Pharmacogenetics of pediatric acute lymphoblastic leukemia in Uruguay: adverse events related to induction phase drugs.

In Uruguay, the pediatric acute lymphoblastic leukemia (ALL) cure rate is 82.2%, similar to those reported in developed countries. However, many patients suffer adverse effects that could be attributed, in part, to genetic variability. This study aims to identify genetic variants related to drugs administered during the induction phase and analyze their contribution to adverse effects, considering individual genetic ancestry. Ten polymorphisms in five genes (ABCB1, CYP3A5, CEP72, ASNS, and GRIA1) related to prednisone, vincristine, and L-asparaginase were genotyped in 200 patients. Ancestry was determined using 45 ancestry informative markers (AIMs). The sample ancestry was 69.2% European, 20.1% Native American, and 10.7% African, but with high heterogeneity. Mucositis, Cushing syndrome, and neurotoxicity were the only adverse effects linked with genetic variants and ancestry. Mucositis was significantly associated with ASNS (rs3832526; 3R/3R vs. 2R carriers; OR: = 6.88 [1.88-25.14], p = 0.004) and CYP3A5 (non-expressors vs. expressors; OR: 4.55 [1.01-20.15], p = 0.049) genes. Regarding Cushing syndrome, patients with the TA genotype (rs1049674, ASNS) had a higher risk of developing Cushing syndrome than those with the TT genotype (OR: 2.60 [1.23-5.51], p = 0.012). Neurotoxicity was significantly associated with ABCB1 (rs9282564; TC vs. TT; OR: 4.25 [1.47-12.29], p = 0.007). Moreover, patients with <20% Native American ancestry had a lower risk of developing neurotoxicity than those with ≥20% (OR: 0.312 [0.120-0.812], p = 0.017). This study shows the importance of knowing individual genetics to improve the efficacy and safety of acute lymphoblastic leukemia.

An updated examination of the perception of barriers for pharmacogenomics implementation and the usefulness of drug/gene pairs in Latin America and the Caribbean.

Pharmacogenomics (PGx) is considered an emergent field in developing countries. Research on PGx in the Latin American and the Caribbean (LAC) region remains scarce, with limited information in some populations. Thus, extrapolations are complicated, especially in mixed populations. In this paper, we reviewed and analyzed pharmacogenomic knowledge among the LAC scientific and clinical community and examined barriers to clinical application. We performed a search for publications and clinical trials in the field worldwide and evaluated the contribution of LAC. Next, we conducted a regional structured survey that evaluated a list of 14 potential barriers to the clinical implementation of biomarkers based on their importance. In addition, a paired list of 54 genes/drugs was analyzed to determine an association between biomarkers and response to genomic medicine. This survey was compared to a previous survey performed in 2014 to assess progress in the region. The search results indicated that Latin American and Caribbean countries have contributed 3.44% of the total publications and 2.45% of the PGx-related clinical trials worldwide thus far. A total of 106 professionals from 17 countries answered the survey. Six major groups of barriers were identified. Despite the region's continuous efforts in the last decade, the primary barrier to PGx implementation in LAC remains the same, the "need for guidelines, processes, and protocols for the clinical application of pharmacogenetics/pharmacogenomics". Cost-effectiveness issues are considered critical factors in the region. Items related to the reluctance of clinicians are currently less relevant. Based on the survey results, the highest ranked (96%-99%) gene/drug pairs perceived as important were CYP2D6/tamoxifen, CYP3A5/tacrolimus, CYP2D6/opioids, DPYD/fluoropyrimidines, TMPT/thiopurines, CYP2D6/tricyclic antidepressants, CYP2C19/tricyclic antidepressants, NUDT15/thiopurines, CYP2B6/efavirenz, and CYP2C19/clopidogrel. In conclusion, although the global contribution of LAC countries remains low in the PGx field, a relevant improvement has been observed in the region. The perception of the usefulness of PGx tests in biomedical community has drastically changed, raising awareness among physicians, which suggests a promising future in the clinical applications of PGx in LAC.

Alpha thalassemia and alpha-MRE haplotypes in Uruguayan patients with microcytosis and hypochromia without anemia.

Alpha thalassemia is the most common genetic disorder across the world, being the α-3.7 deletion the most frequent mutation. In order to analyze the spectrum and origin of alpha thalassemia mutations in Uruguay, we obtained a sample of 168 unrelated outpatients with normal hemoglobin levels with microcytosis and hypochromia from two cities: Montevideo and Salto. The presence of α-thalassemia mutations was investigated by gap-PCR, restriction endonucleases analysis and HBA2 and HBA1 genes sequencing, whereas the alpha-MRE haplotypes were investigated by sequencing. We found 55 individuals (32.7%) with α-thalassemia mutations, 51(30.4%) carrying the -α3.7 deletion, one with the -α4.2 deletion and three having the rare punctual mutation HBA2:c.-59C>T. Regarding alpha-MRE analysis, we observed a significant higher frequency of haplotype D, characteristic of African populations, in the sample with the -α3.7 deletion. These results show that α-thalassemia mutations are an important determinant of microcytosis and hypochromia in Uruguayan patients with microcytosis and hypochromia without anemia, mainly due to the -α3.7 deletion. The alpha-MRE haplotypes and the α-thalassemia mutations spectrum suggest a predominant, but not exclusive, African origin of these mutations in Uruguay.

Ancestry and TPMT-VNTR Polymorphism: Relationship with Hematological Toxicity in Uruguayan Patients with Acute Lymphoblastic Leukemia.

6-Mercaptopurine (6-MP) is a thiopurine drug widely used in childhood acute lymphoblastic leukemia (ALL) therapy. Genes such as TPMT and NUDT15 have an outstanding role in 6-MP metabolism. Mutations in both genes explain a significant portion of hematological toxicities suffered by ALL Uruguayan pediatric patients. A variable number tandem repeat in the TPMT promoter (TPMT-VNTR) has been associated with TPMT expression. This VNTR has a conservative architecture (AnBmC). To explore new causes of hematological toxicities related to ALL therapy, we genotyped the TPMT-VNTR of 130 Uruguayan pediatric patients. Additionally, individual genetic ancestry was estimated by 45 ancestry-informative markers (AIMs). Hematological toxicity was measured as the number of leukopenia events and 6-MP dose along the maintenance phase. As previously reported, we found TPMT*2 and TPMT*3C alleles were associated to TPMT-VNTR A2BC and AB2C, respectively. However, contrasting with other reports, TPMT*3A allele was found in a heterogeneous genetic background in linkage equilibrium. Patients carrying more than 5 A repeats present a significant higher number of leukopenia events among patients without TPMT and/or NUDT15 variants. Native American ancestry and the number of A repeats were significantly correlated with the number of leukopenia events. However, the correlation between Native American ancestry and the number of leukopenia events was lost when the number of A repeats was considered as covariate. This suggests that TPMT-VNTR alleles are more relevant than Native American ancestry in the hematological toxicity. Our results emphasize that TPMT-VNTR may be used as a pharmacogenetic biomarker to predict 6-MP-related hematological toxicity in ALL childhood therapy.

Coledocoduodenostomía guiada por ultrasonografía endoscópica ante fallo o imposibilidad de CPRE / Endoscopic ultrasound-guided choledochoduodenostomy after a failed or impossible ERCP

Introducción: el drenaje biliar endoscópico guiado por ultrasonografía (DBUSE) es una alternativa al drenaje biliar percutáneo transhepático (CTPH) ante fallo de la colangiografía retrógrada endoscópica (CPRE). Métodos: descripción retrospectiva de seis casos de drenaje biliar guiado por ultrasonografía endoscópica, mediante coledocoduodenostomía (USE-CDS), así como de sus características clínicas, procedimiento endoscópico, complicaciones y posterior seguimiento. Resultados: todos nuestros casos presentaban obstrucción biliar distal de etiología maligna. En cuatro de los seis pacientes se concluyó el procedimiento con buen drenaje posterior. Registramos dos complicaciones tardías por migración de prótesis, sin muertes relacionadas con el procedimiento. El tiempo medio de seguimiento fue de seis meses. Conclusión: la USE-CDS se plantea como una opción terapéutica válida, no exenta de complicaciones, en casos seleccionados y en manos de un equipo de endoscopistas expertos ante fallos del drenaje por CPRE, y como alternativa al CTPH

Introduction: endoscopic ultrasound-guided biliary drainage (EUS-BD) is an alternative to percutaneous trans-hepatic biliary drainage (PTBD) in cases of failed endoscopic retrograde cholangiopancreatography (ERCP). Methods: this is a retrospective description of six cases of endoscopic ultrasound-guided biliary drainage via choledochoduodenostomy (EUCD), as well as the clinical characteristics, endoscopic procedure, complications and monitoring. Results: all cases had malignant distal biliary obstruction. The procedure was concluded with good drainage in four out of six patients. Two late complications were recorded that were caused by stent migration and there were no deaths related with the procedure. The average monitoring period was six months. Conclusions: EUCD can be considered as a valid therapeutic choice in some selected cases and when performed by a team of expert endoscopists in cases of failed ERCP drainage or as an alternative to PTBD. However, the procedure has some associated complications

Endoscopic ultrasound-guided choledochoduodenostomy after a failed or impossible ERCP.

INTRODUCTION: endoscopic ultrasound-guided biliary drainage (EUS-BD) is an alternative to percutaneous trans-hepatic biliary drainage (PTBD) in cases of failed endoscopic retrograde cholangiopancreatography (ERCP). METHODS: this is a retrospective description of six cases of endoscopic ultrasound-guided biliary drainage via choledochoduodenostomy (EUCD), as well as the clinical characteristics, endoscopic procedure, complications and monitoring. RESULTS: all cases had malignant distal biliary obstruction. The procedure was concluded with good drainage in four out of six patients. Two late complications were recorded that were caused by stent migration and there were no deaths related with the procedure. The average monitoring period was six months. CONCLUSIONS: EUCD can be considered as a valid therapeutic choice in some selected cases and when performed by a team of expert endoscopists in cases of failed ERCP drainage or as an alternative to PTBD. However, the procedure has some associated complications.

Traumatic Brain Injury Profile of an Elderly Population in Puerto Rico.

OBJECTIVE: Describe the types of traumatic brain injury secondary to falls sustained by the members of an elderly population who received services at the Puerto Rico Medical Center and the demographic profile of that population. METHODS: A group of 332 adults (60 years and over) assessed for traumatic brain injury secondary to falls suffered in 2013 were included in the analysis. The cases were retrieved from the computerized database of the Neurosurgery Section. We analyzed information such as age, gender, type of traumatic brain injury, mechanism of injury, and the performance of surgery (if applicable). Descriptive analysis was performed to derive a general profile of elderly adults who presented with traumatic brain injury secondary to falls. RESULTS: The sample consisted of 332 elderly adults: 73% were men and 27% were women. The mean age was 76.74 (SD=9.95) years: 75.67 (SD=9.78) for men and 79.13 (SD=10.02) for women. The most common traumatic brain injury was subdural hematoma (51%) and the mechanism of injury most prevalent was the groundlevel fall (83%). Other traumatic brain injuries included traumatic subarachnoid hemorrhages (14%), cerebral contusions (18%) and epidural hematomas (3%). Of all the cases, 52% had were managed surgically. CONCLUSION: The elderly population is growing and the risk of falls increases with advancing age. Recurrent falls are an important cause of morbidity, and mortality rates oscillate from 6 to 18%. Elderly patients have longer rehabilitation times, incur more expenses, and have greater levels of disability. This study provides a platform for future epidemiological studies to help develop strategies for the prevention of traumatic brain injury in older adults.

Tumor de células epitelioides perivasculares de íleon. Descripción de un caso / Perivascular epithelioid cell tumor of the ileum. A case report

Los tumores de células epiteliodes perivasculares son tumores de células epiteliales vasculares con características inmunohistoquímicas de músculo liso y células melanocíticas. Los gastrointestinales son infrecuentes. El tratamiento es quirúrgico aunque existen datos que indican buena respuesta a la rapamicina (AU)

Perivascular epithelioid cell tumors (PEComa) are tumors of perivascular epithelioid cells with immunohistochemical features of smooth muscle and melanocytic tumors. The PEComa of the gastrointestinal tract is rare. The treatment is surgical, although there are data that suggest a good response to rapamycin (AU)

Hepatitis crónica por virus de la hepatitis E tratada con ribavirina / Chronic hepatitis caused by hepatitis E virus and treated with ribavirin

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Pancreatitis aguda secundaria a déficit parcial de multidrug resistance 3 p-glycoprotein / Acute pancreatitis secondary to partial multidrug resistance 3 p-glycoprotein deficit

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The -(α)(5.2) Deletion Detected in a Uruguayan Family: First Case Report in the Americas.

In Uruguay, α-thalassemia (α-thal) mutations were introduced predominantly by Mediterranean European immigrant populations and by slave trade of African populations. A patient with anemia with hypochromia and microcytosis, refractory to iron treatment and with normal hemoglobin (Hb) electrophoresis was analyzed for α-thal mutations by multiplex gap-polymerase chain reaction (gap-PCR), automated sequencing and multiplex ligation-dependent probe amplification (MLPA) analyses. Agarose gel electrophoresis of the multiplex gap-PCR showed a band of unexpected size (approximately 700 bp) in the samples from the proband and mother. Automated sequencing of the amplified fragment showed the presence of the -(α)(5.2) deletion (NG_000006.1: g.32867_38062del5196) [an α-thal-1 deletion of 5196 nucleotides (nts)]. The MLPA analysis of the proband's sample also showed the presence of the -(α)(5.2) deletion in heterozygous state. We report here the presence of the -(α)(5.2) deletion, for the first time in the Americas, in a Uruguayan family with Italian ancestry, detected with a previously described multiplex gap-PCR.

Aumento de la incidencia de cáncer colorrectal en la provincia de Salamanca. Comparación de dos periodos: 2004-2006 y 2010-2012 / Increasing incidence of colorectal cancer in the province of Salamanca. Comparison of two periods: 2004-2006 and 2010-2012

Objetivos: comparar incidencia, mortalidad y características epidemiológicas de los pacientes diagnosticados de cáncer colorrectal (CCR) en la provincia de Salamanca entre dos periodos: 2010-2012 y 2004-2006. Métodos: estudio observacional retrospectivo. Incluimos todos los CCR diagnosticados según criterios histopatológicos del 01/01/2004 al 31/12/2006 y del 01/01/2010 al 31/12/2012. Las variables estudiadas fueron género, edad, fecha de diagnóstico y localización del tumor. Se han calculado incidencia acumulada e incidencia específica por grupos de edad comparando los resultados entre periodos. Hemos ajustado las tasas por edad a la población mundial estándar para poder compararla con otras poblaciones. Resultados: detectamos un 38% más de CCR en el periodo de 2010 a 2012 que en el de 2004 a 2006. Las variables (sexo, edad de diagnóstico y localización) han sido similares en ambos grupos. En el periodo de 2010-2012 se realizaron más del doble de colonoscopias que en el de 2004-2006. La mortalidad poblacional por CCR también aumentó, aunque de manera mucho menos importante que la incidencia. Conclusiones: existe un claro aumento de la incidencia del CCR en la provincia de Salamanca entre los años 2004-2006 y 2010-2012 no relacionado con el envejecimiento. El aumento considerable de colonoscopias puede haber sido un factor importante para el aumento en la detección (AU)

Objectives: To compare incidence, mortality and epidemiological characteristics of patients diagnosed with colorectal cancer (CRC) in the province of Salamanca over two different periods: 2010-2012 and 2004-2006. Methods: Retrospective observational study. We include all diagnosed cases of CRC according to histopathological criteria from 01/01/2004 to 31/12/2006 and from 01/01/2010 to 31/12/2012. The studied variables were sex, age, date of diagnosis and tumor location. Cumulative incidence and specific incidence in different age groups were measured and compared between the two periods. The age rates were adjusted to the standard world population so that the results could be compared with those of other populations. Results: We detected 38% more cases of CRC in the 2010-2012 period than in 2004-2006. Variables distribution (sex, age at diagnosis and location) was similar in both groups. More than twice as many colonoscopies were performed in 2010-2012 than in 2004-2006. Population mortality due to CRC also increased, although much less importantly than the incidence of this condition. Conclusions: There has been a clear increase in CRC incidence in the province of Salamanca from 2004-2006 to 2010-2012 which is not related to the ageing of the population. The remarkable increase in colonoscopies may have been an important factor for the increased detection (AU)

Increasing incidence of colorectal cancer in the province of Salamanca. Comparison of two periods: 2004-2006 and 2010-2012.

OBJECTIVES: To compare incidence, mortality and epidemiological characteristics of patients diagnosed with colorectal cancer (CRC) in the province of Salamanca over two different periods: 2010-2012 and 2004-2006. METHODS: Retrospective observational study. We include all diagnosed cases of CRC according to histopathological criteria from 01/01/2004 to 31/12/2006 and from 01/01/2010 to 31/12/2012. The studied variables were sex, age, date of diagnosis and tumor location. Cumulative incidence and specific incidence in different age groups were measured and compared between the two periods. The age rates were adjusted to the standard world population so that the results could be compared with those of other populations. RESULTS: We detected 38% more cases of CRC in the 2010-2012 period than in 2004-2006. Variables distribution (sex, age at diagnosis and location) was similar in both groups. More than twice as many colonoscopies were performed in 2010-2012 than in 2004-2006. Population mortality due to CRC also increased, although much less importantly than the incidence of this condition. CONCLUSIONS: There has been a clear increase in CRC incidence in the province of Salamanca from 2004-2006 to 2010-2012 which is not related to the ageing of the population. The remarkable increase in colonoscopies may have been an important factor for the increased detection.

Perivascular epithelioid cell tumor of the ileum. A case report.

Perivascular epithelioid cell tumors (PEComa) are tumors of perivascular epithelioid cells with immunohistochemical features of smooth muscle and melanocytic tumors. The PEComa of the gastrointestinal tract is rare. The treatment is surgical, although there are data that suggest a good response to rapamycin.

Hemorragia digestiva secundaria a enteritis por herpes virus en paciente inmunodeprimido / Gastrointestinal bleeding secondary to enteritis due to herpes virus in an immunosuppressed man

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Porphyrin formation in actinic keratosis and basal cell carcinoma after topical application of methyl 5-aminolevulinate.

Photodynamic therapy using topical methyl 5-aminolevulinate (MAL) is a new treatment modality for basal cell carcinoma (BCC) and actinic keratosis (AK). MAL induces endogenous porphyrins, which act as photosensitizers. Pharmacokinetic studies of the porphyrin-inducing effect of MAL creams (Metvix) applied in different concentrations (16-160 mg/g) and application times are presented. Surface fluorescence measurements were used to monitor porphyrin accumulation in 18 superficial BCCs and 32 AKs. For both lesion types, the fluorescence increased during the first 13 of 28 hours of continuous MAL application. A 20-fold site-to-site variation was observed, and there were no significant MAL concentration dependencies. The selectivity between lesions and normal skin was 10-fold during the first hours and decreased throughout the application time. Fluorescence microscopy images of tissue sections from 32 nodular BCCs were analyzed to calculate the porphyrin content in tumor tissue as a function of depth. Significant correlation to MAL concentration was seen within the tumors treated for 3 hours. Increase to 18-hour MAL application enhanced the fluorescence levels in superficial tumor layers, but not in deep layers. In conclusion, application of the 160 mg/g cream for 3 hours gave advantageous porphyrin distributions for all types of lesions.