Acquired factor XIII deficiency in patients under therapeutic plasma exchange: A poorly explored etiology.

INTRODUCTION: Factor XIII (FXIII) deficiency may cause bleeding under certain clinical circumstances. Therapeutic plasma exchange (TPE) may lead to a transient deficiency. OBJECTIVES: To describe the clinical evolution of patients with acquired FXIII deficiency secondary to TPE. METHODS: We respectively studied a cohort of consecutive patients from 2014 to 2019 who were treated with TPE with FXIII levels <50%. The FXIII was measured after the start of the TPE course, on days between the TPE sessions, due to suspected acquired deficiency. All TPE were performed using continuous flow cell separator. In all cases, the initial replacement fluid applied was albumin. Apheresis procedures were held at 24to 48 hours intervals. RESULTS: Eighteen patients were included, 13 of them were recipients of kidney transplants. The main TPE prescription was humoral rejection. Median FXIII at diagnosis (measured on days between sessions of the TPE course) was 19%(IQR17-25). The median of apheresis procedures before measurement of FXIII was 3(IQR2-4). Among the total cohort, 10 patients suffered hemorrhages. None of the patients without history of kidney transplants had bleeding (n = 5), however, 10/13 with kidney transplants did. Five kidney transplant patients received therapy with FXIII concentrate because of life-threatening bleeding. In all cases, the bleeding stopped within the first 24 hours. All patients had their FXIII levels measured again after finishing the TPE course, with normal results. CONCLUSIONS: TPE is an under-diagnosed cause of acquired FXIII deficiency since routine coagulation tests remain unaltered. It might cause major bleeding, particularly in patients with a recent history of surgery like kidney transplants.

Complete remission and proviral load negativization after allogeneic-SCT in a patient with Adult T-cell lymphoma: Case report.

Adult T-cell lymphoma is an aggressive and poor prognosis HTLV1-associated lymphoma. There is no standard treatment, but it is known that intensive chemotherapy regimens are necessary, with or without concomitant antiretroviral therapy, plus consolidation with allogeneic stem cell transplantation. Our case report shows a favorable outcome after 2 cycles of chemotherapy and allogeneic stem cell transplantation without antiretroviral agents, achieving complete remission, and a negative proviral load.

[Hemophagocytic lymphohistiocytosis. Experience in 27 patients]. / Características clínicas y mortalidad de pacientes adultos con síndrome hemafagocítico, estudio de cohorte retrospectiva.

BACKGROUND: Hemophagocytic lymphohistiocytosis (HLH) is an aggressive and life-threatening syndrome of excessive immune activation Aim: To describe the clinical characteristics, causes and survival associated with HLH. MATERIAL AND METHODS: Review of medical records of patients with HLH attended between 2004 and 2016. They were classified according to their probable cause in: associated with immunosuppression, cancer, post-infectious or idiopathic. Kaplan-Meier survival analysis was performed. RESULTS: Twenty seven patients with HLH aged 18 to 87 years (59% men), were detected. Fourteen (52%) were secondary to immunosuppression, six (22%) were post-infectious, five (18%) were associated with cancer and two (7%) were of unknown cause. There were no significant differences in clinical or laboratory features between these etiologies. Within the immunosuppressed group, 12 (86%) were patients with oncologic or hematologic diseases or bone marrow transplantation. Associated cancers were mostly oncohematologic diseases. Thirty-day mortality was 53.4% (95% confidence intervals (CI) 32.7-70.3%), despite the treatment. Mortality was significantly associated with the presence of renal failure with a hazard ratio (HR) of 3.4 (95% CI of 1.2-9.9, p =0.025). Treatment of the underlying disease proved to be protective against mortality with an HR of 0.3 (95% CI 0.1 to 0.98, p = 0.046). CONCLUSIONS: The prognosis of HLH could be related to the treatment of the underlying disease. The study of the pathophysiology of this syndrome will allow a better understanding and treatment.

[Renal function and plasma dabigatran level measured at trough by diluted thrombin time assay]. / Función renal y nivel plasmático de dabigatrán en el valle, medido por un ensayo de trombina diluida.

Dabigatran etexilate (direct thrombin inhibitor) is effective in preventing embolic stroke in patients with atrial fibrillation. It does not require laboratory control, but given the high renal elimination, its measurement in plasma is important in renal failure. The objectives of the study were to verify the analytical quality of the diluted thrombin time assay for measurement of dabigatran plasma concentration (cc), correlate cc with classic coagulation assays, prothrombin time (PT) and activated partial thromboplastin time (APTT), and evaluate them according to the creatinine clearance (CLCr). Forty plasma samples of patients (34 consecutive and 6 suspected of drug accumulation) receiving dabigatran at 150 (n = 19) or 110 (n = 21) mg/12 hours were collected. Blood samples were drawn at 10-14 hours of the last intake. Dabigatran concentration was determined by diluted thrombin time (HemosIl DTI, Instrumentation Laboratory (IL). PT and APTT (IL) were performed on two fotooptical coagulometers, ACL TOP 300 and 500 (IL). DTI presented intra-assay coefficient of variation < 5.4% and inter-assay < 6%, linearity range 0-493 ng/ml. Patients' cc: median 83 (4-945) ng/ml. Individuals with CLCr in the lowest tertile (22.6-46.1 ml/min) showed significantly higher median cc: 308 (49-945), compared to the average 72 (12-190) and highest tertile, 60 (4-118) ng/ml. Correlation between cc and APTT or PT were moderate, r2 = 0.59 and -0.66, p < 0.0001, respectively. DTI test allowed us to quantify plasma dabigatran levels, both in patients with normal or altered renal function, representing a useful tool in clinical situations such as renal failure, pre surgery or emergencies.

[Treatment conditioning variables in elderly patients with acute myeloid leukemia. An institutional experience]. / Variables condicionantes del tratamiento en pacientes añosos con leucemia mieloide aguda. Experiencia institucional.

Patients over 60 years old with acute myeloid leukemia (AML) have a worse prognosis due to several factors that determine the therapeutic outcome. The main predictors of mortality in patients with AML reported in the literature were analyzed in our population. The primary objective was to analyze overall survival. The secondary objective was to determine treatment-related mortality, defined as death within eight weeks of starting treatment. It was designed as a retrospective study. A total of 133 treatment naive patients were included, from January 1991 to August 2014. The adjusted analysis showed that the most important variables to determine overall survival were the WBC count = 30 000 at diagnosis [adjusted HR 2.19 (1.06-4.53), p = 0.03)] and the Performance Status (ECOG) 3 or 4 [aHR 4.63 (1.69-12.68), p < 0.001)]. Performance Status 3-4 was the only variable that conditioned treatment related mortality, showing in the univariate analysis an OR 5.44 (CI 1.93-15.28, p < 0.001). It was also the only variable that kept its statistical power in the multivariate analysis adjusted OR (aOR) 12.40 (IC 1.12-137.17, p = 0.04). The inherent poor outcome in elderly patients diagnosed with AML is not fully understood. The best way of assessing these elderly patients should probably include not only age but the best way of assessing these elderly patients should probably include not only age but laboratory, genetic and molecular studies. Especially designed comorbidity and fragility indices should be included, along with functional status. Leukocytosis and poor quality of life were identified as the most powerfull factors for predicting mortality in our study.

Single-center "Argentine" analysis of post-transplant lymphoproliferative disorders: incidence, histopathological characteristics and EBV status.

INTRODUCTION: Post-transplant lymphoproliferative disorders (PTLDs) are a heterogeneous group of lymphoid proliferations occurring after solid organ or bone marrow transplantation. The primary aims of our study were to characterize cumulative incidence of PTLDs, clinical and pathological features according to the Epstein-Barr virus (EBV) status and survival. METHODS: This was a retrospective cohort study on adult and pediatric patients, from January 2001 to December 2017. The cumulative incidence of PTLD was calculated by analyzing all the patients transplanted at our hospital, based on the database of the Organ Donation and Ablation Authority of Argentina (INCUCAI). The Kaplan-Meier method was used to plot the survival. RESULTS: Fifty-eight cases of biopsy-confirmed PTLD were identified and 12 cases of clinical data were incomplete and these patients were excluded. The median age at the time of the PTLD diagnosis was 17.5 years (interquartile range [IQR] 9 - 57). The median interval between transplant and PTLD diagnosis was 39 months (IQR 9 - 113). The most commonly transplanted organ was the liver (24 cases, 52.2%), followed by kidney (20 cases, 43.5%). The Epstein-Barr encoding region in situ hybridization (EBER ISH) was positive in 29 (69.8%) of the 43 evaluable biopsies. The PTLD cumulative incidence was 1.84% (95%CI 1.77 - 1.91) for solid organ and 0.84% (95%CI 0.48 - 1.2) for bone marrow transplant patients. The overall survival rate at 5 years was 0.77 (95%CI 0.61 - 0.87). Subgroups by the EBV EBER status, transplant type, PTLD subtype and age group (adult vs. pediatric) showed no statistically significant association with the overall survival. CONCLUSION: The PTLD incidence was similar to that of previous series and the EBER did not appear as a relevant factor in our patient survival.

Determination and Management of Risks for Practices and Procedures in the Elderly (DRIPP): the impact of a comprehensive geriatric evaluation in elderly with diffuse large B-cell lymphoma.

INTRODUCTION: Diffuse large B-cell lymphoma (DLBCL) treatment in older patients is challenging. The Determination and Management of Risks for Practices and Procedures in the Elderly (DRIPP) is a multidimensional evaluation program that involves patients undergoing oncological treatments. OBJECTIVE: We aimed to evaluate the overall survival and progression-free survival (PFS) of patients evaluated and those not evaluated by the DRIPP. MATERIALS AND METHODS: Retrospective cohort study, patients > 65 years with DLBCL were included. They were divided into 3 groups: patients with a diagnosis prior to the DRIPP implementation (pre-DRIPP), patients with the DRIPP (DRIPP) and patients with a diagnosis after the DRIPP implementation, but who did not undergo the evaluation (non-DRIPP). RESULTS: A total of 125 patients were analyzed. Fourteen (11%) patients in the pre-DRIPP group, 74 (59%) in the DRIPP group, and 37 (30%) in the non-DRIPP group. In 43 (58%) patients of the DRIPP group, some drug dose adjustments were made vs. 19 (15%) in the non-DRIPP (p = 0.03). There were no significant differences in terms of discontinuation of treatment or hematological toxicity between groups. The OS and PFS in one year was 64% (95%CI 34-83) and 50% (95%CI 23-72) for the pre-DRIPP group, 82% (95%CI 71-89) and 72% (95%CI 60-81) for the DRIPP group, 58% (95% CI 41-72) and 56% (95% CI 38-70) for the non-DRIPP group, (p = 0.08). The analysis was adjusted for probable confounders and no differences were found. CONCLUSIONS: This is the first study to evaluate the DRIPP as a decision-making tool in patients with lymphoma and showed a trend towards improvement in the OS in evaluated patients.

Decrease in Mortality from Sepsis: Impact of the Multidisciplinary Program for the Hematologic Patient at Very High Risk.

A program for the hematologic patient at very high risk of infections (HAR, from its initials in Spanish) was implemented, based on a multidisciplinary team and six measures intended to reduce the colonization and subsequent sepsis by multidrug-resistant organisms (MDRO). We aimed at evaluating the effectiveness of the HAR program in terms of MDRO infections mainly caused by Klebsiella pneumoniae carbapenemase-producing and multidrug-resistant Pseudomona aeruginosa, and sepsis-related mortality. We established retrospective comparisons between the pre-HAR period (2016-2018) and the post-HAR period (2018-2019), in patients who received a hematopoietic stem cell transplant (HSCT) and/or intensive chemotherapy to treat non-M3 acute myeloid leukemia (CH-AML). We included 262 patients: 176 pre-HAR and 86 post-HAR. MDRO infection was 4.6% at 30 days and 6.1% at 90 days (all the cases during the pre-HAR period). Sepsis-related mortality was 6.5%, considering a median follow-up of 608 days: 6.1% in the HSCT group and 12.4% in the CH-AML group (p = 0.306). Sepsis-related mortality was 8.7% in the pre-HAR period and 0% in the post-HAR period (p = 0.014). The implementation of this multidisciplinary program based in preventive measures and the appropriate use of antibiotics enabled a decrease in sepsis-related mortality in very high-risk hematologic patients.

Central nervous system relapse in diffuse large B lymphoma: a retrospective cohort study / [Recaída en sistema nervioso central en linfoma difuso de células B grandes: estudio de cohorte retrospectiva]

Introduction: CNS relapse in patients with LDCGB is a poor prognosis event. The incidence of relapse is variable according to the literature. Data in Latin America is lacking. Methods: In order to establish the incidence of CNS relapse in our cohort, time to CNS relapse and the impact of CNS relapse risk factors, a retrospective cohort study was performed, from January 2012 to June 2017. Results: One hundred and forty seven patients were analyzed. The median age was 66 years (ICR 56-76); 76 patients (51.70%) were men. The IPI was low or intermediate/low in 115 (78.2%) cases. The CNS IPI was intermediate in 77 (52.4%) and high in 14 (9.5%) of cases. Thirty-five (23.81%) patients received intrathecal prophylaxis. No patient received systemic prophylaxis. During the follow-up, 8 (4.59%) patients had CNS relapse, none of them with high IPI. The median time to relapse was 6.5 months (ICR 5.5-10). Seven (87.5%) patients relapsed within the year of diagnosis. We found no risk factors for CNS involvement in the bivariate analysis. The incidence of relapse was 2.7% (CI 0.2% -4.6%), 4.8% (CI 1.8% -8.9%) and 5.4% (CI 4.5- 8.9%) at 6, 12 and 24 months, respectively. Discussion: The incidence of CNS relapse was similar to that described in the international series. Our study confirms that the majority of patients relapse during the first year of follow up. We must carry out broader collaborative work to better establish the risk factor for CNS relapse.

Introducción: La recaída del SNC en pacientes con LDCBG en un evento de mal pronóstico. La incidencia de recaída  es variable según la bibliografía. Los datos en América Latina son escasos. Metodología: Para establecer la incidencia de recaída en SNC, el tiempo a la recaída en SNC y el impacto de los factores de riesgo de recaída del SNC, se realizó un estudio de cohorte retrospectiva, de enero del 2012 a junio del 2017. Resultados: Se analizaron 147 pacientes. La mediana de edad fue de 66 años (IIC 56-76); 76 pacientes (51,70%) fueron hombres. El IPI fue bajo o intermedio/bajo en 115 (78,2%) casos. El CNS IPI fue intermedio en 77 (52,4%) y alto en 14 (9,5%) casos. Treinta y cinco (23.81%) pacientes recibieron profilaxis intratecal del SNC, ninguno profilaxis sistémica. Durante el seguimiento, 8 (4,59%) pacientes tuvieron recaída del SNC. La mediana de tiempo a la recaída fue de 6,5 meses (IIC 5,5 - 10). Siete (87,5%) pacientes recayeron dentro del año. No encontramos factores de riesgo para el compromiso del SNC en el análisis bivariado. La incidencia de recaída fue del 2,7% (IC 0,2%-4,6%), 4,8% (IC 1,8%-8,9%) y 5,4% (IC 4,5-8,9%) a los 6, 12 y 24 meses, respectivamente. Discusión: La incidencia de recaída del SNC fue similar a la descrita en las series internacionales. Nuestro estudio confirma que la mayoría de los pacientes que recaen, lo hacen dentro del primer año del diagnóstico. Debemos realizar trabajos colaborativos más amplios para establecer mejor factores de riesgo asociados.

EBER+ extranodal NK/T lymphoma in patient with idiopathic CD4 lymphocytopenia.

Idiopathic CD4 lymphocytopenia (ICL) not related to HIV is an infrequent and severe condition with no etiology defined until now. The concomitant presence of an underlying disease, especially an oncohematological process, could be related to the immune physiopathology and the development of the immunosuppressive state. On the other hand, Epstein Barr virus is a well-known oncogenic pathogen described in the development of several types of lymphoma which might be reactivated in the ICL. There is still no specific treatment for this syndrome, so the therapeutic scope for these patients is the treatment of opportunistic diseases and the administration of specific antimicrobials as prophylaxis. We present a patient with an uncommon association of an ICL and an extranodal T/NK lymphoma with detection of VEB nuclear RNA by in situ hybridization (EBER). Diagnosis was challenging which led the health team to carry out many studies over several months.

La linfocitopenia CD4 idiopática (ICL) no relacionada al HIV es una condición grave e infrecuente sin una etiología aún definida. La presencia de una enfermedad subyacente, especialmente un proceso oncohematológico, podría tener relación en la fisiopatología del proceso inmunológico. Por otro lado, el virus Epstein Barr (VEB) es bien conocido por ser un patógeno oncogénico descrito en el desarrollo de diversos tipos de linfomas, el cual podría ser reactivado en estados de inmunosupresión severa. No existe aún un tratamiento específico para este síndrome, por lo que el objetivo terapéutico en estos pacientes radica en el manejo profiláctico y activo de las distintas enfermedades oportunistas ante las cuales son susceptibles. Se presenta un paciente con un déficit grave de linfocitos CD4 de causa idiopática, y un diagnóstico posterior de linfoma T/NK extraganglionar con detección de RNA nuclear de VEB por hibridización in situ (EBER), una asociación poco descrita en la literatura médica.

Apoptotic regulator BCL-2 blockade as a potential therapy in classical Hodgkin Lymphoma.

The challenge in classical Hodgkin Lymphoma (cHL) management is the 30-40% of refractory/relapsed cases. AIMS: The aim of this work was to determine whether NIK and BCL-2 could be useful as prognosis biomarkers in cHL. In addition, we evaluated BCL-2 as a directed-therapy in cHL cell lines using venetoclax. MAIN METHODS: We evaluated NIK and BCL-2 expression in 112 untreated cHL patients' lymph-node biopsies by immunohistochemistry. cHL cell lines were treated with venetoclax alone or combined with vincristine or doxorubicin. Cell viability, metabolic activity and cell death were analyzed by trypan-blue exclusion method, MTS assay and FDA/IP staining respectively. KEY FINDINGS: No correlation between NIK or BCL-2 expression and the majority of the clinical parameters was found. Patients with ≥60% BCL-2+ HRS-cells had a shorter disease-free survival (DFS) and overall survival (OS) (p = 0.002, p = 0.02 respectively). A decision tree analysis, in a 30 patients subgroup, showed that patients with <60% NIK+ HRS-cells but with ≥60% BCL-2+ HRS-cells had a worse outcome in terms of DFS and OS. These parameters performed better as prognosis indicators as compared to the diagnosis bone marrow status. Human cHL cell lines U-H01, KM-H2, L1236, SUPHD1, L540 showed sensitivity to venetoclax. The co-treatment effect of venetoclax and vincristine or doxorubicin on cell viability was diverse depending on the cell line evaluated. SIGNIFICANCE: BCL-2 should be considered as a prognosis biomarker as well as a potential new therapeutic target in cHL. We report for the first time the cytotoxic effect of venetoclax in human cHL cell lines.

Real-World Data on Adult T-Cell Leukemia/Lymphoma in Latin America: A Study From the Grupo de Estudio Latinoamericano de Linfoproliferativos.

PURPOSE: Adult T-cell leukemia/lymphoma (ATLL) is an aggressive disease caused by the human T-cell leukemia virus type 1. Real-world data of ATLL in Latin America are lacking. PATIENTS AND METHODS: We analyzed patients with ATLL (acute, lymphomatous, chronic, and smoldering) encountered in 11 Latin American countries between 1995 and 2019. Treatment response was assessed according to the 2009 consensus report. Survival curves were estimated using the Kaplan-Meier method and log-rank test. RESULTS: We identified 253 patients; 226 (lymphomatous: n = 122, acute: n = 73, chronic: n = 26, and smoldering: n = 5) had sufficient data for analysis (median age 57 years). Most patients with ATLL were from Peru (63%), Chile (17%), Argentina (8%), and Colombia (7%). Hypercalcemia was positively associated with acute type (57% v lymphomatous 27%, P = .014). The median survival times (months) were 4.3, 7.9, 21.1, and not reached for acute, lymphomatous, chronic, and smoldering forms, with 4-year survival rates of 8%, 22%, 40%, and 80%, respectively. First-line zidovudine (AZT)-interferon alfa (IFN) resulted in an overall response rate of 63% (complete response [CR] 24%) for acute. First-line chemotherapy yielded an overall response rate of 41% (CR 29%) for lymphomatous. CR rate was 42% for etoposide, cyclophosphamide, vincristine, doxorubicin, and prednisone versus 12% for cyclophosphamide, vincristine, doxorubicin, and prednisone-like regimen (P < .001). Progression-free survival at 1 year for acute type patients treated with AZT-IFN was 67%, whereas 2-year progression-free survival in lymphomatous type patients who achieved CR after chemotherapy was 77%. CONCLUSION: This study confirms Latin American ATLL presents at a younger age and has a high incidence of lymphomatous type, low incidence of indolent subtypes, and worse survival rates as compared with Japanese patients. In aggressive ATLL, chemotherapy remains the preferred choice for lymphomatous favoring etoposide-based regimen (etoposide, cyclophosphamide, vincristine, doxorubicin, and prednisone), whereas AZT-IFN remains a good first-line option for acute subtype.

[Ileitis as presentation of lymphoma in Wiskott-Aldrich syndrome]. / Ileítis como presentación de linfoma en síndrome de Wiskott-Aldrich.

Wiskott-Aldrich syndrome is a rare X chromosome-linked primary immunodeficiency syndrome associated with an increased incidence of infections, autoimmune disorders and neoplasms. We present the case of a 41-year-old man with a diagnosis of Wiskott-Aldrich syndrome with ileitis as a form of presentation of a lymphoproliferative syndrome. The ileitis, in the context of the patient, represents a clinical challenge given the large number of differential diagnoses (inflammatory bowel disease, infections, neoplasms and lymphoproliferative diseases), so it usually requires anatomopathological diagnosis and particular considerations regarding the subsequent specific treatment.

El síndrome de Wiskott-Aldrich (SWA) es un raro síndrome de inmunodeficiencia primaria ligado al cromosoma X que se asocia con aumento de incidencia de infecciones, trastornos autoinmunes y neoplasias. Se presenta el caso de un varón de 41 años con diagnóstico de síndrome de Wiskott-Aldrich y cuadro de ileítis como forma de presentación de un síndrome linfoproliferativo. La ileítis, en el contexto del paciente, representa un problema clínico dado el gran número de diagnósticos diferenciales (enfermedad inflamatoria intestinal, infecciones, neoplasias y enfermedades linfoproliferativas) por lo que suele requerir diagnóstico anatomopatológico y consideraciones particulares respecto al posterior tratamiento específico.

Nonimmune-acquired factor XIII deficiency: a cause of high volume and delayed postoperative hemorrhage.

: Factor XIII (FXIII) levels may decrease because of surgical consumption. Acquired FXIII deficiency could be a cause of postoperative hemorrhage usually underdiagnosed in clinical practice. To determine the diagnosis confirmation rate of acquired FXIII deficiency in postsurgical patients with clinical suspicion and to compare the characteristics and evolution of patients with or without FXIII deficiency. We performed a retrospective cohort study, which included 49 inpatients who were attended at our university hospital from 2014 to 2018 with suspicion of acquired FXIII deficiency because of disproportionate postoperative hemorrhage. FXIIIA levels less than 50% was considered a deficiency. Persistence of bleeding for more than 48 h, drop in hematocrit points, red blood cells transfused units, hemoglobin levels 12-36 h after bleeding, and time elapsed from the procedure to the bleeding were assessed as outcome variables. Logistic regression was employed for both univariate and multivariate analyses. Of the 49 patients included, 27(55%) had FXIII deficiency, with a median level of 34% [interquartile range (IQR) 19-42]. Abdominal surgery was the most common [n = 21 (43%)]. All patients had routine coagulation tests within the hemostatic range. FXIII deficiency was associated with a drop of more than 4 points in hematocrit [OR 59.69 (95% CI 4.71-755.30)], red blood transfused units >2 [OR 45.38 (95% CI 3.48-590.65)], and delayed bleeding >36 h after surgery [OR 100.90 (95% CI 3.78-2695.40)]. Plasma-derived FXIII concentrate was administered to eight patients with life-threatening bleeding with resolution within 24 h. Only one deficient patient died from bleeding. FXIII levels were measured 15 days after diagnosis or more in 20 out of 27 deficient patients, with normal results. Acquired FXIII deficiency may be a frequent underdiagnosed entity that should be considered when high-volume and delayed postoperative hemorrhage is present in patients with hemostatic routine coagulation test results.

A Multi-Institutional Validation of the Prognostic Value of the Neutrophil-to-Lymphocyte Ratio in Patients With Diffuse Large B-Cell Lymphoma: A Study From The Latin American Group of Lymphoproliferative Disorders (GELL).

INTRODUCTION: We aimed at investigating the prognostic role of the neutrophil-to-lymphocyte ratio (NLR) in 2 independent cohorts of Latin American patients with diffuse large B-cell lymphoma (DLBCL) treated with chemoimmunotherapy. PATIENTS AND METHODS: The learning cohort was composed of 274 patients and the validation cohort of 323 patients, for a total of 597 patients. An optimal NLR cutoff ≥ 4 was determined using receiver operating characteristic analysis. RESULTS: In multivariate models, NLR ≥ 4 was independently associated with lower odds for complete response to chemoimmunotherapy in the learning (odds ratio, 0.46; P = .006) and the validation cohort (odds ratio, 0.49; P = .01), and independently associated with worse survival in the learning (hazard ratio, 1.55; P = .04) and the validation cohort (hazard ratio, 1.80; P = .003). CONCLUSIONS: The adverse prognostic value of NLR ≥ 4 was independent of the International Prognostic Index and the National Comprehensive Cancer Network-International Prognostic Index score. Based on the results of this multi-institutional study, NLR ≥ 4 emerges as an adverse prognostic factor in Latin American patients with DLBCL treated with chemoimmunotherapy.

Single-center "Argentine" analysis of post-transplant lymphoproliferative disorders: incidence, histopathological characteristics and EBV status

ABSTRACT Introduction: Post-transplant lymphoproliferative disorders (PTLDs) are a heterogeneous group of lymphoid proliferations occurring after solid organ or bone marrow transplantation. The primary aims of our study were to characterize cumulative incidence of PTLDs, clinical and pathological features according to the Epstein-Barr virus (EBV) status and survival. Methods: This was a retrospective cohort study on adult and pediatric patients, from January 2001 to December 2017. The cumulative incidence of PTLD was calculated by analyzing all the patients transplanted at our hospital, based on the database of the Organ Donation and Ablation Authority of Argentina (INCUCAI). The Kaplan-Meier method was used to plot the survival. Results: Fifty-eight cases of biopsy-confirmed PTLD were identified and 12 cases of clinical data were incomplete and these patients were excluded. The median age at the time of the PTLD diagnosis was 17.5 years (interquartile range [IQR] 9 - 57). The median interval between transplant and PTLD diagnosis was 39 months (IQR 9 - 113). The most commonly transplanted organ was the liver (24 cases, 52.2%), followed by kidney (20 cases, 43.5%). The Epstein-Barr encoding region in situ hybridization (EBER ISH) was positive in 29 (69.8%) of the 43 evaluable biopsies. The PTLD cumulative incidence was 1.84% (95%CI 1.77 - 1.91) for solid organ and 0.84% (95%CI 0.48 - 1.2) for bone marrow transplant patients. The overall survival rate at 5 years was 0.77 (95%CI 0.61 - 0.87). Subgroups by the EBV EBER status, transplant type, PTLD subtype and age group (adult vs. pediatric) showed no statistically significant association with the overall survival. Conclusion: The PTLD incidence was similar to that of previous series and the EBER did not appear as a relevant factor in our patient survival.

Clinical and genetic factors influencing acenocoumarol dosing: a cross-sectional study.

: Coumadin oral anticoagulants are widely used in multiple clinical scenarios. Their narrow therapeutic range and a dosing strategy based on 'a posteriori' algorithms, pose them as an interesting group for prediction modelling research. Extensive literature explaining the association between clinical and genetic variables with the dose of warfarin have been published. Limited information exists regarding these factors and acenocoumarol dosing. The aim of the study is to explain through clinical/genetic variables, the weekly dose of acenocoumarol necessary for achieving stable anticoagulation status. We performed a cross-sectional study enrolling adults under treatment with acenocoumarol with at least three consecutive INRs between 2 and 3. To explain the association between demographic, clinical and genotype data (VKORC1, CYP2C9 and CYP4F2) and the mean weekly dose of acenocoumarol, we performed a multiple linear regression model. In our cohort, a higher age, the presence of atrial fibrillation, chronic renal failure and VKORC1 haplotype A were associated with a lower mean weekly dose of acenocoumarol. On the other side, a higher weight was associated with a higher weekly dose. Amongst anticoagulated adult patients, VKORC1 genotype and baseline clinical factors can explain acenocoumarol dosing, and therefore, help clinicians while deciding the initial anticoagulant dose.

Analysis and redesign of a knowledge database for a drug-drug interactions alert system.

Physicians tend to ignore drug-drug interactions alerts, this is due to the large amount of irrelevant interactions displayed and the interface in which these alerts are shown. The high rate of clinically inadequate alerts produce "alerts fatigue". This high number of incorrect alerts predisposes physicians to underestimate the electronic prescription systems as useful tools in their practice. We decided to analyze and redesign our drug-drug interactions alerting system knowledge database. In order to do so, we cleaned our knowledge database according to the clinical significance of drug-drug interactions. New drug interactions taxonomy was created in four levels based on clinical significance and the recommendations given in each single monograph of interaction. We proceeded to recategorize the alerts as Active, which present themselves to the physician interrupting the prescribing process, or Passive, which allow physicians to accept the recommendations, and adopt some action in order of minimizing the interaction risks.

EBER + extranodal NK/T lymphoma in patient with idiopathic CD4 lymphocytopenia / Linfoma T/NK EBER positivo en paciente con linfocitopenia CD4 idiopática

Abstract Idiopathic CD4 lymphocytopenia (ICL) not related to HIV is an infrequent and severe condition with no etiology defined until now. The concomitant presence of an underlying disease, especially an oncohematological process, could be related to the immune physiopathology and the development of the im munosuppressive state. On the other hand, Epstein Barr virus is a well-known oncogenic pathogen described in the development of several types of lymphoma which might be reactivated in the ICL. There is still no specific treatment for this syndrome, so the therapeutic scope for these patients is the treatment of opportunistic diseases and the administration of specific antimicrobials as prophylaxis. We present a patient with an uncommon asso ciation of an ICL and an extranodal T/NK lymphoma with detection of VEB nuclear RNA by in situ hybridization (EBER). Diagnosis was challenging which led the health team to carry out many studies over several months

Resumen La linfocitopenia CD4 idiopática (ICL) no relacionada al HIV es una condición grave e infrecuente sin una etiología aún definida. La presencia de una enfermedad subyacente, especialmente un proceso oncohematológico, podría tener relación en la fisiopatología del proceso inmunológico. Por otro lado, el virus Epstein Barr (VEB) es bien conocido por ser un patógeno oncogénico descrito en el desarrollo de diversos tipos de linfomas, el cual podría ser reactivado en estados de inmunosupresión severa. No existe aún un tratamiento específico para este síndro me, por lo que el objetivo terapéutico en estos pacientes radica en el manejo profiláctico y activo de las distintas enfermedades oportunistas ante las cuales son susceptibles. Se presenta un paciente con un déficit grave de linfocitos CD4 de causa idiopática, y un diagnóstico posterior de linfoma T/NK extraganglionar con detección de RNA nuclear de VEB por hibridización in situ (EBER), una asociación poco descrita en la literatura médica.