Cancer cytogenetics in a genomics world: Wedding the old with the new.

Since the discovery of the Philadelphia chromosome in 1960, cytogenetic studies have been instrumental in detecting chromosomal abnormalities that can inform cancer diagnosis, treatment, and risk assessment efforts. The initial expansion of cancer cytogenetics was with fluorescence in situ hybridization (FISH) to assess submicroscopic alterations in dividing or non-dividing cells and has grown into the incorporation of chromosomal microarrays (CMA), and next generation sequencing (NGS). These molecular technologies add additional dimensions to the genomic assessment of cancers by uncovering cytogenetically invisible molecular markers. Rapid technological and bioinformatic advances in NGS are so promising that the idea of performing whole genome sequencing as part of routine patient care may soon become economically and logistically feasible. However, for now cytogenetic studies continue to play a major role in the diagnostic testing and subsequent assessments in leukemia with other genomic studies serving as complementary testing options for detection of actionable genomic abnormalities. In this review, we discuss the role of conventional cytogenetics (karyotyping, chromosome analysis) and FISH studies in hematological malignancies, highlighting the continued clinical utility of these techniques, the subtleties and complexities that are relevant to treating physicians and the unique strengths of cytogenetics that cannot yet be paralleled by the current high-throughput molecular technologies. Additionally, we describe how CMA, optical genome mapping (OGM), and NGS detect abnormalities that were beyond the capacity of cytogenetic studies and how an integrated approach (broad molecular testing) can contribute to the detection of actionable targets and variants in malignancies. Finally, we discuss advances in the field of genomic testing that are bridging the advantages of individual (single) cell based cytogenetic testing and broad genomic testing.

Dual CD19 and CD123 targeting prevents antigen-loss relapses after CD19-directed immunotherapies.

Potent CD19-directed immunotherapies, such as chimeric antigen receptor T cells (CART) and blinatumomab, have drastically changed the outcome of patients with relapsed/refractory B cell acute lymphoblastic leukemia (B-ALL). However, CD19-negative relapses have emerged as a major problem that is observed in approximately 30% of treated patients. Developing approaches to preventing and treating antigen-loss escapes would therefore represent a vertical advance in the field. Here, we found that in primary patient samples, the IL-3 receptor α chain CD123 was highly expressed on leukemia-initiating cells and CD19-negative blasts in bulk B-ALL at baseline and at relapse after CART19 administration. Using intravital imaging in an antigen-loss CD19-negative relapse xenograft model, we determined that CART123, but not CART19, recognized leukemic blasts, established protracted synapses, and eradicated CD19-negative leukemia, leading to prolonged survival. Furthermore, combining CART19 and CART123 prevented antigen-loss relapses in xenograft models. Finally, we devised a dual CAR-expressing construct that combined CD19- and CD123-mediated T cell activation and demonstrated that it provides superior in vivo activity against B-ALL compared with single-expressing CART or pooled combination CART. In conclusion, these findings indicate that targeting CD19 and CD123 on leukemic blasts represents an effective strategy for treating and preventing antigen-loss relapses occurring after CD19-directed therapies.

Transmission of an expanding donor-derived del(20q) clone through allogeneic hematopoietic stem cell transplantation without the development of a hematologic neoplasm.

Donor cell leukemia is a rare complication of allogeneic hematopoietic stem cell transplantation (HSCT), which may result from the development of a new malignancy in previously healthy donor cells after transplant into the recipient, or it may derive from the transmission of an occult leukemia from donor to recipient. We report a case of donor derived 20q11.2 deletion in a male patient who received an allogeneic HSCT from his HLA-identical sister for the treatment of his chronic lymphocytic leukemia. Bone marrow cells from the donor were found to contain the 20q deletion that expanded over time, but which was absent in her peripheral blood cells. Although cases of donor cell leukemia after HSCT have been reported, in this case there has been no evidence of an associated hematologic neoplasm in either the donor or recipient. Pre-transplant donor bone marrow evaluations are not practical or warranted, however the finding of new cytogenetic abnormalities after transplant mandates a thorough evaluation of the donor.

Rare Complex Mutational Profile in an ALK Inhibitor-resistant Non-small Cell Lung Cancer.

Testing for somatic alterations, including anaplastic lymphoma receptor tyrosine kinase gene (ALK) rearrangements and epidermal growth factor receptor gene (EGFR) mutations, is standard practice in the diagnostic evaluation and therapeutic management of non-small cell lung cancer (NSCLC), where the results of such tests can predict response to targeted-therapy. ALK rearrangements, EGFR mutations and mutations in the Kirsten rat sarcoma viral oncogene homolog (KRAS) are considered mutually exclusive in NSCLC. Herein we identified a KRAS Q22K mutation and frameshift mutations in the genes encoding serine/threonine kinase 11 (STK11) and ataxia telangiectasia mutated serine/threonine kinase (ATM) by next-generation sequencing in a patient with ALK rearrangement-positive oligo-metastatic NSCLC, whose disease progressed while on two ALK-targeted therapies. Such a complex diagnostic genetic profile has not been reported in ALK fusion-positive NSCLC. This case highlights the utility of comprehensive molecular testing in the diagnosis of NSCLC.

Higher burden of hemorrhagic stroke among women. An autopsy-based study in São Paulo, Brazil.

The aim of this study was to verify the gender difference in sudden cardiovascular death, mainly comparing brain infarction and hemorrhagic stroke. We analyzed 970 autopsy cases from a total of 3,802 nonviolent deaths (448 considered as sudden deaths, 296 undetermined, and 226 non-sudden deaths) including patients aged 30-69 years. All cardiovascular diseases were responsible for 69% of sudden deaths, and all types of stroke for only 14%. The proportions of sudden death for all cardiovascular diseases, coronary heart disease and ischemic stroke deaths were similar for both sexes. However, sudden deaths due to all types of stroke (women 20.0%; men 11.1%; p = 0.012) and hemorrhagic stroke (women 15.6%; men 7.9%; p = 0.019) were significantly more frequent among women when compared to men, the main cause being subarachnoid hemorrhage (women 5.6%; men 1.0%; p = 0.011). Hemorrhagic stroke deaths were usually sudden deaths among women.

Hypertension in employees of a University General Hospital.

PURPOSE: To find out the prevalence of hypertension in employees of the Hospital and relate it to social demographic variables. METHODS: Blood pressure measurement was performed with a mercury sphygmomanometer, using an appropriate cuff size for arm circumference, weight, and height in a population sample of 864 individuals out of the 9,905 employees of a University General Hospital stratified by gender, age, and job position. RESULTS: Hypertension prevalence was 26% (62% of these reported being aware of their hypertension and 38% were unaware but had systolic/diastolic blood pressures of >140 and/or >90 mm Hg at the moment of the measurement). Of those who were aware of having hypertension, 51% were found to be hypertensive at the moment of the measurement. The prevalence was found to be 17%, 23%, and 29% (P <.05) in physicians, nursing staff, and "others", respectively. The univariate analysis showed a significant odds ratio for the male gender, age >50 years, work unit being the Institute of Radiology and the Administration Building, educational level 10 years, and body mass index >30 kg/m2. The multivariate logistic regression model revealed a statistically significant association of hypertension with the following variables: gender, age, skin color, family income, and body mass index. CONCLUSIONS: Hypertension prevalence was high, mainly in those who were not physicians or members of the nursing staff. High-risk groups (obese, non-white, men, low family income) should be better advised of prevention and early diagnosis of hypertension by means of special programs.

Hypertension in employees of a University General Hospital

OBJETIVO: Conhecer a prevalência de hipertensão arterial em funcionários de um complexo hospitalar e relacionar com variáveis sócio demográficas. MÉTODOS: Foi medida a pressão arterial com aparelho de coluna de mercúrio e manguito adequado à circunferência do braço, o peso e a altura em amostra de 864 dos 9.905 funcionários do Hospital Universitário estratificada de acordo com sexo, idade e ocupação. RESULTADOS: A prevalência de hipertensão foi de 26% (hipertensão referida = 62% ou pressão sistólica > 140 e/ou > 90 mm Hg no momento da medida = 38%). Dos que referiram 51% estavam hipertensos no momento da medida. A prevalência foi 17, 23 e 29% (p < 0,05) nos médicos, enfermagem e "outros". Análise univariada mostrou "odds ratio" significante para o sexo masculino, idade > 50 anos, unidade de trabalho para o Instituto de Radiologia e Prédio da Administração, escolaridade 10 anos e índice de massa corporal (IMC) maior ou igual a 30 kg/m2. O modelo de regressão logística com procedimento "stepwise" mostrou associação estatisticamente significante com hipertensão arterial para as variáveis: sexo, idade, cor da pele, renda familiar e IMC. CONCLUSÃO: A prevalência de hipertensão foi alta em funcionários do Complexo Hospital das Clínicas, principalmente nos de ocupação diferente de médico e enfermagem. Os grupos de maior risco (homens, cor preta, baixa renda familiar, obesos) precisam ser orientados quanto a prevenção e diagnóstico precoce da doença através de programas especiais.