-up of 55 months, these patients had a shorter time to recurrence (Log-rank p = .026) and a worse DFS (HR = 2.15 [1.32-3.50], p = .002) than those without loss of 10q. These findings were confirmed on clear-cell RCC subgroup with also a worse OS (HR = 2.00 [1.09-3.67], p = .026) with an estimated 34% risk of death at 5 years for patients with loss of 10q. Conclusions: Loss of chromosome 10q is a prognostic factor associated with larger tumor size, higher grade and T-stage, and worse survival in patients with localized RCC. Identifying patients with loss of 10q can provide additional prognostic information to clinicopathologic variables.

Pure distal monosomy of the long arm of chromosome 10 is a rare cytogenetic abnormality. The location and size of the deletions described in this region are variable. Nevertheless, the patients share characteristic facial appearance, variable cognitive impairment and neurobehavioral manifestations. A Minimal Critical Region corresponding to a 600 kb Smallest Region of deletion Overlap (SRO) has been proposed. In this report, we describe four patients with a distal 10q26 deletion, who displayed attention-deficit/hyperactivity disorders (ADHD). One of them had a marked behavioral profile and relatively preserved cognitive functions. Interestingly, the SRO was not included in the deleted segment of this patient suggesting that this deletion could contain candidate genes involved in the control of neurobehavioral functions. One of these candidates was the CALY gene, known for its association with ADHD patients and whose expression level was shown to be correlated with neurobehavioral disturbances in varying animal models. This report emphasizes the importance of the behavioral problems as a cardinal feature of the 10q microdeletion syndrome. Haploinsufficiency of CALY could play a crucial role in the development of the behavioral troubles within these patients.

Nearly 15% of the couples worldwide face the problem of infertility. A number of cytogenetic aberrations in the form of somatic chromosome aneuploidies, sperm aneuploidies, chromosomal translocations and inversions, etc. are known to contribute to male infertility. Couples with normal hormonal profile should be evaluated for possible cytogenetic abnormalities before proceeding to treatment. The identification of cytogenetic abnormality cannot only explain infertility but also guide treatment in the affected cases. This chapter summarizes the cytogenetic factors that increase the risk of male infertility. Towards the end, we have provided a glimpse of the contemporary techniques that have revolutionized the classical field of cytogenetics.

Embryonal tumor with multilayered rosettes (ETMR) is a new entity in the group of primitive neuroectodermal tumors of the central nervous system (CNS). It combines histopathological features of neuroblastoma and ependymoblastoma. This tumor occurs mostly in the first five years of life. A hallmark cytogenetic abnormality at the chromosome locus 19q13.42 has been identified. The authors report a case of ETMR in the parietooccipital region in a 3-year-old girl who presented with features of raised intracranial tension. The exact diagnosis could be made by the finding of true rosettes in a single low power field. ETMR is a newly described rare pediatric CNS tumor and large case studies regarding its differentiation from usual PNETs are lacking. Reporting each case with the morphological features of this tumor would add to the existing data on these tumors as regards pathology, diagnosis and management.

Chromosome/DNA instability could be one of the primary causes of malignant cell transformation. The objective of the present study was to evaluate the spontaneous genetic damages in exfoliated cells of buccal mucosa of head and neck cancer (HNC) by counting micronucleus (MN) and binucleated (BN) cells frequencies. MN and BN frequencies were significantly increased in HNC patients compared with controls (5.53 ± 3.09/1000 cells, 5.63 ± 2.99/1000 cells versus 2.36 ± 2.11/1000 cells, 3.09 ± 1.82/1000 cells,P<0.001). Regarding the gender and the age, the frequencies of the MN and BN were significantly higher than those of controls (P<0.01). The evaluation of the MN and BN frequencies revealed a significant increase (P<0.001) in the cases in relation to the control group after controlling the risk factors (tobacco smoking and chewing and occupational exposure) of HNC. Moreover, MN and BN frequencies were significantly increased in smokers and chewers compared with nonsmokers and nonchewers among patients (P<0.05). MN frequency was significantly (P=0.014) different between patients occupationally exposed (6.99 ± 3.40/1000 cells) and nonexposed (4.70 ± 2.48/1000 cells) among HNC group. The logistic regression model illustrated that HNC was significantly associated with frequencies of MN (OR = 8.63,P<0.0001) and BN (OR = 5.62,P=0.001). Our results suggest that increased chromosome/DNA instabilities may be associated with HNC.

Hall et al. (2010) describe a boy with mosaic trisomy of the proximal part of 19q, with obesity, macrocephaly and global developmental delay. The patient is interesting with regard to his cytogenetic abnormality, which is smaller than those previously reported, and does not include the candidate obesity and insulin-resistance genes identified by other authors (Zung et al., 2007; Davidsson et al., 2010) as possible causes of the overweight/obesity seen in four of five previously documented patients. This suggests that a novel obesity locus may reside in the duplicated region 19q13.11–q13.2. We present a phenotypically similar boy with intrachromosomal insertion of material derived from proximal 19q into proximal 19p, causing mosaic trisomy 19q12–q13.2, and consider the role of USF2, a master transcriptional regulator of metabolic genes, in 19q phenotypes.

Lenalidomide is approved in the United States for various indications, including multiple myeloma (MM), myelodysplastic syndrome associated with a deletion 5q cytogenetic abnormality and relapsed, ...

del(20q) can be observed in hematologic neoplasms, including chronic myelogenous leukemia (CML), and has been reported in patients undergoing blast transformation. We describe 10 patients with CML in hematologic and cytogenetic remission with del(20q) detected by conventional cytogenetics. There were 6 men and 4 women with a median age of 56 years. All patients initially had BCR-ABL1 and t(9;22) (q34;q11.2) and achieved morphologic and cytogenetic remission after therapy. del(20q) was identified before (2/10 [20%]), at the time of (3/10 [30%]), or after (5/10 [50%]) cytogenetic remission and was not associated with morphologic evidence of dysplasia. At last follow-up, no patients had a myelodysplastic syndrome (MDS). Leukocyte and platelet counts were normal; 4 of 10 patients had mild anemia. Nine patients have remained in morphologic and cytogenetic remission with stable del(20q). BCR-ABL1 fusion transcript levels were absent or low (median, 0.01%). Recently, in 1 patient, recurrent CML developed and del(20q) was lost. We conclude that del(20q) in the setting of CML in remission is not predictive of MDS or blast transformation.

We report 23 consecutive pediatric patients with MDS who received allogeneic HSCT on IRB approved protocols between 1992 and 2009 at Children's Memorial Hospital (Chicago, IL). Nine patients had de novo MDS, whereas 14 patients had treatment-related MDS. All patients had a documented cytogenetic abnormality, and monosomy 7/7q- was seen in 12 patients (52%). Fourteen of 23 patients received a myeloablative conditioning regimen; RIC regimens were used for the remaining nine. Five patients relapsed post-transplant, including four patients who received RIC transplant and four patients with treatment-related MDS. For the entire group, estimated five-yr RFS and OS were 47% and 50%, respectively. Treatment-related MDS was associated with decreased RFS in comparison with de novo MDS (33% vs. 70%, p = 0.05). Five-year OS rates reached 80% for those with de novo MDS. RIC regimens were associated with decreased three-yr RFS in comparison with myeloablative regimens (22% vs. 68%, p = 0.02). There was no correlation of survival with blast count at diagnosis, IPSS score, cytogenetic abnormality, donor type, or HLA match. Larger series are needed to confirm prognostic factors so that higher-risk patients can be targeted with novel approaches.

The t(8: 21)(q22;q22) is the most common cytogenetic abnormality, usually with a favorable risk, in acute myeloid leukemia (AML). This translocation is not only of diagnostic significance but also has impact on survival outcomes and therapeutic implications. However, patients with adverse outcome in this category of recurrent genetic abnormalities have additional cytogenetic/molecular aberrations with elevated white blood cells count, CD56 expression, and extramedullary manifestations. This case is reported with aim to describe an elderly female who had a sudden downhill clinical course in de novo AML-FAB class M2 in spite of t(8;21), which was associated with monosomy 7 as an additional chromosomal abnormality and absence of high risk clinically relevant genetic mutations.

Introduction Ibrutinib, a first-in-class, oral, covalent inhibitor of Bruton's tyrosine kinase, is approved in many countries for treatment-naïve (TN) and previously treated CLL, supported by improved response rates, progression-free survival (PFS), and overall survival (OS) vs chlorambucil in RESONATE-2™ (NCT01722487; Burger JA, et al. N Engl J Med. 2015;373:2425-2437) and ofatumumab in RESONATE™ (NCT01578707; Byrd JC, et al. N Engl J Med. 2014;371:213-223). We analyzed survival outcomes for ibrutinib vs RW treatments for TN and relapsed/refractory (R/R) CLL by del11q status, an adverse prognostic factor linked with poor patient outcomes despite conventional chemoimmunotherapy. An adjusted comparison restricted to patients with confirmed del11q status was conducted using patient-level data from RESONATE-2™ and RESONATE™ and RW databases from 2 countries. Methods The Lyon-Sud RW database holds medical records for CLL patients diagnosed between 1980 and 2017 from the Centre Hospitalier Lyon-Sud, France; the Chronic Lymphocytic Leukemia Registry (CLLEAR) RW database holds medical records for CLL patients diagnosed between 1988 and 2017 from 7 academic centers in the Czech Republic. TN CLL database patients were selected using RESONATE-2™ criteria (which excluded those aged < 65 years or del17p positive). For the R/R group, patients ≥ 18 years of age or those with del17p were allowed per RESONATE™ inclusion criteria. PFS and OS outcomes by del11q status were compared between the ibrutinib arms of RESONATE-2™/RESONATE™ and physicians' choice (PC) treatment in the pooled RW databases (excluding ibrutinib). A multivariate Cox proportional hazards model was fitted on pooled RCT/RW data to estimate adjusted hazard ratios (HRs) for effect of ibrutinib vs RW PC treatment using age, sex, and treatment line as covariates. The unit of observation for the RW databases was the treatment line (rather than patient) number; RW patients receiving multiple lines of therapy contributed to multiple observations, and baseline was defined as the line-specific treatment start date. Results For the RW TN cohort, 466 treatment lines were analyzed; 134 (28.8%) patients were del11q positive. In RESONATE-2™, 29/136 (21.3%) TN patients were del11q positive. The table below shows adjusted HRs for PFS and OS for patients with/without del11q. For the del11q-positive subgroup, adjusted HRs for ibrutinib vs RW PC first-line (1L) therapy were 0.02 (95% confidence interval [CI], 0.00-0.17; p = 0.0002) for PFS and not estimable for OS (no deaths on ibrutinib). For the del11q-negative subgroup, adjusted HRs were 0.34 (95% CI, 0.2-0.57; p < 0.0001) for PFS and 0.74 (95% CI, 0.37-1.49; p = 0.3957) for OS. For second-line (2L) PC treatment in the RW R/R cohort, 385 treatment lines were analyzed; 135 (35.1%) were from del11q positive patients. In RESONATE™, 13 (37.1%) 2L patients were del11q positive. For the del11q-positive subgroup, adjusted HRs for ibrutinib vs RW PC of 2L therapy were 0.03 (0.00-0.21; p = 0.0003) for PFS and 0.08 (0.01-0.46; p = 0.0050) for OS. For the del11q-negative subgroup, adjusted HRs were 0.27 (0.14-0.51; p < 0.0001) for PFS and 0.50 (0.24-1.05; p = 0.0670) for OS. For 2L and beyond (2L+) treatment in the RW R/R cohort, 727 treatment lines were analyzed; 291 (40.0%) were from del11q positive patients. In RESONATE™, 63/195 (32.3%) 2L+ patients were del11q positive. For the del11q-positive subgroup, adjusted HRs (95% CIs) for ibrutinib vs RW PC of 2L+ therapy were 0.13 (0.08-0.20; p < 0.0001) for PFS and 0.15 (0.08-0.26; p < 0.0001) for OS. For the del11q-negative subgroup, adjusted HRs were 0.20 (0.14-0.29; p < 0.0001) for PFS and 0.33 (0.21-0.52; p < 0.0001) for OS. Concl usions Adjusted comparisons of the registration trial (RESONATE-2™/RESONATE™) and RW patient-level data suggest that OS and PFS improvements with ibrutinib vs PC therapies are pronounced for patients with CLL harboring del11q compared with those who are del11q negative. The findings inform physicians of the comparative effectiveness of ibrutinib in the RW for patients with this high-risk cytogenetic abnormality. Funding Source: This project was sponsored by Janssen Pharmaceutica NV, and Pharmacyclics LLC, an AbbVie Company. The real-world databases are independently owned. Writing assistance was provided by Emma Fulkes of PAREXEL and funded by Janssen Pharmaceutica NV. Disclosures Salles: Takeda: Honoraria; Acerta: Honoraria; Epizyme: Honoraria; Pfizer: Honoraria; Amgen: Honoraria; AbbVie: Honoraria; Gilead: Honoraria; Roche: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Novartis: Consultancy, Honoraria; Servier: Honoraria; Janssen: Honoraria; Merck: Honoraria; Morphosys: Honoraria. Besson:Janssen Pharmaceutica NV: Employment. Doyle:Janssen Pharmaceutica NV: Employment. Garside:Janssen Pharmaceutica NV: Employment. Spacek:Roche: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Gilead: Consultancy, Honoraria. Doubek:Novartis: Consultancy; AbbVie: Consultancy, Research Funding; Roche: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Affimed: Research Funding; Gilead: Consultancy, Honoraria, Research Funding.

Monosomy 7 and/or deletion of the long arm of chromosome 7 is a common cytogenetic aberration in children with myelodysplastic syndrome (MDS) and is associated with poor outcome. In this report, we present an unusual cytogenetic abnormality leading to loss of both the whole short and whole long arms of chromosome 7, which was found in the bone marrow cells of three pediatric patients with MDS. Using a combination of conventional and molecular cytogenetic methods, a tiny "dot-like" marker chromosome was found and described as der(7)del(7)(p11)del(7)(q11). Together with one previously published case, this chromosomal aberration represents a new rare recurrent karyotypic abnormality involving chromosome 7 in children with MDS.

7068Background: Cytogenetics is the backbone of the R-IPSS for MDS, contributing the most points (0 to 4) to the total scoring system. The current R-IPSS cytogenetics does not factor in the clone s...

e19025Background: The interstitial deletion of the long arm of chromosome 5—del(5q)—is the most common cytogenetic abnormality in MDS occurring either as a sole aberration or as a part of complex k...

We herein report the case of a 35-month-old female child presenting with mesenchymal hamartoma of the liver (MHL), with t(11;19)(q13;q13.4) originating in the caudate lobe. This case is the eighth known description of a cytogenetic abnormality in mesenchymal hamartoma of the liver. It is similar to the seven cases previously reported, in that one of the breakpoints involves the chromosome band 19q13.3 or 19q13.4, but it is the first report of an abnormality originating in the caudate lobe.

Clinical descriptions of individuals with partial deletion of the distal short arm of chromosome three have been reported rarely. A characteristic phenotype has been proposed. We present another patient with this cytogenetic abnormality whose physical and developmental features show similarities with, as well as differences from, previously reported cases. This suggests that the clinical phenotype requires further definition. In addition, gene dosage studies were undertaken on several serum proteins in order to try to map the location of the responsible genes on chromosome three.

Ring chromosome 3, r(3), is an extremely rare cytogenetic abnormality with clinical heterogeneity and only 12 cases reported in the literature. Here, we report a 1-year-old girl presenting distinctive facial features, developmental delay, and congenital heart defects with r(3) and a ∼10-Mb deletion of chromosome 3pterp25.3 (61,891-9,979,408) involving 42 known genes which was detected using G-banding karyotyping and CytoScan 750K-Array. The breakpoints in r(3) were mapped at 3p25.3 and 3q29. We also analyzed the available information on the clinical features of the reported cases with r(3) and 3p deletion syndrome in order to provide more valuable information of genotype-phenotype correlations. To our knowledge, this is the largest detected fragment described in r(3) cases and the second r(3) study using whole-genome microarray.

Myxoinflammatory fibroblastic sarcoma (MIFS) is a rare, low-grade sarcoma characterized by distinctive, large, and bizarre Reed–Sternberg–like cells associated with an intense inflammatory infiltrate. The biology of MIFS is still poorly understood, and only two previous cases had been studied cytogenetically. In the present case, analysis of MIFS in the foot of a 53-year-old man revealed the chromosome translocation t(2;6)(q31;p21.3) as the only cytogenetic abnormality. This finding is distinct from the two cases previously reported. Additional studies are needed to verify whether any of these chromosome rearrangements are involved recurrently in MIFS.

We describe a patient with acute leukemia of ambiguous lineage who had trisomy 4 as the sole cytogenetic abnormality. Clinical, pathological, immunophenotypic and molecular features are presented and compared with the previous 4 published cases. Over expression of c-kit, which is localized to chromosome 4, was documented on the leukemic blasts. Prognosis seems to be poor. Treatment with acute lymphoblastic leukemia like regimens seems to be superior compared to acute myeloid leukemia like regimens and allogeneic stem cell transplant is recommended after achieving remission., Highlights • Acute leukemia of ambiguous lineage with trisomy 4 as the sole abnormality is a rare disease. • Clinical and pathological details of a case are presented and compared with prior 4 published cases. • Over expression of c-kit, localized to chromosome 4, may play a pathogenic role in this disease. • Prognosis seems to be poor. • Treatment with ALL like regimens seems to be superior compared to AML like regimens.

Clinical course and cytogenetic analysis suggest that myelodysplasia (MDS) is one step in a multistep model of malignant transformation of haematopoietic stem cells to acute myeloid leukaemia (AML). We report a further case of MDS associated with trisomy 2, and comment on the significance of the cytogenetic abnormality, which as a sole abnormality only occurs in MDS, but is found in combination with other chromosomal abnormalities in AML. Previous reports on balanced and unbalanced chromosomal abnormalities associated with therapy related MDS and therapy related AML suggest that trisomy 2 is an early chromosomal abnormality in leukaemogenesis.

Mesenchymal chondrosarcoma is a rare malignant tumor that comprises about 3-10% of all sarcomas. Reports of cytogenetic studies of mesenchymal chondrosarcoma are limited and no consistent cytogenetic abnormality has surfaced. Some mesenchymal chondrosarcomas have a t(11;22) translocation suggesting a relationship with the PNET/Ewing tumor family. We report what to our knowledge is the first case of trisomy 8 as the sole cytogenetic abnormality in a mesenchymal chondrosarcoma.

A clear cell sarcoma from the kidney of a 12-month-old male child manifested a balanced translocation, t(10;17)(q22;p13). This is the second report of this cytogenetic abnormality in renal clear cell sarcoma.