Background: The clonal basis of relapse in acute lymphoblastic leukemia (ALL) is complex and not fully understood. Methods: Next-generation sequencing (NGS), array comparative genomic hybridization (aCGH), and multiplex-ligation-dependent probe amplification (MLPA) were carried out in matched diagnosis-relapse samples from 13 B-cell precursor acute lymphoblastic leukemia (BCP-ALL) patients to identify patterns of genetic evolution that could account for the phenotypic changes associated with disease relapse. Findings: The integrative genomic analysis of aCGH, MLPA and NGS revealed that 100% of BCP-ALL patients showed at least one genetic alteration at diagnosis and relapse. In addition, there was a significant increase in the frequency of chromosomal lesions at the time of relapse (median, 6 alterations per sample) relative to that at diagnosis (median, 47 alterations) (p = 0.019). The combination of MLPA and aCGH techniques showed that IKZF1 was the most frequently deleted gene. Notably, TP53 was the most frequently mutated gene at relapse (31%). Two TP53 mutations were detected only at relapse, whereas the three others showed an increase of their mutational burden at relapse. Interpretation: Clonal evolution patterns were heterogeneous, involving acquisition, loss and maintenance of lesions at relapse. Therefore, this study confirmed that BCP-ALL is a genetically dynamic disease with distinct genetic profiles at diagnosis and relapse. The combination of the NGS, aCGH, and MLPA approaches enables better molecular characterization of the genetic profile in ALL patients during the evolution from diagnosis to relapse. Funding Statement: This work was supported in part by a grant from the Consejeria de Educacion, Junta de Castilla y Leon, Fondos FEDER (SA085U16, SA271P18), Proyectos de Investigacion de la Gerencia Regional de Sanidad, SACYL, (GRS 1847/A/18), Fundacion Castellano Leonesa de Hematologia y Hemoterapia (FUCALHH 2017), a grant to AM from the Junta Provincial de Salamanca of the Asociacion Espanola Contra el Cancer (AECC), a grant to MFC from the Universidad Pedagogica y Tecnologica de Colombia – Vicerrectoria de Investigacion y Extension (Grupo de Investigacion en Ciencias Biomedicas UPTC – GICBUPTC, Escuela de Ciencias Biologicas). M. Hernandez-Sanchez is supported by FEHH-Janssen (Sociedad Espanola de Hematologia y Hemoterrapia), and a grant to JR and JMR from Instituto Carlos III (PI14/01971). Declaration of Interests: The authors declare no conflict of interest. Ethics Approval Statement: The study was approved by the local ethical committee, the Comite Etico de Investigacion Clinica, at the Hospital Universitario de Salamanca. Written informed consent was obtained from each patient or their legal guardian before entering the study.

BackgroundSublingual allergen immunotherapy is an effective treatment against allergic respiratory disease. Many studies have shown the safety of this type of therapy, although the factors that might affect the tolerability of high-dose sublingual immunotherapy have not been well established. The aim of this study was to determine the factors that affect the tolerability of sublingual allergen immunotherapy.Patients and methodsA total of 183 subjects aged ≥5 years, diagnosed with allergic rhinitis with/without mild to moderate asthma due to sensitization to grass, olive pollen, or mites, were included in this open, retrospective, multicentric, noninterventional study. Sublingual immunotherapy was administered for at least 3 months.ResultsThe most frequent adverse reaction was oral pruritus (13.7% of the patients). Most of the reactions were local (84.7%) and immediate (93.5%) and occurred during the initiation phase (60.6%). All reactions were mild to moderate in severity. No serious adverse reactions were registered. When comparing factors with potential influence on the occurrence of adverse reactions, the results between the groups of subjects with and without adverse reactions showed no statistically significant differences in sex (P=0.6417), age (P=0.1801), years since the disease was first diagnosed (P=0.3800), treatment composition (P=0.6946), polysensitization (P=0.1730), or clinical diagnosis (P=0.3354). However, it was found that treatment duration had a statistically significant influence (3 months, >3 months: P=0.0442) and the presence of asthma was close to statistical significance (P=0.0847).ConclusionIn our study, treatment duration is significantly associated with the occurrence of adverse reactions after the administration of high doses of sublingual allergen immunotherapy.

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.

To evaluate the efficacy of Dermatophagoides pteronyssinus (DPT) subcutaneous immunotherapy in allergic rhinoconjunctivitis patients. This 17-week double-blind study randomized 136 patients (95 evaluable) to five dose groups of DPT depot extract (0.0625-0.75 skin prick test [SPT] units) or placebo, administered in a six updosing schedule. A dose-response was observed for clinical efficacy (allergen concentration needed to induce a positive nasal provocation test response from baseline to final visit) and safety (adverse reactions). Local and systemic reactions occurred with 14.8 and 6.4% of administered doses, respectively; a single anaphylactic reaction occurred in each of Groups 3, 4 and 5 (0.3% of doses). The risk-benefit profile appeared most favorable with a DPT dose of 0.125 SPT units.

This study was designed with the aim of defining a new surgical procedure for varicose veins and for comparison with classic crossectomy in terms of reducing the recurrence rate of varicose veins. Double-blind randomized clinical trial. For easy access, we selected 150 patients who came to the Phlebology Consultation Unit meeting inclusion criteria. With their informed consent, they were included in a study group using random table numbers. Group 1: (CS) Classic saphenectomy, 75 patients. Group 2: (HCWVS) High crossectomy without vascular sectioning. Both groups were monitorised at 12 and 24 months by Eco-Doppler study. The incidence of varicose vein recurrence at 12 month follow-up was 69.3% in the group of patients undergoing CS, while in the group receiving HCWVS it was 29.3% (p <0.0001). These differences, though minor, remained statistically significant at 24 months of evolution (76% vs. 48%, p = 0.0004). The most common recurrence type was type I, with statistically significant differences at 12 and 24 months. We believe that saphenectomy with crossectomy without vascular sectioning is the appropriate procedure to treat varicose veins, reducing type 1 or reticular relapse rate and maintaining the principles of classic surgery to reduce type 2 or truncular recurrence rate. This technique should be implemented with procedures based on saphenous sclerosis with foam art the saphenous femoral junction, in order to assess the recurrence rate of type 2 or truncular varicose veins.

Hyperglycerolemia is a very rare genetic disorder caused by glycerol kinase deficiency. Although usually is presented unexpectedly in routine checks, there are severe forms, especially in children. In general, glycerol and glycerol kinase activity analyses are not included in routine laboratory determination. Glycerol presents positive interferences with some biochemical analytic techniques, e.g. in serum triglycerides and plasma ethylene glycol levels assays. Here, we report a Spanish patient with a pseudo-hypertriglyceridaemia, a falsely elevated triglycerides concentration that was not corrected with lipid-lowering therapy for 3 years.

An actualized revision of the most important aspects of aneurismal subarachnoid hemorrhage is presented from the guidelines previously published by the group of study of cerebrovascular pathology of the Spanish Society of Neurosurgery. The proposed recommendations should be considered as a general guide for the management of this pathological condition. However, they can be modified, even in a significant manner according to the circumstances relating each clinical case and the variations in the therapeutic and diagnostic procedures available in the center attending each patient.

BACKGROUND. The Spanish neurosurgical society created a multicentre data base on spontaneous SAH to analyze the real problematic of this disease in our country. This paper focuses on the group of patients with idiopathic SAH (ISAH). METHODS. 16 participant hospitals collect their spontaneous SAH cases in a common data base shared in the internet through a secured web page, considering clinical, radiological, evolution and outcome variables. The 220 ISAH cases collected from November 2004 to November 2007 were statistically analyzed as a whole and divided into 3 subgroups depending on the CT blood pattern (aneurysmal, perimesencephalic, or normal). RESULTS. The 220 ISAH patients constitute 19% of all 1149 spontaneous SAH collected in the study period. In 46,8% of ISAH the blood CT pattern was aneurysmal, which was related to older age, worse clinical condition, higher Fisher grade, more hydrocephalus and worse outcome, compared to perimesencephalic (42.7%) or normal CT (10.4%) pattern. Once surpassed the acute phase, outcome of ISAH patients is similarly good in all 3 ISAH subgroups, significantly better as a whole compared to aneurysmal SAH patients. The only variable related to outcome in ISAH after a logistic regression analysis was the admission clinical grade. CONCLUSIONS. ISAH percentage of spontaneous SAH is diminishing in Spain. Classification of ISAH cases depending on the blood CT pattern is important to differentiate higher risk groups although complications are not negligible in any of the ISAH subgroups. Neurological status on admission is the single most valuable prognostic factor for outcome in ISAH patients.

This phase II study investigated the anti-tumour activity and toxicity of CPT-11 (250 mg/m2 i.v. infusion over 60 minutes) administered every 2 weeks as second-line chemotherapy in patients with advanced colorectal cancer (CRC). Patients (n = 63) with histology diagnosis of advanced CRC and proven resistance to previous fluoropyrimidine therapy were enrolled. A total of 510 CPT-11 cycles were administered, with a mean of 8 cycles per patient (range: 1-32). The median relative dose intensity was 93%. Partial response (PR) was obtained in 11 patients (17.5%; 95%CI: 8.1%-26.7%) and 29 patients (46.0%) showed stable disease (clinical benefit of 63.5%). The median duration of response was 6.8 months (95%CI: 6.1-7.5 months), median survival was 8.8 months (95%CI: 6.3-11.5 months) and median time to disease progression was 4.5 months (95%CI: 3.9-5.0 months). Overall, this schedule of CPT-11 chemotherapy was well tolerated by the patient. Neutropenia was the most frequent grade 3/4 haematological toxicity (20.6% of patients and 4.1% of cycles). Neutropenia with concurrent fever or infection occurred in 7 patients (11.1%). Late onset diarrhoea was the most frequent grade 3/4 non-haematological toxicity (19.0% of patients and 2.3% of cycles). Other, lower-incidence, toxicities were anaemia, fever, infection, mucositis, nausea and vomiting. There were no toxic deaths. We found that CPT-11, administered as 250 mg/m2 i.v. infusion over 60 minutes every 2 weeks, was active and well tolerated schedule in the second-line chemotherapy of advanced CRC patients. This bi-weekly scheme could be used as an alternative to the weekly or the every-three-week schedule as well as in combined therapies with other chemotherapeutic agents for the treatment of advanced, metastatic, CRC.