Advances in the management of higher-risk myelodysplastic syndromes: future prospects.

Higher-risk myelodysplastic syndromes (HR-MDS) are defined using a number of prognostic scoring systems that include the degree of cytopenias, percentage of blasts, cytogenetic alterations, and more recently genomic data. HR-MDS encompasses characteristics such as progressive cytopenias, increased bone marrow blasts, unfavorable cytogenetics, and an adverse mutational profile. Survival is generally poor, and patients require therapy to improve outcomes. Hypomethylating agents (HMAs), such as azacitidine, decitabine, and more recently, oral decitabine/cedazuridine, are the only approved therapies for HR-MDS. These are often continued until loss of response, progression, or unacceptable toxicity. Combinations including an HMA plus other drugs have been investigated but have not demonstrated better outcomes compared to single-agent HMA. Moreover, in a disease of high genomic complexity such as HR-MDS, therapy targeting specific genomic abnormalities is of interest. This review will examine the biological underpinnings of HR-MDS, its therapeutic landscape in the frontline and relapsed settings, as well as the impact of hematopoietic stem cell transplantation, the only known curative intervention for this disease.

Therapy-related chronic myelomonocytic leukemia does not have the high-risk features of a therapy-related neoplasm.

ABSTRACT: Therapy-related myeloid neoplasms (t-MNs) arise after exposure to cytotoxic therapies and are associated with high-risk genetic features and poor outcomes. We analyzed a cohort of patients with therapy-related chronic myelomonocytic leukemia (tCMML; n = 71) and compared its features to that of de novo CMML (dnCMML; n = 461). Median time from cytotoxic therapy to tCMML diagnosis was 6.5 years. Compared with dnCMML, chromosome-7 abnormalities (4% vs 13%; P = .005) but not complex karyotype (3% vs 7%; P = .15), were more frequent in tCMML. tCMML was characterized by higher TP53 mutation frequency (4% vs 12%; P = .04) and lower NRAS (6% vs 22%, P = .007) and CBL (4% vs 12%, P = .04) mutation frequency. Prior therapy with antimetabolites (odd ratio [OR], 1.22; 95% confidence interval [CI], 1.05-1.42; P = .01) and mitotic inhibitors (OR, 1.24; 95% CI, 1.06-1.44; P = .009) was associated with NF1 and SETBP1 mutations whereas prior mitotic inhibitor therapy was associated with lower TET2 mutation frequency (OR, 0.71; 95% CI, 0.55-0.92; P = .01). Although no differences in median overall survival (OS) were observed among tCMML and dnCMML (34.7 months vs 35.9 months, P = .26), multivariate analysis for OS revealed that prior chemotherapy was associated with increased risk of death (hazard ratio, 1.76; 95% CI, 1.07-2.89; P = .026). Compared with a cohort of therapy-related myelodysplastic syndrome, tCMML had lower TP53 mutation frequency (12% vs 44.4%, P < .001) and less unfavorable outcomes. In summary, tCMML does not exhibit the high-risk features and poor outcomes of t-MNs.

Cytogenetic and Molecular Associations with Outcomes in Higher-Risk Myelodysplastic Syndromes Treated with Hypomethylating Agents plus Venetoclax.

PURPOSE: Hypomethylating agents (HMA) combined with venetoclax are an emerging therapeutic strategy for higher-risk myelodysplastic syndromes (HR-MDS). The cytogenetic and molecular factors associated with outcomes with this combination for HR-MDS are incompletely understood. EXPERIMENTAL DESIGN: We pooled patient data from 3 prospective trials evaluating HMA-venetoclax in HR-MDS to study associations between cytogenetic and molecular factors and overall response rate (ORR), overall survival (OS), and event-free survival (EFS). The Kaplan-Meier method was used to estimate time-to-event endpoints. Univariate and multivariate analyses using logistic regression (for ORR) or the Cox proportional hazards model (for OS and EFS) were used to identify associations between clinical, cytogenetic, and molecular factors and outcomes. RESULTS: A total of 80 patients (52 HMA-naïve, 28 HMA-failure) were included. ORR was 90% in HMA-naïve and 57% in HMA-failure. Median OS was 28.2 and 8.3 months in HMA-naïve and HMA-failure, respectively. Median EFS was 17.9 and 5.5 months in HMA-naïve and HMA-failure, respectively. In addition, 24/52 (46%) of the HMA-naïve and 3/28 (11%) of the HMA-failure patients proceeded to allogeneic stem cell transplantation (SCT). Factors associated with inferior outcomes were prior HMA failure, complex cytogenetics, trisomy 8, TP53 mutations, and RAS pathway mutations. Mutations in RNA splicing, DNA methylation, and ASXL1 appeared favorable. Blast percentage was not predictive of outcomes. CONCLUSIONS: Knowledge of cytogenetic and molecular alterations may help identify which patients with HR-MDS benefit the most from venetoclax.

Venetoclax abrogates the prognostic impact of splicing factor gene mutations in newly diagnosed acute myeloid leukemia.

Mutations in splicing factor (SF) genes SRSF2, U2AF1, SF3B1, and ZRSR2 are now considered adverse risk in the European LeukemiaNet 2022 acute myeloid leukemia (AML) risk stratification. The prognostic impact of SF mutations in AML has been predominantly derived from younger patients treated with intensive (INT) therapy. We evaluated 994 patients with newly diagnosed AML, including 266 (27%) with a SFmut. Median age was 67 years overall, with patients with SFmut being older at 72 years. SRSF2 (n = 140, 53%) was the most common SFmut. In patients treated with INT, median relapse-free survival (RFS) (9.6 vs 21.4 months, P = .04) and overall survival (OS) (15.9 vs 26.7 months, P = .06) were shorter for patients with SFmut than without SFwt, however this significance abrogated when evaluating patients who received venetoclax with INT therapy (RFS 15.4 vs 20.3 months, P = .36; OS 19.6 vs 30.7 months, P = .98). In patients treated with LI, median RFS (9.3 vs 7.7 months, P = .35) and OS (12.3 vs 8.5 months, P = .14) were similar for patients with and without SFmut , and outcomes improved in all groups with venetoclax. On multivariate analysis, SFmut did not affect hazards of relapse and death for INT arm but reduced both these hazards in LI arm. In a large AML data set with >60% of patients receiving venetoclax with LI/INT therapy, SFmut had no independent negative prognostic impact. Newer prognostic models that consider LI therapy and use of venetoclax among other factors are warranted.

Performance of IPSS-M in patients with myelodysplastic syndrome after hypomethylating agent failure.

Evaluation of IPSS-M and exploratory prognostic model for MDS at the time of HMA failure.

Clinical presentation and outcomes of hospitalized children with COVID-19 in Mexico City.

We describe the demographic, clinical, radiological, and laboratory findings relating them also to the severity and clinical outcome of 129 children (0-18 years) who were admitted to a tertiary care pediatric hospital in Mexico City due to severe acute respiratory syndrome coronavirus 2 infection between April 1, 2020 and March 31, 2021. The infection was confirmed using reverse transcription-polymerase chain reaction Fever (82.2%), tachypnea (72.1%), and cough (71.3%) were the most reported signs at the moment of hospitalization. The most frequent radiological pattern that stood out was the interstitial pattern (66.7%). History of oncologic pathology (25.6%) was the most frequent past medical history. Non-steroidal anti-inflammatory drugs (93%), antibiotics (57.4%), and steroids (40.3%) were the most common medication given. The average hospitalization stay was 14.2 days, and 21.7% of the total patients required transfer to the intensive care unit. At discharge, 20.2% required oxygen on an outpatient basis, and unfortunately, 7.0% of the patients who were admitted to the institute for COVID-19 died. Our findings confirm that COVID-19 in children has a mild presentation except for patients with hematologic/oncologic comorbidities who had severe presentations.

Cardiovascular risk assessment in the resource limited setting of Western Honduras: An epidemiological perspective.

Cardiovascular Disease (CVD) epidemiology varies significantly among Low and Middle-Income Countries. Honduras is the Central American country with the highest Ischemic Heart Disease and CVD mortality rates. The aim of this study was to assess the individual CVD risk factors and calculate Cardiovascular Risk Assessment Scores (CVRAS) from the population. Methods: A cross-sectional study in western Honduras. Estimation of CV risk was performed using Framingham, MESA, ACC/AHA-PCEs and ESC SCORE calculators. Results: 38% were male. For men and women respectively; 49% and 48% had self-reported hypertension (HTN), on measured blood pressure only 18% and 30% had normal readings. Diabetes Mellitus was reported in 19% and 22%. Tobacco use was 14% and 3%. Self-reported regular exercise was 39.9% and 25%. Obesity was diagnosed in 24% and 24%. Lipid profile; total cholesterol was ≥200 mg/dl in 63% of subjects. LDL-C was elevated (>100 mg/dl) in 74% of participants, 9% had LDL-C levels higher than 190 mg/dl. Triglycerides were high (>160 mg/dl) in 60%, of these subjects 22% were taking lipid-lowering medications. 52% reported family-history of CVD. The risk calculation for men and women respectively for each CVRAS were; AHA/ACC-PCEs high risk (score ≥ 7.5%) in 62% and 30%, FRS high risk (score ≥ 20%) 46% and 15%, MESA high risk (Score ≥ 7.5%) in 70.6% and 17.7%, ESC SCORE high risk (score ≥ 5% in 32.4% and 11.8%). Conclusions: CV risk calculations revealed higher than rates than expected with consequently reflected on higher than estimated CVRAS. This represents the first report of its kind in Honduras.

Supervivencia de cáncer gástrico en el occidente de Honduras, estudio piloto: 2002-2012 / Survival of Gastric Cancer in Western Honduras Pilot study: 2002-2012

Antecedentes: El cáncer gástrico es la segunda causa de muerte por cáncer globalmente. En Honduras la incidencia en la década pasada fue de 39 y 21 por 100,000 habitantes para hombres y mujeres, respectivamente. En 2008 IARC (GLOBOCAN) colocó a Honduras como el país con más alta incidencia de cáncer gástrico en Latinoamérica. Objetivo: Determinar la supervivencia en pacientes diagnosticados con cáncer gástrico en el occidente de Honduras entre los años 2002-2012. Métodos: Se diseñó un es- tudio de cohorte retrospectivo de pacientes diagnosticados con cáncer gástrico en el Hospital de Occidente (2002-2012). Una muestra de 144 pacientes fue seleccionada de un total de 490 para obtener un nivel de confianza de 95%. La recolección de datos se obtuvo mediante autopsia verbal. Se analizaron los factores pronósticos de supervivencia mediante modelos de razón de riesgos proporcio - nales de Cox (CI:95%) Resultados: La relación hombre/mujer fue 2.8:1. La media de edad fue 63.29 años. La supervivencia global a cinco años fue 9.39%. Entre los pacientes que recibieron terapia dual (cirugía y quimioterapia), se encontró un aumento estadísti- camente significativo de la supervivencia (10.42%,p=0.048). Entre la localizaci ón proximal (28.95%) y distal (56.58%) se observó diferencia estadísticamente significativa (p=0.03). No hubo diferencia estadísticamente significativa entre hallazgos macroscópicos (Borrmann) y microscópicos (Lauren). Discusión: Este estudio representa el primer esfuerzo para estimar la supervivencia de cáncer gástrico en Honduras. La supervivencia podría estar ligada a la localización de la lesión primaria y al tipo de tratamiento. Se espera desarrollar estudios con mayor cobertura, para responder a estas preguntas...(AU)

Validez de los métodos de predicción para riesgo cardiovascular en América Latina: revisión bibliográfica / Validity of the Methods of Prediction for Cardiovascular Risk in Latin America: Bibliographic Review

Introducción: Las enfermedades cardiovasculares (ECV) constituyen la principal causa de muerte en países industrializados, y en países de ingreso mediano a bajo (LMIC). La validación de métodos de predicción de riesgo cardiovascular (RCV) es importante para establecer las medidas preventivas adecuadas en pacientes asintomáticos pero con alto riesgo de presentar ECV. Fuentes: Se realizó una búsqueda, en español e inglés, en las bibliotecas médicas: PubMed, Science Direct, y SCIELO, en los últimos diez años. Desarrollo: En Colombia y Cuba el método Framingham subestimó a la población al clasificarla en bajo riesgo, a pesar de que la mortalidad por ECV es alta; se considera que una de las causas es que la ecuación no incluye factores de mayor prevalencia como la obesidad e hipertrigliceridemia. En Colombia las ecuaciones de PROCAM demostraron ser una mejor opción para estimar el riesgo de ECV y encontraron una concordancia discretamente mejor al utilizar las ecuaciones de SCORE para pacientes de bajo riesgo. Conclusiones: El uso de métodos de predicción de riesgo cardiovascular provee directrices para ser implementados en los sistemas de salud, tanto en medicina preventiva como en atención primaria. Actualmente no existe un método predictivo que sea aplicable exclusivamente a población Latinoamericana. A finales del 2016, se inició un estudio transversal descriptivo en el departamento de Copán, Honduras con el objetivo de determinar la situación actual de factores de RCV, con un modelo similar al de MESA. Posteriormente esto permitirá realizar una cohorte prospectivo empleando las diferentes escalas de predicción...(AU)

[Survival of Gastric Cancer in Western Honduras Pilot study: 2002-2012]. / SUPERVIVENCIA DE CÁNCER GÁSTRICO EN EL OCCIDENTE DE HONDURAS ESTUDIO PILOTO: 2002­2012.

Background: Gastric cancer is the second leading cause of cancer death globally. In Honduras the incidence in the last decade was 39 and 21 per 100,000 inhabitants for men and women, respectively. In 2008 IARC (GLOBOCAN) placed Honduras as the country with the highest incidence of gastric cancer in Latin America. Methods: A retrospective cohort study of patients diagnosed with gastric cancer at the Hospital de Occidente between 2002-2012 was designed. A sample of 144 patients was selected from a total of 490 to obtain a confidence level of 95%. The data collection was obtained by verbal autopsy. Prognostic factors of survival were analyzed using Cox proportional hazards ratio models (CI: 95%). Outcomes: The male/female ratio was 2.8:1. The mean age was 63.29 years. Overall five-year survival was 9.39%. Among patients receiving dual therapy (surgery and chemotherapy), a statistically significant increase in survival was found (10.42%, p=0.048). Between the proximal (28.95%) and distal (56.58%) locations also a statistically significant difference was observed (p=0.03). There was no statistically significant difference in the macroscopic (Borrmann) and microscopic findings (Lauren). Disscusion: This study represents the first effort to estimate survival of gastric cancer in Honduras. Survival may be linked to the location of the primary lesion and the type of treatment. It is expected to develop studies with greater coverage, to answer these questions.

Marked seasonality of Cyclospora cayetanensis infections: ten-year observation of hospital cases, Honduras.

BACKGROUND: Document seasonality occurrence and epidemiologic characteristics of Cyclospora cayetanensis infections during a 10-year period from patients consulting at the University Hospital, Honduras. METHODS: Retrospective non interventional hospital-based study analyzed laboratory results from the period 2002 to 2011 of fresh and Ziehl-Nielsen carbolfuchsin stained routine stool samples received for parasitologic examination. Sporadically a sample with numerous oocysts was allowed to sporulate in 2.5 % potassium dichromate confirming the presence of bi-cystic bi-zoic oocysts. RESULTS: A total of 35,157 fecal samples were examined during a ten-year span, of which a third (28.4 %) was stained by the Ziehl-Neelsen carbolfuchsin method diagnosing a total of 125 (1.3 %) C.cayetanensis infections. A statistically significant apparent seasonality was observed most years during May to August (range p < 0.036-0.001), with 83.3 % of 125 cases occurring in those rainy months. All C. cayetanensis cases came from urban poor neighborhoods; male/female relation was 1:1 except in 2006, when all patients were females (p = 0.05; r(2) = 22,448). Forty four point eight percent of the stool samples were diarrheic or liquid and 65.6 % infections were identified in children 10 years old or less. Enteric helminths and protozoa co-infected Cyclospora positive patients in 52 instances.: 8 % Ascaris lumbricoides, 8 % Giardia duodenalis, 23.2 % Blastocystis spp. and less frequently Entamoeba histolytica/E. dispar, Strongyloides stercoralis, and Trichuris trichiura. CONCLUSIONS: Results suggest a seasonal pattern for Cyclospora infections diagnosed in a clinical setting during the rainy months in Tegucigalpa and surrounding areas. Community studies should be conducted to support or dispute these observations.