ERIC recommendations for TP53 mutation analysis in chronic lymphocytic leukemia-update on methodological approaches and results interpretation.

In chronic lymphocytic leukemia (CLL), TP53 gene defects, due to deletion of the 17p13 locus and/or mutation(s) within the TP53 gene, are associated with resistance to chemoimmunotherapy and a particularly dismal clinical outcome. On these grounds, analysis of TP53 aberrations has been incorporated into routine clinical diagnostics to improve patient stratification and optimize therapeutic decisions. The predictive implications of TP53 aberrations have increasing significance in the era of novel targeted therapies, i.e., inhibitors of B-cell receptor (BcR) signaling and anti-apoptotic BCL2 family members, owing to their efficacy in patients with TP53 defects. In this report, the TP53 Network of the European Research Initiative on Chronic Lymphocytic Leukemia (ERIC) presents updated recommendations on the methodological approaches for TP53 mutation analysis. Moreover, it provides guidance to ensure that the analysis is performed in a timely manner for all patients requiring treatment and that the data is interpreted and reported in a consistent, standardized, and accurate way. Since next-generation sequencing technologies are gaining prominence within diagnostic laboratories, this report also offers advice and recommendations for the interpretation of TP53 mutation data generated by this methodology.

Design and application of a 23-gene panel by next-generation sequencing for inherited coagulation bleeding disorders.

INTRODUCTION: Molecular testing of Inherited bleeding coagulation disorders (IBCDs) not only offers confirmation of diagnosis but also aids in genetic counselling, prenatal diagnosis and in certain cases genotype-phenotype correlations are important for predicting the clinical course of the disease and to allow tailor-made follow-up of individuals. Until recently, genotyping has been mainly performed by Sanger sequencing, a technique known to be time consuming and expensive. Currently, next-generation sequencing (NGS) offers a new potential approach that enables the simultaneous investigation of multiple genes at manageable cost. AIM: The aim of this study was to design and to analyse the applicability of a 23-gene NGS panel in the molecular diagnosis of patients with IBCDs. METHODS: A custom target enrichment library was designed to capture 31 genes known to be associated with IBCDs. Probes were generated for 296 targets to cover 86.3 kb regions (all exons and flanking regions) of these genes. Twenty patients with an IBCDs phenotype were studied using NGS technology. RESULTS: In all patients, our NGS approach detected causative mutations. Twenty-one pathogenic variants were found; while most of them were missense (18), three deletions were also identified. Six novel mutations affecting F8, FGA, F11, F10 and VWF genes, and 15 previously reported variants were detected. NGS and Sanger sequencing were 100% concordant. CONCLUSION: Our results demonstrate that this approach could be an accurate, reproducible and reliable tool in the rapid genetic diagnosis of IBCDs.

A B-cell epigenetic signature defines three biologic subgroups of chronic lymphocytic leukemia with clinical impact.

Prospective identification of patients with chronic lymphocytic leukemia (CLL) destined to progress would greatly facilitate their clinical management. Recently, whole-genome DNA methylation analyses identified three clinicobiologic CLL subgroups with an epigenetic signature related to different normal B-cell counterparts. Here, we developed a clinically applicable method to identify these subgroups and to study their clinical relevance. Using a support vector machine approach, we built a prediction model using five epigenetic biomarkers that was able to classify CLL patients accurately into the three subgroups, namely naive B-cell-like, intermediate and memory B-cell-like CLL. DNA methylation was quantified by highly reproducible bisulfite pyrosequencing assays in two independent CLL series. In the initial series (n=211), the three subgroups showed differential levels of IGHV (immunoglobulin heavy-chain locus) mutation (P<0.001) and VH usage (P<0.03), as well as different clinical features and outcome in terms of time to first treatment (TTT) and overall survival (P<0.001). A multivariate Cox model showed that epigenetic classification was the strongest predictor of TTT (P<0.001) along with Binet stage (P<0.001). These findings were corroborated in a validation series (n=97). In this study, we developed a simple and robust method using epigenetic biomarkers to categorize CLLs into three subgroups with different clinicobiologic features and outcome.

NOTCH1 mutations identify a genetic subgroup of chronic lymphocytic leukemia patients with high risk of transformation and poor outcome.

NOTCH1 has been found recurrently mutated in a subset of patients with chronic lymphocytic leukemia (CLL). To analyze biological features and clinical impact of NOTCH1 mutations in CLL, we sequenced this gene in 565 patients. NOTCH1 mutations, found in 63 patients (11%), were associated with unmutated IGHV, high expression of CD38 and ZAP-70, trisomy 12, advanced stage and elevated lactate dehydrogenase. Sequential analysis in 200 patients demonstrated acquisition of mutation in one case (0.5%) and disappearance after treatment in two. Binet A and B patients with NOTCH1-mutated had a shorter time to treatment. NOTCH1-mutated patients were more frequently refractory to therapy and showed shorter progression-free and overall survival after complete remission. Overall survival was shorter in NOTCH1-mutated patients, although not independently from IGHV. NOTCH1 mutation increased the risk of transformation to diffuse large B-cell lymphoma independently from IGHV, with this being validated in resampling tests of replicability. In summary, NOTCH1 mutational status, that was rarely acquired during the course of the disease, identify a genetic subgroup with high risk of transformation and poor outcome. This recently identified genetic subgroup of CLL patients deserves prospective studies to define their best management.

Value of the bone scintigraphy in multiple osteochrondromatosis with sarcomatous degeneration.

Multiple osteochondromatosis can become malignant in 20% of the cases, this being more common when the lesion is multiple than when it is solitary. A male patient with multiple osteochondromatosis who had several local recurrences of secondary chondrosarcoma and who is still under follow-up by the Nuclear Medicine Department is presented. The bone scintigraphy findings were compared with the histopathologic results, and the importance of the patient's symptoms was verified when a sarcomatous transformation is suspected. The bone scintigraphy has the potential to detect malignization of the benign bone lesions. It also makes it possible to obtain whole-body images in a single examination, this being very useful to detect the presence of new bone lesions.

Valor de la gammagrafía ósea en la osteocondromatosis múltiple con degeneración sarcomatosa / Value of the bone scintigraphy in multiple osteochrondromatosis with sarcomatous degeneration

La osteocondromatosis múltiple puede malignizar hasta en un 20% de los casos, siendo mucho más frecuente que cuando la lesión es solitaria. Presentamos el caso de un paciente con osteocondromatosis múltiple que ha presentado varias recidivas locales de un condrosarcoma secundario en años sucesivos y que sigue controles gammagráficos en nuestro servicio. Los hallazgos de la gammagrafía ósea se compararon con los resultados anatomopatológicos y se comprobó la importancia de la sintomatología del paciente ante la sospecha de transformación sarcomatosa. La gammagrafía ósea puede aportar datos sobre la posible malignización de las lesiones benignas y permite obtener imágenes de cuerpo completo en una sola exploración, siendo muy útil ante la aparición de nuevas lesiones(AU)

Multiple osteochondromatosis can become malignant in 20% of the cases, this being more common when the lesion is multiple than when it is solitary. A male patient with multiple osteochondromatosis who had several local recurrences of secondary chondrosarcoma and who is still under follow-up by the Nuclear Medicine Department is presented. The bone scintigraphy findings were compared with the histopathologic results, and the importance of the patient‘s symptoms was verified when a sarcomatous transformation is suspected. The bone scintigraphy has the potential to detect malignization of the benign bone lesions. It also makes it possible to obtain whole-body images in a single examination, this being very useful to detect the presence of new bone lesions(AU)

Multiple cranial neuropathy and intracranial hypertension associated with all-trans retinoic acid treatment in a young adult patient with acute promyelocytic leukemia.

All-trans retinoic acid (ATRA) induces complete remission in 64-100 % of patients with acute promyelocytic leukemia (APL), and is considered to be a safe agent. Pseudotumor cerebri is a neurological side effect of ATRA reported in pediatric patients, and which is characterized by raised cerebrospinal fluid pressure in the absence of any intracranial pathology or secondary causes of intracranial hypertension. Involvement of cranial nerves other than II and VI is very uncommon in idiopathic intracranial hypertension (IIH); peripheral facial nerve palsy is exceptional and has rarely been described in the context of treatment with ATRA. We describe the case of a 15-year-old female patient with APL who developed an IIH and involvement of cranial nerves (bilateral papilledema, left facial and right sixth nerves) after receiving induction therapy including ATRA. Viral infections and other causes of secondary cranial nerve lesions were excluded. Symptoms completely subsided with the temporary withdrawal of ATRA and did not recur after reintroducing the drug. To date, the patient has managed to receive the treatment as per protocol. In conclusion, we report an atypical presentation of IIH that merits consideration, especially with respect to young patients with APL receiving ATRA; our most important observation is that the drug could be safely reintroduced once the symptoms had resolved.

Prognostic significance of FLT3 mutational status and expression levels in MLL-AF4+ and MLL-germline acute lymphoblastic leukemia.

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.

Efectividad de la psicoterapia breve en los centros de salud mental II: resultados / Effectiveness of brief psychotherapy in community mental health centers II: results

Introducción: El objetivo de la presente investigación ha sido comparar mediante un ensayo clínico la efectividad de una Psicoterapia Breve con el tratamiento habitual de los Trastornos Mentales Comunes en los Centros de Salud Mental (CSM) de Asturias. La introducción general a este estudio se ha descrito por Fernández-Méndez y cols. (2010) y se remite a los lectores a ese artículo para más detalles respecto al fundamento, diseño, tratamientos y procedimientos de la investigación. Sujetos y método: Se seleccionaron al azar 216 personas mayores de 14 años que consultaban por primera vez en seis CSM y que fueron diagnosticadas de trastornos depresivos, de ansiedad y/o de adaptación. Ciento cuarenta y una cumplían los criterios de inclusión y aceptaron participar en la investigación, siendo asignadas al azar a dos grupos: Psicoterapia breve integradora-ecléctica (n = 76) o Tratamiento habitual en los CSM (n = 65). Se han comparado sus resultados a los 6, 12, 24 y 36 meses en diversos índices de mejoría clínica, funcionamiento psicosocial e indicadores sanitarios indirectos. Los datos se han obtenido del Registro de Casos Psiquiátricos, de la Historia Clínica y del propio paciente. Se han usado los siguientes instrumentos: Impresión Clínica Global (ICG, Guy, 1976), Inventario de Discapacidad de Sheehan (SDI, Sheehan, 1996) y Cuestionario de Satisfacción (Moré y Muñoz, 2000). Resultados: El programa de Psicoterapia breve ha sido más efectivo que el tratamiento habitual: Obtiene una mayor tasa de altas y los sujetos muestran mayores mejorías en estado clínico y discapacidad y mayor satisfacción. Estas diferencias se dan tanto a los seis meses como al año y a los dos años de iniciarse los tratamientos. Además, aunque el número medio de sesiones es igual en ambos grupos (en torno a seis), el tratamiento experimental duró mucho menos tiempo. Conclusiones: La Psicoterapia ha resultado ser un tratamiento viable y efectivo para la mayoría de los casos que consultan en los CSM (AU)

Background: The aim of the current research has been comparing the effectiveness of a brief psychotherapy with the usual treatment of Common Mental Disorders in Mental Health Centers (MHC) of Asturias. The general background of this study has already been described by Fernández-Méndez et al (2010) and readers are referred to that article for details regarding rationale, design, treatments and procedures of the study. Subjects and method: Two hundred and sixteen patients over the age of 14 were selected at random among those who consulted for the first time in six MHC and were diagnosed of depressive, anxiety or adjustment disorders. One hundred and forty-one fulfilled the inclusion criteria and agreed to take part in the study; they were assigned at random into two groups: brief integrative-eclectic psychotherapy (n = 76) or usual treatment in the MHC (n = 65). Their results have been compared at 6, 12, 24 and 36 months against diverse indexes of clinical improvement, psycho-social functioning and sanitary indirect indicators. Information has been obtained from the Psychiatric Cases Record, the Clinical History and from the patients. The following instruments have been used: the Clinical Global Impression of Improvement scale, the Sheehan Disability Inventory and a Satisfaction Survey. Results: Brief psychotherapy was more effective than usual treatment: it resulted in a higher number of discharges and subjects show greater improvements in clinical status and disability, and greater satisfaction. These differences occur both at 6 months to one year and two years of starting treatment. Furthermore, although the average number of sessions is equal in both groups (about six), time-wise the psychological treatment lasted much less (AU)

Efectividad de la psicoterapia breve en los centros de salud mental I: Diseño, tratamientos y procedimiento / Effectiveness of Brief Psychotherapy in Community Mental Health Centers I: design, treatments and procedures

Introducción. El objetivo de la presente investigación ha sido comparar mediante un ensayo clínico la efectividad de una Psicoterapia Breve con el tratamiento habitual de los Trastornos Mentales Comunes en los Centros de Salud Mental (CSM) de Asturias. En este artículo se describen la justificación, el diseño y los procedimientos de ese estudio. Los primeros resultados se publican en Fernández- Méndez y cols. (en prensa). Sujetos y método. Se seleccionaron al azar 216 personas mayores de 14 años que consultaban por primera vez en seis CSM y que fueron diagnosticadas de trastornos depresivos, de ansiedad y/o de adaptación. Ciento cuarenta y una cumplían los criterios de inclusión y aceptaron participar en la investigación, siendo asignadas al azar a dos grupos: Psicoterapia breve integradora- ecléctica (n = 76) o Tratamiento habitual en los CSM (n = 65). Se han comparado sus resultados a los 6, 12, 24 y 36 meses en diversos índices de mejoría clínica, funcionamiento psicosocial e indicadores sanitarios indirectos. Los datos se han obtenido del Registro de Casos Psiquiátricos, de la Historia Clínica y del propio paciente. Se han usado los siguientes instrumentos: Impresión Clínica Global (ICG, Guy, 1976), Inventario de Discapacidad de Sheehan (SDI, Sheehan, 1996) y Cuestionario de Satisfacción (Moré y Muñoz, 2000) (AU)

Background. The aim of the current research has been comparing the effectiveness of a brief psychotherapy with the usual treatment of Common Mental Disorders in Mental Health Centers (MHC) of Asturias. The present article describes the rationale, design and procedures of the study. Initial outcome findings are reported by Fernández- Méndez et al (in press). Subjects and method. Two hundred and sixteen patients over the age of 14 were selected at random among those who consulted for the first time in six MHC and were diagnosed of depressive, anxiety or adjustment disorders. One hundred and forty-one fulfilled the inclusion criteria and agreed to take part in the study; they were assigned at random into two groups: brief integrative-eclectic psychotherapy (n = 76) or usual treatment in the MHC (n = 65). Their results have been compared at 6, 12, 24 and 36 months against diverse indexes of clinical improvement, psycho-social functioning and sanitary indirect indicators. Information has been obtained from the Psychiatric Cases Record, the Clinical History and from the patients. The following instruments have been used: the Clinical Global Impression of Improvement scale, the Sheehan Disability Inventory and a Satisfaction Survey (AU)

Optimización del uso de Agentes estimulantes del Receptor de la Eritropoyetina (AREs) en pacientes con neoplasias hematológicas basado en el nivel de hemoglobina reticulocitaria / Optimizing the use of Erythropoietin-Receptor stimulating Agents (ERAs) in patients with hematopoietic malignancies based on the level of reticulocyte hemoglobin

Los agentes estimulantes del Receptor de la Eritropoyetina (AREs) se usan en el tratamiento de la anemia de hemopatías malignas (HM). Sin embargo, la tasa de respuestas es variable por diversos factores como el déficit funcional de hierro (DFF). El nivel de hemoglobina (Hb) reticulocitaria es un parámetro fácil de obtener que ha mostrado su utilidad en el diagnóstico del DFF. El objetivo de este estudio fue identificar qué pacientes con HM tratados con AREs presentan DFF y si la Hb reticulocitaria predice la respuesta hemoglobínica en estos enfermos. Se incluyeron 42 pacientes con diagnostico de Mieloma Múltiple (n=17), Linfoma no Hodgkin (n=14), Linfoma de Hodgkin (n=3), Leucemia Linfática Crónica (n=4), Síndrome Mielodisplásico (n=2), Leucemia Linfoblástica Aguda (n=1) y Leucemia Mieloblástica Aguda (n=1). Veinticinco fueron tratados con Epoetina-beta, diez y seis con Darbepoetina y uno con Epoetina alfa.La respuesta fue favorable en el 28%, 53% y 58% de lospacientes a las 3, 6 y 12 semanas de tratamiento, respectivamente. Se detectó DFF en el 17% de los pacientes. En cuanto a la respuesta, no hubo diferencias estadísticamente significativas entre los pacientes con y sin DFF, si bien, a mitad de tratamiento, fue ligeramente superior en el grupo sin DFF (57% vs 43%, p>0.05). El nivel basal de Hb reticulocitaria se correlacionó con el grado de respuesta global a las 12 semanas de finalizar el tratamiento. Así, el 79% de los pacientes respondedores tenían una Hb reticulocitaria inicial >36·5 pg, mientras que este porcentaje bajó al 30% en los no respondedores (p = 0.024)En resumen, la Hb reticulocitaria es un método sensible ypreciso para detectar DFF en pacientes con HM bajo tratamiento con AREs. Además, un nivel elevado de Hb reticulocitaria basal es un parámetro que se asocia con respuesta favorable al tratamiento

The Erythropoietin-Receptor stimulating Agents (ERAs) areindicated in the supportive treatment of the anemia in hematological malignancies (HM). However, the response rate is variable due to factors such as the functional iron deficiency (FID). The level of the reticulocyte hemoglobin (RHb) is an easy-to-obtain parameter very useful for the diagnostic of the FID.The purpose of this study was to evaluate which patientswith HM treated with ERAs present FID. In addition, wetried to asses if the level of RH predicts the response in these patients.We included 42 patients with the following diagnostics:Multiple Myeloma (n= 17), Non Hodgkin Lymphoma(n=14), Hodgkin Lymphoma (n=3), Chronic lymphocyticLeukemia (n=4), Myelodisplastic syndrome (n=2), Acutelymphoblastic Leukemia (n=1), and Acute mieloblasticLeuKemia (n=1). Twenty five of them were treated withEpoetin beta, sixteen with darbepoetin alfa and one withEpoetin alfa at standard doses. The response was favorable in 28%, 53% and 58% of patients at the third, sixth and twelfth week of the treatment, respectively. FID was detected in 17% of the patients. Theresponse rate was not statistical significant different between patients with and without FID, although it was slightly superior in the group without FID (57% vs. 43%, p>0.05). Seventy nine percent of patients with a favorable response at twelve weeks showed an initial RH >36·5 pg, while this percentage was only 30% in patients who did not respond (p=0.024).In conclusion, RH is a sensitive and specific method to detect FID in patients with HM who are treated with ERAs.Furthermore, the high level of RH at the baseline is a predictor of favorable response of treatment, in these patients

El consejo para dejar de fumar: por qué, cuándo y cómo debemos darlo a nuestros pacientes / Counselling to stop smoking: why, when, and how we should provide our patients with this

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Immunoglobulin lambda isotype gene rearrangements in B cell malignancies.

The human immunoglobulin lambda (IGL) locus contains seven J-Clambda gene regions of which only J-Clambda1, J-Clambda2 J-CA3 and J-Clambda7 encode the four Iglambda isotypes, ie Mcg, Ke-Oz-, Ke-Oz+, and Mcp, respectively. We used isotype-specific DNA probes for detection of IGL gene rearrangements in 212 B cell malignancies: 76 precursor B cell acute lymphoblastic leukemias (precursor B-ALL), 74 Iglambda+ chronic B cell leukemias (CBL), 34 Iglambda+ non-Hodgkin lymphomas (B-NHL), and 28 Iglambda+ multiple myelomas (MM). The J-Clambda3 gene region was most frequently involved (50%), followed by J-Clambda2 (38%) and J-Clambda1 (9%). There was no involvement of the J-Clambda4 and J-Clambda5 gene regions. Rearrangements to J-Clambda6 (n= 4) were exclusively found in precursor B-ALL (19% of all IGL rearrangements in precursor B-ALL) and only a single J-Clambda7 recombination was detected in an Iglambda+ B-NHL. In the group of Iglambda+ malignancies, a significant shift was observed from predominant J-Clambda3 usage (54%) in mature surface Iglambda+ malignancies (CBL and B-NHL) to 60% J-Clambda2 usage in Iglambda+ secreting MM. The distribution of IGL isotype rearrangements found in MM resembled the Iglambda isotype protein expression reported in MM patients. Based on these extensive Southern blot data, we suggest that a rapid and efficient detection of clonal IGL gene rearrangements can be obtained when a single Bg/II digest is used in combination with the IGLJ2 probe, which detects clonality in >95% of cases with an Iglambda+ malignancy. Higher percentages (>98%) can be reached by including a second digest (HindIII) that reduces the chance of comigration of rearranged and germline bands. In case of precursor B-ALL we recommend including the IGLJ6 probe for the detection of rearrangements to J-Clambda6.

Plasmocitoma extramedular nasofaringeo. reporte de caso / Extramedulary plasmocytoma in the nasopharynx. case report

Los plasmocitomas extramedulares (PEM) son tumores solitarios de células plasmáticas localizada en lugares lejanos al hueso. Un porcentaje variable puede desarrollar con posterioridad un mieloma múltiple. Los PEM representan cerca de un 4 por ciento de los tumores no epiteliales del tracto respiratorio superior. Generalmente se desarrollan en el tejido submucoso de vías aéreas superiores con predilección por la nasofaringe, las fosas nasales, los senos paranasales y las amígdalas. Los tumores rinofaríngeos son raros; una revisión en Medline encontró 10 casos en la nasofaringe, uno de ellos en España. Presentamos el caso clínico de un paciente varón de 69 años, con patología tubárica crónica, cuyo examen clínico reveló la existencia de una lesión polipoide en nasofaringe, sin adenopatías cervicales. La resección endoscópica transnasal permitió el estudio histológico de la pieza, que mostró una proliferación de células plasmáticas. Los estudios séricos y de médula ósea permitieron concluir el diagnóstico de plasmocitoma extramedular. El tratamiento fue completado con radioterapia, no existiendo evidencia de recurrencia de la enfermedad después de 18 meses

Detection of single and associated lesions of the Bcl-1, Bcl-2, Bcl-6, c-myc, p53 and p16 genes in B-cell non-Hodgkin's lymphomas: value of molecular analysis for a better assignment of the histologic subtype.

BACKGROUND AND OBJECTIVE: Molecular genetic abnormalities have been frequently described in non-Hodgkin's lymphomas (NHL). These lesions have been associated with specific entities, allowing a better categorization of NHL. However, these abnormalities are not as specific as initially described and their association is still unknown. DESIGN AND METHODS: By Southern blot and polymerase chain reaction, we have simultaneously analyzed the proto-oncogenes Bcl-1, Bcl-2, Bcl-6, c-myc and MLL and the tumor suppressor genes p53 and p16, in 100 unselected B-cell NHL patients at diagnosis, to establish its incidence throughout the different NHL subtypes, defined both by Working Formulation and REAL classifications, and to assess the frequency of co-existence of two or more genetic lesions within each individual patient. RESULTS: Fifty two cases displayed some genetic abnormality. Bcl-1, altered in 12 cases, was highly specific to mantle cell lymphomas (57% of them), but 6 cases had a different histologic subtype. Bcl-2 was rearranged in 26 cases: 70% in follicular lymphomas (FL) and 20% in diffuse large cell lymphomas; these abnormalities were also present in other subtypes, i.e. marginal lymphomas (30%). Bcl-6 abnormalities were mostly found in diffuse large cell lymphomas (29%) but also found in other subgroups, like FL (14%). C-myc rearrangements were specific to Burkitt's lymphoma. MLL gene was always germline. Deletions and/or rearrangements of p53 and p16 genes were rare (4% and 8% of all cases, respectively). Finally, association of genetic lesions was a relatively common finding (13% of cases), especially in cases with adverse prognostic morphologies according to the REAL. INTERPRETATION AND CONCLUSIONS: Molecular abnormalities are frequent in NHL at diagnosis, not only as unique lesions but also associated. A relative high specificity of some alterations was seen, thereby contributing to a better assessment of the histological subtype.

[The outlook for Spanish primary care starting with a bibliometric analysis of its scientific production (1971-1994)]. / Perspectiva de la atención primaria española a partir del análisis bibliométrico de su producción científica (1971-1994).

OBJECTIVE: To establish the relative weight of the various kinds of primary health care (PHC) research collected in the IME (Spanish medical index), In order to determine their possible relationships with Spain's PHC model. DESIGN: Bibliometric analysis. PARTICIPANTS: PHC documents (1971-1994) from the IME data base (CD-ROM), subdivided by years, journals, themes and Autonomous Communities (AC). RESULTS: 3,015 studies were published, with a first phase (1970s) of under 10 documents per year, a second (1980s) with a big increase and a third (1990s) of stagnation. Of the 117 journals containing studies, Atención Primaria gave a home to almost 58% (60% after 1984). CONCLUSIONS: PHC research production has stagnated recently, though the journal Atención Primaria has maintained its undisputed leadership position. The clinical model predominant in Spanish medicine is generally followed.