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Background: Optical coherence tomography (OCT) enables high-resolution imaging of ocular structures in health and disease. Choroid thickness (CT) is a key vascular retinal parameter that can be assessed by OCT and might be relevant in the evaluation of the vascular component of cognitive decline. We aimed to investigate CT changes in a large cohort of individuals cognitive unimpaired (CU), with mild cognitive impairment due to Alzheimer's (MCI-AD), mild cognitive impairment due to cerebrovascular disease (MCI-Va), Alzheimer's disease dementia (ADD), and vascular dementia (VaD)., Methods: Clinical, demographical, ophthalmological and OCT data from the Neuro-ophthalmological Research at Fundació ACE (NORFACE) project were analyzed. CT was assessed in the macula across nine Early Treatment Diabetic Retinopathy Study (ETDRS) quadrants, average thickness, total volume, and subfoveal choroidal thickness. Differences of CT among the five diagnostic groups were assessed in a multivariate regression model, adjusting for demographic and cardiovascular risk factors and OCT image quality. A comparison between manual and automatic CT measurements in a subset of participants was also performed., Results: The study cohort comprised 1,280 participants: 301 CU, 196 MCI-AD, 112 MCI-Va, 578 ADD, and 93 VaD. CT was significantly increased in individuals with cognitive impairment compared to those CU, particularly in the VaD and MCI-Va groups and in the peripheral ETDRS regions. No significant differences were found in inner superior, center and subfoveal choroidal thickness. The interaction of sex and diagnosis had no effect in differentiating CT. Mini-Mental State Examination (MMSE) scores were not correlated to CT. Manual and automated CT measurements showed good reliability., Discussion: Our findings indicated that peripheral choroidal thickening, especially in patients with cerebrovascular disease, may serve as a potential choroidal biomarker for cognitive decline and suggest different pathogenic pathways in AD and VaD. Further research is required to explore CT as a reliable ocular biomarker for cognitive impairment., Competing Interests: Declarations Ethics approval and consent to participate This study and its informed consent were approved by the Ethics Committee of the Hospital Clínic i Provincial de Barcelona in accordance with Spanish biomedical laws (Law 14/2007, of July 3, on biomedical research; Royal Decree 1716/2011, of November 18) and followed the recommendations of the declaration of Helsinki. All participants signed an informed consent form (in the case of individuals with moderate stages of dementia, informed consent was signed by their legal representative or family member). Consent for publication Not applicable. Competing interests MB has consulted for Araclon, Avid, Grifols, Lilly, Nutricia, Roche, Eisai and Servier. She received fees from lectures and funds for research from Araclon, Biogen, Grifols, Nutricia, Roche and Servier. She reports grants/research funding from Abbvie, Araclon, Biogen Research Limited, Bioiberica, Grifols, Lilly, S.A, Merck Sharp & Dohme, Kyowa Hakko Kirin, Laboratorios Servier, Nutricia SRL, Oryzon Genomics, Piramal Imaging Limited, Roche Pharma SA, and Schwabe Farma Iberica SLU, all outside the submitted work. She has not received personal compensations from these organizations. AR is member of scientific advisory board of Landsteiner Genmed and Grifols SA. AR has stocks of Landsteiner Genmed. MM has consulted for F. Hoffmann-La Roche Ltd. The rest of authors declare that they have no competing interests., (© 2024. The Author(s).)

Colonoscopy screening is an effective method to prevent colon cancer through the detection of polyps on which colon cancer develops in a higher percentage; however, the detection of these lesions varies in the different segments of the colon and the detection rate of them in the right colon is usually lower., Objective: The objective of this study is to evaluate whether double endoscopic revision of the right colon during colonoscopy is a mechanism to improve its performance in terms of polyp detection rate (TDP) and adenoma detection rate (ADR)., Materials and Methods: Systematic review and meta-analysis of the literature including randomized clinical trials that evaluated repeat right-sight examination by colonoscopy compared to standard view to improve detection of polyps and adenomas. The protocol for this decision was published in PROSPERO under the code CRD42022356509., Results: Five studies involving 2729 participants were included. Polyp detection was reported in 585/1197 patients (48.87%) after the second review, compared with 537/1206 (44.52%) of patients who received a single examination (p< 0.05), for a combined RR of 1.09 (95% CI: 0.97-1.23) (I2 was 44%). Detection of adenomas was reported in 830/1513 patients (54.75%) after the second review, compared with 779/1509 (51.62%) of patients who received a single examination (p < 0.05), for a combined RR of 1.06 (95% CI: 1.00-1.13) (I2 was 0%)., Conclusion: Second examination of the right colon by colonoscopy may have a modest improvement in the detection of polyps and adenomas.

Objective: To translate, culturally adapt, and validate a version of the ID Migraine into Latin American Spanish., Background: Although still considered a common diagnosis, half of the patients with migraine in Latin America experience diagnostic delay. The ID Migraine is a test developed in 2003 as a valuable tool for the early diagnosis of migraine at the primary care level; however, there is no validated Spanish or culturally adapted version for the Spanish-speaking population., Methods: This is an analytical, translation, and test-validation study. We performed back translation and cross-cultural adaptation. The Latin American Spanish version ID Migraine MX was applied to headache clinic patients from March 2021 to January 2022 to perform a validation process against the gold standard: blinded expert diagnosis according to the International Classification of Headache Disorders, 3rd edition (ICHD-3), criteria., Results: One hundred seventeen patients from the headache clinic of the National Institute of Neurology and Neurosurgery of Mexico City were screened. We found 62/117 (53%) patients positive for screening with ID Migraine MX, and 47/117 (40%) positive for migraine according to ICHD-3 criteria. A sensitivity (95% CI) of 0.91 (0.80-0.97), specificity of 0.73 (0.61-0.82), positive predictive value of 0.694 (0.57-0.794), and negative predictive value of 0.93 (0.83-0.97) were obtained. The positive likelihood ratio was 3.38 (2.27-4.99), and the negative likelihood ratio was 0.12 (0.04-0.30). After calling the patients 1 month after the first interview, the calculated Kappa test-retest was 0.75 (p = 0.001)., Conclusion: A translated and cross-culturally adapted version into Spanish of the ID Migraine was obtained, with a diagnostic performance similar to the original instrument. Clinicians may use this test at the first level of care to reduce the rate of misdiagnosis and the time from onset of symptoms to diagnosis and treatment of migraine., (© 2023 American Headache Society.)

Objectives: To evaluate the performance of a two-step strategy compared with the International Ovarian Tumor Analysis (IOTA) - Assessment of Different NEoplasias in the adneXa (ADNEX) model for preoperative classification of adnexal masses., Methods: An ambispective diagnostic accuracy study based on ultrasound data collected at one university hospital between 2012 and 2018. Two ultrasonographers classified the adnexal masses using IOTA Simple Rules (first step). Not classifiable masses were evaluated using the IOTA ADNEX model (second step). Also, all masses were classified using the IOTA ADNEX model. The sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV), positive likelihood ratio (LR+) and negative likelihood ratio (LR-), and receiver operating characteristic (ROC) curve were estimated. A P value of <.05 was used to determine statistical significance., Results: The study included 548 patients and 606 masses. Patients' median age was 41 years with an interquartile range between 32 and 51 years. In the first step, 89 (14%) masses were not classifiable. In the second step, 55 (61.8%) masses were classified as malignant. Furthermore, for the totality of 606 masses, the IOTA ADNEX model estimated the probability that 126 (20.8%) masses were malignant. The two-step strategy had a sensitivity, specificity, PPV, NPV, LR+, LR-, and ROC curve of 86.8%, 91.01%, 51.9%, 98.4%, 9.7, 0.1, and 0.889, respectively; compared to IOTA ADNEX model that had values of 91.8%, 87.16%, 44.4%, 99%, 7.1, 0.09, and 0.895, respectively., Conclusion: The two-step strategy shows a similar diagnostic performance when compared to the IOTA ADNEX model. The IOTA ADNEX model involves only one step and can be more practical, and thus would be recommended to use., (© 2021 American Institute of Ultrasound in Medicine.)

Introduction: Patients with chronic diarrhea often undergo colonoscopy evaluation, however, the performance of biopsies or ileoscopy remains controversial., Objective: To evaluate the usefulness of colonoscopy plus biopsies in the study of patients with chronic diarrhea., Materials and Methods: We retrospectively reviewed patients with chronic diarrhea who underwent colonoscopy between 2015 and 2019. Patients with incomplete data, HIV infection, abnormal endoscopic findings, colonoscopy without blind assessment, being on empiric treatment for diarrhea, and poor diagnosis were excluded. preparation. A descriptive analysis of the characteristics of the patients, histopathological findings and comparison of signs and symptoms according to histopathological finding was performed., Results: 535 patients with chronic diarrhea were evaluated, of these, 283 (52.8%) underwent biopsies. In 55.1% (n=156) of the biopsies some final histopathological diagnosis was obtained. Histopathological diagnoses corresponded to ulcerative colitis (n=3), Crohn's disease (n=5), lymphocytic colitis (n=6), collagenous colitis (n=12), eosinophilic colitis (n=13), infectious colitis (n=13), Melanosis coli (n=15), nonspecific colitis (n=57) and other histological changes (n=32). Crohn's disease was only documented in biopsies of the ileum (p<0.001), ulcerative colitis was only diagnosed in biopsies of the sigmoid rectum (p=0.007), infectious colitis in its highest proportion (30.7%) was documented in biopsies of the right colon (p=0.028)., Conclusion: Colonoscopy and biopsies are useful in the investigation of patients with chronic diarrhea, obtaining a histological diagnosis in 55% of patients. Ileoscopy complemented colonoscopy findings to a lesser extent.

Myelodysplastic syndromes (MDS) are hematological disorders at high risk of progression to secondary acute myeloid leukemia (sAML). However, the mutational dynamics and clonal evolution underlying disease progression are poorly understood at present. To elucidate the mutational dynamics of pathways and genes occurring during the evolution to sAML, next generation sequencing was performed on 84 serially paired samples of MDS patients who developed sAML (discovery cohort) and 14 paired samples from MDS patients who did not progress to sAML during follow-up (control cohort). Results were validated in an independent series of 388 MDS patients (validation cohort). We used an integrative analysis to identify how mutations, alone or in combination, contribute to leukemic transformation. The study showed that MDS progression to sAML is characterized by greater genomic instability and the presence of several types of mutational dynamics, highlighting increasing (STAG2) and newly-acquired (NRAS and FLT3) mutations. Moreover, we observed cooperation between genes involved in the cohesin and Ras pathways in 15-20% of MDS patients who evolved to sAML, as well as a high proportion of newly acquired or increasing mutations in the chromatin-modifier genes in MDS patients receiving a disease-modifying therapy before their progression to sAML.

Background: Analyses of the genomic variation in the western Mediterranean population are being used to reveal its evolutionary history and to understand the molecular basis of particular diseases., Aim: To observe the β-thalassemia mutational spectrum in western Andalusia, Spain, in the context of the Mediterranean. In addition, associations between disease and neutral gene variants within the β-globin gene (HBB) were also evaluated., Subjects and Methods: This study included 63 unrelated individuals diagnosed with β-thalassemia. In addition, 97 unrelated, healthy subjects of the same territory were also analysed as proxies of the normal genetic background. Allele associations and population genetic structure analyses were performed using different methodologies., Results: Data have revealed a rather restricted spectrum of β-thalassemia mutations in the analysed sample. Although the detected variants fit well with the Mediterranean pattern, certain singularities support a structure of some specific β-thalassemia alleles. The IVSI-1 (G > A) shows a strong regionalisation. The spatial correlogram revealed a typically narrow wave structure, presumably linked to genetic isolation and genetic drift., Conclusions: The long history of endemic malaria in the study territory, the rather high consanguinity rates among its autochthonous population, and other demographic features have been used here to understand the western Andalusian β-thalassemia molecular portrait.

Severe traumatic brain injury (sTBI) remains prevalent in the young adult population. Indeed, far from descending, the incidence of sTBI remains high. One of the key bases of treatment is to avoid, detect and correct secondary injuries of systemic origin, which aggravate the primary lesion. Much of this can be achieved by maintaining an adequate physiological microenvironment allowing recovery of the damaged brain tissue. General care measures are nonspecific actions designed to meet that objective. The available guidelines on the management of sTBI have not included the topics contemplated in this consensus. In this regard, a group of members of the Latin American Brain Injury Consortium (LABIC), involved in the different aspects of the acute management of sTBI (neurosurgeons, intensivists, anesthesiologists, neurologists, nurses and physiotherapists) were gathered. An exhaustive literature search was made of selected topics in the LILACS, PubMed, Embase, Scopus, Cochrane Controlled Register of Trials and Web of Science databases. To establish recommendations or suggestions with their respective strength or weakness, the GRADE methodology (Grading of Recommendations, Assessment, Development and Evaluation) was applied. Additionally, certain recommendations (included in complementary material) were not assessed by GRADE, because they constitute a set of therapeutic actions of effective compliance, in which it was not possible to apply the said methodology. Thirty-two recommendations were established, 16 strong and 16 weak, with their respective levels of evidence. This consensus attempts to standardize and establish basic general care measures in this particular patient population., (Copyright © 2020 Elsevier España, S.L.U. y SEMICYUC. All rights reserved.)

Background and Aims: Ulcerative Colitis (UC) and Crohn's Disease (CD) have a major impact on quality of life and medical costs. The aim of the study was to estimate the prevalence, incidence and clinical phenotypes of Inflammatory Bowel Disease (IBD) cases in Mexico and Colombia., Methods: We analyzed official administrative and health databases, used mathematical modelling to estimate the incidence and complete prevalence, and performed a case-series of IBD patients at a referral center both in Mexico and Colombia., Results: The age-adjusted complete prevalence of UC per 100,000 inhabitants for 2015/2016 ranged from 15.65 to 71.19 in Mexico and from 27.40 to 69.97 in Colombia depending on the model considered. The prevalence of CD per 100,000 inhabitants in Mexico ranged from 15.45 to 18.08 and from 16.75 to 18.43 in Colombia. In Mexico, the age-adjusted incidence of UC per 100,000 inhabitants per year ranged from 0.90 to 2.30, and from 0.55 to 2.33 in Colombia. The incidence for CD in Mexico ranged from 0.35 to 0.66 whereas in Colombia, the age-adjusted incidence of CD ranged from 0.30 to 0.57. The case-series included 200 IBD patients from Mexico and 204 patients from Colombia. The UC/CD prevalence ratio in Mexico and Colombia was 1.50:1 and 4.5:1 respectively. In Mexico, the female/male prevalence ratio for UC was 1.50:1 and 1.28:1 for CD, while in Colombia this ratio was 0.68:1 for UC and 0.8:1 for CD. In Mexico the relapse rate for UC was 63.3% and 72.5% for CD, while those rates in Colombia were 58.2% for UC and 58.3% for CD., Conclusions: The estimated burden of disease of IBD in Mexico and Colombia is not negligible. Although these findings need to be confirmed by population-based studies, they are useful for decision-makers, practitioners and patients with this condition., Competing Interests: This work was funded by Janssen-Cilag Pharmaceutical. This does not alter our adherence to PLOS ONE policies on sharing data and materials. In the synthesis of the main results of the study as well as in the development of the writing of the manuscript did not interfere any interest. In addition to this, the present study is of the epidemiological type, where the main results are related to the estimation of prevalence and incidence of the disease, so we consider that it is still difficult for them to be influenced by interests outside those of the main researchers. There are no patents, products in development or marketed products evaluated in this research to declare.

Background: In B-cell precursor acute lymphoblastic leukaemia (B-ALL), the identification of additional genetic alterations associated with poor prognosis is still of importance. We determined the frequency and prognostic impact of somatic mutations in children and adult cases with B-ALL treated with Spanish PETHEMA and SEHOP protocols., Methods: Mutational status of hotspot regions of TP53, JAK2, PAX5, LEF1, CRLF2 and IL7R genes was determined by next-generation deep sequencing in 340 B-ALL patients (211 children and 129 adults). The associations between mutation status and clinicopathological features at the time of diagnosis, treatment outcome and survival were assessed. Univariate and multivariate survival analyses were performed to identify independent prognostic factors associated with overall survival (OS), event-free survival (EFS) and relapse rate (RR)., Results: A mutation rate of 12.4% was identified. The frequency of adult mutations was higher (20.2% vs 7.6%, P=0.001). TP53 was the most frequently mutated gene (4.1%), followed by JAK2 (3.8%), CRLF2 (2.9%), PAX5 (2.4%), LEF1 (0.6%) and IL7R (0.3%). All mutations were observed in B-ALL without ETV6-RUNX1 (P=0.047) or BCR-ABL1 fusions (P<0.0001). In children, TP53mut was associated with lower OS (5-year OS: 50% vs 86%, P=0.002) and EFS rates (5-year EFS: 50% vs 78.3%, P=0.009) and higher RR (5-year RR: 33.3% vs 18.6% P=0.037), and was independently associated with higher RR (hazard ratio (HR)=4.5; P=0.04). In adults, TP53mut was associated with a lower OS (5-year OS: 0% vs 43.3%, P=0.019) and a higher RR (5-year RR: 100% vs 61.4%, P=0.029), whereas JAK2mut was associated with a lower EFS (5-year EFS: 0% vs 30.6%, P=0.035) and a higher RR (5-year RR: 100% vs 60.4%, P=0.002). TP53mut was an independent risk factor for shorter OS (HR=2.3; P=0.035) and, together with JAK2mut, also were independent markers of poor prognosis for RR (TP53mut: HR=5.9; P=0.027 and JAK2mut: HR=5.6; P=0.036)., Conclusions: TP53mut and JAK2mut are potential biomarkers associated with poor prognosis in B-ALL patients.

Background: The structure of haplogroup H reveals significant differences between the western and eastern edges of the Mediterranean, as well as between the northern and southern regions. Human populations along the westernmost Mediterranean coasts, which were settled by individuals from two continents separated by a relatively narrow body of water, show the highest frequencies of mitochondrial haplogroup H. These characteristics permit the analysis of ancient migrations between both shores, which may have occurred via primitive sea crafts and early seafaring. We collected a sample of 750 autochthonous people from the southern Iberian Peninsula (Andalusians from Huelva and Granada provinces). We performed a high-resolution analysis of haplogroup H by control region sequencing and coding SNP screening of the 337 individuals harboring this maternal marker. Our results were compared with those of a wide panel of populations, including individuals from Iberia, the Maghreb, and other regions around the Mediterranean, collected from the literature., Results: Both Andalusian subpopulations showed a typical western European profile for the internal composition of clade H, but eastern Andalusians from Granada also revealed interesting traces from the eastern Mediterranean. The basal nodes of the most frequent H sub-haplogroups, H1 and H3, harbored many individuals of Iberian and Maghrebian origins. Derived haplotypes were found in both regions; haplotypes were shared far more frequently between Andalusia and Morocco than between Andalusia and the rest of the Maghreb. These and previous results indicate intense, ancient and sustained contact among populations on both sides of the Mediterranean., Conclusions: Our genetic data on mtDNA diversity, combined with corresponding archaeological similarities, provide support for arguments favoring prehistoric bonds with a genetic legacy traceable in extant populations. Furthermore, the results presented here indicate that the Strait of Gibraltar and the adjacent Alboran Sea, which have often been assumed to be an insurmountable geographic barrier in prehistory, served as a frequently traveled route between continents.

Background: Chronic lymphocytic leukemia (CLL) is a highly genetically heterogeneous disease. Although CLL has been traditionally considered as a mature B cell leukemia, few independent studies have shown that the genetic alterations may appear in CD34+ hematopoietic progenitors. However, the presence of both chromosomal aberrations and gene mutations in CD34+ cells from the same patients has not been explored., Methods: Amplicon-based deep next-generation sequencing (NGS) studies were carried out in magnetically activated-cell-sorting separated CD19+ mature B lymphocytes and CD34+ hematopoietic progenitors (n = 56) to study the mutational status of TP53, NOTCH1, SF3B1, FBXW7, MYD88, and XPO1 genes. In addition, ultra-deep NGS was performed in a subset of seven patients to determine the presence of mutations in flow-sorted CD34+CD19- early hematopoietic progenitors. Fluorescence in situ hybridization (FISH) studies were performed in the CD34+ cells from nine patients of the cohort to examine the presence of cytogenetic abnormalities., Results: NGS studies revealed a total of 28 mutations in 24 CLL patients. Interestingly, 15 of them also showed the same mutations in their corresponding whole population of CD34+ progenitors. The majority of NOTCH1 (7/9) and XPO1 (4/4) mutations presented a similar mutational burden in both cell fractions; by contrast, mutations of TP53 (2/2), FBXW7 (2/2), and SF3B1 (3/4) showed lower mutational allele frequencies, or even none, in the CD34+ cells compared with the CD19+ population. Ultra-deep NGS confirmed the presence of FBXW7, MYD88, NOTCH1, and XPO1 mutations in the subpopulation of CD34+CD19- early hematopoietic progenitors (6/7). Furthermore, FISH studies showed the presence of 11q and 13q deletions (2/2 and 3/5, respectively) in CD34+ progenitors but the absence of IGH cytogenetic alterations (0/2) in the CD34+ cells. Combining all the results from NGS and FISH, a model of the appearance and expansion of genetic alterations in CLL was derived, suggesting that most of the genetic events appear on the hematopoietic progenitors, although these mutations could induce the beginning of tumoral cell expansion at different stage of B cell differentiation., Conclusions: Our study showed the presence of both gene mutations and chromosomal abnormalities in early hematopoietic progenitor cells from CLL patients.

To explore novel genetic abnormalities occurring in myelodysplastic syndromes (MDS) through an integrative study combining array-based comparative genomic hybridization (aCGH) and next-generation sequencing (NGS) in a series of MDS and MDS/myeloproliferative neoplasms (MPN) patients. 301 patients diagnosed with MDS (n = 240) or MDS/MPN (n = 61) were studied at the time of diagnosis. A genome-wide analysis of DNA copy number abnormalities was performed. In addition, a mutational analysis of DNMT3A, TET2, RUNX1, TP53 and BCOR genes was performed by NGS in selected cases. 285 abnormalities were identified in 71 patients (23.6%). Three high-risk MDS cases (1.2%) displayed chromothripsis involving exclusively chromosome 13 and affecting some cancer genes: FLT3, BRCA2 and RB1. All three cases carried TP53 mutations as revealed by NGS. Moreover, in the whole series, the integrative analysis of aCGH and NGS enabled the identification of cryptic recurrent deletions in 2p23.3 (DNMT3A; n = 2.8%), 4q24 (TET2; n = 10%) 17p13 (TP53; n = 8.5%), 21q22 (RUNX1; n = 7%), and Xp11.4 (BCOR; n = 2.8%), while mutations in the non-deleted allele where found only in DNMT3A (n = 1), TET2 (n = 3), and TP53 (n = 4). These cryptic abnormalities were detected mainly in patients with normal (45%) or non-informative (15%) karyotype by conventional cytogenetics, except for those with TP53 deletion and mutation (15%), which had a complex karyotype. In addition to well-known copy number defects, the presence of chromothripsis involving chromosome 13 was a novel recurrent change in high-risk MDS patients. Array CGH analysis revealed the presence of cryptic abnormalities in genomic regions where MDS-related genes, such as TET2, DNMT3A, RUNX1 and BCOR, are located., Competing Interests: The authors have declared no competing financial interests. AK: current employment by AstraZeneca. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Informal caregivers are crucial members of the teams that care for palliative patients with cancer, including those with oncohematological malignancies. Publications concerning specific aspects of this latter group of carers are limited. This literature review indicates that palliative oncohematologic patients' caregivers do not differ from those of patients with solid tumors in ethical and related problems. However, there are specific problems for the former group with regard to negotiating the curative system, which are experienced as distressing, often without support from the health system and without offers of the possibility of being referred to palliative teams that they would have valued as very positive. Although this tendency seems to be changing, there is still considerable work to be done to improve the role of these carers., (© The Author(s) 2015.)

Deletion 13q (13q-) is the most common cytogenetic aberration in chronic lymphocytic leukemia (CLL) and is associated with the most favorable prognosis as the sole cytogenetic abnormality. However, it is heterogeneous whereby CLL patients with higher percentages of 13q- cells (13q-H) have a more aggressive clinical course and a distinct gene expression profile. The microRNA (miRNA) expression profile of CLL gives additional biological and prognostic information, but its expression in 13q- CLL has not been examined in detail. The miRNA expression of clonal B cell lymphocytes (CD19+ cells) of 38 CLL patients and normal B cells of six healthy donors was analyzed. CLL patients with higher percentages of 13q- cells (≥80%) showed a different level of miRNA expression from patients with lower percentages (<80%). Interestingly, miR-143 was downregulated and miR-155 was overexpressed in 13q-H. This deregulation affected important validated target genes involved in apoptosis (BCL2, MDM2, TP53INP1) and proliferation (KRAS, PI3K-AKT signaling), that could lead to decreased apoptosis and increased proliferation in 13q-H patients. This study provides new evidence about the heterogeneity of the 13q deletion in CLL patients, showing that miRNA regulation could be involved in several significant pathways deregulated in CLL patients with a high number of losses in 13q., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Unlabelled: Identifying additional genetic alterations associated with poor prognosis in acute lymphoblastic leukemia (ALL) is still a challenge., Aims: To characterize the presence of additional DNA copy number alterations (CNAs) in children and adults with ALL by whole-genome oligonucleotide array (aCGH) analysis, and to identify their associations with clinical features and outcome. Array-CGH was carried out in 265 newly diagnosed ALLs (142 children and 123 adults). The NimbleGen CGH 12x135K array (Roche) was used to analyze genetic gains and losses. CNAs were analyzed with GISTIC and aCGHweb software. Clinical and biological variables were analyzed. Three of the patients showed chromothripsis (cth6, cth14q and cth15q). CNAs were associated with age, phenotype, genetic subtype and overall survival (OS). In the whole cohort of children, the losses on 14q32.33 (p = 0.019) and 15q13.2 (p = 0.04) were related to shorter OS. In the group of children without good- or poor-risk cytogenetics, the gain on 1p36.11 was a prognostic marker independently associated with shorter OS. In adults, the gains on 19q13.2 (p = 0.001) and Xp21.1 (p = 0.029), and the loss of 17p (p = 0.014) were independent markers of poor prognosis with respect to OS. In summary, CNAs are frequent in ALL and are associated with clinical parameters and survival. Genome-wide DNA copy number analysis allows the identification of genetic markers that predict clinical outcome, suggesting that detection of these genetic lesions will be useful in the management of patients newly diagnosed with ALL.

Determining the timing, identity and direction of migrations in the Mediterranean Basin, the role of "migratory routes" in and among regions of Africa, Europe and Asia, and the effects of sex-specific behaviors of population movements have important implications for our understanding of the present human genetic diversity. A crucial component of the Mediterranean world is its westernmost region. Clear features of transcontinental ancient contacts between North African and Iberian populations surrounding the maritime region of Gibraltar Strait have been identified from archeological data. The attempt to discern origin and dates of migration between close geographically related regions has been a challenge in the field of uniparental-based population genetics. Mitochondrial DNA (mtDNA) studies have been focused on surveying the H1, H3 and V lineages when trying to ascertain north-south migrations, and U6 and L in the opposite direction, assuming that those lineages are good proxies for the ancestry of each side of the Mediterranean. To this end, in the present work we have screened entire mtDNA sequences belonging to U6, M1 and L haplogroups in Andalusians--from Huelva and Granada provinces--and Moroccan Berbers. We present here pioneer data and interpretations on the role of NW Africa and the Iberian Peninsula regarding the time of origin, number of founders and expansion directions of these specific markers. The estimated entrance of the North African U6 lineages into Iberia at 10 ky correlates well with other L African clades, indicating that U6 and some L lineages moved together from Africa to Iberia in the Early Holocene. Still, founder analysis highlights that the high sharing of lineages between North Africa and Iberia results from a complex process continued through time, impairing simplistic interpretations. In particular, our work supports the existence of an ancient, frequently denied, bridge connecting the Maghreb and Andalusia.

Background: The APOE gene has received much attention due to the remarkable spatial variation patterns of some of its genotypes and alleles in human populations and to its relevance in biomedicine., Aim: This work was addressed to investigate the extent of APOE polymorphism between autochthonous Andalusians originating from Huelva and Granada provinces. No data on this marker in these southern Spanish coastal populations are available up to date., Subjects and Methods: This study used genomic DNA from healthy, unrelated Andalusians of both sexes (n = 322). All samples were genotyped for two SNPs, rs429358 and rs7412, which determine the three APOE alleles: ε2, ε3 and ε4. For analyses, a TaqMan-based technique was applied using a RT-PCR. Comparisons with other Mediterranean populations were performed based on multivariate analysis., Results: A relatively high frequency of ε4 in Granada (eastern Andalusia), as well as a low ε2 frequency in Huelva (western Andalusia) were observed. The finding that ε4 allele in Southern Spain and Portugal is higher than expected given its geographical location poses an interesting question for this study, given the well-established APOE-ε4 gradient in Europe., Conclusion: This population study may represent useful information for further prospective anthropological and molecular genetic studies focused on unravelling the relationship between population genetic composition and specific human diseases.

Introduction: Patients with cystic fibrosis (CF) present lower airway infection with Pseudomonas aeruginosa. Treatment of initial infection is fundamental to reduce subsequent damage., Material and Methods: We evaluated the efficacy of eradication treatment of P. aeruginosa in patients with CF from northeast Mexico using two protocols: inhaled colistin/oral ciprofloxacin and nebulized tobramycin 300 mg/oral ciprofloxacin. The intervention group included 17 patients with CF and recent infection with P. aeruginosa. The control group consisted of 23 chronically colonized patients of comparable age., Results: Patients received 27 courses of eradication treatment. P. aeruginosa was eradicated in 21/27 (77.77%). The infection free period was 16.9, 11.7 months (colistin) and 17 ± 9.7 months (tobramycin) with no statistically significant difference (P = 0.97)., Conclusions: Treated patients maintained normal lung function, better nutritional status, and a better chest X-ray score. In the control group 17/23 (73.9%) patients died with no deaths in the study group.

Background: The archeology and history of the ancient Mediterranean have shown that this sea has been a permeable obstacle to human migration. Multiple cultural exchanges around the Mediterranean have taken place with presumably population admixtures. A gravitational territory of those migrations has been the Iberian Peninsula. Here we present a comprehensive analysis of the maternal gene pool, by means of control region sequencing and PCR-RFLP typing, of autochthonous Andalusians originating from the coastal provinces of Huelva and Granada, located respectively in the west and the east of the region., Results: The mtDNA haplogroup composition of these two southern Spanish populations has revealed a wide spectrum of haplogroups from different geographical origins. The registered frequencies of Eurasian markers, together with the high incidence and diversification of African maternal lineages (15% of the total mitochondrial variability) among Huelva Andalusians when compared to its eastwards relatives of Granada and other Iberian populations, constitute relevant findings unknown up-to-date on the characteristics of mtDNA within Andalusia that testifies a female population substructure. Therefore, Andalusia must not be considered a single, unique population., Conclusions: The maternal legacy among Andalusians reflects distinctive local histories, pointing out the role of the westernmost territory of Peninsular Spain as a noticeable recipient of multiple and diverse human migrations. The obtained results underline the necessity of further research on genetic relationships in both sides of the western Mediterranean, using carefully collected samples from autochthonous individuals. Many studies have focused on recent North African gene flow towards Iberia, yet scientific attention should be now directed to thoroughly study the introduction of European genes in northwest Africa across the sea, in order to determine its magnitude, timescale and methods, and to compare them to those terrestrial movements from eastern Africa and southwestern Asia.

Background: Transfusion is not an exceptional circumstance in palliative cancer patients (PCPs). This makes it necessary to confront not only medical aspects but also those of infrastructure and ethical issues. On some occasions, literature needs to be consulted to work out the best approach in a patient's particular case. Our aim was to review the literature contained in PubMed and EMBASE so as to find out about the information available on transfusion in PCPs., Methods: A search for literature was carried out in databases PubMed and EMBASE, using "transfusion," "cancer," "end-of-life care," "terminal care," and "palliative care" as key words. Publications were classified according to the main topic discussed (clinical, infrastructure, and ethics) and the information included in each article critically assessed., Results: We found 334 articles but only 43 were considered valuable for the present study. Of these 43 articles, 21 deal with clinical topics while 12 deal with infrastructure and 10 with ethical issues. There is an absolute lack of randomized controlled trials or clinical guidelines. Trigger parameters for transfusion are not clearly established. Benefits of the procedure are shortly experienced and remain controversial. Home transfusions are encouraged, but this sole procedure has not been demonstrated to be cost effective. Different cultures, cases, and realities illustrate the diversity of the ethical management of transfusion in PCPs., Discussion: Although transfusion is certainly a common practice in PCPs, there is a relative lack of literature on this topic. Publications are unconnected and hardly any prospective studies have been performed. A large part of the little literature available only concerns descriptive and very general aspects of the issue. As transfusional products and financial and human resources are finite, it would be desirable to establish clear research lines on the different aspects considered (clinical, infrastructure, and ethical) that can help clinicians, nurses, patients, and carers to make a decision.

The prognostic impact of the aberrant hypermethylation in response to azacytidine (AZA) remains to be determined. Therefore, we have analyzed the influence of the methylation status prior to AZA treatment on the overall survival and clinical response of myeloid malignancies. DNA methylation status of 24 tumor suppressor genes was analyzed by methylation-specific multiplex ligation-dependent probe amplification in 63 patients with myelodysplastic syndromes and acute myeloid leukemia treated with azacytidine. Most patients (73 %) showed methylation of at least one gene, but only 12 % of patients displayed ≥3 methylated genes. The multivariate analysis demonstrated that the presence of a high number (≥2) of methylated genes (P = 0.022), a high WBC count (P = 0.033), or anemia (P = 0.029) were independent prognostic factors associated with shorter overall survival. The aberrant methylation status did not correlate with the response to AZA, although four of the five patients with ≥3 methylated genes did not respond. By contrast, favorable cytogenetics independently influenced the clinical response to AZA as 64.7 % of patients with good-risk cytogenetic abnormalities responded (P = 0.03). Aberrant methylation status influences the survival of patients treated with AZA, being shorter in those patients with a high number of methylated genes.

There is barely any information about the prognostic significance of FLT3 expression and mutational status in cytogenetically distinct subgroups of acute lymphoblastic leukemia (ALL). We analyzed the presence of FLT3-tyrosine kinase domain (TKD) and FLT3-internal tandem duplication (ITD) mutations as well as FLT3 expression levels in 54 newly diagnosed patients with B-ALL (n=49) or T-ALL (n=5). All B/T-ALL samples tested negative for the presence of FLT3-TKD or FLT3-ITD. None of the T-ALL and E2A-PBX1+ B-ALL overexpressed FLT3. In contrast, mainly MLL-AF4+ B-ALL but also ETV6-RUNX1+, BCR-ABL+ or B-ALL displaying normal cytogenetics exhibited significantly higher FLT3 expression levels than normal bone marrow, supporting that aberrantly increased transcription of FLT3, rather than activating FLT3 mutations, contributes to the pathogenesis of these B-ALL. Using the median FLT3 expression as cut-off value we found that high-level FLT3 expression is associated with an extremely poor 1-year overall survival (OS; 0 vs 71%; P=0.002) and disease-free survival (DFS; 0 vs 43%; P=0.03) in MLL-AF4+ B-ALL but not in MLL-germline B-ALL. Cox regression analysis with OS/DFS as end points showed that age>14 years and high-level FLT3 expression were independent prognostic factors when all ALL patients were analyzed together. Importantly, when the MLL-AF4+ B-ALL subgroup was analyzed separately, high-level FLT3 expression was the only independent prognostic factor for OS and treatment outcome. These findings indicate that high FLT3 expression identifies MLL-AF4+ ALL patients at very high risk of treatment failure and poor survival, emphasizing the value of ongoing/future clinical trials for FLT3 inhibitors.

Idiopathic hypereosinophilic syndrome (HES) is a rare disorder characterized by unexplained, persistent hypereosinophilia associated with multiple organ dysfunctions. The cause of HES is unknown and shows clinical heterogeneity. FIP1L1-PDGFRA fusion is a clonal marker for the diagnosis and treatment of HES. We prospectively studied 78 patients with chronic eosinophilia. In all cases, the most salient clinical and biological characteristics as well as the response to the therapy were analyzed. In addition, we performed conventional cytogenetics and fluorescent in situ hybridization (FISH) with three BACs covering the FIP1-like-1 (FIP1L1)/platelet-derived growth factor receptor-α gene (PDGFRA) fusion. Nineteen of 78 patients (24 %) presented criteria of HES. The majority of patients were male (18) with median age of 49 years (range 19-84 years). FIP1L1-PDGFRA fusion was found in eight patients. Patients with FIP1L1-PDGFRA fusion presented with more bone marrow eosinophils and peripheral blood eosinophilia as well as anemia, leukocytosis and thrombocytopenia. Using of low-dose imatinib mesylate (100 mg/day) a hematological and molecular remission in all patients displaying the FIP1L1-PDGFRA fusion gene was observed. Therefore, imatinib may be effective for use in the treatment of chronic eosinophilic leukemia, and patients should be treated before tissue damage.

Objective: To evaluate the effectiveness and safety of the FLAG-IDA regimen in patients with acute refractory and/or recurrent leukaemia., Method: Descriptive, retrospective, observational study of the clinical histories of patients with the FLAG-IDA regimen during the period of 2005-2010. Effectiveness was measured using objective response, progression-free interval, and global survival. Safety was measured using the NCI classification system of common toxicity criteria for adverse events., Results: We registered 12 patients (52.17±8.26 years in women, and 54.83±7.22 years in men), 11 cases were acute myeloid leukaemia (5 refractory, 3 in recurrence, 1 secondary to chronic refractory myeloid leukaemia (CML) and 2 secondary to myelodysplastic syndrome (MDS), one of which was refractory and the other had not been previously treated) and one case was acute refractory lymphoblastic leukaemia (ALL). Six patients (50%) reached a complete response (CR). One patient reached a partial response (PR), which was followed by another protocol that produced a CR, two died due to disease progression, and three due to secondary complications from treatment. The progression-free interval for patients that reached a CR was 24.38 weeks (6 months). Median global survival was 8.4 weeks. Mean time needed for the recovery of neutropenia was 23 and 37 days in the first and second cycle, respectively. The mean time required for recuperation of thrombocytopenia was 24 and 35 days in each cycle., Conclusions: The FLAG-IDA induction regimen for the treatment of high-risk leukaemia patients is an established protocol, with good tolerance and acceptable toxicity levels that offers an opportunity for facilitating the transplantation of haematopoietic progenitors., (Copyright © 2010 SEFH. Published by Elsevier Espana. All rights reserved.)

We evaluated the clinical results of lenalidomide (Len) as a compassionate salvage therapy in refractory/relapsed multiple myeloma (MM) patients. A nationwide multi-centre, retrospective research study was performed to evaluate clinical data from patients with advanced MM for which compassionate use of lenalidomide was requested. The primary endpoints were the overall response rate (ORR) and the time to progression (TTP). Secondary objectives included safety and overall survival (OS) since starting of lenalidomide therapy. Data collected from the Spanish Compassionate Use Registry included 111 patients treated in 2006-2008. The median (range) number of previous treatment lines was 3 (1-8). The median duration of lenalidomide treatment while on study was of 4.9 months (1-18). Dexamethasone was given concomitantly with Len in 89% of patients. The ORR was 66% (4% of patients had stringent complete, 11% complete and 11% very good partial responses). Median TTP and OS were 13.0 and 17.4 months, respectively. The depth of response was significantly associated with a longer OS. Toxicity, mainly myelosuppression, was predictable and manageable with Len dose adjustments and cytokine support. Lenalidomide as salvage compassionate therapy in refractory/relapsed MM showed, in this series of heavily pre-treated patients, similar efficacy to that reported in pivotal clinical trials with acceptable tolerance.

Wautersia eutropha was able to synthesize medium chain length polyhydroxyalkanoates (PHAs) when canola oil was used as carbon source. W. eutropha was cultivated using fructose and ammonium sulphate as carbon and nitrogen sources, respectively, for growth and inoculum development. The experiments were done in a laboratory scale bioreactor in three stages. Initially, the biomass was adapted in a batch culture. Secondly, a fed-batch was used to increase the cell dry weight and PHA concentration to 4.36 g L(-1) and 0.36 g L(-1), respectively. Finally, after the addition of canola oil as carbon source a final concentration of 18.27 g L(-1) PHA was obtained after 40 h of fermentation. With canola oil as carbon source, the polymer content of the cell dry matter was 90%. The polymer was purified from dried cells and analyzed by FTIR, NMR and DSC using PHB as reference. The polymer produced by W. eutropha from canola oil had four carbon monomers in the structure of the PHA and identified by 1H and 13C NMR analysis as 3-hydroxybutyrate (3HB), 3-hydroxyvalerate (3HV), 3-hydroxyoctanoate (3HO), and 3-hydroxydodecanoate (3HDD)., (Copyright © 2010 Elsevier B.V. All rights reserved.)

This study investigates the population structure of the Tucunaré (Cichla pleiozona) in the Bolivian Amazon (Upper Madera) by using nuclear (EPIC-PCR, 67 individuals) and mitochondrial (Control Region, 41 published and 76 new sequences) DNA analyses, in relation with ecological (water quality: muddy, clear and mix) and geographic factors. Our analyses of both markers showed the highest diversity in clear waters (Yata, Middle and Upper Iténez), and the existence of two populations in muddy waters (Sécure and Ichilo) and one in mix waters (Manuripi). On the other hand, mitochondrial analyses identified three populations in clear waters where nuclear analyses identified a panmictic population. The highest diversity observed in the Yata-Iténez system suggests that an aquatic refuge occurred during the past in this area. The possible explanations for the observed discrepancy between nuclear and mitochondrial markers are discussed, and a sex-biased dispersal seems to be the most plausible hypothesis in the light of the available information and field observations., (Copyright © 2010 Elsevier Inc. All rights reserved.)

This study aims at a high-resolution analysis of Y-chromosome J and E haplogroups among Andalusians to reconstruct Neolithic, protohistorical and historical migrations in the Mediterranean region. Genotyping of two samples from Granada (n=250 males) and Huelva (n=167 males) (Spain) with Y-chromosome binary and microsatellite markers was performed, and the results compared with other Mediterranean populations. The two samples showed genetic differences that can be associated with different evolutionary processes. Migrations toward Andalusia probably originated in the Arabian Peninsula, Fertile Crescent, Balkan region and North Africa, and they would have predominantly occurred in protohistoric and historic times. Maritime travel would have notably contributed to recent gene flow into Iberia. This survey highlight the complexity of the Mediterranean migration processes and demonstrate the impact of the different population sources on the genetic composition of the Spanish population. The main in-migrations to Iberia most likely did not occur through intermediate stages or, if such stages did occur, they would have been very few.

We have analyzed brain and acute leukemia, cytoplasmic (BAALC) gene expression and other genetic markers (ERG, EVI1, MN1, PRAME, WT1, FLT3, and NPM1 mutations) in 127 intermediate-risk acute myeloid leukemia (AML) patients: 98 cytogenetically normal and 29 with intermediate-risk cytogenetic alterations. High versus low BAALC expressers showed a higher refractoriness to induction treatment (31% vs 10%; p = .005), lower complete remission rate after salvage therapy (82% vs 97%; p = .010), and lower 3-year overall (23% vs 58%, p < .001) and relapse-free survival (26% vs 52%, p = .006). Similar results were found when cytogenetic subgroups were analyzed separately. Multivariate models confirmed the unfavorable prognosis of this marker. In conclusion, BAALC is a relevant prognostic marker in intermediate-risk AML.

Background: Gene flow among human populations is generally interpreted in terms of complex patterns, with the observed gene frequencies being the consequence of the entire genetic and demographic histories of the population., Aims: This study performs a high-resolution analysis of the Y-chromosome haplogroup E in Western Andalusians (Huelva province). The genetic information presented here provides new insights into migration processes that took place throughout the Mediterranean space and tries to evaluate its impact on the current genetic composition of the most southwestern population of Spain., Subjects and Methods: 167 unrelated males were previously typed for the presence/absence of the Y-chromosome Alu polymorphism (YAP). The group of YAP (+) Andalusians was genotyped for 16 Y-SNPs and also characterized for 16 Y-STR loci., Results: The distribution of E-M81 haplogroup, a Berber marker, was found at a frequency of 3% in our sample. The distribution of M81 frequencies in Iberia seems to be not concordant with the regions where Islamic rule was most intense and long-lasting. The study also showed that most of M78 derived allele (6.6%) led to the V13* subhaplogroup. We also found the most basal and rare paragroup M78* and others with V12 and V65 mutations. The lineage defined by M34 mutation, which is quite frequent in Jews, was detected as well., Conclusions: The haplogroup E among Western Andalusians revealed a complex admixture of genetic markers from the Mediterranean space, with interesting signatures of populations from the Middle East and the Balkan Peninsula and a surprisingly low influence by Berber populations compared to other areas of the Iberian Peninsula.

Tyrosinase shows a lag period in its action on monophenols (l-tyrosine). We propose an approximate analytical solution for the lag period, which fulfils the dependences with regard to initial enzyme concentration, and initial monophenol concentration. Furthermore, from a study of the dependences of the lag period on these variables, we can determine experimentally the o-diphenol concentration in the steady state. The Michaelis constant of the o-diphenol in the presence of the monophenol can be determined from the relationship between the o-diphenol concentration in the steady state and the initial monophenol concentration, taking into consideration the experimentally calculated Michaelis constant for the monophenol substrate. Although this Michaelis constant is much lower than the Michaelis constant for diphenol in the absence of monophenol, the binding site is the same. A kinetic analysis of the action mechanism of tyrosinase explains this difference in the values of the Michaelis constants.

Purpose: Patients are frequently referred to the haematologist to be studied due to the presence of processes that are not properly haematological. We have studied the group of outpatients with non-oncohaematological pathologies referred to our external haematology clinic to evaluate their knowledge about the reason for consultation, the existence or not of worry upation and its degree at the arrival., Patients and Methods: We have made a prospective study including all patients with non-oncohaematological processes (n = 204) who were referred for the first time to our external consultation between April and October 1997. We evaluated in each patient, using an inquest, the following data: age, sex, origin (hospital consultations or urban or rural health centres), reason for consultation, knowledge of the reason for consultation (yes/partially/no), existence or not of worry (yes/no) and when present, its degree (low, moderate, high). The inquiry was made to the parents in those patients aged under 12 years. We have analyzed all adults, each group of adult patients (rural, urban, hospital) separately and compared one group to each other, all pediatric patients and we have compared as well the overall results obtained with adult patients with those from the parents of pediatric patients., Results: 1) Adult patients (n = 169; 78 referred from hospital, 59 from urban and 32 from rural health centres): with respect to the knowledge of the reason for consultation 49.7% of them knew it perfectly, 20.1% partially, and 30.2% did not know about it. 48.5% of patients arrived worried to the clinic, 16.6% of them with a high degree, 17.8% moderate and 14.2% low. 2) Adults referred from primary health care (urban versus rural health centres): We have found neither significant differences in the knowledge of the reason for consultation, worry or its degree with respect to age, sex or origin (urban or rural), nor in the worry or its degree with respect to the patient knowledge of the reason for consultation. 3) Adults referred from other hospital units: The mean age of patients who knew the reason for consultation was significatively lower than that observed in the group who did not (respectively 43.3 and 57 years) (p = 0.003). These differences did not exist with respect to sex. Differences in the existence or not of worry with respect to sex were almost significant, women arrive more worried than men (57.1% and 31.8% respectively, p = 0.07). No significant differences were found in the existence or not of worry and its degree with respect to age or knowledge of the reason for consultation. 4) Comparison between both groups of adults patients (hospital consultation and health centres): No significant differences in the knowledge of the reason for consultation, existence or not of worry and its degree have been found with respect to the other parameters studied. 5) Paediatric patients (n = 35; 8 referred from hospital, 14 from urban and 13 rural health centres): With respect to the knowledge of the reason for consultation 62.9% of them knew it perfectly, 17.1% partially and 20% did not know about it. 80% of patients' parents arrived worried at consultation, 45.7% with a high degree, 20% moderate and 14.3% low. 6) Comparison between paediatrics and adult patients: we have only found significative differences in the existence or not of worry (80% and 48.5% respectively, p = 0.001) and its degree (65.7% of parents with moderate or high worry and 34.4% of adults, p = 0.0004). Parents of paediatric patients arrive at our consultation more worried and with a higher worry degree than the other adults., Conclusion: We consider that patients referred to our external consultation of haematology for the first time arrive with a poor knowledge of their reason for consultation. This observation does not seem to have any relation with age, sex or origin (hospital consultations, urban or rural health centres). (ABSTRACT TRUNCATED)

Background and Objective: Experience with recombinant human erythropoietin (rHuEPO) in the treatment of the anemia secondary to myelofibrosis with myeloid metaplasia (MMM) is slight up to now. We present our results of the treatment of 6 patients and a review of the literature in search of possible parameters predicting response to this treatment., Design and Methods: From January 1994 to June 1996 all transfusion-dependent patients with MMM diagnosed in our hospital were included in this study. We established a minimum period of 4 weeks of treatment and a maximum of 12 if no response was observed. Initial dosages used were 100 U/kg s.c. 3 times weekly, increasing by 50 U/kg every 4 weeks where no response was observed. Response was defined as a reduction > or = 30% of the previous transfusional needs. The review of the literature was made using a MEDLINE search (January 1990-December 1996) on the keywords erythropoietin, myelofibrosis, and agnogenic myeloid metaplasia. A statistical study was made in search of possible parameters to predict response. The parameters studied include age, sex, hemoglobin, serum erythropoietin (sEPO) levels, transfusional dependency, transfusional requirements per month prior to treatment, maximum dosages used and dosage at which response was obtained., Results: Only 2 of our 6 patients responded, both at a dosage of 600 U/kg/week (200 U/kg 3 times weekly s.c.). In addition to our 6 patients we have found only 28 other patients in the literature. For statistical calculation 2 of our patients were not considered as they did not complete the period of study. The overall rate of response was 17/32 (53.1%). In the univariate analysis comparing responders and non-responders we found a tendency to significance with respect to sex (p = 0.07), sEPO (p = 0.07) and transfusional needs in units of packed red blood cells per month (PRBC/m) (p = 0.13). In this way patients with low sEPO, females and those with low transfusional needs (< 3 PRBC/m) respond better. This better response in females could be explained by the fact that their disease situation was more stable (with both lower sEPO levels and transfusional dependency). The best cut-off point in the sEPO to predict response was 123 mU/mL. No important side-effects have been observed except three cases of aggravation of splenomegaly. In two cases this condition improved when the rHuEPO was discontinued. The association of rHuEPO with hydroxyurea or interferon does not seem to affect the response., Interpretation and Conclusions: Though the number of patients is low, our data suggest that some MMM patients, in particular females and individuals with low sEPO levels and with low transfusional needs, might benefit from rHuEPO in terms of elevation of hemoglobin levels. Unfortunately, transfusion dependent-patients, i.e. those in whom a beneficial effect of rHuEPO would be most welcome, are unlikely to respond, and more generally, treatment is not cost effective in medically responsive patients.

Purpose: The treatment of elderly patients with acute myeloid leukaemia (AML) remains controversial. We present the results of the treatment of a group of patients aged above 70 years with AML diagnosed in our Hospital since 1990., Patients and Methods: We have studied retrospectively the cases of AML in patients older than 70 years diagnosed in our Service since January 1990 to June 1996. Induction treatment was performed, in all cases but one, with two cycles of Ara-C 10 mg/m2/12 h s.c. for 21 days and after haematological recuperation, if complete remission had been achieved, monthly maintenance treatment with Ara-C (25 mg/m2/12 h oral x 5 days), prednisone (40 mg/m2/day x 5 days) y vincristine (1 mg/m2 i.v. x 1 day) was begun., Results: During the period of study 48 patients with AML have been diagnosed in our Service, among them 22 (45.8%) were older than 70 years. One of them could not be considered for the study as not all data from him could be compiled. Among the other 21 patients 5 presented previous haematological processes (4 myelodysplastic syndrome and 1 Waldenström's macroglobulinemia). Initial diagnosis according to FAB classification for AML was as follows: 7 M1, 6 M2, 4 M4, 2 M5 and 2 M6. From these 21 patients 2 received no treatment due to rapid progression and death, among the other 19, one was directly treated with a modification of the maintenance treatment with vincristine and prednisone without response (survival 2 months). The other 18 patients were treated with low-dose Ara-C (described above), among them 3 (16.7%) were not evaluable as they did not finish the first cycle of induction treatment; 8 (44.4%) showed no response; 2 (11.1%) achieved partial remission and 5 (27.8%) complete remission. One patient did not show any response after two cycles of low-dose Ara-C but she obtained complete remission when treated with Ara-C and idaurubicin. Overall mean survival was 5.7 months (median 2; 95% confidence interval 1.6-9.8 months). In the group of patients treated with low-dose Ara-C mean survival was 6.6 months (median 3.5; 95% confidence interval 1.9-11.2 months)., Conclusion: We consider that the treatment with low-dose Ara-C is a valid option in the treatment of elderly patients (aged 70 or above) with AML because 28% complete remissions can be achieved, specially in those ones in which other more aggressive treatments are not possible.