Chromosome banding analysis and genomic microarrays are both useful but not equivalent methods for genomic complexity risk stratification in chronic lymphocytic leukemia patients.

Genome complexity has been associated with poor outcome in patients with chronic lymphocytic leukemia (CLL). Previous cooperative studies established five abnormalities as the cut-off that best predicts an adverse evolution by chromosome banding analysis (CBA) and genomic microarrays (GM). However, data comparing risk stratification by both methods are scarce. Herein, we assessed a cohort of 340 untreated CLL patients highly enriched in cases with complex karyotype (CK) (46.5%) with parallel CBA and GM studies. Abnormalities found by both techniques were compared. Prognostic stratification in three risk groups based on genomic complexity (0-2, 3- 4 and ≥5 abnormalities) was also analyzed. No significant differences in the percentage of patients in each group were detected, but only a moderate agreement was observed between methods when focusing on individual cases (κ=0.507; P<0.001). Discordant classification was obtained in 100 patients (29.4%), including 3% classified in opposite risk groups. Most discrepancies were technique-dependent and no greater correlation in the number of abnormalities was achieved when different filtering strategies were applied for GM. Nonetheless, both methods showed a similar concordance index for prediction of time to first treatment (TTFT) (CBA: 0.67 vs. GM: 0.65) and overall survival (CBA: 0.55 vs. GM: 0.57). High complexity maintained its significance in the multivariate analysis for TTFT including TP53 and IGHV status when defined by CBA (hazard ratio [HR] 3.23; P<0.001) and GM (HR 2.74; P<0.001). Our findings suggest that both methods are useful but not equivalent for risk stratification of CLL patients. Validation studies are needed to establish the prognostic value of genome complexity based on GM data in future prospective studies.

Enumerating bone marrow blasts from nonerythroid cellularity improves outcome prediction in myelodysplastic syndromes and permits a better definition of the intermediate risk category of the Revised International Prognostic Scoring System (IPSS-R).

The Revised International Prognostic Scoring System (IPSS-R) has been recognized as the score with the best outcome prediction capability in MDS, but this brought new concerns about the accurate prognostication of patients classified into the intermediate risk category. The correct enumeration of blasts is essential in prognostication of MDS. Recent data evidenced that considering blasts from nonerythroid cellularity (NECs) improves outcome prediction in the context of IPSS and WHO classification. We assessed the percentage of blasts from total nucleated cells (TNCs) and NECs in 3924 MDS patients from the GESMD, 498 of whom were MDS with erythroid predominance (MDS-E). We assessed if calculating IPSS-R by enumerating blasts from NECs improves prognostication of MDS. Twenty-four percent of patients classified into the intermediate category were reclassified into higher-risk categories and showed shorter overall survival (OS) and time to AML evolution than those who remained into the intermediate one. Likewise, a better distribution of patients was observed, since lower-risk patients showed longer survivals than previously whereas higher-risk ones maintained the outcome expected in this poor prognostic group (median OS < 20 months). Furthermore, our approach was particularly useful for detecting patients at risk of dying with AML. Regarding MDS-E, 51% patients classified into the intermediate category were reclassified into higher-risk ones and showed shorter OS and time to AML. In this subgroup of MDS, IPSS-R was capable of splitting our series in five groups with significant differences in OS only when blasts were assessed from NECs. In conclusion, our easy-applicable approach improves prognostic assessment of MDS patients.

TP53 Abnormalities Are Underlying the Poor Outcome Associated with Chromothripsis in Chronic Lymphocytic Leukemia Patients with Complex Karyotype.

Chromothripsis (cth) has been associated with a dismal outcome and poor prognosis factors in patients with chronic lymphocytic leukemia (CLL). Despite being correlated with high genome instability, previous studies have not assessed the role of cth in the context of genomic complexity. Herein, we analyzed a cohort of 33 CLL patients with cth and compared them against a cohort of 129 non-cth cases with complex karyotypes. Nine cth cases were analyzed using optical genome mapping (OGM). Patterns detected by genomic microarrays were compared and the prognostic value of cth was analyzed. Cth was distributed throughout the genome, with chromosomes 3, 6 and 13 being those most frequently affected. OGM detected 88.1% of the previously known copy number alterations and several additional cth-related rearrangements (median: 9, range: 3-26). Two patterns were identified: one with rearrangements clustered in the region with cth (3/9) and the other involving both chromothriptic and non-chromothriptic chromosomes (6/9). Cases with cth showed a shorter time to first treatment (TTFT) than non-cth patients (median TTFT: 2 m vs. 15 m; p = 0.013). However, when stratifying patients based on TP53 status, cth did not affect TTFT. Only TP53 maintained its significance in the multivariate analysis for TTFT, including cth and genome complexity defined by genomic microarrays (HR: 1.60; p = 0.029). Our findings suggest that TP53 abnormalities, rather than cth itself, underlie the poor prognosis observed in this subset.

Many signs, one mutation: Early onset of de novo GATA2 deficiency syndrome. A case report.

We report a case with a broad spectrum of symptoms, related to GATA2 deficiency syndrome, which emerged as early as at 6 months of age. They ranged from lymphedema, deafness to myelodysplastic syndrome (MDS).

Ultrastructural, cytogenetic, and molecular findings in mast cell leukemia: Case report.

We report a de novo aleukemic form of MCL with a complex monosomic karyotype with LOH for multiple chromosomes and TP53 mutation. Additionally, whereas D816V KIT was not found, the c-Kit transmembrane domain p.M541L variant was detected which is the most common SNP of KIT gene in humans with controversial pathogenic role. In these cases, it is crucial to perform a rapid broad molecular study for an accurate diagnosis which could help to initiate targeted therapy.

Clinical and biological significance of isolated Y chromosome loss in myelodysplastic syndromes and chronic myelomonocytic leukemia. A report from the Spanish MDS Group.

Isolate loss of chromosome Y (-Y) in myelodysplastic syndromes (MDS) is associated to a better outcome but it is also well described as an age-related phenomenon. In this study we aimed to analyze the prognostic impact of -Y in the context of the IPSS-R cytogenetic classification, evaluate the clinical significance of the percentage of metaphases with isolated -Y, and test whether finding -Y may predispose to over-diagnose MDS in patients with borderline morphological features. We evaluated 3581 male patients from the Spanish MDS Registry with a diagnosis of MDS or chronic myelomonocytic leukemia (CMML). -Y was identified in 177 patients (4.9%). Compared with the 2246 male patients with normal karyotype, -Y group showed a reduced risk of leukemic transformation that did not translate into a survival advantage. The overall survival and the risk of leukemic transformation were not influenced by the percentage of metaphases with -Y. The -Y group was not enriched in patients with minor morphologic traits of dysplasia, suggesting that the better outcome in the -Y group cannot be explained by enrichment in cases misdiagnosed as MDS. In conclusion, our results support the current recommendation of classifying patients with -Y within the very good risk category of the IPSS-R for MDS and rule out a selection bias as a possible explanation of this better outcome. An analysis of the molecular basis of MDS with isolated -Y would be of interest as it may provide a biological basis of protection against progression to acute leukemia.

Patients with chronic lymphocytic leukemia and complex karyotype show an adverse outcome even in absence of TP53/ATM FISH deletions.

Genomic complexity identified by chromosome banding analysis (CBA) predicts a worse clinical outcome in CLL patients treated either with standard or new treatments. Herein, we analyzed the clinical impact of complex karyotypes (CK) with or without high-risk FISH deletions (ATM and/or TP53, HR-FISH) in a cohort of 1045 untreated MBL/CLL patients. In all, 99/1045 (9.5%) patients displayed a CK. Despite ATM and TP53 deletions were more common in CK (25% vs 7%; P < 0.001; 40% vs 5%; P < 0.001, respectively), only 44% (40/90) patients with TP53 deletions showed a CK. CK group showed a significant higher two-year cumulative incidence of treatment (48% vs 20%; P < 0.001), as well as a shorter overall survival (OS) (79 mo vs not reached; P < 0.001). When patients were categorized regarding CK and HR-FISH, those with both characteristics showed the worst median OS (52 mo) being clearly distinct from those non-CK and non-HR-FISH (median not reached), but no significant differences were detected between cases with only CK or HR-FISH. Both CK and TP53 deletion remained statistically significant in the multivariate analysis for OS. In conclusion, CK group is globally associated with advanced disease and poor prognostic markers. Further investigation in larger cohorts with CK lacking HR-FISH is needed to elucidate which mechanisms underlie the poor outcome of this subgroup.

Síndrome Metabólica é o Principal Preditor de Isquemia Miocárdica na SPECT / Metabolic Syndrome Is the Main Predictor of Myocardial Ischemia in SPECT

Fundamentos: Dados mostram que a síndrome metabólica (SM) aumenta o risco de doença cardiovascular. Objetivos: Descrever e comparar as alterações cintilográficas e o valor preditivo de isquemia miocárdica emindivíduos com e sem SM, encaminhados para tomografia computadorizada de emissão de fóton único (SPECT)em Hospital Universitário utilizando três critérios diagnósticos de SM.Métodos: Estudo prospectivo observacional de pacientes encaminhados para SPECT de junho a dezembro 2010.Altura, peso e circunferência da cintura foram medidos. Levantamento de fatores de risco e revisão de prontuáriosmédicos foi realizado em busca de parâmetros para diagnóstico laboratorial de SM e relatórios completos deSPECT. Resultados: Foram incluídos 203 pacientes; 138 mulheres (68,0%); média de idade 63,6±11,5 anos. Apresentaram SM, 135 pacientes (66,5%). Entre os 99 exames alterados, 91,9% (n=91) ocorreram em pacientes com SM e 8,1%(n=8) em pacientes sem SM. Houve associação significativa entre a SM e a cintilografia anormal (67,0% vs. 11,8%;p<0,001) e os pacientes com SM tinham anormalidades de maior extensão e gravidade (escore de estresse somado(SSS)=7,3±6,5 vs. 3,0±0,9; p<0,001 e escore de diferença somado (SDS)=3,4±4,3 vs. 0,9±2,5; p<0,001). SM foi preditorindependente de isquemia miocárdica nas três definições estudadas (OR=10,07, 6,25 e 4,26 para NCEP-ATP IIImodificado, NCEP-ATP III e IDF, respectivamente). Conclusões: Pacientes com SM apresentaram mais defeitos de perfusão na SPECT (tanto fixa e reversível); e SMdefinida pelo NCEP-ATP III modificado foi o melhor preditor independente de isquemia miocárdica na cintilografia.

Background: Data show that metabolic syndrome (MS) increases the risk of cardiovascular disease.Objectives: To describe and compare the scintigraphic abnormalities and the predictive value of myocardial ischemia in individuals withand without MS referred for single photon emission computed tomography (SPECT) in a University Hospital using three diagnostic criteria.Methods: Prospective observational study of patients referred for SPECT from June to December 2010. Height, weight and waistcircumference were measured. Risk factors were assessed and medical records were reviewed to look for parameters for laboratorydiagnosis of MS and complete SPECT reports.Results: The study included 203 patients; 138 women (68.0%); mean age 63.6±11.5 years. Metabolic syndrome was found in135 patients (66.5%). Of the 99 abnormal tests, 91.9% (n=91) occurred in patients with MS and 8.1% (n=8) in patients withoutMS. There was a significant association between MS and abnormal scintigraphy (67.0% vs. 11.8%; p<0.001) and patients withMS had abnormalities of greater extent and severity (summed stress score (SSS)=7.3±6.5 vs. 3.0±0.9; p<0.001 and summed differencescore (SDS)=3.4±4.3 vs. 0.9±2.5; p<0.001). MS was an independent predictor of myocardial ischemia in the three definitions studied(OR=10.07, 6.25 and 4.26 for modified NCEP-ATP III, NCEP-ATP III and IDF, respectively).Conclusions: Patients with MS had more perfusion defects on SPECT (both fixed and reversible); and MS defined by the modifiedNCEP-ATP III was the best independent predictor of myocardial ischemia on scintigraphy.

Factores predictores de éxito en el tratamiento del tabaquismo / Predicting factors for success in treating tobacco use and dependence

Introducción: el tratamiento del tabaquismo logra porcentajes de cesación cercanos a 30 a largo plazo. Identificar predictores de éxito del tratamiento permitiría adecuar laintervención terapéutica y mejorar los resultados. Objetivo: conocer la tasa de cesación de un programa de cesación de tabaquismo e identificar predictores de éxito del tratamiento. Material y método: estudio descriptivo, de corte. Las variables estudiadas fueron: edad, sexo, nivel de instrucción, convivencia con fumadores, número de cigarrillos/día (cpd), test deFagerstrõm, períodos de abstinencia previos, enfermedades tabacodependientes, antecedentesde depresión, ejercicio físico, modalidad y adherencia al tratamiento, uso de fármacos. Se contactó telefónicamente a los pacientes al año de finalizado el tratamiento. Se consideró abstinencia (autorreporte) no haber fumado en los últimos 30 días. Resultados: 143 individuos contactados, 55,9 mujeres, la media de edad fue 46 años. Elporcentaje de cesación al año fue 35. Un valor de cpd < 20 y un test de Fagerstrõm < 4 lograron significativamente mejores resultados (p=0,009 y p=0,039, respectivamente) así como la ausencia de antecedentes de depresión (p=0,043), el ejercicio (p=0,011), la adherencia al tratamiento (p<0,001) y el uso de fármacos (p<0,001). El análisis multivariado mostró que la adherencia al tratamiento, el uso de fármacos y la ausencia de antecedentes de depresión aumentan tres a cuatro veces la oportunidad de éxito. Conclusiones: los fármacos específicos, la adherencia al tratamiento y la ausencia de antecedentes de depresión mostraron ser predictores de éxito del tratamiento. Una mayor accesibilidad al tratamiento farmacológico es fundamental para aumentar la posibilidad de abstinencia a largo plazo.

Introduction: current treatments for tobacco use and dependence attain quitting percentages around 30 for thelong term. Identifying predicting factors for success would enable more suitable therapeutic interventions, thus improvingresults. Objective: to learn about quit rates in a tobacco dependenceprogram and to identify the treatmentÆs predicting factors for success.Method: a descriptive study was conducted and cut off points were analyzed. Variables studied included: age, sex, level of education, living with people who smoke, number of cigarettes per day (cpd), Fagerstrõm test, previousperiods of smoking abstinence, tobacco-dependent diseases, history of depression, physical exercise, modalityand adherence to treatment, use of drugs. Patients were contacted by phone, a year after they had finished treat ment. Abstinence (self-reported) was defined as not having smoked in the last 30 days. Results: 143 people were contacted: 55.9 of them were women, average age was 46. Quit rate a year after was 35. Significantly better results (p=0,009 y p=0,039,respectively) were achieved when the cpd was < 20 cpd. The Fagerstrõm test was < 4, and the same was found when there was no history of depression (p=0,043), when people practiced physical exercise(p=0,011), when theyadhered to the treatment (p<0,001) and use of drugs (p<0,001). Multivariate analysis showed that adherence to treatment, use of drugs and the absence of a history of depression increases three to four times the chance for success. Conclusions: specific drugs, adherence to treatment, and the absence of a history of depression proved to be predicting factors for success of treatment. A wider accessto pharmacological treatment is fundamental to increase the abstinence for the long term.

Introdução: o tratamento do tabagismo atinge aproximadamente 30 de êxito a longo prazo. Identificar os fatorespreditores de sucesso do tratamento permitia ajustar a intervenção terapêutica e melhorar os resultados.Objetivo: conhecer a taxa de êxito de um programa de cessação de tabagismo e identificar os fatores preditoresde sucesso do tratamento. Material e método: estudo descritivo, de corte. Asvariáveis estudadas foram: idade, sexo, nível de instrução, convivência com fumantes, número de cigarros/dia (cpd),teste de Fagerstrõm, períodos de abstinência prévios, doenças tabaco-dependentes, antecedentes de depressão, exercício físico, tipo de e adesão ao tratamento e uso defármacos. Depois de um ano de terminado o tratamento os pacientes foram contatados por via telefônica. Considerouse como abstinência (autodeclaração) quando o pacientenão havia fumado nos últimos 30 dias.Resultados: foram contatados 143 indivíduos, sendo 55,9 mulheres, e a média de idade 46 anos. A porcentagemde cessação ao final do primeiro ano foi de 35. Um valor de cpd < 0 e um teste de Fagerstrõm < 4 mostraram resultadossignificativamente melhores (p=0,009 e p=0,039, respectivamente) bem como a ausência de antecedentes dedepressão (p=0,043), o exercício (p=0,011), a adesão ao tratamento (p<0,001) e o emprego de fármacos (p<0,001). A análise multivariada mostrou que a adesão aotratamento, o uso de fármacos e a ausência de antecedentes de depressão aumentam três a quatro vezes a oportunidade de sucesso.Conclusões: os fármacos específicos, a adesão ao tratamento e a ausência de antecedentes de depressão mostraram ser preditores de sucesso do tratamento. Um maior acesso ao tratamento farmacológico é fundamentalpara aumentar a possibilidade de abstinência a longo prazo.

Cáncer de mama en pacientes mayores de 70 años / Breast cancer in patientes over 70 years old

Objetivo primario: comparar el tratamiento efectuado a pacientes mayores de 70 años con las de menor edad, con el fin de determinar si fueron tratadas de manera distinta o en forma subóptima. Objetivo secundario: comparar esta serie con la realizada de similar forma cinco años atrás en la misma institución. Material y método: se efectuó el análisis retrospectivo de las historias clínicas de 73 mujeres mayores de 70 años con cáncer de mama tratadas en el Servicio de Ginecología del Hospital Aeronáutico Central (SGHAC) entre el 01 de enero de 2007 y el 31 de diciembre de 2011, y se las comparó con 55 mujeres menores de dicha edad tratadas en el mismo período. Se analizó el estadio, receptores para estrógeno y progesterona, grado histológico, tamaño tumoral, estatus ganglionar axilar y los tratamientos quirúrgico, radiante, hormonal y quimioterápico efectuados para establecer las posibles diferencias entre ambos grupos etarios. Resultados: el 57% de los casos de cáncer de mama correspondieron a mujeres mayores de 70 años. Aproximadamente 76% se diagnosticaron en estadio I y II. En alrededor del 46% de las pacientes mayores de 70 años las lesiones fueron menor o igual a 2 cm; el 47,95% fue grado tumoral 2 y cerca del 57% no tuvieron compromiso axilar. En 45 casos (61,65%) se efectuó cirugía conservadora, siendo equivalente a las 39 pacientes (70,91%) a las que se efectuaron en mujeres menores de esa edad. Fue similar el porcentaje de mastectomía radical modificada tipo Madden y mayor el de mastectomía simple. En nuestro grupo de pacientes mayores, los datos hallados nos muestran un subtratamiento adyuvante de las mismas. El porcentaje de pacientes a quienes se les instituyó quimioterapia fue significativamente menor en las pacientes de más de 70 años. En las pacientes mayores se utilizó tanto AC como CMF mientras que a las menores se les administró AC. El empleo de taxanos fue mucho mayor en el grupo de las pacientes más jóvenes.