Artículos de revistas: "Cytogenetics"

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Vance, Gail H., Haesook Kim, Gary Hicks, Athena Cherry, Rodney Higgins, Martin S. Tallman, Hugo F. Fernandez, and Gordon Dewald. "Utility of Interphase FISH To Stratify Patients into Cytogenetic Risk Categories at Diagnosis of AML in an ECOG Clinical Trial (E1900)." Blood 106, no. 11 (November 16, 2005): 2377. http://dx.doi.org/10.1182/blood.v106.11.2377.2377.

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Abstract Background: Cytogenetic risk categories based on conventional chromosome studies are widely used in clinical practice to make treatment decisions for AML. We evaluated the efficacy of interphase FISH to detect chromosome anomalies in the workup of young (&lt;60 years) patients with AML. Methods: Study subjects were enrolled in E1900, a front-line Eastern Cooperative Oncology Group (ECOG) clinical trial for AML. This is an on-going Phase III clinical trial with Daunorubicin dose-intensification ± Gemtuzumab-Ozogamicin consolidation therapy prior to stem cell transplant. This trial opened December 2002; as of February 2005, 223 patients were enrolled. The protocol was designed to collect bone marrow for both cytogenetic and FISH studies at study entry (diagnosis). Cytogenetic studies were done by local laboratories with results reviewed centrally by the ECOG Cytogenetics Committee. Each case was classified as acceptable or unacceptable based on predefined ECOG cytogenetic criteria. FISH for each patient was performed in the ECOG FISH laboratory at Mayo Clinic and utilized eight probe sets to detect t(8;21), t(9;22), t(11;var), t(15;17), inv(16), +8, −5/5q, and −7/7q (Vysis, Downer Grove, IL). Results: 64 (29%) of 223 specimens had incomplete cytogenetic and/or FISH results. We analyzed the remaining 159 (71%) specimens with complete cytogenetic and FISH results. Results for each specimen were classified by probe set into one of the following categories: Normal cytogenetics and normal FISH; Abnormal cytogenetics and abnormal FISH for the anomaly the probe was designed to detect; Abnormal cytogenetics and abnormal FISH for an anomaly the probe was not primarily designed to detect; Normal cytogenetics and abnormal FISH; Abnormal cytogenetics and normal FISH; or Abnormal cytogenetics and abnormal FISH that further defined the karyotype. Figure 1: Results for 159 patients by category and FISH probe set: *t(8;21); t(9;22); t(11;var); t(15;17); inv(16); cen(8); del(5/5q); de(7/7q). Figure 1:. Results for 159 patients by category and FISH probe set: *t(8;21); t(9;22); t(11;var); t(15;17); inv(16); cen(8); del(5/5q); de(7/7q). The concordance rate between cytogenetic and FISH results ranged from 97 to 100% for all probe sets and kappa analysis for concordance had a p value of &lt;0.0001. Of the total 159 cases, discrepancies between FISH and cytogenetic results occurred in only 4 cases; two with normal cytogenetics and abnormal FISH and two with abnormal cytogenetics and normal FISH results. Conclusions: The high level of agreement between cytogenetics and FISH demonstrates the accuracy of a panel of 8 FISH probe sets for the detection of significant abnormalities in AML. The data from this investigation support the use of FISH as an adjunct in cases of failed cytogenetic analyses to increase the yield of useful cytogenetic results in large cooperative trials. Furthermore, because of the strong correlation between cytogenetics and FISH, our results demonstrate the potential of FISH as a follow-up study of minimal residual disease in ECOG trials.

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Chennamaneni, Rachana, Sadashivudu Gundeti, Meher Lakshmi Konatam, Stalin Bala, Ashok Kumar, and Lakshmi Srinivas. "Impact of cytogenetics on outcomes in pediatric acute lymphoblastic leukemia." South Asian Journal of Cancer 07, no. 04 (October 2018): 263–66. http://dx.doi.org/10.4103/sajc.sajc_13_18.

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Abstract Context: In acute lymphoblastic leukemia (ALL), the most important prognostic factors are age, leukocyte count at presentation, immunophenotype, and cytogenetic abnormalities. The cytogenetic abnormalities are associated with distinct immunologic phenotypes of ALL and characteristic outcomes. Aims: The present study was primarily aimed at analyzing the impact of cytogenetics on postinduction responses and event-free survival (EFS) in pediatric patients with ALL. The secondary objective was to study the overall survival (OS). Subjects and Methods: A total of 240 patients with age <18 years and diagnosed with ALL between January 2011 and June 2016 were retrospectively analyzed. Cytogenetics was evaluated with conventional karyotyping or reverse transcriptase polymerase chain reaction. Based on cytogenetic abnormalities, the patients were grouped into five categories, and the outcomes were analyzed. Results: Of the 240 patients, 125 (52%) patients had evaluable cytogenetics. Of these, 77 (61.6%) patients had normal cytogenetics, 19 (15.2%) had t(9;22) translocation, 10 (8%) had unfavorable cytogenetics which included t(9;11), hypodiploidy, and complex karyotype, 10 (8%) had favorable cytogenetics which included t(12;21), t(1;19), and high hyperdiploidy, 9 (7.2%) had miscellaneous cytogenetics. Seventy-one percent of patients were treated with MCP 841 protocol, while 29% of patients received BFM-ALL 95 protocol. The 3-year EFS and OS of the entire group were 52% and 58%, respectively. On univariate analysis, EFS and OS were significantly lower in t(9;22) compared to normal cytogenetics (P = 0.033 and P = 0.0253, respectively) and were not significant for other subgroups compared to normal cytogenetics. On multivariate analysis, EFS was significantly lower for t(9;22) and unfavorable subgroups. Conclusions: Cytogenetics plays an important role in the molecular characterization of ALL defining the prognostic subgroups. Patients with unfavorable cytogenetics and with t(9;22) have poorer outcomes.

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Koenecke, Christian, Gudrun Göhring, Liesbeth de Wreede, Anja van Biezen, Christof Scheid, Liisa Volin, Johan Maertens, et al. "Prognostic Value Of Five-Group Cytogenetic Risk Classification In Patients With MDS After Allogeneic Hematopoietic Stem Cell Transplantation: A Retrospective Multicenter Study Of The Chronic Malignancies Working Party Of The EBMT." Blood 122, no. 21 (November 15, 2013): 2092. http://dx.doi.org/10.1182/blood.v122.21.2092.2092.

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Abstract Introduction The only curative treatment approach for patients with myelodysplastic syndromes (MDS) is allogeneic hematopoietic stem cell transplantation (HSCT), but disease relapse after transplantation is a major concern. Predictors for disease outcome after HSCT are limited. However, unfavorable cytogenetic abnormalities have been shown to serve as predictors for MDS-relapse after transplantation. Similar to the data available in MDS-patients not undergoing HSCT (Schanz et al. J Clin Oncol 2012), there is evidence that the novel 5-group cytogenetic classification has a better predictive value for outcome after HSCT than standard IPSS cytogenetics (Deeg et al. Blood 2012). The aim of this large multicentric, international study was to retrospectively determine the impact of the new 5-group cytogenetic MDS classification on outcome after HSCT. Patients and Methods Patients were selected from the EBMT database who had received HSCT for the treatment of MDS between 1982 and 2010 and for whom sufficient cytogenetic information was available. In total, 903 patients were included into the study. At time of HSCT, 97 (10.7%) patients had untreated MDS, 218 (24.1%) patients had advanced MDS or AML evolving from MDS in complete remission, and 227 (25.1%) patients were not in remission after treatment (in 12.3% information on stage of the disease was not available). Median time between diagnosis and transplant was 6.6 months (range 0.2-359.3). Matched related donor HSCT was performed in 574 patients (63.6%), and matched unrelated donor HSCT in 329 patients (36.4%). Bone marrow (35.4%) or peripheral blood (64.6%) served as stem cell graft. Myeloablative preparative regimens were used in 582 patients (64.5%), and a non-myeloablative regimen was given to 320 patients (35.4%). Impact of cytogenetic classification was analyzed in uni- and multivariate models regarding overall survival (OS) and relapse free survival (RFS) after HSCT. Predictive performance of the 2 classifications was compared by means of the cross-validated log partial likelihood. Results Estimated 5-year RFS and OS were 32% and 36% respectively. According to the 5-group cytogenetic classification 19 (2.1%) patients had very good risk cytogenetics, 204 (22.6%) normal risk cytogenetics, 438 (48.5%) intermediate risk cytogenetics, 178 (19.7%) poor risk cytogenetics, and 64 (7.1%) very poor risk cytogenetics. Good, intermediate, and poor risk cytogenetics according to IPSS were found in 192 (38.0%), 500 (40.2%), and 211 (23.7%) patients, respectively. In univariate analysis 5-group cytogenetic information was found to be strongly associated with OS and RFS (OS: log-rank test P<.01, RFS: P<.01) (Figure 1). Further clinicopathologic factors showed a significant impact on impaired OS and RFS: Disease status at HSCT (RA/RARS no pretreatment; RAEB(t)/sAML in CR; RAEB(t)/sAML not in CR, RAEB(t)/sAML untreated) (OS: P<.01, RFS: P<.01) and IPSS cytogenetics (good; intermediate; poor) (OS: P<.01, RFS: P<.01). Patient age showed an impact for RFS (P=.05), but not for OS (P=.09). In multivariate analysis, statistically significant predictors for RFS and OS at HSCT were 5-group cytogenetics, IPSS-cytogenetics, disease status and patient's age. Using 5-group cytogenetics classification, patients with poor risk [(RFS: P=.001, HR=1.40 (95% CI: 1.15-1.71); OS: P=.003, HR=1.38 (95% CI: 1.12-1.70)] or very poor risk cytogenetics [(RFS: P<.001, HR=2.14 (95% CI: 1.6-2.9); OS: P<.001, HR=2.14 (95% CI: 1.59-2.87)] had worse RFS and OS than patients in the other 3 risk groups. Patients with very poor risk cytogenetics had worse RFS and OS compared to patients with poor risk cytogenetics [(RFS: P<.01, HR=1.53 (95-% CI: 1.11-2.11), OS: P<.01, HR=1.55 (95-% CI: 1.11-2.15)]. When comparing the predictive performance of a series of 3 models both for OS and for RFS – (1) with only classical risk factors, (2) these extended with IPSS cytogenetics, (3) extended with 5-group classification instead-, the model with 5-group cytogenetics performed best. Conclusion In this international, multicentric analysis we confirm that MDS patients with poor and very poor risk cytogenetics had significantly worse RFS and OS after HSCT than patients in the other risk groups of the 5-group cytogenetic classifier. New therapeutic strategies to prevent relapse after HSCT in patients with poor or very poor cytogenetics are urgently needed. Disclosures: No relevant conflicts of interest to declare.

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Kim, Sung-Yong, Jong-Wook Lee, Byung-Sik Cho, Ki-Seong Eom, Yoo-Jin Kim, Seok Lee, Chang-Ki Min, et al. "Clinical Implications of Abnormal Cytogenetics at Diagnosis of Aplastic Anemia." Blood 108, no. 11 (November 16, 2006): 986. http://dx.doi.org/10.1182/blood.v108.11.986.986.

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Abstract Because cytogenetic abnormalities of aplastic anemia at diagnosis have been reported fairly infrequently, their clinical implications have not known yet. A retrospective study was performed of the cytogenetics findings and clinical courses in patients with typical morphological and clinical features of aplastic anemia from a single institution for the years 1995 through 2005. The results of chromosome analysis of 610 patients were evaluable. Of the evaluable patients, 584 (95.7 %) had normal karyotypes and 26 (4.3 %) had abnormal karyotypes at diagnosis. The most frequent abnormality was trisomy 8 (n=13) followed by deletion 1q (n=5) and monosomy 7/deletion 7q (n=5). Other chromosome abnormalities were isochromosome 17q (n=1), trisomy 15 (n=1) and monosomy 21 (n=1). Among the 584 patients with typical aplastic anemia and no cytogenetic abnormalities, only two developed MDS/AML during the follow-up period, while 5 (19.2%) of 26 patients with typical aplastic anemia and abnormal cytogenetics subsequently developed MDS/AML. The incidence of secondary MDS/AML was statistically higher in abnormal cytogenetics group compared with normal cytogenetics group (p&lt;0.001). The incidence of secondary MDS/AML was not influenced by immunosuppressive therapy (IST) (p=0.715). The patients with trisomy 8 responded poorly to immunosuppressive therapy (IST) and showed statistically significant lower response rate compared with the patients with other cytogenetics (p=0.033). However, response rates of IST were not statistically different in the patients with normal cytogenetics group and the patients with abnormal cytogenetics other than trisomy 8 (p=1.000). Four patients with abnormal cytogenetics received allogeneic hematopoietic stem cell transplantations (allo-HSCT) with the same conditioning as the patients with normal cytogenetics. Three of them are still alive with normal peripheral blood counts. One of them died of acute GVHD and infection after successful engraftment. Our analysis suggested that cytogenetic abnormalities at diagnosis of aplastic anemia could be a risk factor for development of secondary MDS/AML and the patients with trisomy 8 at diagnosis of aplastic anemia might hardly respond to IST. Outcomes of allo-HSCT for aplastic anemia with abnormal cytogenetics probably are not different compared with aplastic anemia with normal cytogenetics.

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Kim, Sung-Yong, Myungshin Kim, Kyungja Han, Seok Lee, Mark Hong Lee, Jong-Wook Lee, Woo-Sung Min, and Chun-Choo Kim. "Characteristics and Clinical Outcomes of Adult Aplastic Anemia with Abnormal Cytogenetics at Diagnosis." Blood 112, no. 11 (November 16, 2008): 2039. http://dx.doi.org/10.1182/blood.v112.11.2039.2039.

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Abstract Background and methods Occasionally, patients with acquired aplastic anemia (AA) present with abnormal cytogenetics in bone marrow cells at diagnosis. The diagnosis and treatment of such patients have not been established and have been center-dependent. We have treated adult AA patients with abnormal cytogenetics in a same way as those with normal cytogenetics. Presently, the characteristics and clinical outcomes of 600 adult AA patients who had successful cytogenetics at diagnosis were retrospectively evaluated. Our aim was to determine the characteristics and clinical courses of AA patients with cytogenetic abnormalities at diagnosis who were treated as those with normal cytogenetics. Results Characteristics : Of the evaluable patients, 572 (95.3 %) had normal cytogenetics and 28 (4.7 %) had abnormal cytogenetics at diagnosis. The most frequent abnormality was trisomy 8 (n=15) followed by monosomy 7/deletion 7q (n=5) and deletion 1q (n=5). Other chromosome abnormalities were isochromosome 17q (n=1), trisomy 15 (n=1) and monosomy 21 (n=1). There was no significant statistical difference in gender (P=0.562), Hepatitis B or C infection (P=0.402), paroxysmal nocturnal hemoglobinuria (P=0.709) and severity of AA (P=0.325) between patients displaying normal cytogenetics and abnormal cytogenetics. The age of abnormal cytogenetics patients was significantly lower than normal cytogenetics patients (P&lt;0.001). Immunosuppressive therapy : A total of 334 patients received immunosuppressive therapy using antithymocyte globulin and cyclosporine. Six months after commencement of therapy, 165 (50.9 %) patients responded partially or completely. Multivariate analysis revealed abnormal cytogenetics (HR=0.250; 95% CI=0.077–0.808; P=0.021), absence of paroxysmal nocturnal hemoglobinuria and age (≥ 67) as independent predictors for the poor response to immunosuppressive therapy. Leukemic transformation : Kaplan-Meier modeling revealed that abnormal cytogenetics was also associated with higher cumulative leukemic transformation rate (P&lt;0.001) and lower leukemia-free survival (P=0.021). Of note, the cause of all deaths in non-severe AA patients with abnormal cytogenetics was leukemic transformation. Conclusion: Patients with abnormal cytogenetics at diagnosis of AA tend to respond poorly to immunosuppressive therapy and present with a high leukemic transformation risk, which suggests that cytogenetic abnormalities should be emphasized more than morphological features in diagnosis and treatment decision in AA.

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Larson, Melissa L., Ann M. Thomas, Nitin Goyal, Jamile M. Shammo, John J. Maciejewski, Stephanie A. Gregory, and Parameswaran Venugopal. "Efficacy of a Two Day Induction Regimen for De Novo and Secondary AML with Intermediate and Adverse Cytogenetic Profiles." Blood 112, no. 11 (November 16, 2008): 4027. http://dx.doi.org/10.1182/blood.v112.11.4027.4027.

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Abstract Background: Cytogenetic data remains one of the most powerful prognostic factors for predicting response and survival in adult AML patients. The relationship between cytogenetics and induction response to the standard “7+3” regimen has been analyzed in the past. In a CALGB study, patients with favorable cytogenetics achieved a complete remission (CR) rate of 88%, those with intermediate cytogenetics achieved a 67% CR rate and those with adverse cytogenetics had a 32% CR rate (Byrd et al. Blood100: 4325, 2002). We present a retrospective analysis of the correlation between the hierarchical cytogenetic groups and complete remission rate following induction of AML using a novel induction regimen. This regimen was developed based on the concept of timed sequential therapy. The first pulse of chemotherapy recruits leukemic cells into the cell cycle while the second pulse is given at a time of peak cell recruitment. It utilizes two highly active anti-leukemic drugs: cytarabine, a cell cycle-specific drug, and mitoxantrone, which has a favorable cardiac toxicity profile. Patients and Methods: One hundred four patients with AML were treated with two days of chemotherapy given 96 hours apart from April 1997 to April 2008. Each day consisted of two doses of cytarabine 2gm/m2 (at t=0 and t=12) followed by one dose of mitoxantrone 30 mg/m2 administered after the second cytarabine dose (t=15). Bone marrow biopsies were performed for assessment of leukemia-free state (day 14) and to document remission response. Cytogenetic results were classified into favorable, intermediate, and unfavorable categories based on CALGB data. Responses were defined per the Revised IWG Recommendations (Cheson et al, J Clin Onc21: 4642, 2003). Results: Median age of the 104 patients was 57 years [range 17–79]. There were 47 males and 57 females. Forty-two patients (40%) were 60 years of age and older, and the remaining 62 patients (60%) were younger than 60. Sixty-four patients (61.5%) had de novo AML. Five patients had favorable cytogenetics with 100% of them achieving CR. All of the patients with favorable cytogenetics were less than 60 years of age. For the 61 patients with intermediate cytogenetics, the ORR was 83.6% with a CR of 61%. In patients younger than 60, the ORR was 83.8%% (26 CR, 3 CRi, 2 CRp) with CR of 70%. For patients 60 years and older, the ORR was 83.3% (11 CR, 3 CRi, 5 CRp, 1 RMDS). In the 38 patients with unfavorable cytogenetics, the ORR was 57.9% with CR of 37%. For patients younger than 60 and 60 years and older, the overall responses were 75% and 38.8%, respectively. Of the 40 patients with secondary AML due to pre-existing MDS, the ORR was 65% with CR of 27.5%. In patients with de novo AML, the ORR was 81% with CR of 70%. Patients with prior MDS were more likely to have CRi (20% vs 1.5%), TF due to refractory disease (25% vs 15.6%) or aplasia (7.5% vs 1.5%) as compared to patients without MDS. The rates of CRp (10% vs 9%) were similar for both groups. MDS patients with intermediate cytogenetics had an ORR of 77.7% as compared to 54.5% in those with unfavorable cytogenetics. De novo patients with intermediate cytogenetics had ORR of 86% and those with unfavorable cytogenetics had ORR of 62.5%. Conclusion: Our data reflects the overall effectiveness of high dose cytarabine and mitoxantrone for induction therapy of AML. In the favorable cytogenetic group, the CR rate was higher than previously reported response rates; however, the number of patients was small. In the intermediate and unfavorable cytogenetic groups, the response rates for de novo AML compare favorably to historic controls. Patients with secondary AML respond equally well as compared to those with de novo AML; though, the influence of cytogenetics was similar to that seen in de novo AML. This regimen is very effective in producing a high response rates across cytogenetic categories.

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Zhang, Peng, Bernd Friebe, Bikram Gill, and R. F. Park. "Cytogenetics in the age of molecular genetics." Australian Journal of Agricultural Research 58, no. 6 (2007): 498. http://dx.doi.org/10.1071/ar07054.

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From the beginning of the 20th Century, we have seen tremendous advances in knowledge and understanding in almost all biological disciplines, including genetics, molecular biology, structural and functional genomics, and biochemistry. Among these advances, cytogenetics has played an important role. This paper details some of the important milestones of modern cytogenetics. Included are the historical role of cytogenetics in genetic studies in general and the genetics stocks produced using cytogenetic techniques. The basic biological questions cytogenetics can address and the important role and practical applications of cytogenetics in applied sciences, such as in agriculture and in breeding for disease resistance in cereals, are also discussed. The goal of this paper is to show that cytogenetics remains important in the age of molecular genetics, because it is inseparable from overall genome analysis. Cytogenetics complements studies in other disciplines within the field of biology and provides the basis for linking genetics, molecular biology and genomics research.

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Armand, Philippe, Haesook T. Kim, Daniel J. DeAngelo, Vincent T. Ho, Corey S. Cutler, Richard M. Stone, Jerome Ritz, Edwin P. Alyea, Joseph H. Antin, and Robert J. Soiffer. "Impact of Cytogenetics and Prior Therapy on Outcome of AML and MDS after Allogeneic Transplantation." Blood 108, no. 11 (November 16, 2006): 259. http://dx.doi.org/10.1182/blood.v108.11.259.259.

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Abstract Cytogenetics is an important determinant of outcome for patients with AML or MDS. However, the prognostic impact of cytogenetics in patients undergoing allogeneic stem cell transplantation (alloSCT) is less clear. Moreover, the existing cytogenetic risk groups were established on cohorts of patients treated mostly with chemotherapy, and thus may not be optimal for patients undergoing alloSCT. We retrospectively studied 556 consecutive patients with AML or MDS who received an alloSCT at our institution. Using Cox proportional hazards modeling, taking into account cytogenetics and other known prognostic factors (age, disease type and stage, HLA match, conditioning regimen, GVHD prophylaxis regimen, graft source, CMV serostatus, gender, and year of transplantation), we established a three-group cytogenetic classification scheme based on the 476 patients with de novo disease. In this system, patients with AML and t(15;17), t(8;21) alone, or inv(16)/t(16;16) were classified as favorable risk; patients with AML and complex karyotype, t(9;22), or t(6;9), as well as patients with MDS and complex karyotype or abnormality of 7, were classified as adverse risk. Cytogenetics for all other AML and MDS patients were classified as intermediate risk. Patients with AML and abnormal 3q, and patients with MDS and 5q- or 20q-, could not be assigned to a risk group due to inadequate representation in our study. The figure below shows the overall survival of all de novo AML and MDS patients when stratified according to this cytogenetic grouping scheme. Figure Figure In our cohort, this grouping scheme was the strongest prognostic factor (after age) for overall and disease-free survival. It applied to patients regardless of disease (AML, MDS, or AML arising from MDS) and of stage (AML in CR1 versus advanced leukemia). Furthermore, it outperformed the existing grouping schemes for AML (from MRC, CALGB and SWOG/ECOG) and the IPSS grouping scheme for MDS. Using competing risks regression analysis, we found that cytogenetics influences the risk of relapse but not the non-relapse mortality. The group of 80 patients with therapy-related MDS or AML had a higher frequency of adverse cytogenetics. In this population, cytogenetics remained a significant prognostic factor for overall survival. However, in multivariate models that accounted for cytogenetics, prior therapy by itself did not confer an additional adverse prognosis. This conclusion held true regardless of the grouping scheme used. Conclusion: cytogenetics is a key determinant of outcome for patients with AML or MDS undergoing alloSCT, whether with de novo disease or therapy-related disease. For patients with therapy-related disease, prior therapy has no additional prognostic importance after considering cytogenetic risk group. We also propose a new cytogenetic risk grouping scheme specifically applicable to this patient population, that can be validated in a multi-institutional database. Our results argue that patients entering clinical trials of transplantation should be stratified by cytogenetic risk group, and provide a means of doing so.

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Rashidi, Armin, and Amanda F. Cashen. "A Cytogenetic Model Predicts Relapse Risk and Survival in Patients with Acute Myeloid Leukemia Undergoing Hematopoietic Stem Cell Transplantation in Morphologic Complete Remission." Blood 124, no. 21 (December 6, 2014): 2545. http://dx.doi.org/10.1182/blood.v124.21.2545.2545.

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Abstract Objectives: Up to one third of patients with acute myeloid leukemia (AML) and abnormal cytogenetics have persistent cytogenetic abnormalities (pCytAbnl) at morphologic complete remission (mCR). We hypothesized that the prognostic significance of pCytAbnl in patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) in mCR varies with the cytogenetic risk group. Previous studies on the subject have been small, inconclusive, or inconsistent. Methods: We analyzed the data from a large cohort of patients (n = 118) with AML and abnormal cytogenetics who underwent allo-HSCT in mCR, and developed a simple risk stratification model based on pCytAbnl and cytogenetic risk group to compare time to relapse (TTR), relapse-free survival (RFS), and overall survival (OS). Results: The mean (standard deviation) age of patients was 51 (14) years, and 58% were male. AML was therapy-related in 21 (31%) patients. The most frequent FAB subtypes were M0/M1/M2 (46%), followed by M4/M5 (26%). Favorable, intermediate and unfavorable cytogenetic risk disease was present in 18%, 28%, and 54% of patients, respectively. The majority (73%) of patients were in CR1. Conditioning was myeloablative in 67% of patients and reduced-intensity in the remainder. The groups with or without pCytAbnl were similar in all baseline and transplant characteristics except age, CR number and cytogenetic risk group. Specifically, patients with pCytAbnl were significantly older (56 ± 12 vs. 48 ± 15 years; P = 0.004), were in first CR more frequently (86% vs. 67%; P = 0.042), and were more likely to have unfavorable risk cytogenetics (P = 0.027) than patients without pCytAbnl. Univariate analysis was performed using the following variables: age, gender, therapy-related AML (present vs. absent), pCytAbnl (present vs. absent), cytogenetic risk group (unfavorable vs. intermediate/favorable), CR number (≥2 vs. 1), conditioning regimen (myeloablative vs. reduced intensity), and donor type (matched unrelated vs. sibling). There was a significant association between outcome (OS, RFS, and TTR) and the following variables: pCytAbnl, cytogenetic risk group, and the conditioning regimen. Additionally, CR number was significantly associated with TTR. In multivariate regression analysis with these four variables (Table 1), only pCytAbnl, cytogenetic risk group, and the conditioning regimen had a significant impact on outcome. A risk scoring system was then built using pCytAbnl and cytogenetic risk group. The model distinguished 3 groups of patients with distinct outcomes (Figure 1). The group with pCytAbnl and unfavorable risk cytogenetics (R2, n = 24) had the shortest median TTR (3 months), RFS (3 months), and OS (7 months). The group with favorable/intermediate risk cytogenetics and without pCytAbnl (R0, n = 47) had the longest median TTR (not reached), RFS (57 months), and OS (57 months). The group with pCytAbnl and favorable/intermediate risk cytogenetics, or without pCytAbnl but with unfavorable risk cytogenetics (R1, n = 47) experienced intermediate TTR (18 months), RFS (9 months), and OS (14 months). Conclusions: A composite cytogenetic risk model identifies patients with AML in mCR with distinct relapse, RFS, and OS rates following allo-HSCT. Table 1:Multivariate analysis for survival outcomes using variables with a significant association in univariate analysis OS RFS TTRHR (95% CI)PHR (95% CI)PHR (95% CI)PpCytAbnl + vs. -0.54 (0.32-0.91)0.0200.53 (0.32-0.86)0.0100.44 (0.24-0.80)0.007Cytogenetic risk U vs. F/I0.60 (0.36-0.99)0.0470.55 (0.34-0.98)0.0140.45 (0.23-0.95)0.023CR number ≥2 vs. 1----1.51 (0.58-3.95)0.404Conditioning MA vs. RI1.71 (1.04-2.81)0.0352.04 (1.27-3.27)0.0032.85 (1.57-5.15)0.001 CI: confidence interval; F/I: Favorable/Intermediate; HR: hazard ratio; MA: myeloablative; RI: reduced intensity; U: unfavorable Figure 1: Cumulative risk of relapse (A), relapse free survival (B) and overall survival (C) based on persistent cytogenetic abnormalities and cytogenetics. R0, R1, and R2 are defined in the text. Figure 1:. Cumulative risk of relapse (A), relapse free survival (B) and overall survival (C) based on persistent cytogenetic abnormalities and cytogenetics. R0, R1, and R2 are defined in the text. Disclosures No relevant conflicts of interest to declare.

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Bayani, Jane, Ajay Pandita, and Jeremy A. Squire. "Molecular cytogenetic analysis in the study of brain tumors: findings and applications." Neurosurgical Focus 19, no. 5 (November 2005): 1–36. http://dx.doi.org/10.3171/foc.2005.19.5.2.

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Classic cytogenetics has evolved from black and white to technicolor images of chromosomes as a result of advances in fluorescence in situ hybridization (FISH) techniques, and is now called molecular cytogenetics. Improvements in the quality and diversity of probes suitable for FISH, coupled with advances in computerized image analysis, now permit the genome or tissue of interest to be analyzed in detail on a glass slide. It is evident that the growing list of options for cytogenetic analysis has improved the understanding of chromosomal changes in disease initiation, progression, and response to treatment. The contributions of classic and molecular cytogenetics to the study of brain tumors have provided scientists and clinicians alike with new avenues for investigation. In this review the authors summarize the contributions of molecular cytogenetics to the study of brain tumors, encompassing the findings of classic cytogenetics, interphase- and metaphase-based FISH studies, spectral karyotyping, and metaphase- and array-based comparative genomic hybridization. In addition, this review also details the role of molecular cytogenetic techniques in other aspects of understanding the pathogenesis of brain tumors, including xenograft, cancer stem cell, and telomere length studies.

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Mellors, Patrick, Moritz Binder, Rhett P. Ketterling, Patricia Griepp, Linda B. Baughn, Francis K. Buadi, Martha Q. Lacy, et al. "Metaphase Cytogenetics for Risk Stratification in Newly Diagnosed Multiple Myeloma." Blood 134, Supplement_1 (November 13, 2019): 4396. http://dx.doi.org/10.1182/blood-2019-122291.

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Introduction: Abnormal metaphase cytogenetics are associated with inferior survival in newly diagnosed multiple myeloma (MM). These abnormalities are only detected in one third of cases due to the low proliferative rate of plasma cells. It is unknown if metaphase cytogenetics improve risk stratification when using contemporary prognostic models such as the revised international staging system (R-ISS), which incorporates interphase fluorescence in situ hybridization (FISH). Aims: The aims of this study were to 1) characterize the association between abnormalities on metaphase cytogenetics and overall survival (OS) in newly diagnosed MM treated with novel agents and 2) evaluate whether the addition of metaphase cytogenetics to R-ISS, age, and plasma cell labeling index (PCLI) improves model discrimination with respect to OS. Methods: We analyzed a retrospective cohort of 483 newly diagnosed MM patients treated with proteasome inhibitors (PI) and/or immunomodulators (IMID) who had metaphase cytogenetics performed prior to initiation of therapy. Abnormal metaphase cytogenetics were defined as MM specific abnormalities, while normal metaphase cytogenetics included constitutional cytogenetic variants, age-related Y chromosome loss, and normal metaphase karyotypes. Multivariable adjusted proportional hazards regression models were fit for the association between known prognostic factors and OS. Covariates associated with inferior OS on multivariable analysis included R-ISS stage, age ≥ 70, PCLI ≥ 2, and abnormal metaphase cytogenetics. We devised a risk scoring system weighted by their respective hazard ratios (R-ISS II +1, R-ISS III + 2, age ≥ 70 +2, PCLI ≥ 2 +1, metaphase cytogenetic abnormalities + 1). Low (LR), intermediate (IR), and high risk (HR) groups were established based on risk scores of 0-1, 2-3, and 4-5 in modeling without metaphase cytogenetics, and scores of 0-1, 2-3, and 4-6 in modeling incorporating metaphase cytogenetics, respectively. Survival estimates were calculated using the Kaplan-Meier method. Survival analysis was stratified by LR, IR, and HR groups in models 1) excluding metaphase cytogenetics 2) including metaphase cytogenetics and 3) including metaphase cytogenetics, with IR stratified by presence and absence of metaphase cytogenetic abnormalities. Survival estimates were compared between groups using the log-rank test. Harrell's C was used to compare the predictive power of risk modeling with and without metaphase cytogenetics. Results: Median age at diagnosis was 66 (31-95), 281 patients (58%) were men, median follow up was 5.5 years (0.04-14.4), and median OS was 6.4 years (95% CI 5.7-6.8). Ninety-seven patients (20%) were R-ISS stage I, 318 (66%) stage II, and 68 (14%) stage III. One-hundred and fourteen patients (24%) had high-risk abnormalities by FISH, and 115 (24%) had abnormal metaphase cytogenetics. Three-hundred and thirteen patients (65%) received an IMID, 119 (25%) a PI, 51 (10%) received IMID and PI, and 137 (28%) underwent upfront autologous hematopoietic stem cell transplantation (ASCT). On multivariable analysis, R-ISS (HR 1.59, 95% CI 1.29-1.97, p < 0.001), age ≥ 70 (HR 2.32, 95% CI 1.83-2.93, p < 0.001), PCLI ≥ 2, (HR 1.52, 95% CI 1.16-2.00, p=0.002) and abnormalities on metaphase cytogenetics (HR 1.35, 95% CI 1.05-1.75, p=0.019) were associated with inferior OS. IR and HR groups experienced significantly worse survival compared to LR groups in models excluding (Figure 1A) and including (Figure 1B) the effect of metaphase cytogenetics (p < 0.001 for all comparisons). However, the inclusion of metaphase cytogenetics did not improve discrimination. Likewise, subgroup analysis of IR patients by the presence or absence of metaphase cytogenetic abnormalities did not improve risk stratification (Figure 1C) (p < 0.001). The addition of metaphase cytogenetics to risk modeling with R-ISS stage, age ≥ 70, and PCLI ≥ 2 did not improve prognostic performance when evaluated by Harrell's C (c=0.636 without cytogenetics, c=0.642 with cytogenetics, absolute difference 0.005, 95% CI 0.002-0.012, p=0.142). Conclusions: Abnormalities on metaphase cytogenetics at diagnosis are associated with inferior OS in MM when accounting for the effects of R-ISS, age, and PCLI. However, the addition of metaphase cytogenetics to prognostic modeling incorporating these covariates did not significantly improve risk stratification. Disclosures Lacy: Celgene: Research Funding. Dispenzieri:Akcea: Consultancy; Intellia: Consultancy; Alnylam: Research Funding; Celgene: Research Funding; Janssen: Consultancy; Pfizer: Research Funding; Takeda: Research Funding. Kapoor:Celgene: Honoraria; Sanofi: Consultancy, Research Funding; Janssen: Research Funding; Cellectar: Consultancy; Takeda: Honoraria, Research Funding; Amgen: Research Funding; Glaxo Smith Kline: Research Funding. Leung:Prothena: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Omeros: Research Funding; Aduro: Membership on an entity's Board of Directors or advisory committees. Kumar:Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Takeda: Research Funding.

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Malig, Maika, Olga Sala-Torra, Mary Wood, Kyle Langford, Lan W. Beppu, Ellen Cvejanovich Madarang, David Woolston, et al. "Genomic Proximity Mapping (GPM): Evaluation of a Next Generation Cytogenomic Assay for Improved Risk Stratification in Acute Myeloid Leukemia." Blood 144, Supplement 1 (November 5, 2024): 6157. https://doi.org/10.1182/blood-2024-211570.

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Cytogenetics encompasses a suite of diagnostics assays that provides critical diagnostic and prognostic information that can help guide care for acute myeloid leukemias (AML) patients. Routine cytogenetic workup for AML includes karyotyping and fluorescence in situ hybridization (FISH) for known recurrent variants. The workup can be extended to include chromosome genome array testing (CGAT) but because all 3 of these tests have a non-overlapping set of limitations that can necessitate multiple, often iterative, rounds of testing in complex cases and may miss information in cases with cryptic fusions or small copy number alterations. Therefore, there is an unmet need for an accurate, fast and reliable test that can provide a solution to these limitations. In this study, we evaluate Genomic Proximity Mapping (GPM), a novel method that captures much of the same information as karyotyping, FISH, and CGAT in a single assay. GPM uses proximity ligation sequencing to capture ultra-long range contiguity information from conventional short-read sequencing. In brief, 200,000-500,000 cells from bone marrow, peripheral blood, or aphersis samples are crosslinked with formalin prior to library preparation. Because sequences that are closer on a chromosome are more likely to physically interact and be crosslinked, GPM can use the frequency pairwise of crosslinked sequence interactions to determine the structure of chromosomes. In order to evaluate its performance, we benchmarked GPM against standard-of-care cytogenetics conducted on newly diagnosed 166 AML cases in a multicenter, retrospective study utilizing real-world patient samples. There was a strong concordance between GPM and cytogenetic findings, with 100% of European LeukemiaNet (ELN) specified cytogenetic risk variants identified by cytogenetic being identified by GPM. However, GPM also identified additional variants of known clinical significance not observed by standard-of-care cytogenetics. To determine if GPM findings had clinical benefits for risk stratification, we compared overall survival (OS) of patients, risk-stratified using ELN 2022 criteria, using either cytogenetics or GPM to determine the cytogenetic abnormalities. Separation of favorable, intermediate, and adverse risk categories were statistically significant when variants identified either by cytogenetics or GPM were used for risk categorization (GPM, P = 0.0006; cytogenetics P = 0.0009 for GPM and cytogenetics, Mantel-Cox log rank test). However, Kaplan-Meier analysis demonstrated that GPM greater separation in intermediate (median OS 2.1 years for GPM and 2.4 years for cyto), and adverse (median OS 1.1 yrs for GPM and 0.9 years for cytogenetics) categories. The ELN-directed risk based on karyotype and FISH presentation was revised for 14 (8.4%) out of 166 cases with available data based on GPM assay results. These findings argue that GPM can be used as a single assay to accurately stratify AML patient risk and may provide additional benefits over cytogenetics, yielding more accurate risk stratification. Support: NIH/NCI U10CA180888, U10CA180819, U24CA196175, R44CA278140

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Sachs, Zohar, Michelle Dollan, Todd E. De For, Leyla Shune, Sarah Cooley, Daniel J. Weisdorf, Erica D. Warlick, and Celalettin Ustun. "Are IPSS-R and IPSS Cytogenetic Risk Stratification Informative At the Time of Allogeneic Hematopoietic Cell Transplantation?" Blood 120, no. 21 (November 16, 2012): 1400. http://dx.doi.org/10.1182/blood.v120.21.1400.1400.

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Abstract Abstract 1400 Myelodysplastic syndromes (MDS) are a heterogeneous group of hematopoietic stem cell disorders. Cytogenetic aberrations are one of the main elements of risk stratification among published scoring systems including the International Prognostic Scoring System (IPSS) or its recent revision (R-IPSS). R-IPSS cytogenetic risk stratification has 5 cytogenetic subgroups rather than 3 in the IPSS. We hypothesized that R-IPSS and/or IPSS cytogenetic risk stratification at the time of allogeneic hematopoietic cell transplantation (alloHCT) can better predict outcome afterwards. In patients who had cytogenetic results at both diagnosis and alloHCT, we evaluated the cytogenetic changes over time and compared how well the two cytogenetic risk stratification systems predicted outcome. One hundred consecutive patients with MDS undergoing an alloHCT (52% related donor, 13% unrelated donor, and 35% umbilical cord blood) at the University of Minnesota between 1995 and 2011 were evaluated. Their median age was 52 years (range, 18–69 years). Seventy-eight percent of the patients had ≥90% Karnofsky performance score, and 60% had INT-2 or a high IPSS score. Half received reduced-intensity conditioning (RIC). Patients with IPSS good-risk cytogenetics at diagnosis had a significantly better OS (62% at 5-year) compared to patients with intermediate or poor-risk cytogenetics. However, IPSS cytogenetic stratification at the time of transplantation predicted neither overall survival (OS) nor relapse (Table). Patients with IPSS-R very poor risk cytogenetics at either diagnosis or alloHCT had a dismal outcome; no patients in this category at alloHCT survived 5 years, and their relapse rate was also significantly higher (41%) compared to other cytogenetic risk subgroups (Table). In multivariate analysis, the only factor predicting relapse was the intensity of the conditioning regimen: those patients receiving RIC had a higher risk of relapse (HR, 2.5, 95% CI 1.1–5.4, p=0.03) than those who received myeloablative conditioning regimens. This data indicate that IPSS (at diagnosis) and IPSS-R (at both diagnosis and alloHCT) cytogenetic classifications provide important prognostic information in the best and worst subgroups, respectively, but are not as helpful for patients in the intermediate subgroups. Table. OS and Relapse by IPSS and R-PSS cytogenetic stratifications at time points of diagnosis and alloHCT Factor Strata N OS @ 5 year CI 95% P-value Relapse @ 5-year CI 95% P-value IPSS Cytogenetics At alloHCT Good 30 48% 28-65% 0.16 29% 11-47% 0.82 Intermediate 21 19% 6-38% 29% 9-48% Poor 41 23% 11-38% 30% 15-45% IPSS-R Cytogenetics At alloHCT Very good/Good 32 51% 31-67% <0.01 30% 13-48% 0.05 Intermediate 21 17% 5-36% 29% 9-48% Poor 41 41% 22-60% 17% 2-31% Very Poor 18 0% 41% 18-63% IPSS Cytogenetics At Diagnosis Good 25 62% 39-78% <0.01 22% 5-39% 0.16 Intermediate 24 13% 3-29% 29% 10-48% Poor 47 24% 12-38% 30% 16-44% IPSS-R Cytogenetics At Diagnosis Very good/Good 28 54% 33-71% <0.01 27% 9-44% 0.21 Intermediate 20 15% 4-33% 25% 6-44% Poor 29 33% 17-51% 21% 6-35% Very Poor 19 7% 0-28% 45% 22-68% Disclosures: No relevant conflicts of interest to declare.

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Mathew, Mariam T., Melanie Babcock, Ying-Chen Claire Hou, Jesse M. Hunter, Marco L. Leung, Hui Mei, Kathleen Schieffer, and Yassmine Akkari. "Clinical Cytogenetics: Current Practices and Beyond." Journal of Applied Laboratory Medicine 9, no. 1 (January 2024): 61–75. http://dx.doi.org/10.1093/jalm/jfad086.

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Abstract Background Throughout history, the field of cytogenetics has witnessed significant changes due to the constant evolution of technologies used to assess chromosome number and structure. Similar to the evolution of single nucleotide variant detection from Sanger sequencing to next-generation sequencing, the identification of chromosome alterations has progressed from banding to fluorescence in situ hybridization (FISH) to chromosomal microarrays. More recently, emerging technologies such as optical genome mapping and genome sequencing have made noteworthy contributions to clinical laboratory testing in the field of cytogenetics. Content In this review, we journey through some of the most pivotal discoveries that have shaped the development of clinical cytogenetics testing. We also explore the current test offerings, their uses and limitations, and future directions in technology advancements. Summary Cytogenetics methods, including banding and targeted assessments like FISH, continue to hold crucial roles in cytogenetic testing. These methods offer a rapid turnaround time, especially for conditions with a known etiology involving recognized cytogenetic aberrations. Additionally, laboratories have the flexibility to now employ higher-throughput methodologies to enhance resolution for cases with greater complexity.

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15

Sproat, Lisa O., Brian Bolwell, Lisa Rybicki, Matt Kalaycio, Robert Dean, Ronald Sobecks, Brad Pohlman, et al. "No Impact of Postremission Consolidation Chemotherapy Before Allogeneic Transplant in Patients with First Remission Acute Myeloid Leukemia with Intermediate or High Risk Cytogenetics." Blood 112, no. 11 (November 16, 2008): 2164. http://dx.doi.org/10.1182/blood.v112.11.2164.2164.

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Abstract Despite a lack of evidence that postremission consolidation chemotherapy improves outcome of allogeneic transplantation in patients with acute myeloid leukemia (AML) in first remission, high dose cytarabine and other regimens are commonly administered to these patients. We studied a consecutive cohort of 73 adult patients with AML at high risk of relapse by published criteria who underwent allogeneic transplantation in first remision to determine whether specific patient and treatment characteristics identified subgroups of patients who might benefit from consolidation therapy prior to allogeneic transplantation. Pretransplant cytogenetics were available for 56 patients. Transplantation occurred between 1988 and 2008. The primary analysis grouped patients according to cytogenetic risk (poor versus intermediate) and consolidation chemotherapy (yes versus no). Consolidation Chemotherapy No Consolidation Chemotherapy None of the measured outcomes (relapse mortality (RM), non-relapse mortality (NRM), overall survival (OS)) differed significantly between groups. Poor Risk Cytogenetics 9 13 Intermediate Risk 18 16 Cytogenetics P Values for Consolidation Versus No Consolidation by Cytogenetic Risk Poor Risk Cytogenetics Intermediate Risk Cytogenetics When cytogenetic risk was not stratified the results between consolidation and no consolidation were also not significant. RM 0.95 0.74 NRM 0.73 0.19 OS 0.77 0.21 P Values for Consolidation Versus No Consolidation RM 0.70 NRM 0.12 OS 0.14 Neither this study nor others provide evidence that consolidation chemotherapy is beneficial to all patients with AML in first remission who undergo allogeneic transplant or to cytogenetic subgroups. Delays in referral to a transplant center, in tissue typing or physician preference to administer consolidation chemotherapy are not justified and expose patients to the inconvenience, risk, and cost of unnecessary treatment. Clinicians should avoid consolidation chemotherapy and expedite allogeneic transplantion in patients with AML in first remission in whom transplantation is the preferred treatment.

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Hall, K. J., J. S. Parker, and T. H. N. Ellis. "The relationship between genetic and cytogenetic maps of pea. I. Standard and translocation karyotypes." Genome 40, no. 5 (October 1, 1997): 744–54. http://dx.doi.org/10.1139/g97-797.

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A detailed cytogenetical study of inbred lines of pea and their F1 hybrids has been undertaken to study the relationship between the cytogenetic map and the molecular linkage map. The mitotic karyotypes of a standard pea line, JI15, a translocation line, JI61, and line JI281, a line used in the production of a mapping population, are given. A chromosome rearrangement detected by cytogenetic analysis of mitotic chromosomes has been further defined by synaptonemal complex (SC) analysis and the study of metaphase I chromosome behaviour. This meiotic analysis has allowed a comparison of SC physical lengths, observed chiasma frequencies, and recombination frequencies, as estimated from the genetic map, as a means of comparing physical and genetic distances.Key words: Pisum, linkage map, cytogenetics, chromosome rearrangement, synaptonemal complex.

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17

JACKSON, LAIRD. "Cytogenetics and Molecular Cytogenetics." Clinical Obstetrics and Gynecology 45, no. 3 (September 2002): 622–39. http://dx.doi.org/10.1097/00003081-200209000-00006.

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18

Haase, Detlef, Ulrich Germing, Julie Schanz, Michael Pfeilstoecker, Barbara Hildebrandt, Michael Luebbert, Aristoteles Giagounidis, et al. "Evidence for an Underestimation of the Prognostic Impact of Poor Cytogenetics within the IPSS." Blood 108, no. 11 (November 16, 2006): 252. http://dx.doi.org/10.1182/blood.v108.11.252.252.

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Abstract In the IPSS the variables bone marrow blasts, cytogenetics and cytopenias were found to be most relevant for clinical outcome by multivariate analysis. Comparing cytogenetics and blasts scoring points were assigned as follows: 0 (good cytogenetics and less than 5% blasts), 0.5 points (intermediate cytogenetics, and 5–10% blasts), 1.0 points (poor cytogenetics), 1.5 points (11–20% blasts), 2.0 (21–30% blasts). In order to examine the correctness of weighting of cytogenetics in comparison to blast counts we compared the survival curves, median survival times (mst) and differences of mst (mst diff.) related to the mst of 37.5 months (mo) of our entire study population (on the basis of 2124 pts. with MDS from our German-Austrian database) between patient subgroups. The results in the subgroups were as follows: Blasts below 5% (n=609) (mst: 58 mo, mst diff.: +20.5 mo), good cytogenetics (n=768) (mst: 55.3 mo, mst diff.: +17.8 mo), blasts 5–10% (n=231) (mst: 28.0 mo, mst. diff.: −9.5 mo), intermediate cytogenetics (n=222) (mst: 28.0 mo, mst diff.: −9.5 mo), blasts: 11–20% (n=160) (mst: 16.5 mo, mst diff.: −21 mo), poor cytogenetics (n=212) (mst: 11.1 mo, mst diff.: −26.3 mo), blasts 21–30% (n=92) (mst: 11.7, mst diff.: −25.7 mo). Our results clearly show that within the IPSS poor cytogenetics are significantly underweighed. Referring to the survival data unfavorable cytogenetics resulted in a survival disadvantage at the same scale as compared to 21–30% blasts. Thus, in a revised IPSS this cytogenetic feature should get the same scoring points as compared to 21–30% blasts when using the FAB-classification. For a scoring system based on the WHO-classification unfavorable cytogenetics should get an even higher scoring value as compared to the maximum blast count of 19%. Further statistical analyses are on the way to substantiate our conclusions.

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19

Nishio, Jun. "Contributions of Cytogenetics and Molecular Cytogenetics to the Diagnosis of Adipocytic Tumors." Journal of Biomedicine and Biotechnology 2011 (2011): 1–9. http://dx.doi.org/10.1155/2011/524067.

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Over the last 20 years, a number of tumor-specific chromosomal translocations and associated fusion genes have been identified for mesenchymal neoplasms including adipocytic tumors. The addition of molecular cytogenetic techniques, especially fluorescence in situ hybridization (FISH), has further enhanced the sensitivity and accuracy of detecting nonrandom chromosomal translocations and/or other rearrangements in adipocytic tumors. Indeed, most resent molecular cytogenetic analysis has demonstrated a translocation t(11;16)(q13;p13) that produces aC11orf95-MKL2fusion gene in chondroid lipoma. Additionally, it is well recognized that supernumerary ring and/or giant rod chromosomes are characteristic for atypical lipomatous tumor/well-differentiated liposarcoma and dedifferentiated liposarcoma, and amplification of 12q13–15 involving theMDM2,CDK4, andCPMgenes is shown by FISH in these tumors. Moreover, myxoid/round cell liposarcoma is characterized by a translocation t(12;16)(q13;p11) that fuses theDDIT3andFUSgenes. This paper provides an overview of the role of conventional cytogenetics and molecular cytogenetics in the diagnosis of adipocytic tumors.

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Klein, Kim, Martin Zimmermann, Berna Beverloo, Christine von Neuhoff, Valerie De Haas, Romy van Weelderen, Susana C. Raimondi, et al. "The Prognostic Impact of Cytogenetics and Karyotype Changes in Pediatric Patients with Relapsed Acute Myeloid Leukemia: A Retrospective Cohort Study within the Relapsed AML 2001/01 Study." Blood 128, no. 22 (December 2, 2016): 2896. http://dx.doi.org/10.1182/blood.v128.22.2896.2896.

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Abstract Introduction After treatment response, cytogenetics and molecular aberrations are the most important prognostic factors in children with de novo acute myeloid leukemia (AML). However, little is known about the impact of cytogenetics at relapse. This international retrospective study aimed to provide insight into the prognostic impact of cytogenetic profiles and the role of karyotype changes from diagnosis to relapse in pediatric patients with relapsed AML. Methods Cytogenetic reports from patients registered to the Relapsed AML 2001/01 Study and diagnosed between 2001 and 2010 were centrally reviewed and classified by two independent researchers plus a cytogenetic expert. Patients with refractory or relapsed AML and available cytogenetics at relapse were included in order to assess the prognostic impact of different cytogenetic subgroups at relapse. Patients with karyotypes available at both diagnosis and relapse were included in order to study the impact of karyotype changes. Recurrent cytogenetic aberrations present in ≥5 patients defined the subgroups. Changes at relapse were categorized as: no change, gain, loss, both gain and loss, or structural other aberration(s). Primary endpoints were the probabilities of event-free survival (pEFS) and overall survival (pOS). Univariate analyses were conducted using chi-square tests, binary univariate logistic regression or Kaplan Meier estimates with a log-rank test. Multivariable Cox regression analyses were conducted to evaluate the independent impact of cytogenetic profiles and karyotype changes at relapse. For these analyses, cytogenetic subgroups were regrouped into good risk (GR) cytogenetics [t(8;21)(q22;q22) or inv(16)/t(16;16)(p13.1;q22)] or "other". Results Of the 569 registered patients, 402 patients (71%) had available cytogenetic information at relapse. Frequently detected aberrations at relapse were t(8;21) (n=60, 15%) and inv(16)/t(16;16) (n=24, 6%), both indicating a relatively good prognosis. Although patient numbers were small (n=5), t(6;9)(p23;q34) also had a relatively good outcome. Monosomy 7/7q-, t(9;11)(p22;q23), t(10;11)(p12;q23) and complex karyotypes had a relatively poor outcome. Figure 1 shows the Kaplan Meier curves of the investigated cytogenetic subgroups with corresponding patient numbers. In total, 306 patients (54%) with available karyotypes at both diagnosis and relapse were included to study cytogenetic changes. Patients with any change (n=148, 48%) had inferior outcome compared to patients without changes (3-year pEFS 21% [SE, 3.4%] versus 39% [SE, 3.9%]; overall P<0.01). Patients with both loss and gain or structural other aberrations had the worst outcome at the univariate level. After multivariable adjustment (final models including cytogenetics at relapse, time to relapse </≥ 1 year and type of change), having both gain and loss of aberrations remained associated with inferior pEFS and pOS (Hazard Ratio [HR] 2.10 [95% confidence interval (CI) 1.17-3.76] and HR 2.18 [95% CI 1.19-3.99] respectively). Having structural other aberrations at relapse was also associated with inferior pEFS (HR 1.81 [95% CI 1.03-3.18]). GR cytogenetics at relapse were significantly associated with better early treatment response. Subsequently, response to treatment at day 28 (Creutzig et al. Haematologica 2014) was an important mediator. If this prognostic parameter was included in the models, the effect of changes diminished, but GR cytogenetics at relapse remained an important prognostic factor associated with superior outcome (pEFS: HR 0.53 [95% CI 0.35-0.81], pOS: HR 0.51 [95% CI 0.32-0.80]). Conclusion Together with early treatment response, the cytogenetic profile at relapse is an important prognostic factor. In particular t(8;21) and inv(16)/t(16;16) at relapse were associated with a favorable outcome. Furthermore, cytogenetic changes between diagnosis and relapse were associated with inferior outcome. Future studies should explore the mechanism(s) of these changes, being either clonal evolution or clonal selection. Interpretation of our results is hampered by the retrospective design of the study, small subgroup numbers and missing cytogenetic and molecular data. Nonetheless, these findings suggest that assessing cytogenetics at time of relapse is of high importance, and can be used for risk group adapted treatment. Disclosures Reinhardt: Boehringer Ingelheim: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Jazz Pharma: Other: Travel Accomodation; Celgene: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding.

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Kalaycio, Matt, Mikkael Sekeres, Ronald Sobecks, Lisa Rybicki, Brad Pohlman, Anjali Advani, Elizabeth Kuczkowski, and Brian Bolwell. "Cytogenetic Classification Systems and Overall Survival Following Bone Marrow Transplant (BMT) for Acute Myelogenous Leukemia (AML)." Blood 106, no. 11 (November 16, 2005): 4500. http://dx.doi.org/10.1182/blood.v106.11.4500.4500.

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Abstract Risk-adapted therapy for AML in first complete remission generally calls for allogeneic BMT for patients with poor risk cytogenetics. However, poor risk cytogenetics is defined differently in commonly-applied classification schemes. We hypothesized that differences in cytogenetic classification might result in differences in survival after BMT. From September 1991 to December 2003, we treated 47 patients with AML in first complete remission with high-dose busulfan-containing preparative regimens and an HLA-matched sibling BMT. The median age was 42 years (range 18 to 60). At the time of diagnosis, 35 patients had either a normal karyotype or at least one clonal abnormality. Cytogenetic analysis was unavailable for the other 12 patients. The 47 patients were then classified according to the SWOG/ECOG (Blood96:4075, 2000), MRC (Blood92:2322, 1998), or CALGB (Blood100:4325, 2002) cytogenetic classification systems and analyzed for overall survival. With a median follow-up of 4.9 years, 3 year overall survival for various cytogenetic risk groups are displayed in the table: SWOG/ECOG CALGB MRC Intermediate risk 69% 63% 74% Poor risk 43% 42% 18% Unknown risk 45% 52% 45% Concordance indices were 0.58 for CALGB, 0.60 for SWOG, and 0.66 for MRC, demonstrating a slight superiority of the MRC system. Consistent with reports of large, prospective randomized trials of BMT for AML in first remission, patients with poor risk cytogenetics have worse overall survival compared to patients with intermediate risk cytogenetics. Overall survival appears to be different for patients classified as poor risk by MRC criteria. Larger, prospective studies are needed to confirm this observation, but our results suggest that standardized, international cytogenetic risk criteria are needed to develop risk-adapted strategies for the treatment of AML.

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Paner, Gladell P., Valerie Lindgren, Kris Jacobson, Kathleen Harrison, Ying Cao, Steve C. Campbell, Robert C. Flanigan, and Maria M. Picken. "High Incidence of Chromosome 1 Abnormalities in a Series of 27 Renal Oncocytomas: Cytogenetic and Fluorescence In Situ Hybridization Studies." Archives of Pathology & Laboratory Medicine 131, no. 1 (January 1, 2007): 81–85. http://dx.doi.org/10.5858/2007-131-81-hiocai.

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Abstract Context.—It has recently been shown by cytogenetics that there is a high incidence of chromosome 1 abnormalities in renal oncocytomas. Objective.—To confirm the cytogenetic results by fluorescence in situ hybridization (FISH) analysis. Design.—Nine additional cytogenetic analyses were added to those reported in our recent study, with a total of 27 tumors studied, which makes it the largest series of renal oncocytomas studied to date by cytogenetics and/or FISH. We used the LSI 1p36/LSI 1q25 Dual Color Probe Set to make the analyses. Results.—In this study, combined cytogenetics and FISH showed loss of chromosome arm 1p1 in 48% of renal oncocytomas. By FISH, deletion of 1p36.3 was observed in 59% of renal oncocytomas, whereas by cytogenetics, abnormality in chromosome 1 was seen in 32% of tumors. However, the incidence of chromosome 1 abnormalities among 9 bilateral tumors was much higher than in single tumors (88% vs 28%, respectively). Loss of only the 1p36.3 site occurred in 2 renal oncocytomas with translocation of chromosome 1, as shown by cytogenetics. Concordance between the 2 techniques, when they were used simultaneously to detect chromosome 1p1 abnormality, was 82%. Conclusions.—This study further confirmed our prior results demonstrating the widespread occurrence of chromosome 1 abnormalities in renal oncocytomas. Although no abnormalities in chromosome 1 in tumors with normal karyotypes were detected by FISH using the current set of probes, a much higher incidence of such abnormalities was found in bilateral tumors, suggesting that genetic alterations related to the development of renal oncocytoma reside in this region.

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Meggendorfer, Manja, Tamara Alpermann, Karolina Perglerová, Wolfgang Kern, Susanne Schnittger, Claudia Haferlach, and Torsten Haferlach. "Genetic Patterns of Relapsed AML Differ Significantly from First Manifestation and Are Dependent on Cytogenetic Risk Groups at Diagnosis: Results in 175 Patients with Paired Samples." Blood 124, no. 21 (December 6, 2014): 1029. http://dx.doi.org/10.1182/blood.v124.21.1029.1029.

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Abstract Introduction: Genetic changes between diagnosis and relapse in AML have not been analyzed comprehensively yet. Especially in the favorable risk group (acute promyelocytic leukemia (APL) with PML-RARA, and core binding factor (CBF) leukemias with CBFB-MYH11 or RUNX1-RUNX1T1) data is scarce. Aim: To investigate genetic patterns in AML with favorable risk cytogenetics at diagnosis and at relapse in comparison to all other AML subtypes. Patients and Methods: We investigated 175 AML patients diagnosed by cytomorphology, immunophenotyping and cytogenetics following WHO criteria both at diagnosis and at relapse (350 samples). Cytogenetic risk stratification followed MRC as favorable, intermediate, and adverse (Grimwade, Blood 2010). 30 patients were diagnosed as APL or CBF leukemia (favorable), while 122 patients were intermediate, and 23 adverse risk. Data on molecular mutations was available for subsets of patients including ASXL1, CEBPA, DNMT3A, EZH2, FLT3-ITD, FLT3-TKD, KIT, IDH1, IDH2, MLL-PTD, NPM1, NRAS, KRAS, RUNX1, TET2, TP53, and WT1. Gene mutations were analyzed by Sanger sequencing, NGS, melting curve analysis, or gene scan. Cytogenetics was available for all 350 samples. Results: Changes in mutational and cytogenetic patterns of APL and CBF leukemias: 28 relapse samples revealed in total 22 gene mutations in 12 genes, with a median number of 0.8 mutations per patient. 7 patients (25%) showed no mutation, 20 (71%) showed 1 mutation, and 1 (4%) had 2 mutations. Most frequently FLT3-ITD was found (n=5), followed by mutations in KIT (n=3), EZH2, FLT3-TKD, NRAS, TET2 (for each n=2), and ASXL1, DNMT3A, IDH1, KRAS, TP53, and WT1(for each n=1). In 17/20 patients with molecular mutations identified either at relapse or primary diagnosis both samples were analyzed for the specific mutation. 22 mutations were present in this subset. Of these 10 (46%) mutations were already detected at primary diagnosis and thus remained stable, while 3/22 (14%) mutations were gained and 9/22 (41%) were lost at relapse. Including patients with no mutation revealed that 13/24 (54%) patients showed an unchanged mutation pattern while 11/24 (46%) gained or lost mutations. The karyotype was stable in 16/30 (53%) cases with favorable cytogenetics, while 14/30 (47%) showed cytogenetic changes: although the main cytogenetic aberration remained unchanged in all relapse samples the latter patients showed either clonal evolution (n=11), clonal regression (n=2) or both (n=1). Changes in mutational and cytogenetic patterns of AML with intermediate risk cytogenetics: In the intermediate risk group (97/122 patients (80%) had normal karyotype) the cytogenetic changes were slightly less frequent with 44/122 (36%). Interestingly, in this group 3 patients occurred with a totally different karyotype at relapse compared to primary diagnosis. In 2 cases, however, the molecular markers remained stable, while in 1 patient also the mutation pattern changed completely. Therefore, the latter one might be a t-AML, while the other two are most likely relapses. The molecular mutation patterns were unstable in this subgroup with 56/94 (60%) patients showing mutational gains as well as losses. Changes in mutational and cytogenetic patterns of AML with adverse cytogenetics: 11/23 patients (48%) showed cytogenetic changes. Also in this group 1 patient might have acquired a t-AML rather than a relapse as suggested by complete changes in cytogenetics and molecular markers. Only 5/18 (26%) showed changes in the mutational pattern at all. Of notice, while in favorable AML mutation patterns changed at relapse more by losses than by gains of mutations, in the intermediate and adverse groups gains of mutations were more frequent. The latter two groups had more mutations already at primary diagnosis and acquired additional mutations mostly in FLT3-ITD but also in the whole spectrum of analyzed genes, particularly in prognostically unfavorable genes such as TP53, ASXL1, RUNX1, DNMT3A, or WT1. Conclusions: 1) In AML with favorable cytogenetics the defining aberrations persist at relapse but changes in karyotype and mutational pattern occur in 47% and 46% of cases. 2) AML with intermediate risk cytogenetics is characterized by instability predominately on the molecular level. 3) AML with adverse cytogenetics shows only few changes in the molecular profile but high karyotype instability. Disclosures Meggendorfer: MLL Munich Leukemia Laboratory: Employment. Alpermann:MLL Munich Leukemia Laboratory: Employment. Perglerová:MLL2 s.r.o.: Employment. Kern:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Schnittger:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership.

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Gangat, Naseema, Jacob J. Strand, Terra L. Lasho, Christy M. Finke, Ryan A. Knudson, Animesh Pardanani, Chin-Yang Li, Rhett P. Ketterling, and Ayalew Tefferi. "Cytogenetic Studies at Diagnosis in Polycythemia Vera: Clinical and JAK2V617F Allele Burden Correlates." Blood 110, no. 11 (November 16, 2007): 2545. http://dx.doi.org/10.1182/blood.v110.11.2545.2545.

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Abstract Background: Previous cytogenetic studies in polycythemia vera (PV) have included a relatively small number of patients (“n” ranging 10–64). In the current study (n=137), we describe cytogenetic findings at presentation and examine their relationship to clinical and laboratory features, including bone marrow JAK2V617F allele burden. Methods: The study consisted of a consecutive group of patients with PV who fulfilled the World Health Organization (WHO) diagnostic criteria and in whom bone marrow biopsy and cytogenetic studies were performed at diagnosis. Results I: cytogenetic details At diagnosis: A total of 137 patients (median age, 64 years; 49% females) were studied at diagnosis and had adequate metaphases for interpretation. Cytogenetics were normal in 117 patients (85%) and displayed either a sole -Y abnormality in 5 patients (7% of the male patients), and other chromosomal abnormalities in 15 (11%). The latter included trisomy 8 in five patients, trisomy 9 in three patients, two patients each with del(13q), del(20q), and abnormalities of chromosome 1, and one patient each with del(3)(p13p21), dup(13)(q12q14), and del(11)(q21). At follow-up: Repeat cytogenetic studies while still in the chronic phase of the disease were performed in 19 patients at a median of 60 months (range, 8–198) from diagnosis. Of these, 4 had aquired new cytogenetic clones including 3 with normal cytogenetics at time of initial PV diagnosis. The new abnormalities included del(20q), del(5q), del(1p), chromosome 1 abnormality, and inv(3)(q21q26.2). At time of disease transformation: Leukemic transformation was documented in 3 patients of whom cytogenetic information at the time was available in 2 patients; both patients had normal results at time of initial PV diagnosis and complex cytogenetic abnormalities at time of leukemic transformation. In contrast, among 6 patients with available cytogenetic information at time of fibrotic transformation, the results were unchanged from those obtained at time of diagnosis in 5 patients. ii) Correlation between cytogenetics at diagnosis and JAK2V617F allele burden: Allele-specific, quantitative PCR analysis for JAK2V617F was performed in 71 patients using genomic DNA from archived bone marrow obtained at the time of the initial cytogenetic studies. JAK2V617F mutation was detected in 64 of the 71 (90%) patients; median mutant allele burden was 16% (range 3–80%) without significant difference among the different cytogenetic groups: normal vs. –Y vs. other cytogenetic abnormalities (p=0.72). iii) Clinical correlates and prognostic relevance of cytogenetic findings at diagnosis: Among several parameters studied for significant correlations with cytogenetic findings at diagnosis, an association was evident only for age (p=0.02); all –Y abnormalities (n=5) as well as 13 of the 15 (87%) other cytogenetic abnormalities occurred in patients ≥ 60 years of age. Stated another way, the incidence of abnormal cytogenetics (other than -Y) was 4% for patients younger than age 60 years and 15% otherwise. The presence of abnormal cytogenetics at diagnosis had no significant impact on either overall or leukemia-free survival. Conclusions: Abnormal cytogenetic findings at diagnosis are infrequent in PV, especially in patients below age 60 years. Furthermore, their clinical relevance is limited and there is not significant correlation with bone marrow JAK2V617F allele burden.

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Wolanskyj, Alexandra P., Naseema Gangat, Susan M. Schwager, Rhett P. Ketterling, and Ayalew Tefferi. "Cytogenetic Abnormalities in Essential Thrombocythemia: Prevalence and Prognostic Significance." Blood 108, no. 11 (November 16, 2006): 3626. http://dx.doi.org/10.1182/blood.v108.11.3626.3626.

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Abstract Objectives: We conducted a study to describe the cytogenetic findings as well as clinical correlates and long-term prognostic relevance of abnormal cytogenetics at the time of diagnosis of Essential thrombocythemia (ET), in terms of clinical presentation, disease transformation into more aggressive myeloid disorders, and life expectancy. Patients and Methods: The study cohort consisted of a consecutive group of patients with ET who fulfilled the World Health Organization (WHO) diagnostic criteria, in whom bone marrow biopsy was performed at diagnosis, with interpretable cytogenetic analysis obtained in all cases. Results: A total of 403 patients were studied (median age, 56 years; median follow-up 64 months). The prevalence of abnormal cytogenetics at presentation was 6.7 % (27 of 403). The most common cytogenetic anomalies identified included trisomy 9 (4 patients), trisomy 8 (3 patients) and deletion 20q (3 patients). Parameters at diagnosis that were significantly associated with abnormal cytogenetics included palpable splenomegaly (p=0.03), current tobacco use (p=0.04); venous thrombosis (p= 0.019), extreme thrombocytosis (i.e., platelet count >1500 × 109/L, p = 0.03) and anemia with a hemoglobin of less than 10 g/dl (p=0.02); but did not include Jak2 mutation status, nor advanced age (≥ 60 years). During follow up, patients with abnormal cytogenetics were more likely to experience venous thrombosis (p=0.02) but not shorter survival [figure 1], transformation to AML, MDS or MMM, nor a greater requirement for cytotoxic therapy. Conclusion: Cytogenetic anomalies at presentation are relatively uncommon in ET, and do not predict a greater predilection towards evolution into more aggressive myeloid disorders, nor inferior survival. Fig. 1 Overall Survival According to Normal vs Abnormal Karyotype Fig. 1. Overall Survival According to Normal vs Abnormal Karyotype

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Li, Marilyn, and Daniel Pinkel. "Clinical cytogenetics and molecular cytogenetics." Journal of Zhejiang University SCIENCE B 7, no. 2 (February 2006): 162–63. http://dx.doi.org/10.1631/jzus.2006.b0162.

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Dingli, David, Schwager M. Schwager, Mesa A. Ruben, Chin Yang Li, and Ayalew Tefferi. "Presence of Unfavorable Cytogenetic Abnormalities Is the Strongest Predictor of Poor Survival in Secondary Myelofibrosis." Blood 106, no. 11 (November 16, 2005): 2585. http://dx.doi.org/10.1182/blood.v106.11.2585.2585.

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Abstract Post-polycythemic (PPMM) and post-thrombocythemic (PTMM) myeloid metaplasia are consensually referred to as secondary myelofibrosis (sMF). Prognostic variables in sMF are not as well defined as they are for agnogenic myeloid metaplasia (AMM). Such information is particularly crucial for management decisions in transplant-eligible patients. Accordingly, we examined the prognostic impact of several clinical and laboratory variables in 66 young patients (age &lt; 60 years) with sMF including 37 with PPMM and 29 with PTMM. Multivariate analysis of parameters other than cytogenetics identified older age (p=0.02), anemia (hemoglobin level &lt; 10 g/dL; p=0.007), and PPMM (p=0.009) as independent risk factors for shortened survival. However, when such analysis was restricted to patients in whom cytogenetic studies were performed (n=31), the presence of unfavorable cytogenetic abnormalities (i.e. clones other than 20q- and 13q-) became the one and only adverse prognostic factor for survival (p=0.001). Figure Figure The prognostic value of cytogenetics was independent of the Dupriez prognostic score (p=0.003). Figure Figure A similar analysis in a temporal cohort of 50 age-matched patients with AMM also identified unfavorable cytogenetics as an independent predictor of poor survival along with thrombocytopenia and anemia. The current study suggests an important prognostic role for cytogenetics in both de novo and secondary myelofibrosis.

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Walter, Claudia Ulrike, Mouhab Ayas, Amal Alseraihy, Hassan El-Solh, Abdullah Al-Jefri, Ali Al-Ahmari, Asim F. Belgaumi, and Maher Albitar. "Cytogenetic Risk Remains a Major Predictor of Outcome in Pediatric AML and ALL Treated with Allogeneic Stem Cell Transplantation,." Blood 118, no. 21 (November 18, 2011): 3524. http://dx.doi.org/10.1182/blood.v118.21.3524.3524.

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Abstract Abstract 3524 Background: Acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) each represent a heterogeneous group of disorders resulting from diverse mechanisms of leukemogenesis. Cytogenetic abnormalities are considered reliable risk-stratification tools in both AML and ALL. Most studies assessing clinical outcome according to cytogenetic risk consider patients treated with conventional intensive chemotherapy. The impact of cytogenetics on outcome in patients treated uniformly with hematopoietic stem cell transplantation (HSCT), especially in the pediatric group, is not well studied. We evaluated whether allogeneic HSCT has an impact on outcome as predicted by cytogenetic risk at diagnosis. Methods: Bone marrow karyotyping and FISH data from 61 pediatric AML patients and 37 pediatric patients with ALL was reviewed and patients divided into two groups according to their cytogenetic risk: one group combined patients with favorable or intermediate risk and the second group comprised patients with adverse-risk cytogenetics. Cytogenetic risk classification was according to WHO and MRC cytogenetic criteria. The AML cohort included 47 (77%) patients treated in their first remission (CR1) while most non-CR1 AML patients were treated with HSCT in CR2. Of the ALL patients, 18 (49%) were treated with HSCT in CR1. The outcome of patients with either favorable/intermediate cytogenetic risk or adverse cytogenetics was compared for AML and ALL patients, first including all patients, then including only CR1 patients. The median age of patients was 8 years (range: 9 months to 13 years). Results: Patients with ALL and favorable / intermediate cytogenetics had significantly longer overall survival (OS) and event-free survival (EFS) as compared with the adverse-risk group (P=0.02 and P=0.03 for OS and EFS, respectively). A similar trend was observed when only CR1 ALL patients were evaluated, although their number is small. Notably, separation between the CR1 ALL and CR2 ALL groups was stronger when only Philadelphia chromosome positive and MLL positive patients were considered (P=0.01 for OS and EFS for all patients; P=0.003 for OS and EFS for CR1patients only). Also for pediatric AML, combined favorable / intermediate-risk cytogenetics was associated with significantly longer OS (P=0.03) and EFS (P=0.04) when all patients were included (Fig. 1). A similar trend was obtained when only CR1 AML patients were considered (P=0.03 for both OS and EFS). Conclusions: This study suggests that stratification of AML and ALL in pediatric patients according to their cytogenetic risk remains relevant even when treated with HSCT and irrespective if patients were treated in CR1 or CR2 after relapse. In particular, MLL gene rearrangements and the Philadelphia chromosome remain poor prognostic factors in pediatric ALL despite HSCT treatment. Disclosures: No relevant conflicts of interest to declare.

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Tamkus, Deimante, Ahmad Jajeh, Ebenezer Berko, David Osafo, Decebal Griza, Paula Kovarik, and Rose Catchatourian. "Adult Acute Lymphoblastic Leukemia and Cytogenetic Abnormalities in Different Racial and Ethnic Subgroups." Blood 106, no. 11 (November 16, 2005): 4547. http://dx.doi.org/10.1182/blood.v106.11.4547.4547.

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Abstract Inferior survival of African American and Hispanic patients with acute lymphoblastic leukemia (ALL) has been reported. The reason for this is unclear. A retrospective analysis was conducted to see if abnormal cytogenetics account for the differences. We have analyzed cytogenetic studies of 39 adults (16 year and older) with newly diagnosed ALL who were consecutively treated at John Stroger Hospital of Cook County between 1997 and 2005. The study population included 13 (33%) African Americans, 18 (46%) Hispanics, 6 (16%) Caucasians, and 2 (5 %) other ethnic background adults. Male to female ratio was 2:1. Mean age at diagnosis was 26 (range between 16 and 71 years). A clonal cytogenetic abnormality was detected in 27 patients, and 12 patients had normal karyotype. Patients with t (9;22)(q34;q11), BCR-ABL + by FISH, t (4;11)(q21;q23), +8, −7 cytogenetic abnormalities were assigned to an unfavorable cytogenetic group. This group was composed of 14 patients. None of our study patients had favorable cytogenetics: del (12p), t(12p), t(14q11-q23), inv(14)(q11;q32) or t(10;14)(q24;q11). Remaining 25 patients with normal karyotype (n=12) or miscellaneous cytogenetic abnormalities (n=13) were classified as normal risk group. 54 % of African Americans had unfavorable cytogenetics, compared with 33 % Caucasians and 17 % Hispanics. Translocation t (9;22) alone or in association with other cytogenetic abnormalities was most commonly seen. 9 patients had single, and 18 had multiple chromosomal changes. Hispanic group had more complex cytogenetic changes when compared with the African American or Caucasian groups. Unfavorable cytogenetic abnormalities may account for inferior survival in African Americans, but other factors such as compliance or pharmacogenetics should be evaluated, especially in the Hispanic patient population.

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Quessada, Julie, Wendy Cuccuini, Paul Saultier, Marie Loosveld, Christine J. Harrison, and Marina Lafage-Pochitaloff. "Cytogenetics of Pediatric Acute Myeloid Leukemia: A Review of the Current Knowledge." Genes 12, no. 6 (June 17, 2021): 924. http://dx.doi.org/10.3390/genes12060924.

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Pediatric acute myeloid leukemia is a rare and heterogeneous disease in relation to morphology, immunophenotyping, germline and somatic cytogenetic and genetic abnormalities. Over recent decades, outcomes have greatly improved, although survival rates remain around 70% and the relapse rate is high, at around 30%. Cytogenetics is an important factor for diagnosis and indication of prognosis. The main cytogenetic abnormalities are referenced in the current WHO classification of acute myeloid leukemia, where there is an indication for risk-adapted therapy. The aim of this article is to provide an updated review of cytogenetics in pediatric AML, describing well-known WHO entities, as well as new subgroups and germline mutations with therapeutic implications. We describe the main chromosomal abnormalities, their frequency according to age and AML subtypes, and their prognostic relevance within current therapeutic protocols. We focus on de novo AML and on cytogenetic diagnosis, including the practical difficulties encountered, based on the most recent hematological and cytogenetic recommendations.

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Najfeld, Vesna, Joseph Tripodi, Marina Kremanskaya, John Mascarenhas, and Ronald Hoffman. "Peripheral Blood Karyotyping Is Superior To Bone Marrow and Identifies Most Frequent Structural Chromosomal Rearrangements In Myelofibrosis." Blood 122, no. 21 (November 15, 2013): 3727. http://dx.doi.org/10.1182/blood.v122.21.3727.3727.

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Abstract In the past cytogenetic studies of patients with MF were hindered because marrow (BM) specimens were used for karyotyping but frequently could not be obtained due to advanced marrow fibrosis. Since MF is characterized by the constitutive mobilization of immature myeloid cells into the peripheral blood (PB), we compared unstimulated PB specimens with BM specimens to determine their utility in successfully detecting cytogenetic abnormalities in patients with MF. We also simultaneously performed interphase FISH (IFISH) studies in order to determine if IFISH identified additional genomic abnormalities in MF. We evaluated 183 patients who had had successful conventional and molecular cytogenetic analyses. Our myeloproliferative neoplasm ( MPN)-FISH panel consisted of twelve probes (EGR1 at 5q31, D5S23 at 5p15.3, D7Z1 at 7p11-q11, D7S522 at 7q31, D8Z2 at 8p11-q11, CDKN2A at 9p21, CEP9 at 9p11-q11, ATM at 11q22,1, Rb1 at 13q14, and D20S18 at 20q12, CKS1B at 1q21 and CDKN2C at 1p32). BM cytogenetics was studied in 60 pts (33%) and PB cytogenetics were evaluated in 123 pts (67%). Conventional cytogenetics was informative for 96% (123/128) of PB specimens and 97% (60/62) of BM samples. When conventional cytogenetic analysis was compared to IFISH, concordant results were observed in 154 patients (84%). Moreover, conventional karyotyping identified chromosomal abnormalities in an additional 18 patients (10%), which were not targeted by the 12 loci FISH panel. Among these patients, structural abnormalities of chromosome 12 were detected in 6 patients (33%) which represents the most frequent structural abnormality detected in MF and was associated with poor survival. Of the 63 patients with concordant abnormal cytogenetics and FISH the most frequent abnormalities included: del(20)(q11q13) (n=30, 48%), unbalanced 1q translocations resulting in trisomy 1q or duplication of 1q (n=17, 27%), gain of chromosome 8 (n=9, 14%), +8,+9( n=4, 6%), trisomy 9 (n=4, 6%), del(7q)/-7( n=7,11%), deletion 13q (n=9,14%) and complex karyotype (n=16, 25%). The remaining 11pts (6%) had discordant conventional and molecular cytogenetic results and were divided into two categories: A) those with normal cytogenetics (with or without non clonal abnormalities) and an abnormal MPN IFISH panel and B) those with abnormal clonal karyotype with normal lFISH. When compared to BM, PB specimens had a similar rate of abnormal karyotype: 51% in PB vs 48% in BM. Our results unequivocally demonstrated that conventional cytogenetics of MF can be successfully obtained from unstimulated PB specimens in 96% of patients and that analysis of BM does not reveal additional cytogenetic abnormalities. We conclude that FISH analysis has limited value in MF and is only informative for those patients who lack mitotic cells or who are cytogenetically normal, and in these patients, IFISH detects cryptic abnormalities in 4%. Use of PB karyotyping in MF is sufficient to effectively detects clonal hematopoiesis which contributes to prognostic risk stratification and influences therapeutic decision making. Disclosures: No relevant conflicts of interest to declare.

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Laughlin, M. J., D. S. McGaughey, J. R. Crews, N. J. Chao, D. Rizzieri, M. Ross, J. Gockerman, et al. "Secondary myelodysplasia and acute leukemia in breast cancer patients after autologous bone marrow transplant." Journal of Clinical Oncology 16, no. 3 (March 1998): 1008–12. http://dx.doi.org/10.1200/jco.1998.16.3.1008.

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PURPOSE To determine the incidence of myelodysplasia (MDS) and/or acute leukemia (AL) in breast cancer patients after high-dose chemotherapy (HDC) with a single conditioning regimen and autologous bone marrow transplant (ABMT), and analyze the cytogenetic abnormalities that arise after HDC. PATIENTS AND METHODS We retrospectively reviewed the records of 864 breast cancer patients who underwent ABMT at Duke University Medical Center, Durham, NC, from 1985 through 1996 who received the same preparative regimen of cyclophosphamide 1,875 mg/m2 for 3 days, cisplatin 55 mg/m2 for 3 days, and BCNU 600 mg/m2 for 1 day (CPB). Pretransplant cytogenetics were analyzed in all patients and posttransplant cytogenetics were evaluated in four of five patients who developed MDS/AL. RESULTS Five of 864 patients developed MDS/AL after HDC with CPB and ABMT. The crude cumulative incidence of MDS/AL was 0.58%. The Kaplan-Meier curve shows a 4-year probability of developing MDS/AL of 1.6%. Pretransplant cytogenetics performed on these five patients were all normal. Posttransplant cytogenetics were performed on four of five patients and they were abnormal in all four, although only one patient had the most common cytogenetic abnormality associated with secondary MDS/AL (chromosome 5 and/or 7 abnormality). CONCLUSION Whereas MDS/AL is a potential complication of HDC with CPB and ABMT, the incidence in this series of patients with breast cancer was relatively low compared with that reported in patients with non-Hodgkin's lymphoma who underwent ABMT. The cytogenetic abnormalities reported in this group of breast cancer patients were not typical of those seen in prior reports of secondary MDS/AL and appear to have occurred after HDC.

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Schanz, Julie, Christian Steidl, Christa Fonatsch, Michael Pfeilstöcker, Thomas Nösslinger, Heinz Tuechler, Peter Valent, et al. "Coalesced Multicentric Analysis of 2,351 Patients With Myelodysplastic Syndromes Indicates an Underestimation of Poor-Risk Cytogenetics of Myelodysplastic Syndromes in the International Prognostic Scoring System." Journal of Clinical Oncology 29, no. 15 (May 20, 2011): 1963–70. http://dx.doi.org/10.1200/jco.2010.28.3978.

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Purpose The International Prognostic Scoring System (IPSS) remains the most commonly used system for risk classification in myelodysplastic syndromes (MDSs). The IPSS gives more weight to blast count than to cytogenetics. However, previous publications suggested that cytogenetics are underweighted in the IPSS. Here we investigate the prognostic impact of cytogenetic subgroups compared with that of bone marrow blast count in a large, multicentric, international patient cohort. Patients and Methods In total, 2,351 patients with MDS who have records in the German-Austrian and the MD Anderson Cancer Center databases were included and analyzed in univariate and multivariate models regarding overall survival and risk of transformation to acute myeloid leukemia (AML). The data were analyzed separately for patients treated with supportive care without specific therapy, with AML-like chemotherapy, or with other therapy regimens (low-dose chemotherapy, demethylating agents, immune modulating agents, valproic acid, and cyclosporine). Results The prognostic impact of poor-risk cytogenetic findings (as defined by the IPSS classification) on overall survival was as unfavorable as an increased (> 20%) blast count. The hazard ratio (compared with an abnormal karyotype or a bone marrow blast count < 5%) was 3.3 for poor-risk cytogenetics, 4.8 for complex abnormalities harboring chromosomes 5 and/or 7, and 3.1 for a blast count of 21% to 30% (P < .01 for all categories). The predictive power of the IPSS cytogenetic subgroups was unaffected by type of therapy given. Conclusion The independent prognostic impact of poor-risk cytogenetics on overall survival is equivalent to the impact of high blast counts. This finding should be considered in the upcoming revision of the IPSS.

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Strand, Jacob J., Terra L. Lasho, Susan M. Schwager, Michelle M. Elliott, Chin-Yang Li, and Ayalew Tefferi. "Cytogenetic Profile, JAK2V617F Mutational Status, and Response to Drug Therapy in Myelofibrosis with Myeloid Metaplasia." Blood 106, no. 11 (November 16, 2005): 2591. http://dx.doi.org/10.1182/blood.v106.11.2591.2591.

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Abstract Background: One of the utilities of molecular markers in hematological malignancies is their potential to predict response to drug therapy. Accordingly, we inquired about the effect of both cytogenetic profile and JAK2V617F mutational status on drug therapy response in myelofibrosis with myeloid metaplasia (MMM). Methods: Mutation analysis for JAK2V617 was performed in DNA derived from peripheral blood mononuclear cells, granulocytes, or both. Genomic DNA was amplified by PCR and fluorescent dye chemistry sequencing was performed using the same primers used for amplification (Levin et al. Cancer Cell2005;7:387). Abnormal cytogenetic findings were considered to be either favorable (sole 13q- or 20q- abnormalities) or unfavorable (other abnormalities) (Tefferi et al. BJH2001;113:763). Results: i. Patients and treatment: A total of 69 patients with MMM (median age 62 years, range 38–75; 47 males) received the following drugs as first-line therapy for either anemia or symptomatic splenomegaly; erythropoietin (Epo) alone or in combination with hydroxyurea (n=25), hydroxyurea alone (HU; n=17), interferon alpha (IFN; n=11), combination of thalidomide and prednisone (ThalPred; n=7), androgen preparations (Andro; n=5), and etanercept (n=4). ii. Results of cytogenetic studies and JAK2 mutation screening: Cytogenetic findings were abnormal in 35 patients (51%); favorable in 9 and unfavorable in 26. JAK2V617 mutation analysis revealed wild-type allele in 31 patients (45%) and either heterozygous (n=31) or homozygous (n=7) mutation in the remaining 38 patients (55%). iii. Correlation of response to cytogenetic/molecular markers: Overall, 17 patients (25%) achieved either a major (n=8) or minor (n=9) response in anemia from treatment with one of the aforementioned drugs. Regardless of either JAK2V617 mutational status or cytogenetic profile, treatment-induced responses in anemia were poor for IFN (0%) and HU (12%). In contrast, the best anemia responses were documented for ThalPred (57%), Andro (40%), and Epo-based therapy (32%). Among the 25 patients that received Epo-based therapy, all 3 patients with favorable cytogenetic abnormalities achieved major responses in anemia whereas such responses were seen in none of the 9 patients with unfavorable cytogenetic abnormalities and only 1 of 13 patients with normal cytogenetics (p=0.004). Furthermore, 3 of the 4 major responders were heterozygous for JAK2V617 and one carried the wild-type allele. In contrast, none of the 3 JAK2V617 homozygotes showed any type of response but all 3 also displayed unfavorable cytogenetics. None of the 7 ThalPred-treated patients carried favorable cytogenetics and yet 3 achieved major responses including one with unfavorable cytogenetics. JAK2V617 mutational status was heterozygous in 1 and wild-type in the other two. There were no major responses among the 5 Andro-treated patients despite the presence of favorable cytogenetic abnormalities in 2 patients. In order to investigate the relationship between cytogenetic profile and JAK2V617 mutational status further, we referred to an expanded database of 116 patients and found the incidence of unfavorable cytogenetics to be higher in JAK2V617 homozygotes compared to non-homozygotes (57% vs. 31%; p=0.16) Conclusion: The current study suggests clustering of favorable cytogenetic abnormalities in MMM with anemia response to Epo therapy and unfavorable cytogenetic abnormalities with homozygosity for JAK2V617 mutation.

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Liehr, T., V. Trifonov, A. Polityko, L. Brecevic, K. Mrasek, A. Weise, E. Ewers, et al. "Characterization of Small Supernumerary Marker Chromosomes By A Simple Molecular and Molecular Cytogenetics Approach." Balkan Journal of Medical Genetics 10, no. 1 (April 1, 2007): 33–37. http://dx.doi.org/10.2478/v10034-007-0006-5.

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Characterization of Small Supernumerary Marker Chromosomes By A Simple Molecular and Molecular Cytogenetics ApproachSmall supernumerary marker chromosomes (sSMC) are still a major problem especially in prenatal cytogenetic diagnostics and counseling. These structurally abnormal chromosomes cannot be identified or characterized unambiguously by conventional banding cytogenetics alone, and are generally about the size of or smaller than a chromosome 20 in the same metaphase spread. We describe a straightforward algorithm, based on data from 2,211 reported cases (http://www.markerchromosomes.ag.vu) to quickly characterize the sSMC's chromosomal origin.

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Avet-Loiseau, Herve, Cyrille Hulin, Lofti Benboubker, Meletios A. Dimopoulos, Andrew Belch, Donna Reece, John Catalano, et al. "Impact of Cytogenetics on Outcomes of Transplant-Ineligible Patients with Newly Diagnosed Multiple Myeloma Treated with Continuous Lenalidomide Plus Low-Dose Dexamethasone in the First (MM-020) Trial." Blood 126, no. 23 (December 3, 2015): 730. http://dx.doi.org/10.1182/blood.v126.23.730.730.

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Abstract Introduction: Cytogenetic abnormalities in patients (pts) with multiple myeloma (MM) are of prognostic importance and can be associated with poor outcomes (Bergsagel, Blood, 2011). The FIRST trial is a pivotal phase 3 study with the largest data set in transplant-ineligible pts with newly diagnosed MM (NDMM). This subanalysis evaluates the impact of cytogenetics on outcomes in transplant-ineligible pts with NDMM continuously treated with lenalidomide plus low-dose dexamethasone until disease progression (Rd continuous). Methods: Transplant-ineligible pts with NDMM were randomized to 1 of 3 treatment arms: Rd continuous, Rd18 (Rd for 18 cycles [72 weeks]), or melphalan-prednisone-thalidomide (MPT; for 12 cycles [72 weeks]). Cytogenetics were assessed using fluorescence in situ hybridization. Pts were categorized into cytogenetic risk groups according to International Myeloma Working Group criteria. High-risk cytogenetics included del(17p), t(4;14), and t(14;16); all other pts were categorized as non-high risk. The primary endpoint was progression-free survival (PFS; primary comparators were Rd continuous vs MPT), and key secondary endpoints were overall survival (OS), overall response rate (ORR), and safety. Results: A total of 762 of 1623 pts from the intent-to-treat population had validated cytogenetic profiles, with 142 pts in the high-risk group and 620 pts in the non-high-risk group. Baseline characteristics were well balanced across cytogenetic risk groups (Table 1). The median follow-up for OS was 40.2 months for the 762 pts in this analysis (data cutoff, March 03, 2014). In the non-high-risk group, median duration of treatment was 19.4 months with Rd continuous and 16.6 months with both Rd18 and MPT. In the high-risk group, median duration of treatment was 10.0 months with Rd continuous, 8.2 months with Rd18, and 12.0 months with MPT. Rd continuous treatment resulted in a 24% reduced risk of death or progression compared with MPT and an even greater 32% reduced risk in pts without high-risk cytogenetics (Table 2). In non-high-risk pts, median PFS was 31.1 months with Rd continuous compared with 21.2 and 24.9 months with Rd18 and MPT, respectively (Figure). However, in high-risk pts, the observed numerical median PFS favoring Rd18 is mainly due to small pt numbers influenced by long runners (n = 5), and the greatly overlapping 95% CIs from all 3 arms show the difference is likely to be minimal. Rd continuous treatment resulted in a 28% reduced risk of death vs MPT overall and a 34% reduced risk in pts without high-risk cytogenetics. OS was similar across treatment arms for high-risk pts. ORRs in all cytogenetic risk groups favored Rd continuous vs MPT. In pts with high-risk cytogenetics, higher-quality responses were also observed with Rd continuous vs MPT treatment. Similar results were seen with Rd continuous compared with Rd18, although OS and ORR benefits overall and in pts without high-risk cytogenetics were not as pronounced. In all 3 treatment arms, adverse events were consistent across cytogenetic risk groups. Conclusions: Rd continuous treatment resulted in PFS and OS benefits vs MPT in pts with validated cytogenetic profiles. This was largely due to PFS and OS improvements in pts without high-risk cytogenetics. In the high-risk group, the longest PFS was observed with Rd18 treatment and OS was similar across treatment arms. Despite being on the continuous vs fixed duration treatment arm, high-risk pts on Rd continuous received a shorter duration of treatment than those on MPT, which may explain why PFS favored MPT vs Rd continuous. Higher response rates were observed with Rd continuous vs MPT, regardless of cytogenetic risk, and greater quality responses were observed in pts with high-risk cytogenetics. The safety profile of Rd continuous was manageable and consistent between cytogenetic risk groups. Results support Rd continuous as a standard treatment option for pts with NDMM who are ineligible for transplant, especially those without high-risk cytogenetics. Additional PFS and OS benefits may be achieved in pts with high-risk cytogenetics when Rd continuous is used as a backbone for combination therapy with a novel agent. Promising activity in pts with high-risk cytogenetic abnormalities has been demonstrated using this approach (Lonial et al, N Engl J Med, 2015; Stewart et al, N Engl J Med, 2015). Disclosures Hulin: Celgene Corporation: Honoraria; Janssen: Honoraria; Amgen: Honoraria; Bristol Myers Squibb: Honoraria. Dimopoulos:Celgene: Honoraria; Onyx: Honoraria; Novartis: Honoraria; Janssen-Cilag: Honoraria; Amgen: Honoraria; Janssen: Honoraria; Genesis: Honoraria. Reece:Lundbeck: Honoraria; Amgen: Honoraria; Merck: Research Funding; Bristol-Myers Squibb: Research Funding; Janssen-Cilag: Consultancy, Honoraria, Research Funding; Onyx: Consultancy; Celgene: Consultancy, Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Millennium Takeda: Research Funding; Otsuka: Research Funding. Catalano:Roche: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Celgene Corporation: Consultancy, Honoraria. Pinto:Takeda: Honoraria, Research Funding; Celgene Corporation: Honoraria; Spectrum: Honoraria. Ludwig:Takeda: Research Funding; Celgene Corporation: Honoraria, Speakers Bureau; Onyx: Honoraria, Speakers Bureau; Bristol Myers Squibb: Honoraria, Speakers Bureau; Janssen Cilag: Honoraria, Speakers Bureau. Bahlis:Celgene Corporation: Honoraria, Research Funding. Cavo:Janssen-Cilag, Celgene, Amgen, BMS: Honoraria. Moreau:Takeda: Other: Adboard; Janssen: Other: Adboard; Novartis: Other: Adboard; Amgen: Other: Adboard; Celgene: Honoraria, Other: Adboard. Qiu:Johnson & Johnson: Speakers Bureau; Celgene Corporation: Speakers Bureau; Roche: Speakers Bureau. Schots:Celgene Corporation: Research Funding. Marek:Celgene Corporation: Employment, Equity Ownership. Chen:Celgene Corporation: Employment, Equity Ownership. Yiu:Celgene Corporation: Employment, Equity Ownership. Ervin-Haynes:Celgene Corporation: Employment. Facon:Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millenium: Membership on an entity's Board of Directors or advisory committees; Onyx: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Pierre Fabre: Membership on an entity's Board of Directors or advisory committees.

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Marcucci, Guido, Krzysztof Mrózek, Amy S. Ruppert, Kellie J. Archer, Mark J. Pettenati, Nyla A. Heerema, Andrew J. Carroll, et al. "Abnormal Cytogenetics at Date of Morphologic Complete Remission Predicts Short Overall and Disease-Free Survival, and Higher Relapse Rate in Adult Acute Myeloid Leukemia: Results From Cancer and Leukemia Group B Study 8461." Journal of Clinical Oncology 22, no. 12 (June 15, 2004): 2410–18. http://dx.doi.org/10.1200/jco.2004.03.023.

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Purpose As most patients with acute myeloid leukemia (AML) with morphologic complete remission (CR) ultimately relapse, better predictors for outcome are needed. Recently, Cheson et al suggested using cytogenetic remission (CRc) as part of the criteria for CR. To our knowledge, ours is the first relatively large study evaluating the usefulness of CRc attained immediately following induction chemotherapy. Patients and Methods We included AML patients treated on Cancer and Leukemia Group B front-line studies with cytogenetic samples obtained at diagnosis and at the first day of documented CR following induction. Patients with abnormal cytogenetics at diagnosis, and normal cytogenetics at CR (NCR; n = 103) were compared with those with abnormal cytogenetics both at diagnosis and at CR (ACR; n = 15) for overall survival (OS), disease-free survival (DFS), and cumulative incidence of relapse (CIR). Cox proportional hazards models determined the prognostic significance of cytogenetics at CR, adjusting for other covariates. Results Clinical features were similar for both groups, with the exception of favorable cytogenetics [t(8;21), inv(16)/t(16;16), t(15;17)] at diagnosis, which was more frequent (P = .03) in the NCR group. Median follow-up was 3.1 years (range, 1.0 to 11.4 years). ACR patients had significantly shorter OS (P = .006) and DFS (P = .0001), and higher CIR (P = .0001). In multivariable models, the NCR and ACR groups were predictors for OS (P = .03), DFS (P = .02), and CIR (P = .05). The relative risk of relapse or death was 2.1 times higher for ACR patients than for NCR patients (95% CI, 1.1 to 3.9). Conclusion Our data suggest that converting to normal karyotype at the time of first CR is an important prognostic indicator and support the use of CRc as a criterion of CR in AML.

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Heng, JL, YC Chen, TC Quah, TC Liu, and AEJ Yeoh. "Dedicated Cytogenetics Factor is Critical for Improving Karyotyping Results for Childhood Leukaemias – Experience in the National University Hospital, Singapore 1989-2006." Annals of the Academy of Medicine, Singapore 39, no. 2 (February 15, 2010): 102–6. http://dx.doi.org/10.47102/annals-acadmedsg.v39n2p102.

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Introduction: Childhood leukaemia accounts for more than 40% of new childhood cancer cases. Karyotyping of cytogenetic abnormalities in such cases continues to provide critical prognostic information which allows the delivery of an appropriate intensity of treatment. Unfortunately, karyotyping of childhood leukaemia is difficult, laborious and often unsuccessful. Banding resolution tends to be poor unlike routine antenatal cytogenetics. The aim of the study is to highlight the benefit of dedicated cytogenetics in improving karyotyping results. Materials and Methods: We analysed the impact of setting up a team of cytogeneticists in the National University Hospital (NUH) on the success of karyotyping, evaluating cytogenetic data collected from 1989 to 2006. From 1989 to 2006, 4789 cases have been processed. Among them, 369 newly diagnosed and relapsed childhood acute leukaemia cases [281 acute lymphoblastic leukaemia (ALL) and 88 acute myeloid leukaemia (AML)] have been diagnosed at NUH. A dedicated cytogenetics laboratory with clearly defi ned standard operating procedures and quality control was set up in 2002. It used the established recommendation of a complete analysis of at least 20 metaphases per analysis. Results: Overall, the frequency of successful karyotyping was significantly higher (P = 0.002) at 90.7% (185/204) from 2002-2006 compared to 79.4% (131/165) from 1989-2001. For ALL cases, the success rate improved from 77.6% (97/125) in 1989 to 2001 to 89.1% (139/156) in the 2002 to 2006 cohort. For AML, the success rate also was significantly improved (P = 0.04) from 85% (34/40) to 95.8% (46/48). Significantly, this high rate of success is still maintained despite a yearly increase in volume. Conclusion: The establishment of a dedicated cytogenetics service leads to an improvement in results. Key words: Childhood leukaemia, Dedicated cytogenetics service, Successful karyotyping

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39

Bhowmick, Biplab Kumar, and Sumita Jha. "A critical review on cytogenetics of Cucurbitaceae with updates on Indian taxa." Comparative Cytogenetics 16, no. 2 (April 26, 2022): 93–125. http://dx.doi.org/10.3897/compcytogen.v16.i2.79033.

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The cytogenetic relationships in the species of Cucurbitaceae are becoming immensely important to answer questions pertaining to genome evolution. Here, a simplified and updated data resource on cytogenetics of Cucurbitaceae is presented on the basis of foundational parameters (basic, zygotic and gametic chromosome numbers, ploidy, genome size, karyotype) and molecular cytogenetics. We have revised and collated our own findings on seven agriculturally important Indian cucurbit species in a comparative account with the globally published reports. Chromosome count (of around 19% species) shows nearly three-fold differences while genome size (of nearly 5% species) shows 5.84-fold differences across the species. There is no significant correlation between chromosome numbers and nuclear genome sizes. The possible trend of evolution is discussed here based on molecular cytogenetics data, especially the types and distribution of nucleolus organizer regions (NORs). The review supersedes the scopes of general chromosome databases and invites scopes for continuous updates. The offline resource serves as an exclusive toolkit for research and breeding communities across the globe and also opens scope for future establishment of web-database on Cucurbitaceae cytogenetics.

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40

Bhowmick, Biplab Kumar, and Sumita Jha. "A critical review on cytogenetics of Cucurbitaceae with updates on Indian taxa." Comparative Cytogenetics 16, no. 2 (April 26, 2022): 93–125. http://dx.doi.org/10.3897/compcytogen.v16.i2.79033.

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The cytogenetic relationships in the species of Cucurbitaceae are becoming immensely important to answer questions pertaining to genome evolution. Here, a simplified and updated data resource on cytogenetics of Cucurbitaceae is presented on the basis of foundational parameters (basic, zygotic and gametic chromosome numbers, ploidy, genome size, karyotype) and molecular cytogenetics. We have revised and collated our own findings on seven agriculturally important Indian cucurbit species in a comparative account with the globally published reports. Chromosome count (of around 19% species) shows nearly three-fold differences while genome size (of nearly 5% species) shows 5.84-fold differences across the species. There is no significant correlation between chromosome numbers and nuclear genome sizes. The possible trend of evolution is discussed here based on molecular cytogenetics data, especially the types and distribution of nucleolus organizer regions (NORs). The review supersedes the scopes of general chromosome databases and invites scopes for continuous updates. The offline resource serves as an exclusive toolkit for research and breeding communities across the globe and also opens scope for future establishment of web-database on Cucurbitaceae cytogenetics.

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41

Bhowmick, Biplab Kumar, and Sumita Jha. "A critical review on cytogenetics of Cucurbitaceae with updates on Indian taxa." Comparative Cytogenetics 16, no. (2) (April 26, 2022): 93–125. https://doi.org/10.3897/compcytogen.v16.i2.79033.

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The cytogenetic relationships in the species of Cucurbitaceae are becoming immensely important to answer questions pertaining to genome evolution. Here, a simplified and updated data resource on cytogenetics of Cucurbitaceae is presented on the basis of foundational parameters (basic, zygotic and gametic chromosome numbers, ploidy, genome size, karyotype) and molecular cytogenetics. We have revised and collated our own findings on seven agriculturally important Indian cucurbit species in a comparative account with the globally published reports. Chromosome count (of around 19% species) shows nearly three-fold differences while genome size (of nearly 5% species) shows 5.84-fold differences across the species. There is no significant correlation between chromosome numbers and nuclear genome sizes. The possible trend of evolution is discussed here based on molecular cytogenetics data, especially the types and distribution of nucleolus organizer regions (NORs). The review supersedes the scopes of general chromosome databases and invites scopes for continuous updates. The offline resource serves as an exclusive toolkit for research and breeding communities across the globe and also opens scope for future establishment of web-database on Cucurbitaceae cytogenetics.

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42

Barz Leahy, Allison, Kaitlin J. Stanley, Regina M. Myers, Amanda M. DiNofia, Lisa Wray, Susan R. Rheingold, Colleen Callahan, et al. "Cytogenetic Characteristics and Outcomes of Patients Receiving CTL019 CAR T Cell Therapy." Blood 134, Supplement_1 (November 13, 2019): 1464. http://dx.doi.org/10.1182/blood-2019-130060.

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Background: CTL019 is a therapy derived from autologous T cells expressing a CD19-specific chimeric antigen receptor (CAR) that was approved by the FDA in August 2017 (tisagenlecleucel). Complete and durable remissions have been seen in the setting of pediatric and young adult patients with relapsed and refractory B cell acute lymphoblastic leukemia (ALL) (Maude NEJM 2018). Initial case reports suggested that there may be differential outcomes mediated by cytogenetic characteristics of the leukemia at CAR T cell infusion. Here, we report results from a single institution experience of 112 patients. Methods: Patients with relapsed/refractory ALL were identified as having received CTL019 either in the context of a clinical trial (NCT02906371) or commercial product (tisagenlecleucel) at Children's Hospital of Philadelphia from October 2016 to April 2019. Patients who received prior CAR T therapy were excluded. Demographic, cytogenetic, and outcome data were manually abstracted from the medical record or clinical trial datasets. High risk lesions were defined as MLL(KMT2A) rearrangements, Philadelphia-chromosome (Ph+), Ph-like, hypodiploidy, and TCF3/HLF fusion. Favorable cytogenetics were defined as the presence of hyperdiploidy or ETV6/RUNX1fusion and intermediate were defined as iAMP21, IKZF1deletion, or TCF3/PBX1. Patients were classified according to their highest risk cytogenetic characteristic and stratified by cytogenetic risk category present at CAR T cell infusion. Relapse-free survival (RFS) and overall survival (OS) was described for cohorts with more than 10 patients. Results: One hundred and twelve patients were included in the analysis, with a median age of 11 years (range 1-29) at infusion, of which 32% had had a previous allogeneic hematopoietic stem cell transplant (alloHSCT). Disease burden at the time of CTL019 infusion was heterogenous, with 61% having detectable disease in the bone marrow and 21% having more than 25% blasts by flow cytometry. Thirty-six patients (32%) had leukemias with high-risk genetic lesions at infusion, including 12 with MLL rearrangements and 18 with Ph+ or Ph-like lesions (Table 2). Thirty-one patients (28%) had hyperdiploidy or ETV6/RUNX1; 3 additional were in conjunction with high-risk cytogenetics (t(17;19) and 2 with Ph+), and 3 in the setting of intermediate-risk cytogenetics (iAmp21, TCF3/PBX1, IKZF1deletion). Figure 1 demonstrates RFS for those patients in remission at day 28 following infusion, stratified by cytogenetic risk category. Complete remission (CR) rate in the high-risk cytogenetics group was 94%. RFS at 12 months was 69% (0.50-0.82), 69% (0.40-0.86), and 67% (0.48-0.80) for non-informative, favorable, and high-risk cytogenetic groups, respectively. Figure 2 shows OS of patients infused with CTL019, again stratified by cytogenetic categories of interest, with a maximum follow-up time of 30 months. OS at 12 months was 84% (0.68-0.93) and 76% (0.56-0.88) for the non-informative and high-risk cytogenetic groups, respectively. There were no deaths in that time period for the favorable risk category. There was no statistically significant difference in RFS or OS for patients with high-risk cytogenetics. The intermediate-risk cytogenetics group (n&lt;10) was excluded from these analyses. Conclusion: Durable remissions can be achieved with CTL019 across several high-risk cytogenetic subtypes of B-ALL. Stratifying outcomes by cytogenetic risk category in this unadjusted analysis does not show a statistically significant difference in either RFS nor OS. Further investigation is needed to parse out the contribution of individual cytogenetic lesions as well as the effects of other relapse and survival risk factors at play. Figure Disclosures Rheingold: Novartis: Consultancy; Pfizer: Research Funding. Callahan:Novartis: Consultancy. Hunger:Bristol Myers Squibb: Consultancy; Amgen: Consultancy, Equity Ownership; Jazz: Honoraria; Novartis: Consultancy. Grupp:Novartis: Consultancy, Research Funding; Roche: Consultancy; GSK: Consultancy; Cure Genetics: Consultancy; Humanigen: Consultancy; CBMG: Consultancy; Novartis: Research Funding; Kite: Research Funding; Servier: Research Funding; Jazz: Other: study steering committees or scientific advisory boards; Adaptimmune: Other: study steering committees or scientific advisory boards. Maude:Kite: Consultancy; Novartis: Consultancy.

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Tallman, Martin, Gordon Dewald, Hillard Lazarus, Sharavi Gandham, Gene Nelson, Brent Logan, Jacob Rowe, et al. "Impact of Cytogenetics on Outcome of Mismatched Unrelated Donor Hematopoietic Stem Cell Transplantation for Adults with AML." Blood 104, no. 11 (November 16, 2004): 830. http://dx.doi.org/10.1182/blood.v104.11.830.830.

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Abstract Matched unrelated donor hematopoietic stem cell transplantation (MUD HSCT) is a potentially curative treatment for patients with acute myeloid leukemia (AML). The graft-versus-leukemia (GVL) effect may be potent enough to overcome the otherwise poor prognosis associated with AML though its efficacy for high risk cytogenetic subgroups is uncertain. To test this hypothesis, we analyzed outcomes by cytogenetic risk group in 324 patients in first complete remission (CR1), and 440 in CR2 undergoing NMDP-facilitated MUD HSCT between 1988–2002. Using the SWOG/ECOG classification of cytogenetic risk groups (Slovak et al. Blood, 2000) cytogenetics were classified as favorable in 14% of patients, intermediate in 71% and unfavorable in 16%. 56% of the patients were male and 42% were > 35 years at HSCT. 76% of patients and donors were matched at HLA-A, -B and -DRB1, 17% were mismatched at one or more loci and 7% were potentially matched (serologically matched at HLA-A and -B and potentially allele matched at -DR). Disease Status N Kaplan-Meier Estimate for Survival at 5 years Kaplan-Meier Estimate for Disease-Free Survival at 5 years Cumulative Incidence for 100 Day Transplant-Related Mortality Cumulative Incidence for Relapse at 5 years * p-value indeterminate; ** p=0.01 CR1 324 32 ± 6% 32 ± 5% 32 ± 5% 18 ± 4% Intermediate 227 33 ± 7% 32 ± 7% 31 ± 6% 16 ± 5%* Unfavorable 85 31 ± 11% 31 ± 10% 29 ± 10% 23 ± 9%* CR2 440 36 ± 5% 35 ± 5% 25 ± 4% 16 ± 3% Favorable 93 46 ± 10% 44 ± 10% 25 ± 9% 10 ± 6%** Intermediate 313 33 ± 6% 32 ± 5% 27 ± 5% 16 ± 4%** Unfavorable 34 37 ± 17% 38 ± 16% 15 ± 12% 32 ± 15%** These data suggest that with the exception of the 5-year relapse rate, results of cytogenetics have little apparent influence on the outcome for patients undergoing MUD HSCT for AML in CR1. In CR2, results in patients with favorable cytogenetics appear to be better than those with intermediate or unfavorable cytogenetics, but are not statistically significantly different. Effective GVL and protection against relapse is observed, even in high risk cytogenetic subgroups. In this retrospective study, other prognostic factors may influence the outcome, but overall survival for patients with unfavorable cytogenetics appears at least as good as previously reported for matched sibling HSCT.

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&NA;. "Cytogenetics." Journal of Pediatric Hematology/Oncology 25, no. 4 (April 2003): S14—S15. http://dx.doi.org/10.1097/00043426-200304000-00032.

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Glassman, Armand B. "Cytogenetics." Clinics in Laboratory Medicine 17, no. 1 (March 1997): 21–37. http://dx.doi.org/10.1016/s0272-2712(18)30229-4.

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Mecucci, Cristina, and Herman Van den Berghe. "Cytogenetics." Hematology/Oncology Clinics of North America 6, no. 3 (June 1992): 523–41. http://dx.doi.org/10.1016/s0889-8588(18)30326-5.

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Astbury, Caroline. "Cytogenetics." Clinics in Laboratory Medicine 31, no. 4 (December 2011): xiii—xv. http://dx.doi.org/10.1016/j.cll.2011.08.017.

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48

&NA;. "Cytogenetics." Pathology 22 (1990): 25. http://dx.doi.org/10.3109/00313029009060109.

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49

&NA;. "Cytogenetics." Pathology 25, Suppl 1 (1993): 17–18. http://dx.doi.org/10.3109/00313029309107648.

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Roa, Fernando, and Mariana Pires de Campos Telles. "The Cerrado (Brazil) plant cytogenetics database." Comparative Cytogenetics 11, no. 2 (April 25, 2017): 285–97. http://dx.doi.org/10.3897/compcytogen.11(2).11395.

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Cerrado is a biodiversity hotspot that has lost ca. 50% of its original vegetation cover and hosts ca. 11,000 species belonging to 1,423 genera of phanerogams. For a fraction of those species some cytogenetic characteristics like chromosome numbers and C-value were available in databases, while other valuable information such as karyotype formula and banding patterns are missing. In order to integrate and share all cytogenetic information published for Cerrado species, including frequency of cytogenetic attributes and scientometrics aspects, Cerrado plant species were searched in bibliographic sources, including the 50 richest genera (with more than 45 taxa) and 273 genera with only one species in Cerrado. Determination of frequencies and the database website (http://cyto.shinyapps.io/cerrado) were developed in R. Studies were pooled by employed technique and decade, showing a rise in non-conventional cytogenetics since 2000. However, C-value estimation, heterochromatin staining and molecular cytogenetics are still not common for any family. For the richest and best sampled families, the following modal 2n counts were observed: Oxalidaceae 2n = 12, Lythraceae 2n = 30, Sapindaceae 2n = 24, Solanaceae 2n = 24, Cyperaceae 2n = 10, Poaceae 2n = 20, Asteraceae 2n = 18 and Fabaceae 2n = 26. Chromosome number information is available for only 16.1% of species, while there are genome size data for only 1.25%, being lower than the global percentages. In general, genome sizes were small, ranging from 2C = ca. 1.5 to ca. 3.5 pg. Intra-specific 2n number variation and higher 2n counts were mainly related to polyploidy, which relates to the prevalence of even haploid numbers above the mode of 2n in most major plant clades. Several orphan genera with almost no cytogenetic studies for Cerrado were identified. This effort represents a complete diagnosis for cytogenetic attributes of plants of Cerrado.

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