Frequency and clinical impact of CDKN2A/ARF/CDKN2B gene deletions as assessed by in-depth genetic analyses in adult T cell acute lymphoblastic leukemia.

Recurrent deletions of the CDKN2A/ARF/CDKN2B genes encoded at chromosome 9p21 have been described in both pediatric and adult acute lymphoblastic leukemia (ALL), but their prognostic value remains controversial, with limited data on adult T-ALL. Here, we investigated the presence of homozygous and heterozygous deletions of the CDKN2A/ARF and CDKN2B genes in 64 adult T-ALL patients enrolled in two consecutive trials from the Spanish PETHEMA group. Alterations in CDKN2A/ARF/CDKN2B were detected in 35/64 patients (55%). Most of them consisted of 9p21 losses involving homozygous deletions of the CDKNA/ARF gene (26/64), as confirmed by single nucleotide polymorphism (SNP) arrays and interphase fluorescence in situ hybridization (iFISH). Deletions involving the CDKN2A/ARF/CDKN2B locus correlated with a higher frequency of cortical T cell phenotype and a better clearance of minimal residual disease (MRD) after induction therapy. Moreover, the combination of an altered copy-number-value (CNV) involving the CDKN2A/ARF/CDKN2B gene locus and undetectable MRD (≤ 0.01%) values allowed the identification of a subset of T-ALL with better overall survival in the absence of hematopoietic stem cell transplantation.

The cost effectiveness of vacuum-assisted versus core-needle versus surgical biopsy of breast lesions. / Estudio de costo-efectividad de la biopsia mamaria asistida por vacío versus biopsia con aguja gruesa o arpón.

OBJECTIVES: To determine the cost effectiveness of breast biopsy by 9G vacuum-assisted guided by vertical stereotaxy or ultrasonography in comparison with breast biopsy by 14G core-needle biopsy and surgical biopsy. MATERIAL AND METHODS: We analyzed a total of 997 biopsies (181 vacuum-assisted, 626 core, and 190 surgical biopsies). We calculated the total costs (indirect and direct) of the three types of biopsy. We did not calculate intangible costs. We measured the percentage of correct diagnoses obtained with each technique. To identify the most cost-effective option, we calculated the mean ratios for the three types of biopsies. RESULTS: Total costs were €225.09 for core biopsy, €638.90 for vacuum-assisted biopsy, and €1780.01 for surgical biopsy. The overall percentage of correct diagnoses was 91.81% for core biopsy, 94.03% for vacuum-assisted biopsy, and 100% for surgical biopsy; however, these differences did not reach statistical significance (p=0.3485). For microcalcifications, the percentage of correct diagnoses was 50% for core biopsy and 96.77% for vacuum-assisted biopsy (p<0.0001). For nodules, there were no significant differences among techniques. The mean cost-effectiveness ratio considering all lesions was 2.45 for core biopsy, 6.79 for vacuum-assisted biopsy, and 17.80 for surgical biopsy. CONCLUSION: Core biopsy was the dominant option for the diagnosis of suspicious breast lesions in general. However, in cases with microcalcifications, the low percentage of correct diagnoses achieved by core biopsy (50%) advises against its use in this context, where vacuum-assisted biopsy would be the technique of choice because it is more cost-effective than surgical biopsy, the other technique indicated for biopsying microcalcifications.

National climate policies across Europe and their impacts on cities strategies.

Globally, efforts are underway to reduce anthropogenic greenhouse gas emissions and to adapt to climate change impacts at the local level. However, there is a poor understanding of the relationship between city strategies on climate change mitigation and adaptation and the relevant policies at national and European level. This paper describes a comparative study and evaluation of cross-national policy. It reports the findings of studying the climate change strategies or plans from 200 European cities from Austria, Belgium, Estonia, Finland, France, Germany, Ireland, Italy, Netherlands, Spain and the United Kingdom. The study highlights the shared responsibility of global, European, national, regional and city policies. An interpretation and illustration of the influences from international and national networks and policy makers in stimulating the development of local strategies and actions is proposed. It was found that there is no archetypical way of planning for climate change, and multiple interests and motivations are inevitable. Our research warrants the need for a multi-scale approach to climate policy in the future, mainly ensuring sufficient capacity and resource to enable local authorities to plan and respond to their specific climate change agenda for maximising the management potentials for translating environmental challenges into opportunities.

Involvement of the -420C>G RETN polymorphism in myocardial fibrosis in patients with hypertrophic cardiomyopathy.

AIMS: Hypertrophic cardiomyopathy (HCM) is characterized by left ventricular hypertrophy and fibrosis. HCM is an autosomal-dominant disease caused by more than 400 mutations in sarcomeric genes. Changes in nonsarcomeric genes contribute to its phenotypic heterogeneity. Cardiac fibrosis can be studied using late gadolinium enhancement (LGE) cardiac magnetic resonance imaging. We evaluated the potential role of two polymorphisms in nonsarcomeric genes on interstitial fibrosis in HCM. MATERIALS AND METHODS: Two polymorphisms in nonsarcomeric genes [ACE (deletion of 287 bp in the 16th intron) and RETN (-420C>G)] were analysed in 146 HCM patients. Cardiac fibrosis was assessed using LGE to determine the number of affected segments. RESULTS: Allelic frequencies in ACE and RETN polymorphisms were consistent with the Hardy-Weinberg equilibrium (both P > 0.05). We found that the presence of the polymorphic allele in the -420C>G RETN polymorphism was independently associated with the number of affected segments of LGE (P = 0.038). Increased circulating resistin concentration, measured by enzyme-linked immunosorbent assay, was associated with a higher degree of cardiac fibrosis. Myocardial fibrosis, assessed by Masson's trichrome staining, was associated with the -420C>G RETN polymorphism in 46 tissue samples obtained by septal myectomy (P = 0.044). CONCLUSIONS: The -420C>G RETN polymorphism was independently associated with the degree of cardiac fibrosis, assessed by LGE, in patients with HCM. In addition, there was an association between the polymorphism and the circulating resistin levels as well as with myocardial fibrosis in tissues obtained by myectomy. Investigating the physiological implication of the RETN polymorphism in HCM in combination with the use of imaging technologies might help to establish the severity of disease in patients with HCM.

Mitigating and adapting to climate change: multi-functional and multi-scale assessment of green urban infrastructure.

In order to develop climate resilient urban areas and reduce emissions, several opportunities exist starting from conscious planning and design of green (and blue) spaces in these landscapes. Green urban infrastructure has been regarded as beneficial, e.g. by balancing water flows, providing thermal comfort. This article explores the existing evidence on the contribution of green spaces to climate change mitigation and adaptation services. We suggest a framework of ecosystem services for systematizing the evidence on the provision of bio-physical benefits (e.g. CO2 sequestration) as well as social and psychological benefits (e.g. improved health) that enable coping with (adaptation) or reducing the adverse effects (mitigation) of climate change. The multi-functional and multi-scale nature of green urban infrastructure complicates the categorization of services and benefits, since in reality the interactions between various benefits are manifold and appear on different scales. We will show the relevance of the benefits from green urban infrastructures on three spatial scales (i.e. city, neighborhood and site specific scales). We will further report on co-benefits and trade-offs between the various services indicating that a benefit could in turn be detrimental in relation to other functions. The manuscript identifies avenues for further research on the role of green urban infrastructure, in different types of cities, climates and social contexts. Our systematic understanding of the bio-physical and social processes defining various services allows targeting stressors that may hamper the provision of green urban infrastructure services in individual behavior as well as in wider planning and environmental management in urban areas.

A complete software application for automatic registration of x-ray mammography and magnetic resonance images.

PURPOSE: This work presents a complete and automatic software application to aid radiologists in breast cancer diagnosis. The application is a fully automated method that performs a complete registration of magnetic resonance (MR) images and x-ray (XR) images in both directions (from MR to XR and from XR to MR) and for both x-ray mammograms, craniocaudal (CC), and mediolateral oblique (MLO). This new approximation allows radiologists to mark points in the MR images and, without any manual intervention, it provides their corresponding points in both types of XR mammograms and vice versa. METHODS: The application automatically segments magnetic resonance images and x-ray images using the C-Means method and the Otsu method, respectively. It compresses the magnetic resonance images in both directions, CC and MLO, using a biomechanical model of the breast that distinguishes the specific biomechanical behavior of each one of its three tissues (skin, fat, and glandular tissue) separately. It makes a projection of both compressions and registers them with the original XR images using affine transformations and nonrigid registration methods. RESULTS: The application has been validated by two expert radiologists. This was carried out through a quantitative validation on 14 data sets in which the Euclidean distance between points marked by the radiologists and the corresponding points obtained by the application were measured. The results showed a mean error of 4.2 ± 1.9 mm for the MRI to CC registration, 4.8 ± 1.3 mm for the MRI to MLO registration, and 4.1 ± 1.3 mm for the CC and MLO to MRI registration. CONCLUSIONS: A complete software application that automatically registers XR and MR images of the breast has been implemented. The application permits radiologists to estimate the position of a lesion that is suspected of being a tumor in an imaging modality based on its position in another different modality with a clinically acceptable error. The results show that the application can accelerate the mammographic screening process for high risk populations or for dense breasts.

Prognostic value of two polymorphisms in non-sarcomeric genes for the development of atrial fibrillation in patients with hypertrophic cardiomyopathy.

BACKGROUND: Several non-sarcomeric genes have been postulated to act as modifiers in the phenotypic manifestations of hypertrophic cardiomyopathy (HCM). The development of atrial fibrillation (AF) in HCM has adverse prognostic implications with increased thromboembolism and functional class impairment. AIM: We tested the hypothesis that 2 non-sarcomeric genes [CYP11B2 (-344T>C) and COL1A1 (2046G>T)] are associated with the development of AF. DESIGN: Prospective study. METHODS: Two polymorphisms in non-sarcomeric genes [CYP11B2 (-344T>C) and COL1A1 (2046G>T)] were analysed in 159 HCM patients (49.3 ± 14.9 years, 70.6% male) and 136 controls. All subjects were clinically stable and in sinus rhythm at entry in the study, without ischemic heart disease or other significant co-morbidities that could mask the effect of the analysed polymorphisms (i.e. previous AF). Thirty-nine patients (24.4%) developed AF during a median follow-up of 49.5 months. RESULTS: Patients with the -344T>C polymorphism in CYP11B2 gene had a higher risk for AF development [HR: 3.31 (95% CI 1.29-8.50); P = 0.008]. In a multivariate analysis, the presence of the C allele in CYP11B2 gene [HR: 3.02 (1.01-8.99); P = 0.047], previous AF [HR: 2.81 (1.09-7.23); P = 0.033] and a left atrial diameter of ≥42 mm [HR: 2.69 (1.01-7.18); P = 0.048] were independent predictors of AF development. The presence of the polymorphic allele was associated with higher aldosterone serum levels. CONCLUSION: We have shown for the first time that the CYP11B2 polymorphism is an independent predictor for AF development in HCM patients. This highlights the importance of non-sarcomeric genes in the phenotypic heterogeneity of HCM. The association with higher aldosterone serum levels could relate to greater fibrosis and cardiac remodelling.

Segmentation of the breast skin and its influence in the simulation of the breast compression during an X-ray mammography.

A novel method of skin segmentation is presented aimed to obtain as many pixels belonging to the real skin as possible. This method is validated by experts in radiology. In addition, a biomechanical model of the breast, which considers the skin segmented in this way, is constructed to study the influence of considering real skin in the simulation of the breast compression during an X-ray mammography. The reaction forces of the plates are obtained and compared with the reaction forces obtained using classical methods that model the skin as a 2D membranes that cover all the breast. The results of this work show that, in most of the cases, the method of skin segmentation is accurate and that real skin should be considered in the simulation of the breast compression during the X-ray mammographies.

MRI skin segmentation for the virtual deformation of the breast under mammographic compression.

Breast Magnetic Resonance Image skin has similar intensity levels than dense tissue, and may produce segmentation errors if not managed correctly. In this work a novel skin segmentation method is presented and validated by experts, aimed to obtain as many pixels belonging to the real skin as possible. Segmented skin will be used to build a breast biomechanical model to register X-Ray Images with Magnetic Resonance Images in the future, using a virtually deformed Magnetic Resonance Image.

Bone marrow changes in anorexia nervosa are correlated with the amount of weight loss and not with other clinical findings.

The clinical history and biochemical and hematologic variables for 44 consecutive patients diagnosed with anorexia nervosa were recorded. Bone marrow aspirates and biopsy specimens were analyzed by standard morphologic procedures, and bone marrow adipocytes were studied morphometrically. The bone marrow of the 44 patients was classified as normal (5 cases [11%]), hypoplastic or aplastic (17 [39%]), with partial or focal gelatinous degeneration (13 [30%]), or with complete gelatinous degeneration of the bone marrow (GDBM; 9 [20%]). These patterns correlated with amount of weight loss (P = .005) but not other clinical findings. WBC counts were lower in patients with GDBM (P = .0189), but this and other peripheral blood variables did not always reflect the severity of bone marrow damage. Hypoplastic or aplastic bone marrow showed an increase in bone marrow fat fraction due to an increase in adipocyte diameters, while in GDBM, fat fraction and adipocyte diameters decreased. Morphologic changes in bone marrow and stereologic alterations in bone marrow adipocytes may be observed in anorexia nervosa. The extent of damage is related to the amount of weight loss, not to other factors. Peripheral blood cell counts may not reflect the extent of damage. In some patients, this process may be reversible with reestablishment of adequate nutritional intake.

Early and delayed consolidation chemotherapy significantly improves the outcome of children with intermediate risk acute lymphoblastic leukemia. Final results of the prospective randomized PETHEMA ALL-89 TRIAL.

BACKGROUND AND OBJECTIVES: To evaluate the impact of early and delayed consolidation chemotherapy on the outcome of children with acute lymphoblastic leukemia (ALL) stratified according to risk groups. DESIGN AND METHODS: From 1989 to 1994, 195 children (< or = 15 years old) diagnosed as having ALL (ALL-L3 excluded) in 15 Spanish hospitals entered the prospective, randomized PETHEMA ALL-89 trial. Patients were stratified into low-risk (LR), intermediate-risk (IR) and high-risk (HR) groups according to their initial features and the rate of response to induction therapy. LR-ALL patients were randomized to receive or not early consolidation chemotherapy (C-1). After receiving C-1, IR patients were randomized to receive or not delayed consolidation chemotherapy (C-2). HR patients received C-1 and C-2 chemotherapy. Standard maintenance chemotherapy was administered to all patients for 2 years. High doses of intravenous methotrexate and 12 triple intrathecal doses were given as prophylaxis against central nervous system (CNS) disease. RESULTS: The mean (and standard deviation) age was 6 (4) years and 120 patients were males. Fourteen patients had early pre-B-ALL, 149 common or pre-B-ALL, and 32 T-ALL. Complete remission (CR) was attained in 189 patients (97%), 11 of whom (6%) had a slow response. Risk group stratification after CR was: LR 89, IR 50 and HR 56 patients (including a subset of 26 patients at very high risk). Ten-year event-free survival (EFS) and overall survival (OS) probabilities for the whole series were 58% (95% CI: 52-64%) and 69% (61-77), respectively, with a median follow-up of 8.7 years. Dividing the patients according to risk group, the 10-year EFS and OS probabilities in the LR group were 71% (63-79) and 86% (80-92), respectively; in the IR group 69% (57-81) and 76% (64-88), respectively, and in the HR group 30% (18-42) and 44% (32-57), respectively. For LR patients receiving C-1, EFS and OS were 79% (57-92) and 90% (82-98), respectively, versus 62% (48-76) and 66% (51-81) in patients not receiving C-1 (p= 0.06). For IR patients, EFS and OS were significantly improved in those receiving early and delayed consolidation (EFS 87% (74-88) vs. 52% (41-70), and OS 92% (87-97) vs. 61% (51-71)(p=0.036). Prognostic factors for EFS identified in multivariable analyses were: age >10 years in the LR group (OR 3.5, 95% CI 1.3-9.5, p=0.01), and treatment with C-2 in IR patients (OR 5.0, 95% CI 1.4-17.8, p=0.01). The CNS relapse rate was 4% for all the series (including the HR subset). Tolerance to treatment was good. INTERPRETATION AND CONCLUSIONS: In this study, early consolidation seemed to improve the prognosis of children with LR-ALL, but differences in EFS were not significant. Delayed consolidation had a favorable influence on the outcome of IR-ALL. CNS preventive treatment without cranial irradiation was effective in all the groups of ALL patients.

Influence of highly active anti-retroviral therapy on response to treatment and survival in patients with acquired immunodeficiency syndrome-related non-Hodgkin's lymphoma treated with cyclophosphamide, hydroxydoxorubicin, vincristine and prednisone.

Combined highly active anti-retroviral therapy (HAART) with protease and reverse transcriptase inhibitors has modified the natural history of opportunistic infections and neoplasms in human immunodeficiency virus (HIV)-infected patients. We analysed the influence of HAART on the response to treatment and survival in a series of 58 patients with acquired immune deficiency syndrome (AIDS)-related non-Hodgkin's lymphoma (NHL) treated with CHOP (cyclophosphamide, hydroxydoxorubicin, vincristine and prednisone). Two groups of patients were included: (i) forty-one patients diagnosed with NHL between 1988 and 1996 who were not treated with HAART; (ii) seventeen patients diagnosed since 1996, who were receiving or commenced HAART when NHL was diagnosed. The response rate to CHOP was higher in group 2 (13 out of 17 cases; 75%) than in group 1 (14 out of 41 cases; 34%) (P = 0.003). The 2-year probability of event-free survival (EFS) [95% confidence interval (CI)] for group 1 was 0.5 (0.24-0.74), whereas for group 2 it was 0.85 (0.61-0.90) (P = 0.024). The lymphoma-free survival (LFS) was also significantly different for both groups (2-year LFS probability 0.53 vs. 1.0, P = 0.04). The median (95% CI) overall survival (OS) for group 1 was 7 months (range, 3-10.8 months), whereas it was not reached in group 2 (P = 0.0015). In the multivariate analysis for remission attainment, the only variables with a higher probability to achieve complete remission (CR) were HAART (P = 0.01) and International Prognostic Index score 1 (P = 0.02). The only statistically significant variable in the multivariate analysis for EFS was HAART (P = 0.049) and the variables with prognostic value for OS in the multivariate analysis were B symptoms (P = 0.01) and HAART (P = 0.003). Patients with AIDS-related NHL treated with CHOP and HAART had a higher CR rate than those treated only with CHOP. In this study, HAART was an independent prognostic factor for CR, OS and EFS in patients with AIDS-related NHL.

Usefulness and reproducibility of cytomorphologic evaluations to differentiate myeloma from monoclonal gammopathies of unknown significance.

We attempted to differentiate monoclonal gammopathies of unknown significance (MGUS) and multiple myeloma (MM) on morphologic grounds and to determine interobserver reproducibility of the differentiation. Cytologists blindly evaluated bone marrow smears from 154 patients with bone marrow plasmacytosis for the proportion of plasma cells with predefined cellular atypias. The single morphologic characteristic that most strongly differentiated MM from MGUS was the presence of nucleoli. The percentage of plasma cells, cytoplasmic contour irregularities, and anisocytosis also predicted a diagnosis of myeloma in multivariate analysis. Six cytologists independently evaluated 68 consecutive cases to determine sensitivity and specificity of these cytomorphologic features. The interobserver coefficient of variation for the plasma cell count was 33%. On consideration of the diagnosis, 36 of 41 MGUS cases and all 24 cases of myeloma were classified correctly. The use of a predesigned score system did not present such a bias, although it did not improve overall efficiency. The plasma cell count is the most predictive characteristic of myeloma from a cytologic viewpoint, but the interobserver variability is high. Interobserver variability is also high in the assessment of morphologic atypia, and atypical traits are not uncommon in plasma cells in MGUS.

Detection of inv(16) and t(16;16) by fluorescence in situ hybridization in acute myeloid leukemia M4Eo.

BACKGROUND AND OBJECTIVE: It has been established that cytogenetic findings at the time of diagnosis of acute myeloid leukemia (AML) are powerful prognostic indicators. Pericentric inversion of chromosome 16 and translocation t(16;16) resulting in chimeric fusion of CBFB and MYH11 genes are typically seen in the M4-Eo FAB classification subset of AML and are associated with low-risk disease. These subtle chromosomal abnormalities may be difficult to detect in poor-quality metaphase preparations and if missed could lead to incorrect assignment to risk groups and influence the therapy decision-making process. DESIGN AND METHODS: We prospectively studied, at diagnosis, 10 patients with AML-M4 Eo by cytogenetics and fluorescent in situ hybridization (FISH) with two cosmids (36 and 40). As a control group, 7 patients (5 with a diagnosis of AML other than M4 Eo and two cases of reactive eosinophilia) were analyzed. In addition reverse transcriptase chain reaction (RT-PCR) studies were carried out in 6 cases. RESULTS: Karyotypic analysis detected the inv(16) in all but one of the patients with M4-Eo while none of the control cases showed any abnormality on chromosome 16. FISH studies showed that all 10 patients had abnormalities on chromosome 16; the patient with normal karyotype showed an inv(16) by FISH, while a case with inv(16) by cytogenetics had a t(16;16) by FISH. RT-PCR demonstrated amplification of the CBFB/MYH11 product in all cases analyzed. INTERPRETATION AND CONCLUSIONS: In patients with M4Eo and rearrangements of chromosome 16, FISH studies may afford more complete information than conventional cytogenetics and can be an alternative to RT-PCR studies.

[Hodgkin's disease in patients infected by the human immunodeficiency virus. Study of fifteen cases]. / Enfermedad de Hodgkin en pacientes con infección por el virus de la inmunodeficiencia humana. Estudio de 15 casos.

BACKGROUND: In spite of not being considered as an AIDS defining illness, Hodgkin's disease (HD) has specific clinical and biological features in HIV-infected patients. PATIENTS AND METHODS: Study of clinicopathologic and analytic characteristics, Epstein-Barr virus (EBV) detection (polymerase chain reaction), and prognosis in 15 patients with HD and HIV infection. RESULTS: Thirteen patients had B symptoms, 10 extranodal involvement and 12 advanced HD. The most frequent histologic subtypes were mixed cellularity (6) and lymphocyte depletion (6). The mean (SD) of CD4 lymphocytes was 0.10 (0.08) x 10(9)/l. The presence of EBV in lymph node biopsy was demonstrated in 3 out of 4 patients investigated. Complete remission (CR) was achieved in 7 out of 14 treated cases (50%), the median overall survival was 26 months and the 2 year event-free survival probability was 60%. CONCLUSIONS: In HIV-infected patients, HD presents in advanced stages, unfavourable histologic subtypes, frequent extranodal involvement and B symptoms. The prognosis is poor, mainly because of a low CR rate.