Encuesta colombiana de neurología 2016-2020 / Colombian neurology survey 2016-2020

RESUMEN INTRODUCCIÓN: La práctica de la neurología como especialidad clínica es relativamente reciente en Colombia, a pesar de que esta área ha mostrado progresos académicos significativos; la información sociodemográfica es limitada. OBJETIVO: Describir las características sociodemográficas de los neurólogos laboralmente activos en Colombia. METODOLOGÍA: Estudio descriptivo en dos periodos. La información se obtuvo mediante encuestas autodiligenciadas a los asistentes al Congreso Nacional de Neurología del año 2016; la del 2020 se recolectó empleando cuestionarios en línea a través de formularios Google. RESULTADOS: Se contabilizaron 549 neurólogos laboralmente activos en el territorio colombiano. El análisis de las muestras 2016 y 2020 mostró que la mayor proporción de estos especialistas se concentraba en Bogotá (45,4 %), Medellín (13,4 %) y Cali (8,4 %), con una ocupación escasa en ciudades no capitales. La comparación de horas laborales e ingresos económicos al analizar 2016 y 2020 no mostró diferencias. El mayor tiempo de ejercicio se correlacionó con mayores ingresos, tanto en el 2016 (p < 0,001) como en el 2020 (p < 0,01). CONCLUSIONES: Excepto por el incremento en la población de nuevos neurólogos, las características socio-demográficas de los neurólogos en Colombia se mantienen sin variaciones al comparar los años 2016 y 2020.

ABSTRACT INTRODUCTION: Neurology practice is relatively recent in Colombia. Even though this area has shown significant academic advances, information regarding sociodemographic conditions is limited. OBJECTIVE: To describe sociodemographic characteristics of neurologists who are currently active in Colombia. METHODS: Descriptive study over two time periods. The information was obtained by means of self-administered surveys to the neurologists attending the neurology national congress in 2016. In 2020, data was collected by means of on-line questionnaires using google forms. RESULTS: The sample included 549 neurologists. The largest proportion of these specialists were located in Bogotá (45.4 %), Medellín (13.4 %) and Cali (8.4 %). After comparing working hours per week and income we did not identify differences between these 2 years. The time of work experience was correlated with economic income both in 2016 (p<0.001) as in 2020 (p<0.01). CONCLUSION: Except for increasing number of neurologists of recent graduation, the sociodemographic characteristics of Colombian neurologists remain stable when comparing 2016 and 2020.

Tétanos generalizado: reporte de caso y análisis clínico para su diferenciación con otras entidades como las crisis epilépticas / Tetanus as a seizure crisis simulator in a 70-year-old patient, case report

RESUMEN INTRODUCCIÓN: El tétanos es una enfermedad que afecta el sistema nervioso. Su presentación clínica se caracteriza por espasmos musculares en respuesta a la liberación de la neurotoxina producida por la formación de esporas de la bacteria Clostridium tetani. DESCRIPCIÓN DEL CASO: Presentamos el caso de un hombre de 70 años que luego de una caída presentó una herida en la región ocular. Al ingreso se evidenciaron signos de infección local y contracción involuntaria en los músculos maseteros, con imposibilidad de apertura oral. Posteriormente, presentó insuficiencia respiratoria, contracciones generalizadas y necesidad de traslado a unidad de cuidado intensivo. Debido a que entre los diagnósticos diferenciales se encontraba la presencia de crisis epilépticas motoras, se hicieron estudios complementarios para descartar esta posibilidad. DISCUSIÓN: El diagnóstico del tétanos es clínico, es importante sospecharlo en pacientes con antecedentes de lesión en piel e inmunización inadecuada. Por su amplia presentación clínica, puede llevar a confusión con otras patologías. Entre los diagnósticos diferenciales están las crisis epilépticas, sin embargo, el tétano no cumple con las características semiológicas, no compromete el estado de conciencia y no progresa a estado epiléptico, asociado con la normalidad de estudios complementarios como las neuroimágenes, el estudio de líquido cefalorraquídeo y el registro electroencefalográfico. CONCLUSIÓN: El tétanos es una enfermedad altamente prevenible y un reto diagnóstico para el profesional de la salud por su amplio debut de síntomas. Por ello, en el abordaje diagnóstico es importante reconocer los diagnósticos diferenciales, teniendo como base la historia clínica, lo que permite un diagnóstico temprano y oportuno.

ABSTRACT INTRODUCTION: Tetanus is a disease that affects the nervous system and its clinical presentation is characterized by muscle spasms caused by the release of a neurotoxin produced by the formation of spores of the Clostridium tetani bacteria. CASE DESCRIPTION: We present the case of a 70-year-old man who after a fall, presented an injury to the ocular region. On admission, signs of local infection and involuntary contraction of the masseter muscles were evident, with impossibility of oral opening. Subsequently, he presented respiratory failure, generalized contractions and transfer to the intensive care unit, due to its similarity to convulsive events, pathology at the level of the central nervous system is suspected, for which it requires complementary studies and clinical analysis to rule it out. DISCUSSION: The diagnosis of tetanus is clinical, it is important to suspect it in patients with a history of skin lesions and inadequate immunization, due to its extensive clinical presentation, it can lead to confusion with other pathologies. Among the differential diagnoses are epileptic seizures, however, tetanus does not meet the semiological characteristics, does not compromise the state of consciousness and does not progress to status epilepticus, associated with the normality of complementary studies such as neuroimaging, cerebrospinal fluid study and registry electroencephalographic. CONCLUSION: Tetanus is a highly preventable disease and a diagnostic challenge for the health professional due to its wide onset of symptoms. That is why the diagnostic approach is important to recognize the differential diagnoses based on the clinical history, which allows an early and timely diagnosis.

Inhibition of Cancer Cell Adhesion, Migration and Proliferation by a Bispecific Antibody that Targets two Distinct Epitopes on αv Integrins.

Members of the αv family of integrins regulate activation of transforming growth factor beta (TGFß) and are directly involved in pro-tumorigenic phenotypes. Thus, αv integrins may be therapeutic targets for fibrosis and cancer, yet the isolation of selective inhibitors is currently a challenge. We generated synthetic antibodies selective for αv integrins by phage display selections on cell lines that displayed integrin heterodimers. We identified antibodies that targeted two distinct epitopes on cell-surface αv integrins and partially inhibited cell adhesion mediated by interactions between integrins and the latency-associated peptide, part of the pro-form of TGFß. Using the isolated antibody paratope sequences we engineered a bispecific antibody capable of binding to both epitopes simultaneously; this antibody potently and completely inhibited cell adhesion mediated by integrins αvß1, αvß3 and αvß5. In addition, the bispecific antibody inhibited proliferation and migration of lung carcinoma lines, where the highest and lowest potencies observed correlated with integrin-αv cell surface expression levels. Taken together, our results demonstrate that phage display selections with live cells can yield high quality anti-integrin antibodies, which we used as biparatopic building blocks to construct a bispecific antibody that strongly inhibited integrin function and may be a therapeutic candidate for cancer and fibrosis.

Síndrome de burnout en los neurólogos colombianos: prevalência y factores asociados / Burnout syndrome in Colombian neurologists: prevalence and associated factors

RESUMEN INTRODUCCIÓN: El síndrome de burnout es una condición de prevalência creciente que afecta la calidad de vida y los resultados laborales de quienes lo padecen. OBJETIVO: Describir la prevalencia y factores asociados del síndrome de burnout en neurólogos colombianos. METODOLOGÍA: Mediante encuesta autoadministrada se obtuvo información de 119 neurólogos laboralmente activos en Colombia. Se incluyeron datos correspondientes a variables sociodemográficas junto con la escala Maslasch Burnout Inventory. Para calcular la correlación estadística de variables se utilizó regresión logística. RESULTADOS: El síndrome de burnout se determinó en el 49,6 % de los entrevistados (afectación de 2 o más dimensiones). Esta condición se correlacionó con el sexo femenino (P=0,036), el número de horas trabajadas por semana (P=0,040) y la frecuencia de satisfacción con el trabajo (P<0,001). La práctica de actividades de esparcimiento fue estadísticamente significativa (P=0,024) como factor protector. CONCLUSIÓN: El síndrome de burnout es una condición prevalente en los neurólogos en Colombia. Esta información es útil para la creación de políticas encaminadas a mejorar las condiciones del ejercicio de esta especialidad en nuestro país.

SUMMARY INTRODUCTION: Burnout syndrome is a condition of increasing prevalence that affects quality of life and labor outcomes. OBJECTIVE: To describe the prevalence and factors related to burnout syndrome in Colombian neurologists. METHODOLOGY: By mean of a self-administered survey we obtained information from 119 neurologists currently working in Colombia. Sociodemographic and Maslasch Burnout Inventory data were collected. To calculate statistical correlation of variables related to the syndrome a logistic regression model was used. RESULTS: Burnout syndrome was determined in 49.6% of interviewed neurologists (2 or more affected dimensions).This condition was related to female gender (P=0.036), number of hours worked weekly (P=0.040) and level of work satisfaction (P<0.001). Having a hobby was determined as protector for burnout (P=0.024). CONCLUSION: Burnout syndrome is a prevalent condition in Colombian neurologists. This information should be considered for designing policies directed to better labor conditions for this specialty in our country.

CellectSeq: In silico discovery of antibodies targeting integral membrane proteins combining in situ selections and next-generation sequencing.

Synthetic antibody (Ab) technologies are efficient and cost-effective platforms for the generation of monoclonal Abs against human antigens. Yet, they typically depend on purified proteins, which exclude integral membrane proteins that require the lipid bilayers to support their native structure and function. Here, we present an Ab discovery strategy, termed CellectSeq, for targeting integral membrane proteins on native cells in complex environment. As proof of concept, we targeted three transmembrane proteins linked to cancer, tetraspanin CD151, carbonic anhydrase 9, and integrin-α11. First, we performed in situ cell-based selections to enrich phage-displayed synthetic Ab pools for antigen-specific binders. Then, we designed next-generation sequencing procedures to explore Ab diversities and abundances. Finally, we developed motif-based scoring and sequencing error-filtering algorithms for the comprehensive interrogation of next-generation sequencing pools to identify Abs with high diversities and specificities, even at extremely low abundances, which are very difficult to identify using manual sampling or sequence abundances.

The EphA2 and cancer connection: potential for immune-based interventions.

The Eph (erythropoietin-producing human hepatocellular) receptors form the largest known subfamily of receptor tyrosine kinases. These receptors interact with membrane-bound ephrin ligands via direct cell-cell interactions resulting in bi-directional activation of signal pathways. Importantly, the Eph receptors play critical roles in embryonic tissue organization and homeostasis, and in the maintenance of adult processes such as long-term potentiation, angiogenesis, and stem cell differentiation. The Eph receptors also display properties of both tumor promoters and suppressors depending on the cellular context. Characterization of EphA2 receptor in regard to EphA2 dysregulation has revealed associations with various pathological processes, especially cancer. The analysis of various tumor types generally identify EphA2 receptor as overexpressed and/or mutated, and for certain types of cancers EphA2 is linked with poor prognosis and decreased patient survival. Thus, here we highlight the role of EphA2 in malignant tissues that are specific to cancer; these include glioblastoma multiforme, prostate cancer, ovarian and uterine cancers, gastric carcinoma, melanoma, and breast cancer. Due to its large extracellular domain, therapeutic targeting of EphA2 with monoclonal antibodies (mAbs), which may function as inhibitors of ligand activation or as molecular agonists, has been an oft-attempted strategy. Therefore, we review the most current mAb-based therapies against EphA2 expressing cancers currently in pre-clinical and/or clinical stages. Finally, we discuss the latest peptides and cyclical-peptides that function as selective agonists for EphA2 receptor.

Critical role of EphA3 in cancer and current state of EphA3 drug therapeutics.

The erythropoietin-producing human hepatocellular (Eph) receptors are transmembrane glycoprotein members of the tyrosine kinase receptors family. The Ephs may bind to various ephrin ligands resulting in the phosphorylation of their tyrosine kinase domain and the activation of the Eph receptor. In this review we focus on EphA3, one receptor of the 14 different Ephs, as it carries out both redundant and restricted functions in the germline development of mammals and in the maintenance of various adult tissues. The loss of EphA3 regulation is correlated with various human malignancies, the most notable being cancer. This receptor is overexpressed and/or mutated in multiple tumors, and is also associated with poor prognosis and decreased survival in patients. Here we highlight the role of EphA3 in normal and malignant tissues that are specific to cancer; these include hematologic disorders, gastric cancer, glioblastoma multiforme, colorectal cancer, lung cancer, renal cell carcinoma, and prostate cancer. Moreover, various anticancer agents against EphA3 have been developed to either inhibit its kinase domain activity or to function as agonists. Thus, we examine the most potent small molecule drugs and mAb-based therapeutics against EphA3 that are currently in pre-clinical or clinical stages.

Epidermal growth factor receptor (EGFR) involvement in epithelial-derived cancers and its current antibody-based immunotherapies.

The epidermal growth factor receptor (EGFR) is a transmembrane glycoprotein that is part of the family of tyrosine kinase receptors. The binding of EGFR to its cognate ligands leads to its autophosphorylation and subsequent activation of the signal transduction pathways involved in regulating cellular proliferation, differentiation, and survival. Accordingly, this receptor carries out both redundant and restricted functions in the germline development of mammals and in the maintenance of various adult tissues. Correspondingly, the loss of EGFR regulation results in many human diseases, with the most notable cancer. This receptor is overexpressed and/or mutated in multiple epithelial-derived tumors, and associated with poor prognosis and survival in cancer patients. Here, we discuss in detail the role of EGFR in specific epithelial-derived cancer pathologies; these include lung cancer, colorectal cancer, and squamous cell carcinomas. The development of multiple anticancer agents against EGFR diminished the progression and metastasis of tumors. Some of the most versatile therapeutic anti-EGFR agents include the monoclonal antibodies (mAbs), demonstrating success in clinical settings when used in combination with cytotoxic treatments, such as chemotherapy and/or radiation. We thus discuss the development and application of two of the most notable therapeutic mAbs, cetuximab, and panitumumab, currently utilized in various EGFR-related epithelial cancers.

In situ antibody phage display yields optimal inhibitors of integrin α11/ß1.

Integrins are transmembrane multi-conformation receptors that mediate interactions with the extracellular matrix. In cancer, integrins influence metastasis, proliferation, and survival. Collagen-binding integrin-α11/ß1, a marker of aggressive tumors that is involved in stroma-tumor crosstalk, may be an attractive target for anti-cancer therapeutic antibodies. We performed selections with phage-displayed synthetic antibody libraries for binding to either purified integrin-α11/ß1 or in situ on live cells. The in-situ strategy yielded many diverse antibodies, and strikingly, most of these antibodies did not recognize purified integrin-α11/ß1. Conversely, none of the antibodies selected for binding to purified integrin-α11/ß1 were able to efficiently recognize native cell-surface antigen. Most importantly, only the in-situ selection yielded functional antibodies that were able to compete with collagen-I for binding to cell-surface integrin-α11/ß1, and thus inhibited cell adhesion. In-depth characterization of a subset of in situ-derived clones as full-length immunoglobulins revealed high affinity cellular binding and inhibitory activities in the single-digit nanomolar range. Moreover, the antibodies showed high selectivity for integrin-α11/ß1 with minimal cross-reactivity for close homologs. Taken together, our findings highlight the advantages of in-situ selections for generation of anti-integrin antibodies optimized for recognition and inhibition of native cell-surface proteins, and our work establishes general methods that could be extended to many other membrane proteins.

The perception of parents and guardians about the health and quality of life of their adolescent children enrolled in school / Percepciones de padres o acudientes sobre la salud y calidad de vida de sus hijos adolescentes escolarizados / Percepções de pais ou responsáveis sobre a saúde e a qualidade de vida de seus filhos adolescentes escolarizados

Introduction. The perception of parents or guardians about their children's quality of life allows to assess the children's health, bearing in mind the abilities to fully participate in age-appropriate physical, social and psychosocial functions and activities. Research on quality of life (QL) and children's quality of life as regards their health is a field that, although recent, has made significant progress in the past years. Various measurement instruments have been developed from a quantitative perspective to assess it, but few studies analyze the perceptions from a qualitative focus. Objective. To recognize the perception of parents and guardians about the health and quality of life of their adolescent children. Methodology. Qualitative study with the focus group technique in which nine parents or caregivers participated. A focus group was created and the interview was recorded and transcribed. Results. Eleven categories that cover the health and quality of life in the stage of adolescents enrolled in school were detected. Dimensions appeared that are not reported by health-related quality of life instruments, such as spirituality and technology. Discussion. In the area of spirituality, studies have demonstrated a strong positive correlation between parents, religiosity and the reduction of risky conducts in their children. Conclusions. Addressing parents or caregivers helped identify other aspects of health and quality of life that can affect their adolescent children. [Jaimes-Valencia ML, Fajardo-Nates S, Argüello JF, Mejía-Arciniegas CN, Rojas-Arenas LC, Gallo-Eugenio LM, León- Santos NR. The perception of parents and guardians about the health and quality of life of their adolescent children enrolled in school. MedUNAB. 2019;21(3):314-333. doi: 10.29375/01237047.2736]

Introducción. La percepción que tienen los padres o acudientes sobre la calidad de vida de sus hijos, permite realizar una valoración de la salud de los niños teniendo en cuenta las habilidades de participar plenamente en funciones y actividades físicas, sociales y psicosociales apropiadas para la edad. La investigación en la Calidad de Vida (CV) y calidad de vida relacionada con la salud en niños es un campo que, aunque reciente, ha tenido progresos importantes en los últimos años; para su valoración se han creado varios instrumentos de medición desde la perspectiva cuantitativa, pero son escasos los estudios que analizan las percepciones desde un enfoque cualitativo. Objetivo. Reconocer las percepciones que tienen los padres o acudientes sobre la salud y calidad de vida de sus hijos adolescentes. Metodología. Estudio cualitativo con la técnica de grupo focal en la que participaron 9 padres o acudientes. Se realizó un grupo focal, se grabó y transcribió la entrevista. Resultados. Se detectaron 11 categorías que hacen parte de la salud y calidad de vida en la etapa de los adolescentes escolarizados. Surgieron dimensiones que no son reportadas por instrumentos de calidad de vida relacionada con la salud como es la espiritualidad y la tecnología. Respecto a la espiritualidad, estudios han demostrado una correlación positiva fuerte entre los padres, religiosidad y reducción de conductas de riesgo de sus hijos/as. Conclusiones. Abordar a los padres o acudientes permitió identificar otros aspectos de la salud y calidad de vida que pueden afectar a sus hijos en la adolescencia. [Jaimes-Valencia ML, Fajardo-Nates S, Argüello JF, Mejía-Arciniegas CN, Rojas-Arenas LC, Gallo- Eugenio LM, León-Santos NR. Percepciones de padres o acudientes sobre la salud y calidad de vida de sus hijos adolescentes escolarizados. MedUNAB. 2019;21(3):314- 333. doi: 10.29375/01237047.2736]

Introdução. A percepção que os pais ou responsáveis têm sobre a qualidade de vida de seus filhos permite uma avaliação da saúde das crianças, considerando as habilidades para participar plenamente de eventos e atividades físicas, sociais e psicossociais adequadas à idade. A pesquisa sobre qualidade de vida (QV) e qualidade de vida relacionada à saúde em crianças é um campo que, apesar de recente, teve importantes avanços nos últimos anos. Para sua avaliação, tem sido criados vários instrumentos de medição da perspectiva quantitativa, mas há poucos estudos que analisam percepções a partir de uma perspectiva qualitativa. Objetivo. Reconhecer as percepções que os pais ou responsáveis têm sobre a saúde e a qualidade de vida de seus filhos adolescentes. Metodologia. Estudo qualitativo com a técnica de grupo focal em que participaram nove pais ou responsáveis. Foi organizado um grupo focal, e a entrevista foi gravada e transcrita. Resultados. Foram detectadas onze categorias que fazem parte da saúde e qualidade de vida na fase de adolescentes escolarizados. Emergiram dimensões que não são relatadas através de instrumentos de qualidade de vida relacionada à saúde, como espiritualidade e tecnologia. Discussão. Em relação à espiritualidade, estudos têm mostrado uma forte correlação positiva entre pais, religiosidade e redução de comportamentos de risco de seus filhos. Conclusões. Dirigirse aos pais ou responsáveis que participaram, ajudou a identificar outros aspectos da saúde e da qualidade de vida que podem afetar seus filhos durante a adolescência. [Jaimes-Valencia ML, Fajardo- Nates S, Argüello JF, Mejía-Arciniegas CN, Rojas-Arenas LC, Gallo-Eugenio LM, León-Santos NR. Percepções de pais ou responsáveis sobre a saúde e a qualidade de vida de seus filhos adolescentes escolarizados. MedUNAB. 2019;21(3):314-333. doi: 10.29375/01237047.2736]

Differential requirements for Th1 and Th17 responses to a systemic self-antigen.

T cell-APC interactions are essential for the initiation of effector responses against foreign and self-antigens, but the role of these interactions in generating different populations of effector T cells in vivo remains unclear. Using a model of CD4(+) T cell responses to a systemic self-antigen without adjuvants or infection, we demonstrate that activation of APCs augments Th17 responses much more than Th1 responses. Recognition of systemic Ag induces tolerance in self-reactive CD4(+) T cells, but induction of CD40 signaling, even under tolerogenic conditions, results in a strong, Ag-specific IL-17 response without large numbers of IFN-γ-producing cells. Transfer of the same CD4(+) T cells into lymphopenic recipients expressing the self-antigen results in uncontrolled production of IL-17, IFN-γ, and systemic inflammation. If the Ag-specific T cells lack CD40L, production of IL-17 but not IFN-γ is decreased, and the survival time of recipient mice is significantly increased. In addition, transient blockade of the initial MHC class II-dependent T cell-APC interaction results in a greater reduction of IL-17 than of IFN-γ production. These data suggest that Th17 differentiation is more sensitive to T cell interactions with APCs than is the Th1 response, and interrupting this interaction, specifically the CD40 pathway, may be key to controlling Th17-mediated autoimmunity.

Front-line treatment of acute promyelocytic leukemia with AIDA induction followed by risk-adapted consolidation for adults younger than 61 years: results of the AIDA-2000 trial of the GIMEMA Group.

After the identification of discrete relapse-risk categories in patients with acute promyelocytic leukemia (APL) receiving all-trans retinoic and idarubicin (AIDA)-like therapies, the Gruppo Italiano Malattie Ematologiche dell'Adulto (GIMEMA) designed a protocol for newly diagnosed APL (AIDA-2000) in which postremission treatment was risk-adapted. Patients with low/intermediate risk received remission at 3 anthracycline-based consolidation courses, whereas high-risk patients received the same schedule as in the previous, non-risk-adapted AIDA-0493 trial including cytarabine. In addition, all patients in the AIDA-2000 received all-trans retinoic acid (ATRA) for 15 days during each consolidation. After induction, 600 of 636 (94.3%) and 420 of 445 (94.4%) patients achieved complete remission in the AIDA-0493 and AIDA-2000, respectively. The 6-year overall survival and cumulative incidence of relapse (CIR) rates were 78.1% versus 87.4% (P = .001) and 27.7% versus 10.7% (P < .0001). Significantly lower CIR rates for patients in the AIDA-2000 were most evident in the high-risk group (49.7% vs 9.3%, respectively, P < .0001). Our data confirm that anthracycline-based consolidation is at least equally effective as cytarabine-containing regimens for low-/intermediate-risk patients and suggest that a risk-adapted strategy including ATRA for consolidation improves outcome in newly diagnosed APL. Furthermore, our results highlight the role of cytarabine coupled to anthracyclines and ATRA during consolidation in the high-risk group.

Matrix metalloproteinases contribute distinct roles in neuroendocrine prostate carcinogenesis, metastasis, and angiogenesis progression.

Prostate cancer is the leading form of cancer in men. Prostate tumors often contain neuroendocrine differentiation, which correlates with androgen-independent progression and poor prognosis. Matrix metalloproteinases (MMP), a family of enzymes that remodel the microenvironment, are associated with tumorigenesis and metastasis. To evaluate MMPs during metastatic prostatic neuroendocrine cancer development, we used transgenic mice expressing SV40 large T antigen in their prostatic neuroendocrine cells, under the control of transcriptional regulatory elements from the mouse cryptdin-2 gene (CR2-TAg). These mice have a stereotypical pattern of tumorigenesis and metastasis. MMP-2, MMP-7, and MMP-9 activities increased concurrently with the transition to invasive metastatic carcinoma, but they were expressed in different prostatic cell types: stromal, luminal epithelium, and macrophages, respectively. CR2-TAg mice treated with AG3340/Prinomastat, an MMP inhibitor that blocks activity of MMP-2, MMP-9, MMP-13, and MMP-14, had reduced tumor burden. CR2-TAg animals were crossed to mice homozygous for null alleles of MMP-2, MMP-7, or MMP-9 genes. At 24 weeks CR2-TAg; MMP-2(-/-) mice showed reduced tumor burden, prolonged survival, decreased lung metastasis, and decreased blood vessel density, whereas deficiencies in MMP-7 or MMP-9 did not influence tumor growth or survival. Mice deficient for MMP-7 had reduced endothelial area coverage and decreased vessel size, and mice lacking MMP-9 had increased numbers of invasive foci and increased perivascular invasion, as well as decreased tumor blood vessel size. Together, these results suggest distinct contributions by MMPs to the progression of aggressive prostate tumor and to helping tumors cleverly find alternative routes to malignant progression.

High dose sequential chemotherapy with autologous transplantation versus dose-dense chemotherapy MegaCEOP as first line treatment in poor-prognosis diffuse large cell lymphoma: an "Intergruppo Italiano Linfomi" randomized trial.

BACKGROUND AND OBJECTIVES: Poor prognosis diffuse large cell lymphoma (DLCL) responds poorly to standard chemotherapy. Randomized studies comparing high-dose chemotherapy with autologous stem-cell transplantation (ASCT) against standard chemotherapy have produced conflicting results. Dose-dense chemotherapy with granulocyte colony-stimulating factor (G-CSF) support seems to hold promise. The purpose of this multicenter, randomized trial was to compare failure-free and overall survival in patients with poor prognosis DLCL treated with high-dose sequential (HDS) chemotherapy followed by ASCT or an outpatient dose-dense chemotherapy regimen (MegaCEOP). DESIGN AND METHODS: Between 1996 and 2001, 130 DLCL patients, aged < or = 60 years, with intermediate-high or high-risk disease, according to the International Prognostic Index score, and/or bone marrow involvement were enrolled. Sixty were randomized to HDS chemotherapy plus high-dose mitoxantrone and melphalan with ASCT (arm A) and 66 to the MegaCEOP regimen (6-8 courses of an escalated dose of cyclophosphamide and epirubicin plus vincristine and prednisone with G-CSF every 2-weeks) (arm B); 4 patients were considered ineligible. RESULTS: The complete remission rate was 59% in arm A and 70% in arm B (p = 0.18). After a median follow-up of 78 months, the 6-year failure-free survival was 45% in arm A and 48% in arm B (hazard ratio = 1.15, 95% confidence intervals = 0.72-1.84, p = 0.56). The 5-year overall survival was 49% in arm A and 63% in arm B (hazard ratio = 1.67, 95% confidence interval = 0.98-2.85, p = 0.06). Two cases of secondary acute myeloid leukemia were observed after treatment in group A. INTERPRETATION AND CONCLUSIONS: HDS and ASCT as initial therapy for patients with poor-prognosis DLCL does not provide a benefit over that of outpatient dose-dense MegaCEOP chemotherapy.

A large-scale study of bone marrow involvement in patients with Hodgkin's lymphoma.

This study was designed to identify variables that can predict bone marrow involvement (BMI) in Hodgkin's lymphoma (HL), and to analyze the benefit of bilateral over unilateral bone marrow trephine biopsy (BMB). From 1982 to 2000, BMB had been performed at diagnosis in 1161 patients with HL who had been followed from the institutions participating in the Piemonte Hodgkin's Disease Registry. Six hundred and sixteen patients (53%) had received bilateral BMB, and the remaining 545 patients (47%) received unilateral BMB. The relationships between BMB results and other clinical features were retrospectively studied with both univariate and multivariate analyses. Ninety-two patients (8%) showed BMI: 51 of them were staged with bilateral and 41 with unilateral BMB. Among the 92 patients with BMI, a second extranodal involvement was present in only 25 patients (27%). In multivariate analysis, the 5 independent factors that predicted for BMI were B symptoms, infradiaphragmatic involvement, mixed cellularity (MC) and lymphocyte depleted (LD) histology, involvement of > or = 4 lymphatic areas, and liver involvement. The probability of BMI according to the presence of these variables was distributed as follows: 0.3%, 2.5%, 7.6%, and 27% in patients positive for 0, 1, 2, and > or = 3 factors, respectively. Among 51 patients staged with bilateral BMB, BMI was shown in both specimens in 33 cases (65%), whereas the positivity was limited to only 1 of the 2 specimens in the remaining 18 cases (35%). A score based on 5 variables can predict the probability of BMI, and BMB could be avoided in patients with a score of 0 and a probability of BMI of < 0.5%. When BMB is needed, the superiority of bilateral over unilateral biopsy is suggested.

High-dose sequential chemotherapy and peripheral blood progenitor cell autografting in patients with refractory and/or recurrent Hodgkin lymphoma: a multicenter study of the intergruppo Italiano Linfomi showing prolonged disease free survival in patients treated at first recurrence.

BACKGROUND: The objective of the current study was to evaluate in a multicenter setting the feasibility and efficacy of a high-dose sequential (HDS) chemotherapy regimen that combined intensive debulking and high-dose therapy (HDT) with peripheral blood progenitor cell (PBPC) autografting in patients with refractory or recurrent Hodgkin lymphoma (HL). METHODS: Data were collected from 102 patients with HL who were treated with the HDS regimen at 14 centers associated with the Intergruppo Italiano Linfomi. Twenty-four patients had primary refractory HL, 59 patients had their first recurrence of HL (within 1 year in 32 patients and > 1 year in 27 patients), and 19 patients had multiple disease recurrences. The HDS regimen included the sequential delivery of high-dose (hd) cyclophosphamide with PBPC harvesting, methotrexate, etoposide, then HDT (usually hd mitoxantrone plus L-phenylalanine mustard) with PBPC autografting. In addition, radiotherapy was delivered to 36 patients at sites of bulky or persistent disease. RESULTS: Ninety-two patients (90%) completed the HDS program. There were five toxic deaths (treatment-related mortality rate, 4.9%) and six secondary malignan cies (five patients developed myelodysplastic syndrome/acute myelogenous leukemia, and one patient developed colorectal carcinoma). At a median follow-up of 5 years, the 5-year overall survival (OS) and event-free survival (EFS) projections were 64% (95% confidence interval [95% CI], 54-74%) and 53% (95% CI, 43-63%), respectively. Patients with their first recurrence had the most favorable outcome, with 5-year OS and EFS projections of 77% (95% CI, 66-88%) and 63% (95% CI, 50-76%), respectively. There were no significant differences between patients with early first recurrence and late first recurrence. The poorest outcome was observed in patients with refractory HL, with 5-year OS and EFS projections of 36% (95% CI, 16-55%) and 33% (95% CI, 14-52%), respectively. Patients who received HDS chemotherapy after multiple recurrences had an intermediate outcome. Multivariate analysis showed that refractory disease and systemic symptoms at the time of initial presentation were associated significantly associated with poor OS and EFS. CONCLUSIONS: The use of HDS chemotherapy for patients with refractory and/or recurrent HL is feasible at the multicenter level. The combination of intensive debulking and HDT with PBPC autografting offers a good chance of prolonged disease free survival for patients with their first recurrence of HL.

Allogeneic compared with autologous stem cell transplantation in the treatment of patients younger than 46 years with acute myeloid leukemia (AML) in first complete remission (CR1): an intention-to-treat analysis of the EORTC/GIMEMAAML-10 trial.

In the European Organization for Research and Treatment of Cancer Leukemia Group and Gruppo Italiano Malattie Ematologiche dell' Adulto (EORTC-LG/GIMEMA) acute myeloid leukemia (AML)-10 trial, patients in first complete remission (CR1) received a single intensive consolidation (IC) course. Subsequently, those patients younger than 46 years with an HLA-identical sibling donor were assigned to undergo allogeneic (allo) stem cell transplantation (SCT), and patients without such a donor were planned for autologous (auto) SCT. Between November 1993 and December 1999, of 1198 patients aged younger than 46 years, 822 achieved CR. The study group constituted 734 patients who received IC: 293 had a sibling donor and 441 did not. Allo-SCT and auto-SCT were performed in 68.9% and 55.8%, respectively. Cytogenetic determination was successfully performed in 446 patients. Risk groups were good (t(8;21), inv16), intermediate (NN or -Y only), and bad/very bad (all others). Median follow-up was 4 years; 289 patients relapsed, 66 died in CR1, and 293 died. Intention-to-treat analysis revealed that the 4-year disease-free survival (DFS) rate of patients with a donor versus those without a donor was 52.2% versus 42.2%, P =.044; hazard ratio = 0.80, 95% confidence interval (0.64, 0.995), the relapse incidence was 30.4% versus 52.5%, death in CR1 was 17.4% versus 5.3%, and the survival rate was 58.3% versus 50.8% (P =.18). The DFS rates in patients with and without a sibling donor were similar in patients with good/intermediate risk but were 43.4% and 18.4%, respectively, in patients with bad/very bad risk cytogenetics. In younger patients (15-35 years), the difference was more pronounced. The strategy to perform early allo-SCT led to better overall results than auto-SCT, especially for younger patients or those with bad/very bad risk cytogenetics.

Induction therapy with idarubicin alone significantly influences event-free survival duration in patients with newly diagnosed hypergranular acute promyelocytic leukemia: final results of the GIMEMA randomized study LAP 0389 with 7 years of minimal follow-up.

Shortly before the all-trans retinoic acid (ATRA) era, the GIMEMA cooperative group initiated a randomized study comparing idarubicin (IDA) alone with IDA plus arabinosylcytosine (Ara-C) as induction treatment in patients with newly diagnosed hypergranular acute promyelocytic leukemia (APL). Of the 257 patients evaluable for induction treatment, 131 were randomized to receive IDA alone (arm A) and 126 to receive IDA + Ara-C (arm B). Treatment in arm A consisted of 10 mg/m(2) IDA daily for 6 consecutive days, whereas in arm B it consisted of 12 mg/m(2) IDA daily for 4 days combined with 200 mg/m(2) Ara-C daily in continuous infusion for 7 days. Once in complete remission (CR), patients received 3 consolidation courses of standard chemotherapy, and those still in CR at the end of the consolidation were randomized to receive or not receive 1 mg/kg 6-mercaptopurine daily and intramuscular injections of 0.25 mg/kg methotrexate weekly for 2 years. Overall, 100 (76.3%) patients in arm A and 84 (66.6%) patients in arm B achieved CR (P = NS). Event-free survival (EFS) rates were 35% and 23% for patients in arm A and arm B, respectively (P =.0352). Multivariate analysis revealed that EFS was favorably influenced by induction treatment with IDA alone (P =.0352) and unfavorably influenced by white blood cell (WBC) counts greater than 3000/microL (P =.0001) and increasing age (P =.0251). These results indicate that anthracycline monochemotherapy with IDA favorably influences the EFS of patients with newly diagnosed hypergranular APL.

MDR1 protein expression is an independent predictor of complete remission in newly diagnosed adult acute lymphoblastic leukemia.

Little is known about the prognostic role of multidrug resistance (MDR) in adults with newly diagnosed acute lymphoblastic leukemia (ALL). In the context of the GIMEMA ALL0496 protocol, we evaluated the impact of MDR1 (protein expression and function) on the achievement of complete remission (CR) and clinical outcome. Flow cytometric analysis of MDR1 expression (D) and function (rhodamine-123 efflux) was obtained in 203 and 158 patients, respectively. MDR1 expression was detected in 44 (21.7%) of 203 patients, and function was found in 23 (14.6%) of 158 (14.6%) patients. Expression of the multidrug resistance-associated protein 1 (MRP1) and lung-resistance protein (LRP) evaluated in 43 samples was found in 13 and 26 patients, respectively. Among the 200 patients evaluable for the clinical correlation study, 125 (79.6%) of 157 without MDR1 expression achieved CR compared with 23 (53.5%) of 43 with MDR1 expression (P =.001). At univariate analysis, MDR1 expression was significantly associated with CR when considered as a dichotomized (P =.001) or continuous (P =.01) variable. At multivariate analysis, dichotomized evaluation of MDR1 expression independently predicted CR (P =.004) with age (P =.03) and CD34 (P =.03); as a continuous variable, MDR1 expression (P =.03) was the only significant factor other than CD34 (P =.01). MDR1 function failed to predict achievement of CR or of MRP1 and LRP expression. MDR1 expression did not correlate with CR duration, nor did it predict for survival duration. These results demonstrate that MDR1 expression in de novo adult ALL is an independent predictor of CR achievement.

Detection of minimal residual disease in peripheral blood stem cells from two acute myeloid leukemia patients with trisomy 8 predicts early relapse after autologous bone marrow transplantation.

We report two cases of acute myeloid leukemia (AML) French-American-British M4 classification with trisomy 8 at diagnosis as the sole chromosome abnormality. Both patients were treated with the GIMEMA AML-10 protocol and underwent autologous bone marrow transplantation (ABMT) in hematologic remission. Peripheral blood stem cells (PBSC), and bone marrow in one patient, were collected after consolidation therapy and tested by fluorescence in situ hybridization (FISH) analysis with an alpha-satellite probe for chromosome 8. It revealed that all samples were positive for minimal residual disease (MRD) as the value of trisomic cells exceeded the mean +3 standard deviations of the controls. ABMT was done following a myeloablative regimen (busulphan/cyclophosphamide) and PBSC were reinfused. Both patients relapsed, 4 and 2 months, respectively, after autotransplant. Although more data are needed, these results suggest that the persistence of MRD, as detected by FISH, in stem cell collections, is associated with a poor outcome in AML patients with trisomy 8 undergoing ABMT.