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El objetivo de este trabajo es analizar, bajo la perspectiva de la Economía de los Costes de Transacción, si las distintas prácticas contractuales con las que las cadenas hoteleras organizan sus establecimientos influyen sobre su eficiencia. El análisis se ha llevado a cabo utilizando Data Envelopment Analysis (DEA), aplicándolo a la cadena líder en España, Sol Meliá. Los resultados obtenidos ponen de manifiesto que la cadena analizada logra en todos los establecimientos en unos altos niveles de eficiencia, pero no se puede afirmar que los gestionados por bajo otras fórmulas contractuales sean más eficientes que otras. Este trabajo permite concluir que la forma contractual no contribuye a la eficiencia de los establecimientos en el caso de Sol Meliá. Más bien parece depender de otras variables técnicas que del tipo de contrato establecido.

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Despite its often low efficacy and high toxicity, the standard treatment for acute myeloid leukemia (AML) is induction chemotherapy with cytarabine and idarubicin. Here, we have investigated the role of transporters and drug-metabolizing enzymes in this poor outcome. The expression levels (RT-qPCR) of potentially responsible genes in blasts collected at diagnosis were related to the subsequent response to two-cycle induction chemotherapy. The high expression of uptake carriers (ENT2), export ATP-binding cassette (ABC) pumps (MDR1), and enzymes (DCK, 5-NT, and CDA) in the blasts was associated with a lower response. Moreover, the sensitivity to cytarabine in AML cell lines was associated with ENT2 expression, whereas the expression of ABC pumps and enzymes was reduced. No ability of any AML cell line to export idarubicin through the ABC pumps, MDR1 and MRP, was found. The exposure of AML cells to cytarabine or idarubicin upregulated the detoxifying enzymes (5-NT and DCK). In AML patients, 5-NT and DCK expression was associated with the lack of response to induction chemotherapy (high sensitivity and specificity). In conclusion, in the blasts of AML patients, the reduction of the intracellular concentration of the active metabolite of cytarabine, mainly due to the increased expression of inactivating enzymes, can determine the response to induction chemotherapy.

In the future, rapid electrical characterization of cells with impedance flow cytometry promises to be a fast and accurate method for the evaluation of cell properties. In this paper, we investigate how the conductivity of the suspending medium along with the heat exposure time affects the viability classification of heat-treated E. coli . Using a theoretical model, we show that perforation of the bacteria membrane during heat exposure changes the impedance of the bacterial cell from effectively less conducting than the suspension medium to effectively more conducting. Consequently, this results in a shift in the differential argument of the complex electrical current that can be measured with impedance flow cytometry. We observe this shift experimentally through measurements on E. coli samples with varying medium conductivity and heat exposure times. We show that increased exposure time and lower medium conductivity results in improved classification between untreated and heat-treated bacteria. The best classification was achieved with a medium conductivity of 0.045 S/m after 30 min of heat exposure., Competing Interests: The authors declare the following competing financial interest(s): Christian V. Bertelsen and Gustav E. Skands are co-founders of SBT Instruments A/S and both own shares in the company., (© 2023 The Authors. Published by American Chemical Society.)

Chronic lymphocytic leukemia (CLL) is the most common leukemia in the Western world. Studies of CLL antibody reactivity have shown differential targets to autoantigens and antimicrobial molecular motifs that support the current hypothesis of CLL pathogenesis., Methods: In this study, we conducted a quantitative serum analysis of 7 immunoglobulins in CLL and monoclonal B-cell lymphocytosis (MBL) patients (bead-suspension protein arrays) and a serological profile (IgG and IgM) study of autoantibodies and antimicrobial antigens (protein microarrays)., Results: Significant differences in the IgA levels were observed according to disease progression and evolution as well as significant alterations in IgG1 according to IGHV mutational status. More representative IgG autoantibodies in the cohort were against nonmutagenic proteins and IgM autoantibodies were against vesicle proteins. Antimicrobial IgG and IgM were detected against microbes associated with respiratory tract infections., Conclusions: Quantitative differences in immunoglobulin serum levels could be potential biomarkers for disease progression. In the top 5 tumoral antigens, we detected autoantibodies (IgM and IgG) against proteins related to cell homeostasis and metabolism in the studied cohort. The top 5 microbial antigens were associated with respiratory and gastrointestinal infections; moreover, the subsets with better prognostics were characterized by a reactivation of Cytomegalovirus. The viral humoral response could be a potential prognosis biomarker for disease progression.

Next-Generation Sequencing has recently been introduced to efficiently and simultaneously detect genetic variations in acute myeloid leukemia. However, its implementation in the clinical routine raises new challenges focused on the diversity of assays and variant reporting criteria. To overcome this challenge, the PETHEMA group established a nationwide network of reference laboratories aimed to deliver molecular results in the clinics. We report the technical cross-validation results for next-generation sequencing panel genes during the standardization process and the clinical validation in 823 samples of 751 patients with newly diagnosed or refractory/relapse acute myeloid leukemia. Two cross-validation rounds were performed in seven nationwide reference laboratories in order to reach a consensus regarding quality metrics criteria and variant reporting. In the pre-standardization cross-validation round, an overall concordance of 60.98% was obtained with a great variability in selected genes and conditions across laboratories. After consensus of relevant genes and optimization of quality parameters the overall concordance rose to 85.57% in the second cross-validation round. We show that a diagnostic network with harmonized next-generation sequencing analysis and reporting in seven experienced laboratories is feasible in the context of a scientific group. This cooperative nationwide strategy provides advanced molecular diagnostic for acute myeloid leukemia patients of the PETHEMA group.

The HCDR3 sequences of the B-cell receptor (BCR) undergo constraints in length, amino acid use, and charge during maturation of B-cell precursors and after antigen encounter, leading to BCR and antibodies with high affinity to specific antigens. Chronic lymphocytic leukemia consists of an expansion of B-cells with a mixed immature and "antigen-experienced" phenotype, with either a mutated (M-CLL) or unmutated (U-CLL) tumor BCR, associated with distinct patient outcomes. Here, we investigated the hydropathy index of the BCR of 138 CLL patients and its association with the IGHV mutational status and patient outcome. Overall, two clearly distinct subgroups of M-CLL patients emerged, based on a neutral (mean hydropathy index of -0.1) vs. negatively charged BCR (mean hydropathy index of -1.1) with molecular features closer to those of B-cell precursors and peripheral/mature B-cells, respectively. Despite that M-CLL with neutral HCDR3 did not show traits associated with a mature B-cell repertoire, important differences in IGHV gene usage of tumor cells and patient outcome were observed in this subgroup of patients once compared to both U-CLL and M-CLL with negatively charged HCDR3 sequences. Compared to M-CLL with negatively charged HCDR3 sequences, M-CLL with neutral HCDR3 sequences showed predominance of men, more advanced stages of the disease, and a greater frequency of genetic alterations-e.g., del(17p)-together with a higher rate of disease progression and shorter time to therapy (TTT), independently of other prognostic factors. Our data suggest that the hydropathy index of the HCDR3 sequences of CLL cells allows the identification of a subgroup of M-CLL with intermediate prognostic features between U-CLL and the more favorable subgroup of M-CLL with a negatively charged BCR., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Rodríguez-Caballero, Fuentes Herrero, Oliva Ariza, Criado, Alcoceba, Prieto, Pérez Caro, García-Montero, González Díaz, Forconi, Sarmento-Ribeiro, Almeida and Orfao.)

The role of decentralized assessment of measurable residual disease (MRD) for risk stratification in acute myeloid leukemia (AML) remains largely unknown, and so it does which methodological aspects are critical to empower the evaluation of MRD with prognostic significance, particularly if using multiparameter flow cytometry (MFC). We analyzed 1076 AML patients in first remission after induction chemotherapy, in whom MRD was evaluated by MFC in local laboratories of 60 Hospitals participating in the PETHEMA registry. We also conducted a survey on technical aspects of MRD testing to determine the impact of methodological heterogeneity in the prognostic value of MFC. Our results confirmed the recommended cutoff of 0.1% to discriminate patients with significantly different cumulative-incidence of relapse (-CIR- HR:0.71, P < 0.001) and overall survival (HR: 0.73, P = 0.001), but uncovered the limited prognostic value of MFC based MRD in multivariate and recursive partitioning models including other clinical, genetic and treatment related factors. Virtually all aspects related with methodological, interpretation, and reporting of MFC based MRD testing impacted in its ability to discriminate patients with different CIR. Thus, this study demonstrated that "real-world" assessment of MRD using MFC is prognostic in patients at first remission, and urges greater standardization for improved risk-stratification toward clinical decisions in AML., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Recommended genetic categorization of acute myeloid leukaemias (AML) includes a favourable-risk category, but not all these patients have good prognosis. Here, we used next-generation sequencing to evaluate the mutational profile of 166 low-risk AML patients: 30 core-binding factor (CBF)-AMLs, 33 nucleophosmin (NPM1)-AMLs, 4 biCEBPα-AMLs and 101 acute promyelocytic leukaemias (APLs). Functional categories of mutated genes differed among subgroups. NPM1-AMLs showed frequent variations in DNA-methylation genes (DNMT3A, TET2, IDH1/2) (79%), although without prognostic impact. Within this group, splicing-gene mutations were an independent factor for relapse-free (RFS) and overall survival (OS). In CBF-AML, poor independent factors for RFS and OS were mutations in RAS pathway and cohesin genes, respectively. In APL, the mutational profile differed according to the risk groups. High-risk APLs showed a high mutation rate in cell-signalling genes (P = 0·002), highlighting an increased incidence of FLT3 internal tandem duplication (ITD) (65%, P < 0·0001). Remarkably, in low-risk APLs (n = 28), NRAS mutations were strongly correlated with a shorter five-year RFS (25% vs. 100%, P < 0·0001). Overall, a high number of mutations (≥3) was the worst prognostic factor RFS (HR = 2·6, P = 0·003). These results suggest that gene mutations may identify conventional low-risk AML patients with poor prognosis and might be useful for better risk stratification and treatment decisions., (© 2020 British Society for Haematology and John Wiley & Sons Ltd.)

Acute myeloid leukemias (AMLs) are currently genomically characterized by karyotype, fluorescence in situ hybridization (FISH), real-time quantitative PCR, and DNA sequencing. Next-generation sequencing offers the promise of detecting all genomic lesions in a single run. However, technical limitations have hampered the detection of chromosomal rearrangements, so most studies are limited to somatic mutation assessment or require the use of RNA-based strategies. To overcome these limitations, we designed a targeted-DNA capture next-generation sequencing approach associated with easy-to-perform public bioinformatic tools for one-step identification of translocations, inversions, and somatic mutations in AML. Thirty well-characterized newly diagnosed myeloid leukemia patients (27 AML and 3 chronic myeloid leukemia) were tested with the panel. Twenty-three of 24 known rearrangements, as well as one novel fusion gene that could not be detected by karyotype/fluorescence in situ hybridization/real-time quantitative PCR, were detected. This strategy also identified all chromosomal breakpoints as potential targets for future high-sensitive minimal residual disease studies. In addition, mutation analysis revealed the presence of missense protein-coding alterations in at least 1 of the 32 genes evaluated in 21 of 30 patients (70%). This strategy may represent a time- and cost-effective diagnostic method for molecular characterization in AML., (Copyright © 2020 American Society for Investigative Pathology and the Association for Molecular Pathology. Published by Elsevier Inc. All rights reserved.)

Competing Interests: There are no conflicts of interest.

In recent years, several attempts have been made to identify novel prognostic markers in patients with intermediate-risk acute myeloid leukemia (IR-AML), to implement risk-adapted strategies. The non-receptor tyrosine kinases are proteins involved in regulation of cell growth, adhesion, migration and apoptosis. They associate with metastatic dissemination in solid tumors and poor prognosis. However, their role in haematological malignancies has been scarcely studied. We hypothesized that PTK2/FAK , PTK2B/PYK2 , LYN or SRC could be new prognostic markers in IR-AML. We assessed PTK2 , PTK2B , LYN and SRC gene expression in a cohort of 324 patients, adults up to the age of 70, classified in the IR-AML cytogenetic group. Univariate and multivariate analyses showed that PTK2B , LYN and PTK2 gene expression are independent prognostic factors in IR-AML patients. PTK2B and LYN identify a patient subgroup with good prognosis within the cohort with non-favorable FLT3/NPM1 combined mutations. In contrast, PTK2 identifies a patient subgroup with poor prognosis within the worst prognosis cohort who display non-favorable FLT3/NPM1 combined mutations and underexpression of PTK2B or LYN . The combined use of these markers can refine the highly heterogeneous intermediate-risk subgroup of AML patients, and allow the development of risk-adapted post-remission chemotherapy protocols to improve their response to treatment.

Small lymphocytic lymphoma (SLL) is considered as the non-leukemic form of presentation of chronic lymphocytic leukemia (CLL). We have compared the features, genomic alterations, and outcome of 890 patients with CLL and SLL. One hundred and thirteen patients presented as SLL and more frequently had unmutated-IGHV, CD38 high , ZAP-70 high , CD49d high , +12, alterations in genes of NOTCH1, cell cycle, RNA metabolism, and NFkB pathways than CLL. During the follow-up, 46% of SLL patients developed CLL. Time to first treatment (TTFT) was shorter in SLL (10-year: 75% vs 62%; p = .006). Binet stage, SLL, and IGHV were independent predictive factors for TTFT. Transformation to diffuse large B-cell lymphoma was higher (10-year: 12% vs 6%; p = .003), and overall survival was shorter in SLL (10-year: 55% vs 66%; p = .004). When A0 CLL patients were excluded, only CD38 and CD49d expression, +12, and 10-year TTFT remained different between the SLL and CLL patients. In summary, SLL showed only minor clinicobiological differences when compared with CLL in similar clinical stages.