La Marseillaise (Subtitulado en francés y español)

TODOS NACEMOS IGUALES

REVOLUCION FRANCESA: TOMA DE LA BASTILLA

14 de julio de 1789 Caída de la Bastilla en Paris
Fecha conmemorativa de la Revolución Francesa uno de cuyos logros y antecedente de movimientos libertarios fue la

Declaración de los Derechos del Hombre del
26 de agosto de 1789
Los representantes del pueblo francés, constituidos en Asamblea nacional, considerando que la ignorancia, el olvido o el menosprecio de los derechos del hombre son las únicas causas de las calamidades públicas y de la corrupción de los gobiernos, han resuelto exponer, en una declaración solemne, los derechos naturales, inalienables y sagrados del hombre, a fin de que esta declaración, constantemente presente para todos los miembros del cuerpo social, les recuerde sin cesar sus derechos y sus deberes; a fin de que los actos del poder legislativo y del poder ejecutivo, al poder cotejarse a cada instante con la finalidad de toda institución política, sean más respetados y para que las reclamaciones de los ciudadanos, en adelante fundadas en principios simples e indiscutibles, redunden siempre en beneficio del mantenimiento de la Constitución y de la felicidad de todos.
En consecuencia, la Asamblea nacional reconoce y declara, en presencia del Ser Supremo y bajo sus auspicios, los siguientes derechos del hombre y del ciudadano:
Artículo primero.- Los hombres nacen y permanecen libres e iguales en derechos. Las distinciones sociales sólo pueden fundarse en la utilidad común.
Artículo 2.- La finalidad de toda asociación política es la conservación de los derechos naturales e imprescriptibles del hombre. Tales derechos son la libertad, la propiedad, la seguridad y la resistencia a la opresión.
Artículo 3.- El principio de toda soberanía reside esencialmente en la Nación. Ningún cuerpo, ningún individuo, pueden ejercer una autoridad que no emane expresamente de ella.
Artículo 4.- La libertad consiste en poder hacer todo aquello que no perjudique a otro: por eso, el ejercicio de los derechos naturales de cada hombre no tiene otros límites que los que garantizan a los demás miembros de la sociedad el goce de estos mismos derechos. Tales límites sólo pueden ser determinados por la ley.
Artículo 5.- La ley sólo tiene derecho a prohibir los actos perjudiciales para la sociedad. Nada que no esté prohibido por la ley puede ser impedido, y nadie puede ser constreñido a hacer algo que ésta no ordene.
Artículo 6.- La ley es la expresión de la voluntad general. Todos los ciudadanos tienen derecho a contribuir a su elaboración, personalmente o por medio de sus representantes. Debe ser la misma para todos, ya sea que proteja o que sancione. Como todos los ciudadanos son iguales ante ella, todos son igualmente admisibles en toda dignidad, cargo o empleo públicos, según sus capacidades y sin otra distinción que la de sus virtudes y sus talentos.
Artículo 7.- Ningún hombre puede ser acusado, arrestado o detenido, como no sea en los casos determinados por la ley y con arreglo a las formas que ésta ha prescrito. Quienes soliciten, cursen, ejecuten o hagan ejecutar órdenes arbitrarias deberán ser castigados; pero todo ciudadano convocado o aprehendido en virtud de la ley debe obedecer de inmediato; es culpable si opone resistencia.
Artículo 8.- La ley sólo debe establecer penas estricta y evidentemente necesarias, y nadie puede ser castigado sino en virtud de una ley establecida y promulgada con anterioridad al delito, y aplicada legalmente.
Artículo 9.- Puesto que todo hombre se presume inocente mientras no sea declarado culpable, si se juzga indispensable detenerlo, todo rigor que no sea necesario para apoderarse de su persona debe ser severamente reprimido por la ley.
Artículo 10.- Nadie debe ser incomodado por sus opiniones, inclusive religiosas, a condición de que su manifestación no perturbe el orden público establecido por la ley.
Artículo 11.- La libre comunicación de pensamientos y de opiniones es uno de los derechos más preciosos del hombre; en consecuencia, todo ciudadano puede hablar, escribir e imprimir libremente, a trueque de responder del abuso de esta libertad en los casos determinados por la ley.
Artículo 12.- La garantía de los derechos del hombre y del ciudadano necesita de una fuerza pública; por lo tanto, esta fuerza ha sido instituida en beneficio de todos, y no para el provecho particular de aquellos a quienes ha sido encomendada.
Artículo 13.- Para el mantenimiento de la fuerza pública y para los gastos de administración, resulta indispensable una contribución común; ésta debe repartirse equitativamente entre los ciudadanos, proporcionalmente a su capacidad.
Artículo 14.- Los ciudadanos tienen el derecho de comprobar, por sí mismos o a través de sus representantes, la necesidad de la contribución pública, de aceptarla libremente, de vigilar su empleo y de determinar su prorrata, su base, su recaudación y su duración.
Artículo 15.- La sociedad tiene derecho a pedir cuentas de su gestión a todo agente público.
Artículo 16.- Toda sociedad en la cual no esté establecida la garantía de los derechos, ni determinada la separación de los poderes, carece de Constitución.
Artículo 17.- Siendo la propiedad un derecho inviolable y sagrado, nadie puede ser privado de ella, salvo cuando la necesidad pública, legalmente comprobada, lo exija de modo evidente, y a condición de una justa y previa indemnización.

POESIA BRASILEÑA : UN PAR DE CLICS

Tensar un arco: tres poetas brasileños
Jair Cortés
Son muchos los beneficios que nuestro momento histórico nos ofrece como lectores de poesía: acceso irrestricto a variadas bibliotecas virtuales; páginas de literatura en todos los idiomas; blogs de autores en los que se publican textos literarios, bitácoras y diarios personales y un sin número de foros en los que podemos interactuar y convertirnos en parte sustancial de la inabarcable red de información. Ahora no debemos esperar años o décadas para conocer la literatura escrita en otras partes de nuestro continente, no es necesario el traslado físico para acercarnos a otros poetas, bastan un dato y un par de clics para abrir las ventanas del tiempo y saber qué es exactamente lo que en materia de poesía se escribe en la actualidad. Quizá sea esta misma ventaja la que, bien mirada, sea la principal barrera para conocer una totalidad. Si toda selección implica una omisión, no serán pocas las partes omitidas al querer mostrar una generalidad. Esta circunstancia habrá de impedir que volvamos a afirmar, con la seguridad que veníamos haciéndolo, frases como Nueva poesía mexicana, Poesía brasileña reciente o Nueva poesía catalana. No son posibles ya la antología, la selección y la muestra como terrenos seguros y confiables, en los que se anuncie un panorama amplio que ilustre lo mayormente posible de un quehacer escritural. Consciente del fangoso terreno que describo, me limito a presentar a tres de los jóvenes poetas brasileños que he leído recientemente. La familiaridad entre el idioma portugués y el español nos permite indagar con menos dificultad cuáles son los registros sobre los que se mueve la poesía de Brasil, misma que no ha sido extraña para los lectores de México. Joao Cabral Melo de Neto, Carlos Drummond de Andrade, Haroldo y Augusto de Campos, Ledo Ivo, Vinicius de Moraes, entre otros, son nombres que nos resultan cercanos. La presente traducción intenta estrechar aún más esa cercanía, en la que ya figuran poetas que comenzaron a publicar en la década de los años noventa, como Franklin Alves, Leonardo Gandolfi, Diego Vinhas, Delmo Montenegro, Bárbara Lia, Eduardo Jorge, Adriana Zapparoli, Simone Homem de Mello, Virna Teixeira, André Dick y Fabiano Calixto.
Claudio Daniel, poeta y ensayista, ha dicho: “ Los nuevos poetas leen a João Cabral y la Poesía Concreta , y también autores como el cubano Lezama Lima, el portugués Herberto Helder y el rumano Paul Celan, en busca de nuevas posibilidades creativas”; además, agrega, que los autores que pertenecen a la reciente generación de poetas brasileños (en la que incluye a Virna Teixeira, Eduardo Jorge y Adriana Zapparoli), se interesan por “las arquitecturas más complejas del sonido y la imagen, más allá del registro fotográfico de lo cotidiano o de la parodia de la crónica periodística” y, por otro lado saben “la importancia de la Poesía Concreta , del Neobarroco, del Language Poetry, sin rechazar el diálogo con esas tendencias inventivas ni la presencia del Pop”.
Virna Teixeira ha publicado dos libros de poesía: Visita (2000) y Distancia (2005), en los que apuesta por la concreción del poema. En breves repasos a la realidad muestra imágenes, como fogonazos, para evocar o aludir estados de ánimo, casi todos relacionados con lo nostálgico. Situaciones que dan noticia de cómo vivimos la modernidad y que actualizan al “hombre solitario de la multitud” señalado por Baudelaire y Poe. Teixeira se distancia del mundo, pero la experiencia con la palabra habrá de reunirla sólo con fragmentos de aquel.
Los poemas de Eduardo Jorge describen pacientemente imágenes y paisajes que intentan, con mayor soltura verbal, revelar un misterio; su decir es pausado, descriptivo, creando un ambiente eficaz dentro del poema. En 2004 publicó un extenso poema titulado “San Pedro”, en el que la intertextualidad, el uso del verso de largo aliento, combinado con la prosa poética y los versos breves, conforman una estructura sólida en donde las ideas y ambientes surrealistas son sus características más notables.
Adriana Zapparoli está incluida en diversas antologías de poesía brasileña y tiene una activa participación en medios electrónicos, como las revistas virtuales Zunai y A cigarra. Zapparoli propone una estructura poética basada en el vertiginoso uso de palabras y en la acumulación de descripciones para crear una estética de la saturación: un motivo desencadena una avalancha de significados, una especie de zoología de la palabra.
Leyendo a estos tres poetas veo un arco poético que se tensa: va de la concentración verbal de Virna Teixeira a la soltura de Eduardo Jorge, para terminar en la desbordada discursividad de Adriana Zapparoli. Hay aquí tres ejemplos claros de la renovada tradición poética brasileña, siempre dueña de una voluntad por explorar otros sitios y nuevas formas del decir a través del poema.

Virna Teixeira
Muros
Despuésdel portón
las lágrimas desembocan
*
Distancia
una llamada telefónica detres minutos
después,el silencio
del otro ladode la línea
Detox
Cubrió los moretones con gasa. Heridas cicatrizan con el tiempo. Aun cuando queden marcas. Memorias dibujadas en los huesos, adornos.
Tomó fotografías como registros. Meses después del trauma. Sin sangre en las conjuntivas.
Dejó atrás la cámara. Almohada, sábana blanca, el agua tibia del baño.
Invierno, recuerdo nocturno.
La transformación del rostro. Cuando retiró los vendajes, las suturas.
El día de la partida, árboles. De lado en el tren, la luz sobre los cabellos, castaños.
Virna Teixeira nació en Fortaleza (CE), en 1971, y reside en São Paulo. Es autora de Visita (2000) y Distancia (2005), ambos publicados por la editorial Sette Letras. Esta selección forma parte do su próximo libro de poemas, Transitos.

Eduardo Jorge
Engullir la presa viva:dos condiciones
–primer condición– (mitad del cuerpo dentro del otro) a la inversa del parto; duplica la vida dentro de sí, antes del inicio de la digestión arrancar cada parte del cuerpo–con perforaciones en línea –segunda condición– ver asustada la glotis dar con la cabeza en la laringe: prever máximas perforaciones
calmar las patas–aire por última vez: la serpiente sepultura
Naja esfinge
el enigma es el ardor de la tierra caliente bajo los pies pétreos e hinchados: acompañar los ojos de la presa su cansancio peregrino –y con costillas abiertas lanzar el desafío: abrir las cavidades en amenaza el visitante del vacío asume la postura estatua– siempre ella camino: si destino fuera, rumbos serían templos, serpientes de roca. en las presas el thelos –fijos, los músculos: al desistir seguirían horas, –veneno redentor en fuga subestimación, la esfinge, naja asalta: el perdedor ciego, la carne en breve despedida: huesos aran la estructura de la tierra y la flauta enmudecida: puerta arena: reloj de arena obstruido
Eduardo Jorge, poeta, nació en Fortaleza en 1978 (CE), donde edita la revista literaria Gazua.

Adriana Zapparoli
Lutra-lutra
unos de los caminos era aquel: acuático. respiraba distante y delante de su pelaje espeso, brillante y uniformemente castaño, con excepción de la región del vientre. dÉl el cuerpo, la cabeza y los ojos pequeños, se movía el timón la larga cola, afilada en la punta, casi espada. indecisa la presencia dElla. en cuanto se zambullía inmersa en su interior, el impulso de las patas. dÉl sentía el movimiento sinuoso del cuerpo. contenía aquella una nutriafagia poética de pez-anfibio, reptílica ave acuática. ética lírica. sus sistemas de galerías, sus entradas a zonas rocosas, sus entrañas, unas subacuáticas y otras al nivel del suelo.
*
Scorpion
la peregrina del desierto negro abandonaba, algunas veces, sus ojos lagartos al respirar la esencia de aquellas sílabas. la gramática monosilábica de aquél pensamiento escorpión de palpos comprimidos, demasiado horrendo y paralizante, se demoraba en su mente. sumergida en las aguas profundas de piedras marsupiales, capturaba a la luz de un oscuro hueco de protección. s us sueños prematuros estaban casi licuados. Vagaba por la noche, cuando un sollozo escapó de sus labios de atmósfera y pétalos triturados. mudando sus escamas atravesó una puerta fechada tras de sí. y fue entonces que él, lleno de coraje, se levantó, Asclépio, en la orilla de aquellas aguas.
Adriana Zapparoli es poeta y profesora de biología en la Unicamp. Su obra está incluida en la antología Poesía so poesía (Novas letras SP, 2004). Su página en internet es http://zeniteblog.zip.net/
Selección de Jair Cortés,versiones de Berenice Huerta y Jair Cortés

LA JORNADA SEMANAL, 12 DE JULIO 2009

FRANCO VOLPI : DILEMAS ETICOS

El pensar apasionado de Franco Volpi
Ángel Xolocotzi Yáñez
El 14 de abril de 2009 la filosofía mundial se llenó de luto. El pequeño hombre de mirada profunda que fascinaba a sus escuchas dejaba la vida, con apenas 57 años, a consecuencia de un absurdo accidente en bicicleta. Franco Volpi moría en Italia. De inmediato se difundió la noticia. La consternación fue general: Klaus Held, Jean François Courtine, Alejandro Vigo, Héctor Zagal, Félix Duque, Guillermo Hoyos, Alberto Constante Friedrich-Wilhelm von Herrmann, Jean Grondin, Rodolfo Santander y muchos otros que lo apreciaban estaban sin palabras. Era difícil creer que aquel hombre que recientemente había editado El arte de envejecer, de Arthur Schopenhauer no alcanzaría a poner plenamente en práctica tales recomendaciones. Sin embargo, los que lo conocimos coincidimos en que sin duda siguió las reglas de otro texto de Schopenhauer que había editado en 1997: El arte de ser feliz.
Franco Volpi era filósofo no sólo por vocación, sino por pasión. Su vida giró en torno al trabajo filosófico en múltiples facetas: investigador, provocador, editor, escritor, catedrático, conferenciante, traductor y pensador. Su obra trunca, que ahora pasa a ser obra completa, es un verdadero ejemplo de inquietud y constancia. Sus corazonadas siempre dieron frutos determinantes. Ya desde su tesis doctoral comenzó con fuertes provocaciones. Ninguno de los viejos alumnos de Heidegger podía aceptar que la cuasi divina radicalidad del maestro de la Selva Negra derivara de sus lecturas aristotélicas. Volpi se mantuvo firme frente a las críticas de Max Müller, Heinrich Rombach y Rudolf Berlinger. Estaba convencido de que Ser y tiempo provenía de una lectura cuidadosa de la Ética nicomaquea, de Aristóteles. Diez años después de este atrevimiento, la publicación de las primeras lecciones de Heidegger comenzó a darle la razón. Ahora, a treinta años de distancia, eso ya no está en discusión.
Vivió abriendo caminos y preparó senderos en múltiples direcciones. Muestra clara de ello son no sólo las ediciones de textos inéditos de Schopenhauer, sino también la difusión de autores latinoamericanos, como el colombiano Nicolás Gómez Dávila. No me avergüenzo si reconozco que supe de él precisamente a través de Franco. Para Volpi era imperativo dar a conocer pensamientos agudos. Si cada vez más el pensar se vuelve una excepción, lo poco que haya debe ser rescatado, sin importar de dónde provenga. Eso hacía de Franco un hombre interesado por todo en múltiples niveles: quizás en algo de eso podía esconderse alguna idea importante. La consecuencia de tal actitud era patente al convertirse el interesado en un muy apreciado dialogador. No se trataba de un académico acartonado, sino de un pensador apasionado. Quizás por ello Heidegger seguía siendo su pensador eje; compartía con él lo que ya Hannah Arendt había diagnosticado de su maestro: el pensar y el estar vivo son una y la misma cosa.
Las pasiones del pensar condujeron a Volpi a realizar obras fascinantes. Ya durante su estancia en la Universidad de Witten/Herdecke inició la coordinación de la monumental Enciclopedia de obras de filosofía que, como sabemos ahora, es una herramienta de consulta fundamental comparable con el monumental Historisches Wörterbuch der Philosophie que inició Joachim Ritter, alumno del joven Heidegger. A la par de tal empresa, Volpi llevaba a cabo su labor docente y de investigador en diversas direcciones. Por un lado preparaba de modo vivo el terreno para una mejor comprensión de la relación entre vida y obra de Heidegger. Las entrevistas que Franco realizó a Hermann Heidegger, Ernst Jünger, Hans-Georg Gadamer, Ernst Nolte y Armin Mohler son testimonios de ello. Asimismo, al ser víctima del encantamiento heideggeriano, gran parte de su trabajo lo centró en el cuidado y difusión de la obra del maestro alemán. Prueba fehaciente de ello es la coordinación y traducción de múltiples textos de Heidegger, así como la publicación de su Guida a Heidegger y un sinnúmero de artículos en revistas distribuidas por todo el mundo. De ese modo, el nombre Franco Volpi era familiar para muchos. Sin embargo, la diferencia con respecto a otros pensadores es que Franco era tan respetado como querido.
Por lo menos desde 2003 comienza a frecuentar México. Aquí en Latinoamérica se sentía en casa. Cuando recibía invitaciones de varios lugares, primero nos preguntaba si estábamos organizando algo para así darnos prioridad. Volpi tuvo la experiencia latinoamericana de otros filósofos europeos como Klaus Held, Arturo Leyte o Miguel García-Baró: aquí la filosofía no es un mero asunto académico, sino vital. Esa afortunada coincidencia agendó las visitas anuales de Volpi a nuestro país.
La muerte de Franco Volpi trunca una obra importante en ciernes. Volpi se encontraba en ese momento como Heidegger antes de Ser y tiempo o Gadamer antes de Verdad y método. Así, a pesar de ser conocido por su elocuencia y dotes de investigador, su obra principal venía en camino. Se trataba de una propuesta propia en torno a la filosofía práctica. Tal obra no aparecerá; sin embargo han quedado suficientes ideas y trabajo para recordar a Franco como a uno de los grandes filósofos. No sólo sus investigaciones sobre el aristotelismo de Heidegger, sino sus propuestas sobre el nihilismo y el compromiso práctico de la filosofía seguirán vigentes. Asimismo, su cuidado de la tradición filosófica, de Platón a Jünger, será dignificado en su ejemplaridad.
Si parte de la grandeza de un pensador no se mide sólo por lo que ha publicado, sino por los impulsos que ha dado, entonces indudablemente Franco Volpi entrará en este rango. Quedará su ausencia muy presente, pero también quedarán los caminos abiertos con sus propuestas y trabajo. Y todavía algo más: la repetida invitación de Franco a embellecer la vida, pues decía: “La vida no es bella, pero hay que hacerla bella.” Eso es motivo suficiente para agradecerle su generosidad como amigo y como pensador, y honrarlo como corresponde: pensando su obra. Adiós Franco.

Diálogo con Franco Volpi(fragmentos)
Ángel Xolocotzi Yáñez
– ¿Cómo fue que te interesaste en Heidegger y cómo llegaste a la fenomenología?
– Mi formación fue primariamente filológica. Sin embargo, en Italia se imparte, ya en el colegio, Historia de la filosofía, la cual estudié a la par de la filología clásica. Mi maestro de filosofía en el colegio era un excelente especialista en Platón y en Plotino, había publicado entre otros textos una edición crítica de las Eneadas. Gracias a él empecé a orientar mis intereses hacia la filosofía y decidí estudiar en Padua, en donde había una escuela de tradición aristotélica. El primero que me sugirió ocuparme de Heidegger fue Enrico Berti, un aristotélico italiano reconocido en el mundo. Él estaba interesado en la reconstrucción de la tradición del aristotelismo de manera filológicamente fundada. En aquella época yo había leído la carta que Heidegger escribió al padre Richardson, donde Heidegger menciona que sus primeros pasos fueron determinados por la tesis doctoral de Franz Brentano. Recuerdo que Berti me dijo: “¡Ah! ¡Ese podría ser el tema de tu tesis doctoral!, indagar en qué medida Aristóteles ha sido importante para Heidegger.” Este fue el tema de mi tesis.
– ¿Qué sentido tiene filosofar en el mundo contemporáneo?
–La filosofía tiene que ser crítica consigo misma, no debe pretender ofrecer más de lo que honestamente puede dar. Aunque te diré que efectivamente uno espera siempre algo de la filosofía. Por ello tenemos que delimitar bien los ámbitos en los que puede hacer contribuciones. Por ejemplo, al definir la Constitución europea surgieron preguntas sobre quiénes somos, qué es Europa y qué valores la fundamentan. Nos preguntamos si la unidad era sólo económica, si poco a poco se iba volviendo más política y qué tan benéfico sería hablar o proponer la idea de una unidad cultural. En este contexto me parece importante la participación de los filósofos, porque creo que ellos tienen conocimiento del pasado europeo y su tarea es importante en la medida en que humildemente quieran trabajar a la par con políticos, juristas, teólogos. Los filósofos pueden indicar perspectivas históricas y conceptuales para ayudar a formular esta carta. Como de hecho aconteció después de la segunda guerra mundial en la redacción de la declaración de los derechos universales del hombre. Jacques Maritain fue uno de los filósofos involucrados en la elaboración de este documento fundamental. Y se puede ver que ahí las palabras “hombre”, “individuo”, “persona” tienen una función específicamente pensada: la primera remite al ser humano en un sentido general, la segunda refleja una semántica liberal y la tercera una tradición católica cristiana. De ahí la importancia de que cartas de este tipo sean fundamentadas desde una perspectiva conceptual y filosófica.
– Pero en la vida cotidiana ¿tiene algo que decir la filosofía?
–La filosofía no sólo es indispensable en estas grandes ocasiones. Hay también un gran trabajo por hacer en ámbitos más sencillos y menos visibles como lo es el ámbito de la medicina. Aquí la filosofía práctica tiene una función regulativa importante en la aplicación de las normas generales a casos particulares. Durante un tiempo pertenecí a un comité ético de un hospital y tuve una experiencia directa de lo que eso implica. El conocimiento de los principios generales tiene que ser aplicado a los casos concretos, se debe ayudar a pensar y determinar qué se hace en cada situación. Por ejemplo, cómo puedo ayudar a una madre que a través de un diagnóstico prenatal sabe que su hijo va a nacer discapacitado. ¿Es permisible el llamado aborto terapéutico? ¿En nombre de qué valores se puede justificar? ¿La calidad de vida o la felicidad del individuo son criterios para tomar una decisión tan importante? Obviamente la madre es quien decide, pero es necesario que esté informada y que haya recibido una orientación para que asuma una decisión de manera consciente. Es común que en estos comités haya un abogado, un teólogo, un psicólogo, pero es importante que también haya un filósofo y que éste no tenga pretensiones de poseer un saber más alto, sino que contribuya con su capacidad para tomar mejores decisiones.
La filosofía ya ha perdido el papel tradicional de reina de las ciencias. Sin embargo, conserva una competencia histórica y conceptual que nos da luces para razonar sobre problemas concretos y buscar soluciones a casos particulares. Este trabajo es más humilde pero no menos importante, y además convierte a la filosofía en una disciplina viva que busca en su pasado intuiciones y recursos simbólicos que le permitan leer los problemas actuales a los que se enfrenta. Así puede ejercer una función de orientación o de consejo. Con ello la filosofía recupera su originaria y tradicional cercanía con la vida, de la que se distanció en la época moderna y de la que permanece distante aún en la contemporánea. Con el tiempo la filosofía se ha ocupado sólo de la construcción de un edificio teórico, pues había sido originariamente una forma de vida. Creo, con Kant, que cada ser humano tiene la capacidad de pensar por sí mismo y, en la medida en que activa esa capacidad, independientemente de la profesión o función social que tenga, es él mismo un filósofo. Entonces la filosofía no está reservada a especialistas de historia de la filosofía, ni es algo que se practique únicamente en el cubículo del profesor catedrático, sino que pertenece a cualquier ser humano en tanto éste se proponga razonar de manera auténtica: ¡Sapere aude!, declara Kant, “¡Ten el valor de servirte de tu razón de manera autónoma!”, para salir del estado de minoría en el que está la mayoría de la gente. Se trata de un don invaluable del ser humano, que es el pensar por uno mismo. Así, la filosofía interpretada como ejercicio de la capacidad crítica del pensar pertenece potencialmente a cualquier ser humano.

LA JORNADA SEMANAL,12 DE JULIO 2009

OSTEOGENESIS IMPERFECTA

NEW ENG J MED,Volume 361:74-79
July 2, 2009
Number 1
A Fragile Balance
Asaf Bitton, M.D., Maria Yialamas, M.D., Bruce D. Levy, M.D., Joel T. Katz, M.D., and Joseph Loscalzo, M.D., Ph.D.
A 31-year-old man presented to the emergency department with pain in the left shoulder. He had tripped over the shoulder strap of his backpack earlier in the day and noted immediate severe pain around his left shoulder, without paresthesias or neck pain. Physical examination revealed bony point tenderness over the humeral head and limited range of motion due to pain; crepitus was present. Shoulder radiographs revealed an impacted fracture of the left humerus and evidence of osteopenia (Figure 1).
Figure 1. Radiograph of the Left Shoulder.
The impacted humeral fracture (large arrow) and osteopenia (small arrow) are shown.
This man had a traumatic fracture of his left humerus and was noted to have radiographic evidence of osteopenia. Plain radiographs are not sensitive for bone loss; the fact that osteopenia was detected on such imaging suggests considerable bone loss, and a formal assessment of bone mineral density (e.g., by means of dual-energy x-ray absorptiometry) is warranted. When osteopenia is suspected in a male patient who is younger than 50 years, a careful history taking is essential. The key components should include questions about fractures and the circumstances in which they occurred, growth and pubertal development in childhood, medication use, a thorough review of systems to screen for systemic diseases (particularly endocrinologic, gastrointestinal, hematologic, renal, and genetic diseases that might disrupt bone homeostasis or formation), and a family history of fractures or systemic diseases.
The patient reported normal pubertal development but was underweight as a child, with difficulty gaining weight. He had remained thin in adulthood until 2 years previously, when he unintentionally gained 20 lb (9 kg), which he maintained. There were no changes in his diet or exercise pattern. He reported chronic fatigue, general weakness, diminished libido, and easy bruising. No diarrhea, oral ulcers, arthralgias, or rashes were reported. He did not engage in excessive exercise or contact sports or have a history suggestive of an eating disorder. His medical history was notable for multiple fractures of the femur, elbow, and wrist, without previous evaluation. Additional history included pericarditis, erectile dysfunction, perforated tympanic membranes, hypertension, retinal tears with partial early detachments, myopia, kyphoscoliosis, β-thalassemia trait, and esophageal reflux. The patient was a university graduate student. He took no medications. He smoked 10 cigarettes per day and did not use ethanol or illicit drugs. There was no history of fractures in his mother, father, or 36-year-old brother. His mother had hypothyroidism and fibromyalgia, and his father had melanoma and benign prostatic hypertrophy.
The history of fractures should prompt a detailed assessment of known or occult causes of trauma, such as abuse, as well as initiation of a metabolic and genetic evaluation. If the diagnosis of severe osteopenia or osteoporosis is established by means of dual-energy x-ray absorptiometry, evaluation is warranted for secondary causes of bone loss.
On physical examination, one should look for signs of systemic diseases. Blue sclerae are suggestive, but not pathognomonic, signs of osteogenesis imperfecta. Moon facies, central obesity, and wide purple striae are suggestive of hypercortisolism.
On physical examination, the patient appeared to be in mild discomfort from his fracture. His height was 175 cm, weight 76 kg, and body-mass index (the weight in kilograms divided by the square of the height in meters) 24.9. His blood pressure was 134/98 mm Hg, and his pulse 86 beats per minute and regular. He did not have moon facies or scleral discoloration. The pupils were equal and reactive to light. The oropharynx and teeth appeared normal. There was no lymphadenopathy in the cervical, axillary, or inguinal areas. The thyroid was normal in size and without nodules. The lung fields were clear on auscultation. No gynecomastia was present. Cardiac examination revealed a nondisplaced point of maximal impulse, regular rate and rhythm, and no murmurs, rubs, or gallops. Back examination revealed kyphosis and scoliosis of the thoracic spine. Multiple areas of tenderness were palpated over the posterior left ribs. The abdomen was soft and nontender, with normal bowel sounds and no hepatosplenomegaly or masses. The bilateral testicular volume was normal. The skin was pale, with multiple nevi as well as ecchymoses over the left shoulder. No striae or rashes were observed. Examination of the shoulder was limited by the patient's pain, but the nerves and vascular structures of the left arm appeared to be intact. Reflexes were normal, and there was no proximal-muscle weakness or joint laxity or hypermobility.
The physical examination shows no obvious signs of endocrinologic or genetic disorders. However, the patient does have evidence of kyphoscoliosis, suggesting possible past vertebral compression fractures. Furthermore, the pain over his thoracic ribs could indicate additional fractures from his recent trauma or past rib fractures that have healed incompletely. The initial laboratory evaluation should include an assessment for secondary causes of bone loss in young men, with tests of thyroid, parathyroid, renal, and gonadal function, as well as vitamin D levels.
The white-cell count was 7710 per cubic millimeter, hematocrit was 41.5% with a mean corpuscular volume of 60 µm3, and platelet count was 233,000 per cubic millimeter. The level of blood urea nitrogen was 15 mg per deciliter (5.4 mmol per liter), creatinine 1.1 mg per deciliter (97 µmol per liter), calcium 8.8 mg per deciliter (2.2 mmol per liter), albumin 4.5 g per deciliter, and phosphate 3.6 mg per deciliter (1.2 mmol per liter). Electrolytes and liver-function results were normal except for a slight elevation in the aspartate aminotransferase level, at 53 U per liter (normal range, 7 to 52). Total protein and thyrotropin levels were normal. The 25-hydroxyvitamin D level was 35 ng per milliliter (87 nmol per liter) (normal range, 25 to 80 ng per milliliter [62 to 200 nmol per liter]), and the parathyroid hormone level was 56 pg per milliliter (normal range, 11 to 80). The morning cortisol level was 11.7 µg per deciliter (322.8 nmol per liter). A urinalysis was normal. A morning total testosterone level was 1569 pg per milliliter (5440 pmol per liter) (normal range, 2220 to 6650 pg per milliliter [7697 to 23,056 pmol per liter]). The level of luteinizing hormone was 3.2 mU per milliliter (normal range, 1.7 to 8.6), and the follicle-stimulating hormone level was 1.7 mIU per milliliter (normal range, 3.1 to 12.2).
The patient had an uncomplicated open reduction and internal fixation of the left humeral head. Morphine and oxycodone were prescribed for pain control. Bone fragments resected during surgery were evaluated for metabolic bone disease with the use of static histomorphometry. The bone marrow contained fat necrosis, reactive-appearing spindle cells, and granulation tissue, findings that were consistent with reactive changes. No clear diagnosis could be made on the basis of these findings. Dual-energy x-ray absorptiometry, performed after surgery, showed T scores of –4.4 in the spine, –2.7 in the hip, and –3.1 in the neck of the femur.
This patient's dual-energy x-ray absorptiometry scan shows osteoporosis (i.e., a T score >2.5 SD below the mean for a sex-matched healthy young adult). The severity of the patient's osteoporosis, early age at diagnosis, and extensive history of fractures point to a secondary cause.
A notable laboratory abnormality is the low level of total testosterone, with the normal level of luteinizing hormone and the subnormal level of follicle-stimulating hormone, which are not consistent with the low level of testosterone. These findings are suggestive of central hypogonadism, which could explain the osteoporosis as well as the patient's symptoms of erectile dysfunction, low libido, and fatigue. However, this single testosterone value has not been confirmed, and levels may be temporarily suppressed owing to acute stress, the use of narcotic analgesic drugs, or the time of day when the sample was drawn (since testosterone levels vary diurnally and peak in the morning). In addition, most testosterone is bound to albumin and sex hormone–binding globulin; thus, conditions that affect levels of albumin or sex hormone–binding globulin also can influence testosterone levels. Repeat measurement of a morning total testosterone level is warranted before concluding that the patient has hypogonadism.
In addition to the diagnoses mentioned above, other underlying systemic conditions should be considered as possible causes of the patient's bone loss. Celiac disease is possible, given his history of being underweight, although he had no diarrhea or rash, and his vitamin D levels were normal. Alcoholism is another potential cause, but he reported that he did not consume ethanol, and it is unusual for ethanol overuse to cause severe bone loss at his young age. Cushing's syndrome is unlikely because of the normal proximal-muscle strength and the absence of other signs of cortisol excess. Multiple myeloma is extremely rare at this patient's age and is unlikely given his normal level of total serum protein. Other rare conditions to be considered include mastocytosis and hypercalciuria. Radiographic assessment for abnormal bone mineralization, pathologic fractures (or impending fractures), and lytic bone lesions should be performed as well.
A repeat outpatient measurement of the morning testosterone level was normal, at 3356 pg per milliliter (11,635 pmol per liter). An overnight dexamethasone suppression test and 24-hour urinary calcium and 1,25-dihydroxyvitamin D levels were normal. Results of serum and urinary protein electrophoresis and the insulin-like growth factor 1 (somatomedin C) level were normal. Tests for endomysial and tissue transglutaminase antibodies were negative. The tryptase level was normal. A skeletal survey showed multiple compression fractures of the thoracic spine without any lytic lesions (Figure 2). The patient was treated with risedronate at a dose of 35 mg weekly, calcium carbonate at a dose of 600 mg twice daily, and vitamin D2 at a dose of 50,000 IU weekly for 6 weeks, followed by a combination of calcium (500 mg) and vitamin D3 (200 IU) twice daily.
Figure 2. Radiograph of the Thoracic Spine.
The arrows point to compression fractures.
The normal testosterone level rules out hypogonadism as the cause of the patient's osteoporosis. The remaining laboratory findings are also unrevealing. The skeletal survey supports the presence of severe osteoporosis but does not show lesions suggestive of a malignant condition as a cause.
Additional history is needed, specifically focused on the circumstances of his previous fractures and on genetic or metabolic bone disease in his extended family. Therapy with a bisphosphonate, calcium, and vitamin D is reasonable to attempt to stop further bone loss while the evaluation continues. Smoking-cessation counseling should be offered to this patient, given the connection between tobacco use and bone loss. Although 400 IU of vitamin D was previously the recommended daily amount, in accordance with current recommendations, I would recommend at least 800 IU of vitamin D daily.
In response to more focused questions posed by the endocrinologist, the patient recalled that he had had multiple small fractures of his fingers while playing a musical instrument during his adolescence. He reported that approximately 10 years previously, he had sustained a rib fracture with minimal trauma while rolling on the floor. He also stated that a dentist had once told him that he had "thin tooth enamel."
This history of numerous fractures with minimal trauma and thin enamel, together with the history of retinal tears and eardrum perforations, suggests a particular defect in collagen fibers seen in osteogenesis imperfecta. The Ehlers–Danlos syndrome or Marfan's syndrome is less likely because of the patient's relatively normal stature and the absence of joint hypermobility and heart murmur. At this point, I would recommend sequencing of his collagen genes for osteogenesis imperfecta mutations. His parents should be referred for bone mineral density and genetic testing as well.
The patient underwent testing for osteogenesis imperfecta with sequencing of the genes for type I collagen (COL1A1 and COL1A2). Assessment for mutations that have previously been reported to be associated with osteogenesis imperfecta was negative, but mutations were detected in both collagen genes. His father had normal bone mineral density, and his mother had mild osteopenia, with T scores of –1.1 in the hip and –1.7 in the spine. The patient's parents did not undergo genetic testing.
The diagnosis of osteogenesis imperfecta is often made clinically without corresponding genetic information. This initial genotyping does not establish the diagnosis of osteogenesis imperfecta, although it may be consistent with the diagnosis. In addition, either of the amino acid changes could be consistent with a newly identified mutation; such mutations are detected in 60% of cases of osteogenesis imperfecta. A functional test of the patient's collagen fibers in a fibroblast–collagen synthesis assay could better characterize the physiological consequence of the amino acid changes and is an accepted means of establishing the diagnosis of osteogenesis imperfecta.
A skin biopsy was performed for functional testing of fibroblasts, which showed decreased production of type 1 procollagen. This finding, in combination with the patient's clinical history of normal growth, height, and fractures beginning in late childhood, was consistent with the diagnosis of type I osteogenesis imperfecta. Because he had gastrointestinal side effects with weekly oral risedronate, yearly infusion of zoledronic acid (2 mg intravenously) was initiated. Ten months after initiation of the bisphosphonate treatment, repeat dual-energy x-ray absorptiometry showed no significant change in the spine, femoral neck, or total hip but showed a 4.3% improvement in the trochanter. He has not had further fractures in the 36 months since beginning these therapies, and his bone pain has diminished.
Commentary
Although osteoporosis is more common in women than in men, it is an important cause of disability and death among both men and women. In the United States, osteoporosis is reported to affect 2 million men, 75% of whom are older than 65 years of age.1 Primary osteoporosis is characterized by age-related or idiopathic bone loss leading to decreased bone mass and thinning of the trabecular bone architecture. Causes of secondary osteoporosis in men can be wide-ranging; the three most common causes are corticosteroid use, excessive alcohol use, and hypogonadism.2 Other less common secondary causes include vitamin D deficiency, hyperthyroidism, hyperparathyroidism, certain medications, chronic liver disease, renal failure, a malignant condition, tobacco use, and Cushing's syndrome.2 An extensive search for secondary causes should be undertaken in young patients and should include consideration of genetic collagen disorders.
Osteogenesis imperfecta is a genetic disorder of collagen production (most often type I), occurring in approximately 1 of 20,000 live births.3 Osteogenesis imperfecta is categorized into eight major variants and multiple subvariants, ranging from minor phenotypic manifestations to lethal mutations. Most patients with osteogenesis imperfecta have mutations in the COL1A1 and COL1A2 genes that encode for alpha chains of type I collagen.4 Production of abnormal or reduced numbers of alpha chains results in thin and insufficiently mineralized bone, which leads to frequent fractures. The abnormal collagen alpha chains also are involved in the alterations seen in sclera, tympanic membranes, skin, and other highly collagenous tissue.
In this patient, initial tests were unrevealing or inconclusive, and the diagnosis of osteogenesis imperfecta was arrived at by following clues from a careful history taking and physical examination. A fibroblast functional assay was helpful in confirming the diagnosis after the initial findings of previously unreported mutations in the collagen genes. It is important to keep in mind that osteogenesis imperfecta is a clinical diagnosis, especially since many cases of the disorder arise from new mutations.
The diagnosis of osteogenesis imperfecta should be considered in patients who present with bone fragility, low bone density, and other clinical manifestations, such as joint laxity, thin dental enamel, early hearing loss, easy bruising, and scoliosis. Blue or gray scleral changes, if present, can suggest osteogenesis imperfecta, but these changes are often subtle in appearance, and in some patients they are absent. A family history of early osteoporosis and bone fragility is helpful but not necessary for the diagnosis. Although osteogenesis imperfecta most often presents in early childhood, some variants are more insidious and are not recognized until adulthood.
The differential diagnosis of osteogenesis imperfecta in children includes abuse, osteomalacia, rickets, and other rare skeletal syndromes. In patients with a family history and typical manifestations of osteogenesis imperfecta, genetic testing is not necessary to establish the diagnosis. As was seen in this patient, new mutations or atypical or mild features such as occasional minimally traumatic fractures or marked scoliosis present a diagnostic challenge. Functional analysis of type I collagen synthesis in a skin-biopsy specimen and genetic sequencing for mutations in COL1A1 and COL1A2 are most commonly used to establish the diagnosis, although a normal genetic sequencing test result does not rule out the diagnosis of osteogenesis imperfecta in the presence of other clinical findings that are consistent with this diagnosis.
Early diagnosis and treatment may reduce the risk of fracture, alleviate bone pain, reduce bone malformation, and increase mobility.3 Periodic audiometry, dual-energy x-ray absorptiometry, and spirometry are indicated as well. Echocardiography should be performed in patients with a severe variant of osteogenesis imperfecta (Sillence classification type III)4 that is associated with cardiac valvular dysfunction and dilatation of the aortic root.
The cornerstones of therapy for osteogenesis imperfecta are calcium, vitamin D, and bisphosphonates. Bisphosphonates are indicated for patients with moderate-to-severe osteogenesis imperfecta, with increasing evidence of efficacy even in mild cases.5 Observational studies in children and adults with osteogenesis imperfecta suggest that pamidronate increases cortical thickness of bone, decreases the incidence of long-bone fractures, and improves mobility.4 In small controlled trials, children with osteogenesis imperfecta who received intravenous pamidronate6 or oral alendronate,7 as compared with placebo, had a reduced number of upper-extremity fractures and less severe radiographic signs of osteopenia but no gain in functional strength or improvement in pain scores. A recent review of trials of bisphosphonate therapy for osteogenesis imperfecta showed that bisphosphonates increase bone mineral density in both adults and children, but the available data do not prove that fractures are reduced.8 Further studies in adults are needed to assess fracture end points as well as the safety and efficacy of long-term treatment with bisphosphonates. Gene therapy for osteogenesis imperfecta remains investigational.9,10,11 In the meantime, screening for and treating bone loss may tip the therapeutic balance in favor of improved outcomes in this fragile population.
References
Kamel HK. Male osteoporosis: new trends in diagnosis and therapy. Drugs Aging 2005;22:741-748. [CrossRef][Web of Science][Medline]
Ebeling PR. Osteoporosis in men. N Engl J Med 2008;358:1474-1482. [Free Full Text]
Marini JC. Osteogenesis imperfecta: comprehensive management. Adv Pediatr 1988;35:391-426. [Medline]
Rauch F, Glorieux FH. Osteogenesis imperfecta. Lancet 2004;363:1377-1385. [CrossRef][Web of Science][Medline]
Rauch F, Munns C, Land C, Cheung M, Glorieux F. Risedronate in the treatment of mild pediatric osteogenesis imperfecta: a randomized placebo-controlled study. J Bone Miner Res. 2009 March 3 (Epub ahead of print).

INFECCION DESPUES DE ABORTO MEDICO

NEW ENG JMED,Volume 361:145-151
July 9, 2009
Number 2
Rates of Serious Infection after Changes in Regimens for Medical Abortion
Mary Fjerstad, N.P., M.H.S., James Trussell, Ph.D., Irving Sivin, M.A., E. Steve Lichtenberg, M.D., M.P.H., and Vanessa Cullins, M.D., M.P.H., M.B.A.
>ABSTRACT
Background From 2001 through March 2006, Planned Parenthood health centers throughout the United States provided medical abortion (abortion by means of medication) principally by a regimen of oral mifepristone followed 24 to 48 hours later by vaginal misoprostol. In response to concern about serious infections, in early 2006 Planned Parenthood changed the route of misoprostol administration from vaginal to buccal and required either routine provision of antibiotics or universal screening and treatment for chlamydia; in July 2007, Planned Parenthood began requiring routine treatment with antibiotics for all medical abortions.
Methods We performed a retrospective analysis assessing the rates of serious infection after medical abortion during a time when misoprostol was administered vaginally (through March 2006), as compared with rates after a change to buccal administration of misoprostol and after initiation of additional infection-reduction measures.
Results Rates of serious infection dropped significantly after the joint change to buccal misoprostol from vaginal misoprostol and to either testing for sexually transmitted infection or routine provision of antibiotics as part of the medical abortion regimen. The rate declined 73%, from 0.93 per 1000 abortions to 0.25 per 1000 (absolute reduction, 0.67 per 1000; 95% confidence interval [CI], 0.44 to 0.94; P<0.001). p="0.03).">1
Antibiotics have been routinely administered at the time of surgical abortions since the publication of a meta-analysis showing that their use resulted in a 42% reduction in postabortion infection rates.2 When medical abortion was first introduced, there was little concern about the risk of infection, because there is no use of instruments in the cervix or uterus unless the procedure fails. However, it is clear that serious infections do occur.3,4,5,6
Data are lacking to compare the rates of serious infection with antibiotic treatment and the rates without such treatment among women undergoing medical abortion. The Food and Drug Administration (FDA) states that it "does not have sufficient information to recommend the use of prophylactic antibiotics for women having a medical abortion."7 The current American College of Obstetricians and Gynecologists Practice Bulletin on medical abortion states that no data exist to support the routine use of preventive antibiotics for medical abortion.8
By late 2005, four women in the United States and one in Canada had died from a rare bacterial infection, with Clostridium sordellii, after medical abortion with mifepristone and misoprostol.9 In contrast, no such deaths had been reported in Europe, where medical abortion had been available longer and far more women had used it. One hypothesis for the difference was that vaginal administration of misoprostol was very common in the United States but not so common in Europe.10 Another hypothesis was that periprocedural antibiotics were routinely provided in the United Kingdom but not in the United States.
Prompted by the deaths that occurred after medical abortion and internal data that show a higher-than-expected rate of serious infection, PPFA changed its medical abortion protocol at the end of March 2006. Vaginal administration of misoprostol was discontinued and replaced by buccal (or, much less commonly, oral) administration, and all health centers were required to use one of the following two regimens, with the intention of reducing the risk of infection: the routine administration of antibiotics or universal testing for chlamydia (and for gonorrhea when considered appropriate), with treatment dependent on test results. After reviewing the rates of serious infection among health centers that were using these two infection-reduction regimens, PPFA in July 2007 required all health centers to provide routine preventive antibiotic treatment. This report compares rates of serious infection before and after these changes in protocol.
Methods
Study Design
We obtained information about all patients who had a medical abortion from all 78 Planned Parenthood affiliates that provided this service at any time during the entire study period. A quarterly survey has been conducted by an administrator since 2001 to determine the number of patients undergoing medical abortion and the number of health centers providing it. In addition, all Planned Parenthood affiliates send a yearly report to the national office detailing the number of each clinical procedure provided (including medical and surgical abortions), and that report was used to verify the number of medical abortions in the quarterly surveys. Concordance between the two sources is high, with the annual reports containing 1.3% fewer cases than the quarterly reports; we used the caseload reported in the quarterly report, because the administrator of that report had much more frequent contact with the health professionals who reported these data than did the national office, collected data on a quarterly rather than an annual basis, and collected information only about medical abortions.
The Allendale Investigational Review Board approved the study protocol and design as a retrospective analysis of data routinely collected for quality control. The board determined that the use of these data did not require patients' consent.
The provisions of FDA approval stipulate that any physician who orders, provides, or supervises the provision of mifepristone must sign an agreement with the sole U.S. distributor of mifepristone (Danco Laboratories) to report all serious adverse events associated with its use. Serious adverse events include all ongoing pregnancies (pregnancies that continue after the use of mifepristone or misoprostol), hemorrhage requiring emergency treatment, serious infections, hospitalizations, potentially life-threatening events, and death. Danco submits all such reports to the FDA. Staff members at Planned Parenthood health centers were trained in accurate and complete reporting of serious adverse events. Adverse-event reports are centrally tracked and monitored. Planned Parenthood health centers are audited on site for internal accreditation by the PPFA. Since 2005, concurrent with the starting date of our analysis, the accreditation process has included auditing to verify that adverse events related to the use of mifepristone for medical abortions are submitted as required.
Because the diagnosis of mild postabortion infection is clinically highly subjective and there is substantial variation in how it is defined, we focused solely on serious infections. We classified as serious infections cases in which the patient had fever accompanied by pelvic pain and was treated with intravenous antibiotics either in an emergency department or inpatient unit, or cases in which sepsis or death caused by infection was documented. Information that generates reports of serious infection may arise from the patient, from the Planned Parenthood physician providing initial care or aftercare, or from a physician providing care for the patient in a hospital emergency department or inpatient unit. Many Planned Parenthood sites provide training to obstetrics and gynecology residents, and they were often the source of reports when Planned Parenthood patients were seen in the emergency department or hospitalized.
Follow-up visits routinely scheduled 1 to 2 weeks after ingestion of mifepristone provide an additional opportunity to evaluate whether a serious adverse event has occurred. The importance of the follow-up visit is emphasized to patients, and staff members are required to make three attempts to reach patients who have not returned for follow-up by the end of 2 weeks. However, information on the proportion of women who did not return for follow-up was not available through quarterly or yearly reports. The required attempts to contact patients uncovered several reports of emergency procedures at hospitals that meet the criteria for serious adverse events. In addition, surveillance by the Centers for Disease Control and Prevention (CDC) through multiple channels to identify deaths from infection-related causes after medical abortion did not find any cases other than those already known.
After March 2006, PPFA changed the route of administration of misoprostol from vaginal to buccal (200 mg of mifepristone followed 24 to 48 hours later by 800 µg of buccal misoprostol) or, much less commonly, to oral administration. In addition, Planned Parenthood health centers that provide medical abortion were required either to screen all patients for chlamydia (and gonorrhea if endemic rates or the patient's history or symptoms indicated the need) or to routinely provide prophylactic use of doxycycline (100 mg orally twice a day for 7 days, starting the same day as mifepristone administration) to all women. Doxycycline was chosen because it provides treatment against chlamydia, the most commonly reported sexually transmitted infection (STI) in the United States, and most gonorrhea strains11; doxycycline also has in vitro efficacy against C. sordellii.12 Theoretically, it might prevent an ascending infection and sepsis. Patients who had a positive test for an STI were treated with the standard CDC treatment recommendations, consisting of doxycycline for chlamydia (100 mg orally twice daily for 7 days), and ceftriaxone for gonorrhea (125 mg intramuscularly in a single dose).
Study Procedures
We conducted analyses of events for the years 2005 to mid-2008 during four periods. Period 1 (January 1, 2005, through March 31, 2006) was the baseline 15-month period during which vaginal misoprostol and standard antiseptic measures were used for the abortion of fetuses through 63 days of gestation. Period 2 (April 1, 2006, through June 30, 2007) was the 15-month period during which buccal misoprostol was used through 56 days of gestation13 (or, much less commonly, oral misoprostol was used through 49 days of gestation); some Planned Parenthood clinics used the infection-reduction measure of universal screening for STI and treatment when screening was positive, whereas others routinely provided antibiotics consisting nearly uniformly of 100 mg of oral doxycycline twice a day for 7 days. Period 3 (July 1, 2007, through December 31, 2007) was the 6-month period during which buccal misoprostol was used through 56 days of gestation and all health centers routinely provided the doxycycline regimen. Period 4 (January 1, 2008, through June 30, 2008) was the 6-month period during which buccal misoprostol was used through 63 days of gestation14 and all health centers routinely provided the doxycycline regimen.
Rates of serious infection in all four periods were evaluated overall. They were also evaluated separately among two groups of health centers — health centers that switched in Period 2 to universal testing for STI (screen-and-treat) (Group 1), and health centers that switched in Period 2 to routine provision of antibiotics (Group 2).
Data were obtained from all Planned Parenthood health centers that provide medical abortion. For the present analyses, we excluded affiliates that did not provide medical abortion in all four periods and centers that in Period 2 provided routine antibiotics to only a subgroup of clients (e.g., those less than 25 years of age).
Statistical Analysis
We calculated 95% confidence intervals for rates as exact binomial confidence intervals. Fisher's exact test was used to assess the significance of differences in proportions. We tested for differences in relative declines in rates between the two groups using a test for homogeneity of risk ratios. Two-sided P values of less than 0.05 were considered to indicate statistical significance. Calculations were performed with the use of Cytel Studio software, version 8 (Cytel), or Stata 10 software (StataCorp).
Results
During the course of the study, 243,692 women underwent medical abortion at Planned Parenthood centers. After the exclusion of 15,869 women who did not meet eligibility criteria (<7%),>Table 1 and Figure 1.
Table 1. Rates of Serious Infection in Two Groups of Patients Undergoing Medical Abortion at Planned Parenthood Health Centers during Four Periods.
Figure 1. Rates of Serious Infection after Medical Abortion among Patients in Two Groups of Planned Parenthood Health Centers.
Period 1 (January 1, 2005, through March 31, 2006) was the baseline period during which vaginal misoprostol and standard antiseptic measures were used for the abortion of fetuses through 63 days of gestation. During Period 2 (April 1, 2006, through June 30, 2007), buccal misoprostol was used through 56 days of gestation; some Planned Parenthood clinics used the infection-reduction measure of universal screening for sexually transmitted infections (STIs) and treatment when screening was positive, whereas others provided routine antibiotics consisting nearly uniformly of 100 mg of oral doxycycline twice a day for 7 days. During Period 3 (July 1, 2007, through December 31, 2007), buccal misoprostol was used through 56 days of gestation and all health centers routinely provided the doxycycline regimen. During Period 4 (January 1, 2008, through June 30, 2008) buccal misoprostol was used through 63 days of gestation, and all health centers routinely provided the doxycycline regimen. Group 1 comprises health centers that switched in Period 2 to universal testing for STI, and Group 2 comprises health centers that switched in Period 2 to routine provision of antibiotics. An asterisk denotes a significant decrease from the previous period. There were no serious infections in Periods 3 and 4 in Group 2.
The 93% relative decrease in the rate of serious infection between Period 1 and Period 4 was an absolute reduction of 0.86 per 1000 (95% confidence interval [CI], 0.64 to 1.12; P<0.001). p="0.03).">0.99).
Between Periods 1 and 2, there were significant declines in the rates of serious infection in both Group 1 and Group 2, but the relative decline was significantly greater in Group 2 (93% decline) than in Group 1 (61% decline) (relative risk ratio, 0.19; 95% CI, 0.04 to 0.89; P=0.04). Between Periods 2 and 3, there were further declines in both Group 1 (significant) and Group 2 (nonsignificant), but the relative declines did not differ significantly (75% and 100%, respectively; P=0.07); the combined relative risk in Period 3 as compared with Period 2 was 0.24 (95% CI, 0.03 to 0.97). In Group 1, the rate of serious infection fell from 1.15 per 1000 in Period 1 to 0.11 per 1000 in Period 3. Of this absolute decline in rate of 1.04 per 1000, 33% occurred between Periods 2 and 3.
Hospital records were available for review for 45 of the 92 cases of serious infection, and for an additional 30 cases, detailed summaries of the records were provided by a Planned Parenthood clinician either after consultation with a physician who provided treatment in the hospital or emergency department or after review of the records at the hospital. In 17 cases (18%), patients reported treatment with intravenous antibiotics in the emergency department, but medical-record verification was not available. In a secondary analysis excluding these 17 cases, results were materially unchanged, although the relative decline from Period 1 to Period 2 was no longer significantly greater in Group 2 than in Group 1.
Discussion
We observed significant and clinically important reductions in the risk of serious infections among patients who had undergone medical abortion after a change from vaginal to buccal administration of misoprostol and after the adoption of routine preventive treatment with antibiotics. Although the observational design of our study precludes a determination of cause and effect, it is plausible that the changes in practice patterns could explain the reductions in the rate of serious infection. Because PPFA instituted more than one measure at a time, it is difficult to estimate from our analyses the relative values of different interventions. However, the fact that Planned Parenthood health centers adopted two infection-reduction measures in Period 2 allows further exploration of this issue.
In Group 1 — the group of health centers that used the screen-and-treat strategy in Period 2 — one third of the decline in the rate of serious infection from Period 1 to Period 3 occurred between Periods 2 and 3, when the only regimen change was from screen-and-treat to routine antibiotic coverage. Moreover, the relative decline in the reported rate of serious infection from Period 1 to Period 2 was significantly greater in Group 2 than in Group 1 (in the analysis including all cases). These findings indicate that routine provision of antibiotics was associated with a greater reduction in serious infection than was the use of the screen-and-treat method. This finding could be explained by the fact that, with the screen-and-treat strategy, not all those who test positive return for treatment; also, even among those who do return for treatment, treatment is delayed for at least 2 days while they await test results.
Between Period 3 and Period 4, the only change in the regimen was an increase in the maximum gestational age at the time of medical abortion, from 56 to 63 days. Because there was no significant increase in the rate of serious infection from Period 3 to Period 4, it is unlikely that a decline in the maximum gestational age from 63 days in Period 1 to 56 days in Period 2 explains the decline over time in the rates of serious infection observed in both groups.
The rate of serious infection in Period 1 was substantially higher than the rates previously published,3,4,5,6 even in one study that used Planned Parenthood data.6 (This finding, along with the deaths from C. sordellii after medical abortion, prompted the changes in Period 2.) It is likely that previously reported rates are underestimates and that apparent increases from previously reported data reflect improved reporting of serious adverse events to PPFA. Specifically, the official Planned Parenthood medical standards and guidelines were changed in 2004 to require that all serious adverse events be reported centrally; also, as stated earlier, since 2005, the accreditation process has included auditing to verify that adverse events related to the use of mifepristone are submitted as required.
Potential limitations of our study should be noted. We do not have data available on the rates of follow-up of women after medical abortion, and it is possible that the reporting of serious infections is incomplete. A potential concern is that serious infections might have been more likely to be underreported during Periods 2 through 4, since the intense scrutiny that occurred during Period 1 (after the reports of deaths from clostridial infections) had waned. However, we consider this unlikely, since national conference calls and meetings that were focused on the risk of infection were ongoing during the time of the study. Moreover, during Period 2 a non–Planned Parenthood patient died from C. sordellii infection after she had had a medical abortion with buccal misoprostol but was not treated with antibiotics until she presented to an emergency department in toxic shock; information about that death was widely distributed throughout the Planned Parenthood community.
Although a randomized clinical trial would be the preferred approach to determine whether the use of buccal rather than vaginal administration of misoprostol might reduce the rate of serious infection and whether a strategy of routine antibiotic coverage is superior to a strategy of screening before treating, this study design would not have been feasible. Given the low rates of serious infection, such a design would have required a prohibitively large sample. The large population that receives care at Planned Parenthood centers allowed the discerning of changes over time in the rates of serious infection after medical abortion. In summary, the current report shows that changes in PPFA policies for medical abortion that involve replacing vaginal administration of misoprostol with buccal administration and, later, providing routine antibiotics coupled with a highly monitored, systemwide surveillance network were associated with significant reductions in the rates of serious infections.
References
1.-Fjerstad M, Sivin I, Lichtenberg ES, Trussell J, Cleland K, Cullins V. Effectiveness of medical abortion with mifepristone and buccal misoprostol through 59 gestational days. Contraception (in press).
2.-Sawaya GF, Grady D, Kerlikowske K, Grimes DA. Antibiotics at the time of induced abortion: the case for universal prophylaxis based on a meta-analysis. Obstet Gynecol 1996;87:884-890. [Web of Science][Medline]
3.-Spitz IM, Bardin CW, Benton L, Robbins A. Early pregnancy termination with mifepristone and misoprostol in the United States. N Engl J Med 1998;338:1241-1247. [Free Full Text]
4.-Hausknecht R. Mifepristone and misoprostol for early medical abortion: 18 months experience in the United States. Contraception 2003;67:463-465. [CrossRef][Web of Science][Medline]
5.-Shannon C, Brothers LP, Philip NM, Winikoff B. Infection after medical abortion: a review of the literature. Contraception 2004;70:183-190. [CrossRef][Web of Science][Medline]
6.-Henderson JT, Hwang AC, Harper CC, Stewart FH. Safety of mifepristone abortions in clinical use. Contraception 2005;72:175-178. [CrossRef][Web of Science][Medline]

CANCER DE OVARIO : TAMIZAJE

NEW ENG J MED,Volume 361:170-177
July 9, 2009
Number 2
Screening for Ovarian Cancer
Daniel L. Clarke-Pearson, M.D.
A 56-year-old woman presents to her physician, requesting screening for ovarian cancer. She reports the recent death of a friend from ovarian cancer at the age of 65 years. The patient has no family history of ovarian or breast cancer. The physical examination, including pelvic and rectal examination, is normal. Should the physician recommend screening for ovarian cancer?
The Clinical Problem
Ovarian cancer accounts for 3% of cancers in American women, but it is the leading cause of death from gynecologic cancers and the fifth leading cause of all cancer-related deaths among women. The American Cancer Society estimates that 21,650 new cases of ovarian cancer were diagnosed and 15,520 women died of the disease in the United States in 2008.1 In the United States, the lifetime risk of invasive ovarian cancer is approximately 1.4% (1 in 71), and the lifetime risk of dying from invasive ovarian cancer is about 1 in 95.
Two thirds of cases of ovarian cancer are diagnosed in women over the age of 55 years. A family history of ovarian or breast cancer in a first-degree relative approximately triples the risk.2 The risk is particularly high among carriers of a BRCA gene mutation, with a lifetime risk of 39 to 46% among women with the BRCA1 mutation and a risk of 12 to 20% among those with the BRCA2 mutation. The risk is decreased among women who have used oral contraceptives, have been pregnant, or have a history of breast-feeding.
More than two thirds of cases of ovarian cancer are diagnosed when the disease has progressed to stage III or IV and involves the peritoneal cavity or other organs.3 Symptoms that are associated with ovarian cancer are typically nonspecific, and the association is often not recognized until the disease has advanced. In one case–control study, investigators developed an index to try to establish a correlation between symptoms and the diagnosis of ovarian cancer. If women who were 50 years of age or older reported having had pelvic or abdominal pain, urinary frequency or urgency, increased abdominal size or bloating, or difficulty eating or feeling full more than 12 times in a month within the previous year, the index had a sensitivity of 67% and a specificity of 90%. The sensitivity was lower in those with early-stage disease (57%), and the specificity was lower in younger women (87%).4
Current treatment includes surgical resection (debulking), followed by multiagent chemotherapy, usually involving intravenous or intraperitoneal platin compounds and a taxane. Prognostic factors include the stage and histologic grade of the cancer at diagnosis, the presence or absence of residual disease at the completion of the initial surgery, the patient's functional status and age, and the use or nonuse of platin-based chemotherapy. When ovarian cancer is detected and treated while it is still confined to the ovary (stage I), the 5-year survival rate is approximately 90%, in contrast to the rate of approximately 33% when the disease is diagnosed at stage III or IV (Table 1). Since ovarian cancer is often initially diagnosed at an advanced stage, when the prognosis is poor even with aggressive therapy, a screening method that facilitates early diagnosis has been actively sought.
Table 1. Stage of Ovarian Cancer at Diagnosis and Survival at 5 Years.
Strategies and Evidence
Routine Screening
Criteria for disease screening that have been proposed by the World Health Organization5 are listed in Table 2. Some of these criteria are met for ovarian cancer, since the condition is frequently fatal, treatment is available that is effective at an early stage of disease, and early intervention improves the outcome.
Table 2. World Health Organization's Criteria for Disease Screening.
However, several features of ovarian cancer complicate the question of screening. First, the transition time from stage I to stage III is unclear, since it is not known whether there is an evolution from an early to an advanced stage or whether the disease may initially arise as a diffuse process in the peritoneal cavity (stage III). Furthermore, because there is no obvious precursor lesion, screening must focus on early detection of invasive cancer. Risk factors other than age, a family history of ovarian or breast cancer, and the presence of a BRCA mutation are poorly understood, and approximately 90% of ovarian cancers appear to be sporadic. Thus, screening algorithms must be geared toward a general population of women.
Because only a small fraction of cases of ovarian cancer occur in premenopausal women, most investigators have suggested that screening be limited to postmenopausal women. Moreover, because of the low prevalence of ovarian cancer (40 cases per year per 100,000 women over the age of 50 years), a screening test must have both high sensitivity and high specificity to be clinically useful. It is estimated that a screening test for ovarian cancer would require a sensitivity of at least 75% and a specificity of more than 99.6% to achieve a positive predictive value of 10% (the minimum positive predictive value set by most epidemiologists to support a screening test). Since a definitive diagnosis of ovarian cancer requires surgical excision of the ovary and fallopian tube, a screening test with a positive predictive value of 10% would result in 10 surgeries for every 1 case of cancer detected. Currently available screening tests for ovarian cancer must be considered in light of these issues.
Ultrasonography
Imaging of the ovary has been proposed as a strategy to detect changes in size and architecture that might precede the development of symptoms and detection by pelvic examination. Transvaginal ultrasonography is superior to transabdominal ultrasonography for detecting subtle details of ovarian structure and size. Studies involving healthy women have established the upper limit of ovarian volume as 20 cm3 in premenopausal women and 10 cm3 in postmenopausal women.6 In addition to size, the use of morphologic characteristics of ovarian masses has been proposed to differentiate benign from malignant neoplasms7 (Figure 1). In one study, in which measurement of ovarian volume, cyst-wall characteristics, and the presence of septae were used to calculate a risk score, the sensitivity was 89% and the specificity was 70% (Table 3). Another morphologic index was reported to have a sensitivity of 100% and a specificity of 83% in differentiating benign from malignant lesions.8 However, there has been considerable variation among observers in interpreting and scoring ultrasonographic images, and the sensitivity of several measures has been considerably lower in external validation studies.9 It has also been suggested that increased blood flow in the ovary on Doppler imaging indicates the presence of a malignant lesion, but this finding has been inconsistent, and the benefit, if any, of the addition of Doppler imaging to conventional ultrasonography has been limited.10,11,12,13
Figure 1. Transvaginal Ultrasonogram of a Right Ovarian Mass.
The 3.5-cm mass is partially cystic but also contains a solid, 2.3-cm nodule in the cyst wall (arrow).
Table 3. Morphologic Index for Ultrasonographic Identification of Ovarian Cancer.
Several studies have evaluated pelvic ultrasonography to screen asymptomatic women for ovarian cancer. In one study, 5479 women over the age of 45 years were screened annually with transabdominal ultrasonography.14 Nine ovarian cancers (five in stage I) were detected during a 3-year period. However, there were also 317 false positive results (positive predictive value, 1.5%). Several studies15,16,17,18,19,20,21,22 of transvaginal ultrasonography that involved more than 136,000 women had mixed results, with some but not others showing a nonsignificant trend toward the diagnosis of ovarian cancer at an early stage. The positive predictive value of ultrasonography in these studies ranged from 1.0%20 to 27%.18 The interpretation of these results is complicated by differences with respect to inclusion criteria, with some studies enrolling only women at high risk (on the basis of a family history),16,19 some enrolling only women at average risk,15,20,21,22 and others enrolling both women at high risk and those at average risk.17,18
In a large prospective study, 25,327 women (including those over the age of 50 years who were at average risk and those over the age of 25 years with a family history of ovarian cancer) were screened with annual transvaginal ultrasonography.18 If an enlarged ovary was identified,6 its architectural features were described (cystic features, solid features, septations, papillations, nodules, or free peritoneal fluid).7 Among women with suspicious findings, surgical resection of the abnormal ovary was performed in 364 patients; 29 were found to have invasive ovarian cancer, among whom 14 (48%) had stage I disease. Nine patients received the diagnosis of ovarian cancer within 12 months after a negative ultrasonographic assessment. On the basis of stringent ultrasonographic criteria (i.e., unilocular ovarian cysts measuring less than 5 cm in diameter were not considered suspicious), the positive predictive value for ultrasonography was 27%, and the sensitivity was 85%. However, the fact that many patients were at high risk suggests that this positive predictive value is higher than the value that would be expected in the general population. Among women whose ovarian cancers were detected by screening, the 5-year survival rate was 77%, as compared with a rate of 49% in a historical control group from the same institution. However, the lack of randomization and an appropriate control group precludes a conclusion that screening resulted in improved survival.
Tumor Markers
CA-125
Serum tumor markers have been evaluated for the early detection of ovarian cancer. This strategy is potentially attractive in that measurement of markers is broadly available, can be repeated at appropriate intervals, and is minimally invasive. In addition, such measurement does not depend on operator interpretation and is less costly than ultrasonography.
In an initial report, cancer antigen 125 (CA-125), a protein that is found in greater concentration in ovarian cancer cells than in other cells, was found to be elevated in the serum of approximately 80% of women with advanced-stage ovarian cancer and in only 1 to 2% of the normal population.23 However, several limitations of this test have reduced enthusiasm for its use in screening. Although CA-125 is frequently elevated in advanced-stage ovarian cancer, the protein is elevated in less than 50% of stage I ovarian cancers.24,25 Moreover, the specificity of the test is poor, since a number of benign and malignant conditions may result in falsely elevated CA-125 values (Table 4).
Table 4. Conditions Associated with an Elevated Level of Cancer Antigen 125.
In a retrospective analysis of serum samples from 5550 women who were enrolled in a population-based registry in Sweden,26 175 women had elevated CA-125 values. Ovarian cancer was ultimately diagnosed in six of these women and also developed in three women with normal CA-125 values. The specificity of the test was 98.5% for women over the age of 50 years but was lower (94.5%) for those who were younger than 50 (i.e., it had a low positive predictive value). As compared with women with an elevated CA-125 value in whom ovarian cancer was not diagnosed, the women who ultimately were found to have ovarian cancer were more likely to have progressive elevation of the CA-125 value over time.
Measurement of CA-125 values in an individual patient over time (rather than a single measurement) appears to improve the estimation of a patient's risk of ovarian cancer.27 In a retrospective examination of 33,621 serum samples from 9233 women, with the use of an algorithm to assess the trend in CA-125 levels over time, an increase in values had a sensitivity of 86% for the preclinical detection of ovarian cancer,28 as compared with a sensitivity of 62% for a single CA-125 value. This algorithm, called ROC, for risk of ovarian cancer, was confirmed to have a reasonably high positive predictive value (19%) in a subsequent prospective pilot study involving more than 13,000 postmenopausal women.29
Other Markers
More than 30 serum tumor markers have been evaluated in combination with CA-125 in tumor-marker panels, with the goal of improving sensitivity, specificity, and positive predictive value.30 The use of tumor-marker panels relies on the interpretation of the pattern of different marker levels in relationship to one another, rather than on the absolute levels of each marker. In general, the use of such panels has increased sensitivity by 5 to 10 percentage points over that of CA-125 alone but has been associated with a decline in specificity. In one study, a tumor-marker panel that included CA-125, leptin, prolactin, osteopontin, insulin-like growth factor II, and macrophage migration inhibitory factor, as compared with CA-125 alone, resulted in significantly improved sensitivity and specificity.31 The model (marketed by LabCorp under the trade name OvaSure) correctly classified 221 of 224 specimens in the test set (98.7%). However, subsequent reports have pointed out serious methodologic limitations of the study that led to greatly overestimated results,32,33 including the finding that the reported positive predictive value of 99.3% was based on a prevalence of ovarian cancer of 50%. The positive predictive value was only 6.5% after recalculation on the basis of the true prevalence of ovarian cancer in the population.34 Such tumor-marker panels have yet to be evaluated prospectively in large population-based studies, and their use in improving early detection and survival has not been established.
Ongoing Screening Trials
Two large, randomized trials that were designed to determine whether ovarian-cancer screening improves survival have completed the enrollment of patients. Preliminary findings have been reported, but final results (including survival) are not expected until 2014. In the Prostate, Lung, Colon, and Ovarian (PLCO) Cancer Screening Trial (ClinicalTrials.gov number, NCT00002540 [ClinicalTrials.gov] ), 34,261 healthy women between the ages of 55 and 74 years were randomly assigned to undergo either annual CA-125 testing plus transvaginal ultrasonography or to receive "usual care."20 A positive finding was defined as a CA-125 level of more than 35 U per milliliter or transvaginal ultrasonographic evidence of an abnormal ovarian volume or an ovarian cyst with papillary projections or solid components. During 4 years of screening, 3388 women had positive results on the basis of these criteria. Of these women, 1170 (34.5%) underwent oophorectomy at the discretion of their gynecologist. Of the women who underwent surgery, 60 (5.1%) were found to have ovarian cancer; 72% of these tumors were stage III or IV. An additional 29 cases of ovarian cancer that were diagnosed during this study period were not detected by screening. The positive predictive value of a positive screening test was 1.0 to 1.3% during the 4 years of screening. Results from the control group and overall survival have not been reported.
In the United Kingdom Collaborative Trial of Ovarian Cancer Screening (NCT00058032 [ClinicalTrials.gov] ), 202,638 postmenopausal women between the ages of 50 and 74 years who were deemed to be at average risk for ovarian cancer were randomly assigned to undergo annual pelvic examination (control group), annual transvaginal ultrasonography (ultrasonography group), or annual measurement of CA-125 (evaluated over time with the use of the ROC algorithm) plus transvaginal ultrasonography in cases in which the CA-125 level was elevated (multimodality group).35 Women with abnormal results underwent further evaluation by a gynecologist and oophorectomy in cases in which such surgery was considered to be appropriate. In a preliminary report describing outcomes in the ultrasonography and multimodality groups in the first 4 years, surgery was performed in 845 of 48,230 women (1.8%) in the ultrasonography group, 24 of whom were found to have invasive ovarian cancer; in comparison, surgery was performed in 97 of 50,078 women (0.2%) in the multimodality group, 34 of whom were found to have invasive ovarian cancer. Of 58 invasive cancers that were detected by screening in the two groups, 28 (48%) were stage I or II, with no significant difference between the groups. In the year after screening, ovarian cancer was diagnosed in 13 subjects with negative results on screening (8 in the ultrasonography group and 5 in the multimodality group). As compared with ultrasonography alone, multimodality screening had a significantly greater specificity (99.8% vs. 98.2%) and a higher positive predictive value (35.1% vs. 2.8%) (P<0.001);>36 although evidence is lacking to demonstrate that such screening results in a survival benefit for these women.37,38,39,40,41 The National Comprehensive Cancer Network also recommends strong consideration of risk-reducing bilateral salpingo-oophorectomy in women between the ages of 35 and 40 years, at the completion of childbearing or on the basis of the earliest age at which cancer was diagnosed in affected family members.36
Areas of Uncertainty
Pending the final results of large, ongoing randomized trials, it remains unclear whether ovarian-cancer screening reduces mortality.20,35 Surgical complications in women who had false positive results on screening have not been noted in the preliminary reports. The risks of surgery (including anesthetic complications and injury to adjacent bowel, bladder, ureter, and vessels) and its expense must be considered in decision making. The roles of new tumor markers that might be included in tumor-marker panels31,42,43 and of proteonomic methods in predicting the risk of ovarian cancer44 remain unclear.
Guidelines
Routine screening of the general population for ovarian cancer is not recommended by any professional society.36,45,46,47 Current screening recommendations from professional organizations are listed in Table 5.
Table 5. Recommendations for Ovarian-Cancer Screening.
Conclusions and Recommendations
Ovarian cancer that is diagnosed on the basis of symptoms is often at an advanced stage. Early detection, which is associated with improved survival, depends on effective screening strategies. Studies have shown that screening with the use of serum tumor markers (especially CA-125), ovarian imaging with transvaginal ultrasonography, or a multimodal strategy can detect ovarian cancer at an earlier stage, but trials that have been completed to date have not included a control group for direct comparison, and no trial has yet shown improved overall survival for women undergoing screening. Pending the results of the two large ongoing, randomized, controlled trials,20,35 I would advise against screening in a patient who is at average risk, such as the woman described in the vignette.
References
1.-Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2008. CA Cancer J Clin 2008;58:71-96. [Free Full Text]
2.-Whittemore AS. Characteristics relating to ovarian cancer risk: implications for prevention and detection. Gynecol Oncol 1994;55:S15-S19. [CrossRef][Web of Science][Medline]
3.-Heintz APM, Odicino F, Maisonneuve P, et al. Carcinoma of the ovary. Int J Gynaecol Obstet 2006;95:Suppl 1:S161-S192. [CrossRef][Medline]
4.-Goff BA, Mandel LS, Drescher CW, et al. Development of an ovarian cancer symptom index: possibilities for earlier detection. Cancer 2007;109:221-227. [CrossRef][Web of Science][Medline]
5.-Wilson JMG, Junger G. Principles and practice of screening for disease. Geneva: World Health Organization, 1968.

FIBROSIS QUISTICA : 1989

Published online 8 July 2009 Nature 460, 164-169 (2009)
Human genetics: One gene, twenty years

HELEN PEARSON
When the cystic fibrosis gene was found in 1989, therapy seemed around the corner. Two decades on, biologists still have a long way to go, finds Helen Pearson.
During the day, Lap-Chee Tsui and Francis Collins were attending a gene-mapping workshop. At night they were scrutinizing the pages churning out of a fax machine they had set up in a dorm room. Their hunt for the cause of cystic fibrosis had reached a gene that looked from its sequence like it might have a role in transporting ions through cell membranes, a process that goes awry in those with the disease. The fax they received that night from Tsui's lab showed that many people who have cystic fibrosis lack three base pairs from both copies of this gene, whereas those without the disease always have at least one copy intact. With that fax, on a rainy night in May 1989, "I was convinced — that was the moment," Collins says.
Four months later a four-year-old boy with cystic fibrosis, Danny Bessette, was shown sitting cross-legged on the cover of Science, framed by a rainbow of chromosomes. Inside the magazine, three papers1,2,3 laid out the details of the discovery of the gene responsible for Bessette's condition — the first gene for a human disease discovered without the help of an already-known protein sequence or any clue to its whereabouts. "In this issue … there is a story that does not begin at the beginning or end at the end, but has a very happy middle," wrote Science's editor Daniel Koshland4. "One in 2000 children born each year with a fatal defect now has a greater chance for a happy future." By that stage, news of the finding had already leaked to the media, been the subject of two hastily assembled press conferences and been trumpeted in newspapers worldwide. "It would be difficult to overstate the importance of the cloning of the cystic fibrosis gene," wrote geneticist Peter Goodfellow in Nature that month5. "The implications of this research are profound: there will be large spin offs in basic biology, especially in cell physiology, but the largest impact will be medical."
So far, Goodfellow's prediction has proved wrong, at least as far as medical impact is concerned. As Jack Riordan, who collaborated with Tsui and Collins on the original discovery, puts it: "The disease has contributed much more to science than science has contributed to the disease."
This is not to deny that medical progress has been impressive. An American born with cystic fibrosis today has a life expectancy at least ten years longer than one born in 1989 did. Such advancements help explain why Bessette — now 24, and pictured opposite — has a future at all. But many researchers concede that relatively little of that improvement can be laid at the door of the cystic-fibrosis transmembrane regulator gene, or CFTR. Gene therapy — the source of so much of the hope in 1989 — has so far bought no one with this condition a single additional year of life; no therapies targeted at the CFTR protein have yet been approved. Researchers have not even fully agreed on a hypothesis to explain how mutations in the gene cause the condition. But the gene itself "found its way into all departments", says Riordan, leading to progress in fields as diverse as protein trafficking and membrane transport. And the gene-hunting techniques that Tsui, Collins, Riordan and their colleagues pioneered have laid the foundation for a genetic understanding of all human disease.
“The disease has contributed much more to science than science has contributed to the disease.”
Jack Riordan
Twenty years, although a long time in the life of a young man such as Bessette, is not the whole story. Several hundred million dollars have been spent trying to find a therapy that directly tackles the molecular defects that underlie cystic fibrosis; Collins, for one, thinks that this means the hopes on which gene therapy never delivered are about to be fulfilled. Like many researchers, he is excited by clinical results coming through on a pair of small molecules that could get mutant versions of the CFTR protein to work properly. Should the molecules be approved, "it will be a pair of home runs, a milestone for all genetic disease", Collins says. And those home runs would never have been hit without the gene and the opportunity to study the protein that needs fixing. "You can paint a direct pathway from the gene discovery [to those drugs]," he says.
To call the path direct might be overstating it. Researchers have taken many paths from CFTR, and their travels have shown that behind this gene and every one found since lie dauntingly complex biological stories. "I think one of the lessons of cystic fibrosis is the recognition of the enormous challenge that faces us in human biology," says Riordan, now at the University of North Carolina, Chapel Hill. "It's not like going to the Moon — it's going to Mars." The size of the challenge can sap enthusiasm. "Looking back, it was an important contribution," says Tsui, "but I'm disappointed because at this time, from my own research, I was not able to help very much." Riordan says that he now views "the latest hot gene" with a "jaundiced eye". But one thing that shines through when speaking to these three and other researchers is their continued optimism, their passion and their sense of urgency. "Perhaps," says Collins, "we've taken our blinkers off. Perhaps we couldn't deal with it before, and now we have a lot more tools to dissect the complexity."
"It's not that it hasn't worked," says Riordan."It's only been 20 years."
Blind beginnings
Geneticists have been interested in cystic fibrosis since the disease was first identified in the 1930s. The disease is common in Caucasian populations — about 1 in every 25 people carries a mutated copy — and its pattern of inheritance is straightforwardly Mendelian: those with one mutated gene are healthy carriers; those who inherit two will have the condition. Doctors knew that although the pancreas often fails and the gut is unable to absorb nutrients, the lung is the organ that is crippled with recurrent and persistent infections, "and that's unfortunately the one that kills them", says Richard Boucher, a pulmonary physician and cystic fibrosis researcher at the University of North Carolina. But for decades no one knew exactly what was wrong with the cells, so no one knew what type of gene to look for.
Paul Quinton helped change that. As a kid, Quinton had always coughed a lot, and his sweat was so salty that his clothes corroded the wire hangers they dried on. When, in 1965, as a 19-year-old at the University of Austin, Texas, he met a girl and his thoughts turned to marriage, he decided to find out what was wrong with him. The description of cystic fibrosis he found in the medical library fit his symptoms perfectly and he diagnosed himself with a disease that should already have killed him, but that he would spend the rest of his life studying.
Quinton collected fresh sweat glands from visitors, from colleagues (Riordan, who visited Quinton's ranch, says he still bears the scars of Quinton's biopsies with a cork borer) and from other people with cystic fibrosis to explore why his sweat, and that of others with the disease, was so salty. In 1982, while working at the University of California, Riverside, an experiment measuring the ability of sodium and chloride to pass through the glands led him to finger a channel that was unable to conduct chloride ions across the epithelium of the skin, and that might also underlie problems in the lungs and the other affected organs6. "I feel silly saying it but I literally jumped up and ran up and down the hall shouting 'Eureka'," says Quinton, who now also works at the University of California, San Diego. "I still get chills; it was one of those moments you get once in a lifetime." The disease is evident when he speaks: he still clears his throat and coughs a lot.
Lap-Chee Tsui, Francis Collins and Jack Riordan (left to right) celebrate their 1989 discovery of the cystic fibrosis gene with a patient.CANADIAN CYSTIC FIBROSIS FOUNDATION
Quinton's discovery and others like it told geneticists what they should be looking for: a gene that is involved in the movement of chloride, and perhaps other ions, across the epithelium. By now an intense and competitive hunt was under way. It was the 1980s, when the human genetic sequence was largely uncharted territory, and the human genome project was still a twinkle in various eyes, including Collins's. Finding the gene would be a technical and intellectual challenge as well as a medical breakthrough. Until that point, almost all of the genes that had been associated with human diseases had been identified by first isolating the protein responsible. A protein's amino-acid sequence reveals much of the gene's probable nucleotide sequence, and that made pinpointing the gene easier. The few exceptions, such as those found for Duchenne muscular dystrophy and retinoblastoma, were helped by a few patients with chromosomal abnormalities that pointed to the gene's position. For cystic fibrosis, researchers were working blind: they had no protein and no location. This was to be a big test of new 'reverse genetics' techniques, in which a gene is found by searching for markers in the genome that are consistently inherited with the disease in affected families and using them as signposts to the gene itself.
Tsui, then at the Hospital for Sick Children in Toronto, Canada, and now at the University of Hong Kong, was a key player in the hunt; so were Robert Williamson at St Mary's Hospital Medical School in London, and a handful of other researchers. By 1985, several groups7,8,9 had shown that the gene mapped to a region of chromosome seven, but it was still a vast genetic wilderness somewhere between one and two million base pairs wide. In 1987, Williamson announced that he had landed on the gene, but soon after had to admit he had got it wrong. Nevertheless, many groups assumed that Williamson was close and dropped out of the race at that point. Says Collins: "Lap-Chee and I were more stubborn".
“Perhaps we couldn't deal with it before, and now we have a lot more tools to dissect the complexity.”
Francis Collins
Collins, then at the University of Michigan in Ann Arbor and until last year the head of the National Human Genome Research Institute in Bethesda, Maryland, met Tsui at that year's meeeting of the American Society of Human Genetics. A few years previously, Collins had described the technique of 'chromosome jumping', a way of leaping across the vast genetic distances from one marker sequence in a region to another that was much faster than the conventional way of chromosome 'walking'10,11. They agreed to collaborate: Collins's lab would bound to new positions, and Tsui's would walk forwards and backwards from the landing points looking for the gene. Two years later, on that rainy night in the dorm room, their fax machine told them they had found it.
The Science papers showed that the gene looked like others encoding membrane proteins that transport ions. The three base pairs missing in the vast majority of people with cystic fibrosis eliminated an amino acid at position 508 of the protein's amino-acid sequence, a mutation called ∆F508. "It was exciting times," says Robert Beall, then executive vice-president for medical affairs at the Cystic Fibrosis Foundation in Bethesda, Maryland, and now its director. "We had been at a bottleneck. We didn't know why chloride wasn't getting out of cells, and that gene solved it."
The scramble of competition continued as researchers rushed to work with the gene. John Hanrahan at McGill University in Montreal, Quebec, recalls the time he was collaborating with Riordan on a paper for Cell12. Riordan called him to ask him to fax through a figure for the manuscript as he was worried about a scoop from a competing paper at Science. "I raced to the airport in a snowstorm to send the originals by same-day courier, but it was the faxed version that went to press," Hanrahan says. "When people look at the traces they must wonder, 'Why are they so pixelated?'" But Hanrahan, like most researchers, says that the competition was a healthy one, even if it deprived them of a little sleep. "I think a lot of data were published and some mistakes were made, but there was tremendous excitement and the field moved ahead rapidly."
From the beginning, the goal was gene therapy. Get a good gene into the patients and they would make the proper protein; with the proper protein they'd be cured. But the path from gene to therapy wasn't smooth. It took more than a year just to get bacteria to produce the protein from the cloned gene, because of 'cryptic' sequences within the gene that prevented the bacteria from expressing it. But by 1993 the first clinical trials were under way.
"The expectation was that all you needed to do was get a little bit of stuff to act in the lungs and 'hey presto' you'd have a Nobel prize," says Steven Hyde, who works on cystic fibrosis gene therapy at the University of Oxford, UK. Among other things, the lung, researchers now realize, is just about the worst possible target for such an approach. Its sophisticated defences against infection have evolved precisely to prevent the sort of uptake and expression of foreign material the gene therapists were after. Mike Welsh at the University of Iowa and his colleagues, who in one of the first trials pushed the gene into cells in the nasal passage as a surrogate for those in the lung, later realized that the cells that had taken up the gene were probably damaged during the procedure. "A whole slew of people did similar trials and everyone got a little disillusioned." Hyde says.
Disillusionment isn't enough to kill off an idea — but death is. In 1999, a severe immunological reaction killed Jesse Gelsinger in a gene-therapy trial for an inherited liver disease, casting a pall over the entire field. In the United States, the field has never fully recovered. In other countries — the United Kingdom and France, for example — researchers have been much more active in pursuing the technique.
Around the same time, Beall decided to turn the gene into a way to find a therapy, rather than being the therapy itself. He wanted to take advantage of new tools coming online for high-throughput drug screening. Researchers inserted the gene into cells, expressed the mutated protein, then screened for drugs that could correct the way the protein is made or the way it works. "People thought we were crazy," Beall says. What started as US$2-million grant in 1999 has turned into an $76-million programme, and Beall proudly points to a chart showing the drugs working their way through the pipeline as a result.
By far the most common mutation is ∆F508. It causes the protein to fold up poorly, and a drug known as a corrector is needed to help it fold correctly and get to the membrane it needs to sit in. Other mutations — there are now more than 1,500 known in the gene — require different approaches. Versions of the gene in which protein translation stops short need drugs to override the stop signal. Then there are proteins that get made, fold up and reach the membrane but just don't work properly. They need what are called potentiators.
In March 2008, investigators presented results from a phase II trial of the potentiator VX-770 to a room of several hundred researchers at a meeting of the Cystic Fibrosis Foundation. Just two weeks of treatment in 20 people with a rare mutation called G551D had dramatically lowered some people's sweat chloride and produced some improvement in lung function — something that clinicians found particularly remarkable given the battered state of their airways. "When they showed those data and I saw the emotions from those physicians, it was unbelievable," Beall says. "It was the most emotional time since the discovery of that gene. It's telling you we can change the course of this disease." Collins agrees. "It was wildly better than even the most optimistic perspective for a small-molecule trial," he says. Phase III trials of VX-770, developed by Vertex Pharmaceuticals of Cambridge, Massachusetts, are now recruiting patients. Beall and others say that the drug might find a much wider market if it is also used in people with other mutations, including ∆F508, in conjunction with a corrector. That corrector could be another Vertex drug called VX-809, which is just starting phase II trials.
A special case
Must it take 20 years to get from gene to drug? No. Various things have made cystic fibrosis peculiarly difficult. One has been a lack of a complete understanding of how the CFTR protein leads to the disease. Many think that the defective channel causes the lungs to absorb too much water; others have argued that the primary problem is an incorrect ion composition that disables the lungs' normal defences against infection. This debate became so fierce it was described as the 'salt wars'. At least part of the problem seems to lie in another ion channel that CFTR interacts with. "If you ask 20 people you'll get 20 different hypotheses," says Welsh. "Everybody's got their favourite — I think we don't know."
“If you ask 20 people you'll get 20 different hypotheses. Everybody's got their favourite.”
Mike Welsh
Then there are some purely technical problems. Mice with mutated versions of CFTR have few obvious lung problems and thus make poor models of the disease. (The models have, however, revealed something about why the mutated gene is so common — see 'A killer advantage'.) The CFTR protein is huge and is embedded in a membrane, making its structure difficult to determine with X-ray crystallography; plus the fact that airway cells tend to contain only a hundred or so copies of the protein, so there is very little of the stuff to play with. Together, these mean that no one has been able to resolve a complete high-resolution structure for the protein, which has hampered understanding of how it works and the design of drugs.
Other genes have had it easier. Collins points to the gene for Hutchinson–Gilford Progeria Syndrome (HGPS), an extremely rare single-gene disease that causes young children to shows signs of old age. The gene was discovered by Collins's team at the National Human Genome Research Institute in 2003 (ref. 13) and by another group in France14, and a treatment based on it went into a phase II clinical trial in 2007 — a notably fast pace of translation. Collins puts much of the speed down to serendipity. The mutated protein was an extremely well-studied one called lamin A, and a cancer drug that had already reached late-stage clinical trials was found to work against the mutated protein, saving some laborious drug screening and safety testing. What's more, the task required of the drug is simpler. Drugs for cystic fibrosis have to compensate for or restore the function of a mutated protein, whereas those for HGPS simply have to block the action of one that has turned toxic.
More than 1,500 mutations of various types have been found in the CFTR gene.CYSTIC FIBROSIS MUTATION DATABASE
The discovery of CFTR deserves at least some credit in the HGPS story, though, as it does for accelerating the pace of translation after almost every gene discovery since 1989. That's because hard work and mistakes made in this field have saved effort in every other. "If you found a new gene tomorrow you could compress those 20 years hugely because of what's been done with cystic fibrosis," says Hyde.
And gene therapy may yet prove possible for cystic fibrosis. In 2001, the Cystic Fibrosis Trust in Bromley, UK, asked Hyde's group and two others in Britain that were still working in the field to stop competing and start working together. They complied and have spent several years and around £30 million (US$49 million) working methodically through some of the problems — such as devising better ways to measure changes in lung function. Earlier this year, researchers at Imperial College London treated the first of 27 people with cystic fibrosis in what is expected to become the largest gene-therapy trial ever undertaken for the disease. The aim is to test whether the gene can be delivered safely, in a fatty particle called a liposome. If it is, the researchers will scale up to a 100-person randomized controlled trial to see whether it is effective. "I think we have now tempered the optimism of the early 90s with a heavy dose of realism," says Eric Alton, who directs the trial.
Clinical changes
Throughout this time there have been dramatic changes in the way that cystic fibrosis is treated in the clinic. In 1994, Genentech introduced Pulmozyme (dornase alfa), an enzyme that breaks up some of the lung-clogging mucus that encourages infections. A few years later, aerosolized antibiotics were introduced to fight these infections more aggressively. Earlier this decade doctors in Australia started noticing that their patients who surfed felt better during the surf season — leading researchers to test the idea that the daily inhalation of super-salty water, called hypertonic saline, could help lubricate the lungs. It did15,16, and this is now standard therapy for many patients. Not all of them benefit from this approach, though: Bessette stopped taking hypertonic saline after a few years because it made him cough blood from a burst vessel in his lung. Pulmozyme does feature in his 40–50 pill-per-day regime, and he anticipates more advances that might improve his lung function. "Yes, we all hope for a cure, but if they can just help us stay healthy that in itself is quite an accomplishment," Bessette says.
“We have now tempered the optimism of the early '90s with a heavy dose of realism.”
Eric Alton
Quinton, too, follows a rigorous regimen, inhaling hypertonic saline every day and taking intravenous antibiotics every few months. He rides his bike to work, but he can't run far or play basketball. Both upper lobes of his lung have been removed because of chronic inflammation. For someone born when he was, though, things could have been much worse — and thanks to research into the CFTR gene, Quinton knows why they're not. Although he has one copy of ∆F508, the mutation in his other gene, R17H, has relatively mild effects. He found this out when, several years after the gene was found, Garry Cutting at Johns Hopkins University School of Medicine in Baltimore, Maryland, analysed his genes as part of work on genetic testing for the disease.
These tests are "probably the most common form of genetic testing in the world today", says Cutting, who now drafts clinical-testing guidelines for cystic fibrosis. In the United States and some European countries many pregnant women and their partners are offered testing for mutations in CFTR, forcing clinical geneticists to confront issues about genetic counselling and genetic risk that are likely to escalate as more and more genes become as well studied. Working with a gene that has so many mutations, most of which are still little understood, underlines the futility of testing for something with no known clinical severity and therefore no rational basis on which to make decisions about ending a pregnancy. "The agony I've seen for some couples where one is a carrier and one has a mutation of unknown significance," Cutting says, "it is just immense." Newborn screening, which is also commonplace in some countries and typically involves a biochemical test followed by a genetic one, throws up similar issues for clinicians who may be unable to advise parents how severely their child is likely to be affected.
New studies are making the molecular landscape look even more complicated. Two years ago, the Cystic Fibrosis Foundation helped to launch a North American consortium to search for 'modifier genes' at work in the disease that might explain why some people with two copies of the ∆F508 mutation die at 16 whereas others have pretty healthy lungs into their 20s. The consortium members recently screened more than 4,500 people to look for genetic variations that are strongly linked with severity of the disease, says consortium member Michael Knowles from the University of North Carolina. One of the strongest variants to have emerged from previous studies of modifier genes, called TCF7L2, is also thought to strongly predispose carriers to type 2 diabetes17. The link may lie in the failure of the pancreas and consequent diabetes that cystic fibrosis frequently causes.
Results such as these suggest that once the CFTR gene and its protein are viewed in context, cystic fibrosis will spiral into a new realm of dizzying complexity. If studies of one gene have expanded to fill 20 years, how many years can be filled once the tens or even hundreds of modifier genes are factored in, let alone whatever other influences there may be outside the genetic code? For Knowles, though, the results present an exciting opportunity rather than a daunting complexity. He sees cystic fibrosis as "leading the way" for researchers investigating more genetically complex diseases. If he and others can get to grips with the numerous mutations in CFTR and its modifiers, they say that cystic fibrosis could serve as a case study for personalized medicine. Newborns identified with the disease could have their CFTR gene and other major modifier genes analysed to choose the most appropriate therapies — assuming, that is, that such a range exists by that point.
Although he has discovered molecular truths about himself that he might never have expected, "it would be hard for me to say I have benefited from the work I've done", Quinton says. Nonetheless, he, Riordan and others whose careers in this field stretch back farther than 1989 are still hopeful. Like most researchers and clinicians, they are focused on what they can achieve in the next 2–5 years, not what they should have achieved already. "I'd say don't give up," Quinton says. "This really is the only solution. As we succeed on one platform, it will make it much easier to succeed on another."
"It's a helluva lot more complicated than we realized," he says. "We went to the Moon in '69 and the conceit was we could do anything — we corrected polio, we wiped out smallpox. But when you start taking the system apart we've been really naive."
"But that's biology — it's not fair."
Corrected:
Robert Beall is now president and chief executive of the Cystic Fibrosis Foundation — not its director.
References
Rommens, J. M. et al. Science 245, 1059-1065 (1989). Article PubMed ISI ChemPort
Riordan, J. R. et al. Science 245, 1066-1073 (1985). Article
Kerem, B. et al. Science 245, 1073-1080 (1985). Article
Koshland, D. E. Science 245, 1029 (1989). Article PubMed
Goodfellow P. N. Nature 341, 102-103 (1989). Article PubMed ChemPort
Quinton, P. M. Nature 301, 421-422 (1983). Article PubMed ISI ChemPort
Tsui, L.-C., et al. Science 230, 1054-1057

PEDOFILIA,HEBEFILIA Y EFEBOFILIA: PARAFILIAS

July 1, 2009 Pedophiles, Hebephiles and Ephebophiles, Oh My: Erotic Age Orientation
Why most "pedophiles" aren't really pedophiles, technically speaking
By Jesse Bering
Michael Jackson probably wasn’t a pedophile—at least, not in the strict, biological sense of the word. It’s a morally loaded term, pedophile, that has become synonymous with the very basest of evils. (In fact it’s hard to even say it aloud without cringing, isn’t it?) But according to sex researchers, it’s also a grossly misused term. If Jackson did fall outside the norm in his “erotic age orientation”—and we may never know if he did—he was almost certainly what’s called a hebephile, a newly proposed diagnostic classification in which people display a sexual preference for children at the cusp of puberty, between the ages of, roughly, 11 to 14 years of age. Pedophiles, in contrast, show a sexual preference for clearly prepubescent children. There are also ephebophiles (from ephebos, meaning “one arrived at puberty” in Greek), who are mostly attracted to 15- to 16-year-olds; teleiophiles (from teleios, meaning, “full grown” in Greek), who prefer those 17 years of age or older); and even the very rare gerontophile (from gerontos, meaning “old man” in Greek), someone whose sexual preference is for the elderly. So although child sex offenders are often lumped into the single classification of pedophilia, biologically speaking it’s a rather complicated affair. Some have even proposed an additional subcategory of pedophilia, “infantophilia,” to distinguish those individuals most intensely attracted to children below six years of age.Based on this classification scheme of erotic age orientations, even the world’s best-known fictitious “pedophile,” Humbert Humbert from Nabokov’s masterpiece, Lolita, would more properly be considered a hebephile. (Likewise the protagonist from Thomas Mann’s Death in Venice, a work that I’ve always viewed as something of the “gay Lolita”). Consider Humbert’s telltale description of a “nymphet.” After a brief introduction to those “pale pubescent girls with matted eyelashes,” Humbert explains:
Between the age limits of nine and fourteen there occur maidens who, to certain bewitched travelers, twice or many times older than they, reveal their true nature which is not human, but nymphic (that is, demoniac); and these chosen creatures I propose to designate as “nymphets.”
Although Michael Jackson might have suffered more disgrace from his hebephilic orientation than most, and his name will probably forever be entangled darkly with the sinister phrase “little boys,” he wasn’t the first celebrity or famous figure that could be seen as falling into this hebephilic category. In fact, ironically, Michael Jackson’s first wife, Lisa Marie Presley, is the product of a hebephilic attraction. After all, let’s not forget that Priscilla caught Elvis’s very grownup eye when she was just fourteen, only a year or two older than the boys that Michael Jackson was accused of sexually molesting. Then there’s of course also the scandalous Jerry Lee Lewis incident in which the 23-year-old “Great Balls of Fire” singer married his 13-year-old first cousin.
In the psychiatric community, there’s recently been a hubbub of commotion concerning whether hebephelia should be designated as a medical disorder or, instead, seen simply as a normal variant of sexual orientation and not indicative of brain pathology. There are important policy implications of adding hebephilia to the checklist of mental illnesses, since doing so might allow people who sexually abuse pubescent children to invoke a mental illness defense.

One researcher who is arguing vociferously for the inclusion of hebephilia in the American Psychiatric Association's revised diagnostic manual (the DSM-V) is University of Toronto psychologist Ray Blanchard. In last month’s issue of Archives of Sexual Behavior, Blanchard and his colleagues provide new evidence that many people diagnosed under the traditional label of pedophilia are in fact not as interested in prepubescent children as they are early adolescents.
To tease apart these erotic age orientation differences, Blanchard and his colleagues studied 881 men (straight and gay) in his laboratory using phallometric testing (also known as penile plethysmography) while showing them visual images of differently aged nude models. Because this technique measures penile blood volume changes, it’s seen as being a fairly objective index of sexual arousal to what’s being shown on the screen—which, for those attracted to children and young adolescents, the participant might verbally deny being attracted to. In other words, the penis isn’t a very good liar. So, for example, in Blanchard’s study, the image of a naked 12-year-old girl (nothing prurient, but rather resembling a subject in a medical textbook) was accompanied by the following audiotaped narrative:
“You are watching a late movie on TV with your neighbors’ 12-year-old daughter. You have your arm around her shoulders, and your fingers brush against her chest. You realize that her breasts have begun to develop…”
Blanchard and his coauthors found that the men in their sample fell into somewhat discrete categories of erotic age orientation—some had the strongest penile response to the prepubescent children (the pedophiles), others to the pubescent children (the hebephiles), and the remainder to the adults shown on screen (the teleiophiles). These categories weren’t mutually exclusive. For example, some teleiophiles showed some arousal to pubescent children, some hebephiles showed some attraction to prepubescent children, and so on. But the authors did find that it’s possible to distinguish empirically between a “true pedophile” and a hebephile using this technique, in terms of the age ranges for which men exhibited their strongest arousal. They also conclude that, based on the findings from this study, hebephilia “is relatively common compared with other forms of erotic interest in children.”
In the second half of their article, Blanchard and his colleagues argue that hebephilia should be added to the newly revised DSM-V as a genuine paraphilic mental disorder—differentiating it from pedophilia. But many of his colleagues working in this area are strongly opposed to doing this.
Men who find themselves primarily attracted to young or middle-aged adolescents are clearly disadvantaged in today’s society, but historically (and evolutionarily) this almost certainly wasn’t the case. In fact, hebephiles—or at least ephebephiles—would have had a leg up over their competition. Evolutionary psychologists have found repeatedly that markers of youth correlate highly with perceptions of beauty and attractiveness. For straight men, this makes sense, since a woman’s reproductive value declines steadily after the age of about twenty. Obviously having sex with a prepubescent child would be fruitless—literally. But, whether we like it or not, this isn’t so for a teenage girl who has just come of age, who is reproductively viable and whose brand-new state of fertility can more or less ensure paternity for the male. These evolved motives were portrayed in the film Pretty Baby, in which a young Brooke Shields plays the role of twelve-old-old Violet Neil, a prostitute’s daughter in 1917’s New Orleans whose coveted virginity goes up for auction to the highest bidder.

Understanding adult gay men’s attraction to young males is more of a puzzle. Evolutionary psychologist Frank Muscarella’s “alliance formation theory” is the only one that I’m aware of that attempts to do this. This theory holds that homoerotic behavior between older, high status men and teenage boys serves as a way for the latter to move up in ranks, a sort of power-for-sex bargaining chip. The most obvious example of this type of homosexual dynamic was found in ancient Greece, but male relationships in a handful of New Guinea tribes display these homoerotic patterns as well. There are also, ahem, plenty of present-day examples of this in Congress. Oscar Wilde probably would have signed on to this theoretical perspective. After all, his famous “love that dare not speak its name” wasn’t homosexuality, per se, but rather a “great affection of an elder for a younger man”:
...as there was between David and Jonathan, such as Plato made the very basis of his philosophy, and such as you find in the sonnets of Michelangelo and Shakespeare. It is that deep, spiritual affection that is as pure as it is perfect. It dictates and pervades great works of art like those of Shakespeare and Michelangelo… It is beautiful, it is fine, it is the noblest form of affection. There is nothing unnatural about it. It is intellectual, and it repeatedly exists between an elder and a younger man, when the elder man has intellect, and the younger man has all the joy, hope and glamour of life before him. That it should be so, the world does not understand. The world mocks at it and sometimes puts one in the pillory for it.
But, generally speaking, Muscarella’s theory doesn’t seem to pull a lot of weight. Not many teenage boys in any culture seem terribly interested in taking this particular route to success. Rather—and I may be wrong about this—but I think most teenage boys would prefer to scrub toilets for the rest of their lives or sell soft bagels at the mall than become the sexual plaything of an “older gentlemen.”
In any event, given the biological (even adaptive) verities of being attracted to adolescents, most experts in this area find it completely illogical for Blanchard to recommend adding hebephilia to the revised DSM-V. (Especially since other more clearly maladaptive paraphilias—such as gerontophilia, in which men are attracted primarily to elderly, post-menopausal women—are not presently included in the diagnostic manual.) The push to pathologize hebephilia, argues forensic psychologist Karen Franklin, appears to be motivated more by “a booming cottage industry” in forensic psychology, not coincidentally linked with a “punitive era of moral panic." Because “civil incapacitation” (basically, the government’s ability to strip a person of his or her civil rights in the interests of public safety) requires that the person be suffering from a diagnosable mental disorder or abnormality, Franklin calls Blanchard’s proposal “a textbook example of subjective values masquerading as science.” Another critic, forensic psychologist Gregory DeClue, suggests that such medical classifications are being based on arbitrary distinctions dictated by cultural standards:
Pedophilia is a mental disorder. Homosexuality is not. Should hebephilia of ephebophilia or gerontophilia be considered mental disorders? How about sexual preference for people with different (or with the same) ethnic characteristics as oneself?
And Marquette University psychologist Thomas Zander, points out that since chronological age doesn’t always perfectly match physical age, including these subtle shades of erotic age preferences would be problematic from a diagnostic perspective:
Imagine how much more impractical it would be to require forensic evaluators to determine the existence of pedophilia based on the stage of adolescence of the examinee’s victim. Such determinations could literally devolve into a splitting of pubic hairs.

One unexplored question, and one inseparable from the case of Michael Jackson, is whether we tend to be more forgiving of a person’s sexual peccadilloes when that individual has some invaluable or culturally irreplaceable abilities. For example, consider the following true story:
There once was a man who fancied young boys. Being that laws were more lax in other nations, this man decided to travel to a foreign country, leaving his wife and young daughter behind, where he met up with another Westerner who shared in his predilections for pederasty, and there the two of them spent their happy vacation scouring the seedy underground of this country searching for pimps and renting out boys for sex.
Now if you’re like most people, you’re probably experiencing a shiver of disgust and a spark of rage. You likely feel these men should have their testicles drawn and quartered by wild mares, be thrown to a burly group of rapists, castrated with garden sheers or, if you’re the pragmatic sort, treated as any other sick animal in the herd would be treated, with a humane bullet to the temple or perhaps a swift and sure current of potassium chloride injected into the arm.
But notice the subtle change in your perceptions when I tell you that these events are from the autobiography of André Gide, who in 1947—long after he’d publicized these very details—won the Nobel prize in literature. Gide is in fact bowdlerizing his time in Algiers with none other than Oscar Wilde.
Wilde took a key out of his pocket and showed me into a tiny apartment of two rooms… The youths followed him, each of them wrapped in a burnous that hid his face. Then the guide left us and Wilde sent me into the further room with little Mohammed and shut himself up in the other with the [other boy]. Every time since then that I have sought after pleasure, it is the memory of that night I have pursued.
It’s not that we think it’s perfectly fine for Gide and Wilde to have sex with minors or even that they shouldn’t have been punished for such behaviors. (In fact Wilde was sentenced in London to two years hard labor for related offenses not long after this Maghreb excursion with Gide and died in penniless ignominy.) But somehow, as with our commingled feelings for Michael Jackson, “the greatest entertainer of all time,” the fact that these men were national treasures somehow dilutes our moralistic anger, as though we’re more willing to suffer their vices given the remarkable literary gifts they bestowed.
Would you really have wanted Oscar Wilde euthanized as though he were a sick animal? Should André Gide, whom the New York Times hailed in their obituary as a man “judged the greatest French writer of this century by the literary cognoscenti,” have been deprived of his pen, torn to pieces by illiterate thugs? It’s complicated. And although in principle we know that all men are equal in the eyes of the law, just as we did for Michael Jackson during his child molestation trials, I have a hunch that many people tend to feel (and uncomfortably so) a little sympathy for the Devil under such circumstances.
In this column presented by Scientific American Mind magazine, research psychologist Jesse Bering of Queen's University Belfast ponders some of the more obscure aspects of everyday human behavior. Ever wonder why yawning is contagious, why we point with our index fingers instead of our thumbs or whether being breastfed as an infant influences your sexual preferences as an adult? Get a closer look at the latest data as “Bering in Mind” tackles these and other quirky questions about human nature. Sign up for the RSS feed or friend Dr. Bering on Facebook and never miss an installment again

Correction (posted 7/2/09): When this story was originally posted, we incorrectly stated that the DSM-IV is published by the American Psychological Association, rather than the American Psychiatric Association. Scientific American regrets the error.
ABOUT THE AUTHOR(S)Jesse Bering is director of the Institute of Cognition and Culture at Queen's University Belfast in Northern Ireland, where he studies how the evolved human mind plays a part in various aspects of social behavior. His new book, Under God's Skin, is forthcoming from W. W. Norton in spring 2010.

Pedofilia
De Wikipedia, la enciclopedia libre
La exactitud de la información de este artículo está discutida.

En la página de discusión puedes consultar el debate al respecto.
Este artículo trata la atracción sexual hacia menores. Para el abuso sexual de menores, véase pederastia.
La paidofilia o pedofilia (del griego παιδοφιλια y éste de παις-παιδος páis-paidós, «muchacho» o «niño», y φιλíα filía, «amistad») es la inclinación sexual por parte de adultos a sentir una atracción sexual primaria hacia niños.
Se considera que paidofilia es un término etimológicamente más correcto que pedofilia, si bien esta segunda forma es más usada.[1] [2] En el lenguaje común, pedófilos son considerados aquellos que abusan sexualmente de niños.
El término «pedofilia» se ha visto confundido con el término «pederastia». A pesar de que etimológicamente significan lo mismo (ya que ambas se basan en paidós, «niño» o «adolescente»), la primera no se refiere al abuso sexual, sino a la mera atracción sexual que siente un hombre adulto hacia un niño, es decir, hacia alguien en quien aún no se han desarrollado los caracteres sexuales secundarios[3] [4] [1] [2] [5] (en la Grecia antigua, generalmente un erastes y su pupilo).
En relación con la atracción hacia los adolescentes, también suele usarse el término «hebefilia» o «efebofilia».
Desde el año 1999, los seguidores de este tipo de inclinación sexual celebran el 24 de Junio, como el Día del Orgullo Pedófilo.[6] Algunas fuentes sostienen que hay dos celebraciones de este tipo al año, en coincidencia con los solsticios.
Regulación jurídica
La mayor parte de los países civilizados conservan un derecho penal de acto por lo que se castiga la pederastia, es decir, el acto de abusar sexualmente de un menor, y no la mera tendencia sexual pedófila, lo que sería más propio de un inadecuado derecho penal de autor. Por ello, un acto de abuso sexual infantil no es calificado como pedofilia por las leyes. Sin embargo, en algunos códigos penales sí se contemplan delitos que castigan dicha conducta.[7]
Pese a lo anterior, algunos periódicos y otros medios hacen un uso erróneo de los términos «acusado de pedofilia» o «pedófilo convicto» en referencia a individuos acusados o convictos por abuso sexual infantil e incluso otros términos como «pedófilo en serie». Sin embargo, pederastia se utiliza de forma preferente en el sentido de delito, y menos frecuentemente como enfermedad; en la prensa se habla de «delitos de pederastia», «condenado a 40 años por pederastia», «acusado de pederastia» y «red de pederastia». Esta preferencia de emplear pedofilia para referirse a la atracción sexual o la enfermedad puede deberse al hecho de que este término es actualmente el más utilizado en psiquiatría para designar el trastorno mental y, por influencia médica, es la palabra escogida por los periodistas para hablar en términos psiquiátricos.[8]
La pedofilia como parafilia
El término «paidofilia erótica» fue acuñado en 1896 por el psiquiatra vienés Richard von Krafft-Ebing, en su obra Psychopathía sexualis, donde se enumeran las siguientes características:
El interés sexual se dirige hacia los niños, tanto prepubescentes como al principio de su pubertad.
Interés sexual primario (es decir, dirigido de manera exclusiva o principal) hacia niños.
Interés sexual que permanece a lo largo del tiempo.
Algunos sexólogos, como el doctor John Money, consideran que no sólo los adultos, sino los jóvenes pospúberes podrían distinguirse como posibles pedófilos.
A pesar de que la psiquiatría considera la pedofilia como una parafilia,[9] [10] [11] [12] [13] [14] hay autores que no comparten esta opinión.[15]
Sólo la atracción primaria es pedofilia
Una persona no es necesariamente pedófila por sentirse atraída sexualmente por los niños o las niñas, sino porque esa atracción sexual es primaria (o sea, la atracción principal, aunque también esté atraído o atraída por otros objetos sexuales). Estadísticamente —según Freund y Costell (1970), Kinsey y otros (1975) y Hall y otros (1995)— al menos una cuarta parte de las personas adultas pueden sentirse sexualmente atraídas hacia niños o niñas y no por ello ser pedófilas. Nótese que es posible diagnosticar la paidofilia por la mera presencia de "fantasías o deseos sexuales" del sujeto, sin necesidad de que lleve a cabo actos sexuales con niños.
La cuarta edición revisada del Manual diagnóstico y estadístico de los trastornos mentales de la Asociación Psiquiátrica Estadounidense (American Psychiatric Association) incluye un diagnóstico estándar basado en 3,022 casos de pedofilia:
Fantasías sexuales intensas o recurrentes, impulsos sexuales o comportamientos que implican actividad sexual con uno o varios niños prepubescentes (generalmente de 13 años o menores) durante un periodo de al menos 6 meses.
La persona ha actuado por estos impulsos, o los impulsos o fantasías sexuales provocan ansiedad o dificultades interpersonales.
La persona tiene por lo menos 16 años y es como mínimo 5 años mayor que el niño o niños del punto A.
Nota: no se incluye a individuos al final de su adolescencia implicados en una relación sexual activa con un sujeto de 12 o 13 años.
La frontera real entre niñez y adolescencia puede variar en cada caso, y es difícil de definir en términos estrictos de edad. La Organización Mundial de la Salud, por ejemplo, define la adolescencia como el periodo comprendido entre los 10 y los 20 años de edad.
Efebofilia
La efebofilia, también conocida como hebefilia, es la condición en la cual personas adultas experimentan atracción sexual hacia adolescentes que ya han pasado la etapa de la pubertad. La pederastia -en la Antigua Grecia- era la atracción hacia adolescentes masculinos. La atracción hacia adolescentes femeninas cuyo físico corresponde más bien al de una preadolescente (niña, puberta o prepuberta) es conocido como complejo de Lolita. Por definición, estos términos no son sinónimos de pedofilia. No obstante, en los países occidentales se ha usado con frecuencia la palabra pedofilia para referirse a la efebofilia y, en general, para referirse a la atracción sexual hacia cualquier persona cuya edad sea menor a la edad de consentimiento sexual.
Categoría:Pedofilia
Abuso y maltrato infantil
Pornografía infantil
Prostitución infantil
Síndrome de alienación parental
Edad de consentimiento sexual (para conocer los debates acerca de cuál es la edad en la que un menor puede decidir si tendrá o no tendrá relaciones sexuales)
Referencias
↑ a b V. Seco, M., O. Ándres, G. Ramos. Diccionario del español actual. Madrid, Aguilar, 1999.
↑ a b Real Academia Española. Diccionario de la lengua española. Madrid, Espasa, 2001
↑ Universidad Complutense de Madrid José Antonio Rojo, Investigador Titular, CSIC.

JOSE EMILIO PACHECO Y LOS JOVENES

José Emilio Pacheco y los jóvenes
Elena Poniatowska

LA JORNADA SEMANAL, 5 DE JULIO 2009
Los jóvenes se arrodillan ante José Emilio Pacheco. “Alta traición” es objeto de culto y lo saben de memoria. El poeta José Emilio pide perdón, se echa para atrás, dice que no, que por favor, que no es para tanto, que le falta, que no es nada, que todos nos vamos a morir. Los jóvenes lo buscan para abrazarlo y afirmarle que lo adoran. Confuso, José Emilio responde que “algo se está quebrando en todas partes. Se agrieta nuestra edad”. Les advierte que no van a durar y que “sobre su rostro/crecerá otra cara”.
Los jóvenes que todavía viven sus recuerdos de infancia se encuentran a sí mismos en El viento distante, El principio del placer, Las batallas en el desierto y hasta en la colonia Condesa de Morirás lejos y le brindan al novelista y al cuentista un testimonio de gratitud interminable. Es raro sentir gratitud por un escritor vivo pero José Emilio reúne todas las devociones. Cuando el niño Carlos de Las batallas en el desierto confiesa: “Nunca pensé que la madre de Jim fuera tan joven, tan elegante y sobre todo tan hermosa. No supe qué decirle. No puedo describir lo que sentí cuando ella me dio la mano”, los lectores reviven el tormento de su primer amor. Lo mismo sucede con los cuentos de La sangre de Medusa escritos de 1956 a 1984. José Emilio toca fibras en las que se reconocen, en las que tú y él y yo, ustedes y nosotros nos identificamos. Al leerlo, cada quién escribe de nuevo “Tarde o temprano”. Lo suyo es nuestro. Hacemos el libro con él, somos su parte, nos convierte en autores, nos refleja, nos toma en cuenta, nos completa, nos quita lo manco, lo cojo, lo tuerto, lo bisoño. Le debemos a él ser lectores, por lo tanto le debemos a él la vida.
Según él, los amores verdaderamente desdichados, los amores terribles son los de los niños porque no tienen ninguna esperanza. “En cualquier otra época de tu vida puedes tener alguna mínima posibilidad de reunirte con la persona que amas, pero cuando eres niño tu historia de amor no tiene porvenir.”
Desde Las batallas en el desierto José Emilio se manifiesta en contra de la nostalgia. Nos lo dice en la última página. “Demolieron la escuela, demolieron el edificio de Mariana, demolieron mi casa, demolieron la colonia Roma. Se acabó esa ciudad. Terminó aquel país. No hay memoria del México de aquellos años. Y a nadie le importa: de ese horror, quién puede tener nostalgia. Todo pasó como pasan los discos en la sinfonola. Nunca sabré si aún vive Mariana. Si viviera tendría sesenta años.”
José Emilio cree en la memoria, a la nostalgia la repudia.
“EL YO SE VUELVE TÚ”
Los jóvenes lo quieren porque crea en torno suyo un ambiente fraterno. No habla desde el podio, no discurre, pregunta. Se dirige en tono familiar al que tiene enfrente, casi de inmediato entra en contacto, contigo, conmigo. Los jóvenes saben que ha tenido la generosidad de decir que “todo lo escribimos entre todos” así como su admirado Alfonso Reyes lo antecedió diciendo que “todo lo sabemos entre todos”, porque su lenguaje es desnudo y nos desnuda, porque leerlo les ofrece la posibilidad de no sentirse solos, pero también de no hacer concesiones, de no incurrir en lo fácil, de no caer en la rutina, de mantener un espíritu alerta y bien informado. Los jóvenes lo quieren porque los invita, se pone en su lugar, generaciones vienen y generaciones van y José Emilio que fue un niño preguntón y molesto (según él) sigue interrogándose, interrogándolos, interrogándonos y sintetiza las principales noticias del mundo para crear nuevas formas de comunicación. Para él la primera, la esencial, es la lectura silenciosa. “Me gusta que la poesía sea la voz interior, la voz que nadie oye, la voz de la persona que la lee. Así el yo se vuelve tú, el tú se transforma en yo y del acto de leer nace el nosotros que sólo existe en ese momento íntimo y pleno de la lectura”.
Jóvenes disfrutan el concierto de cierre del maratón de lectura con motivo del cumpleaños 70 de José Emilio Pacheco en el CenartFoto: María Luisa Severiano/ archivo La Jornada
Los jóvenes saben que José Emilio Pacheco los considera infinitamente valiosos y dignos de respeto y que siempre van a adelantarse: “A lo mejor soy yo el que está equivocado.” En los sesenta y en los setenta, en la sede del suplemento La cultura en México primero en la calle de Balderas y luego en México en la cultura en la calle de Vallarta, Carlos Monsiváis y él se reparten el trabajo. “Al conocer a Carlos sofoqué en mí toda esa parte de parodia y burla que él neutralizó inconscientemente. Siento mayor compasión por los demás que por mí mismo”, dice José Emilio, quien sufre y vuelve a sufrir con los textos ajenos y los rehace por completo. Está de vuelta de todo como si tú, si nosotros, si ustedes, si yo fuéramos a alguna parte. Seguro el autor es alguien que “traspasó el límite de edad o proviene de un país que ya no existe” o es un desempleado o una costurera sin su Singer. “Tíralo a la basura”, grita Benítez y Pacheco vuelve a inclinarse sobre la página y corta, añade, cambia. Seguro de tanto corregir se volvió implacable contra sí mismo. Está al tanto de todo, nada se le va, se compunge hasta la tortura cuando Fernando Benítez hace mofa de un colaborador. Monsiváis ríe y su risa se oye hasta el Zócalo. Qué malo es Monsiváis, José Emilio es malo a ratitos y yo lo soy en contra de mí misma. Pacheco se equivoca al decir que Monsiváis sofocó en él su vena paródica. No hay más que leer sus “Inventarios” para comprobarlo. Desde 1957, caminan juntos por la avenida Juárez y huyen cuando ven a Carlos Fuentes y a Fernando Benítez sin saber que, diez años más tarde, Benítez los llamará sus maestros y ellos serán quienes hacen el suplemento, levantan el edificio de cristal de la cultura y lo abren a los que vienen detrás. “Escribir es una manera de saber y de estudiar y de investigar.” “Quise dedicarme a algo que estimulara la lectura, que hiciera que los libros se abran, no se cierren.” A fines de los cincuenta, México es el de los bailes de quince años, el de los juegos florales, el de la Oda a la Feria de San Marcos, el del Canto a la Mujer Mazatleca , el del día de la madre. Al ganador lo escuchan declamar con gestos ensayados su poema por el que recibe 15 mil pesos de los de entonces. Es el México de los concursos de oratoria. También es el México de las tesis. “Dedico esta tesis con todo mi corazón y mi amor a la persona más importante de mi vida, mi madre, a Dios, a mi abuelita que me acompañó a estudiar en la noche, a mi novio, a mi tía Cuquis, etcétera”. Es de ese México, el México de la disipación y del estar sin estar o estando en otra parte que brotan las dos flores más bellas y voraces del ejido: los dos niños precoces y terribles, los catedráticos que conocen la respuesta y si no, la buscan, los monstruos de la laguna negra como los llamaría Rosario Castellanos, los testigos, los que no sucumben, los que sí toman terriblemente en serio la literatura y la vida y actúan en consecuencia, José Emilio Pacheco y Carlos Monsiváis.
Al perder la timidez que los caracterizó en 1957, inician el diálogo ininterrumpido que tienen con sus lectores. José Emilio rechaza las entrevistas porque ¿quién es él para dar consejos? Todo sucede entre iguales, todo se hace entre todos. Tanto Pacheco como Monsiváis son santos de devoción, días de guardar, fiestas de calendario, ruedas de la fortuna. Desde hace cincuenta años los jóvenes le apuestan a ambos en su poesía, su prosa, sus inventarios, sus críticas, su fidelidad y su continuidad, su amor a la literatura como actitud ante la vida.
Los jóvenes llegan desde temprano y abarrotan las conferencias de José Emilio. En pleno centro, en el Colegio Nacional en Luis González Obregón, calle a la que cuesta tanto trabajo llegar, sus conferencias están llenas. En 1995, en el aula magna Santa Teresa de la Ibero , los niños y las niñas fresa no caben y gritan: “¡Explanada, explanada!” José Emilio se quita la corbata y ofrece dos conferencias, una para los que están sentados y otra para los que están de pie, los que quedaron afuera, los que se acomodaron en las escaleras, los que esperan en la calle. En la UNAM sucede lo mismo, no cabe un alfiler y lo escuchan decir en 1995 lo que podría suscribir en 2009 porque nada ha cambiado, sus palabras son el retrato mismo de lo que hoy padecemos. “El mundo que produjo el neoliberalismo se parece al mundo de los años treinta que hizo posible el régimen totalitario. Las caídas del socialismo real y el fracaso del mercado libre han creado un vacío de poder que está en riesgo de ser llenado por regímenes totalitarios.” “Al caos económico del desempleo, la falta de oportunidades para los jóvenes; las desilusiones por las falsas promesas de seguridad creadas por el proceso democratizador se suman factores que no existían hace setenta años”. Entre ellos José Emilio nombra a la sobrepoblación y dice que somos más desechables que nunca, habla de la “invasión que el Tercer Mundo ha realizado sobre el primero en busca de trabajos” y finalmente menciona “la presencia de los medios electrónicos y una monumental industria del entretenimiento que se basa en gran medida en la estatización y la trivialización de la violencia”. Claro que también regresa a las consignas del '68: “Seamos realistas, pidamos lo imposible.” Dejemos que el “otra vez” sea sustituido por el “nunca más”. E insiste: “Dejarlo todo para mañana es el camino de después para llegar a la casa de nunca”.
EL JOVEN DE SETENTA
Desde joven, el propio José Emilio tuvo setenta años, desde joven se vio a sí mismo como testigo, fue un niño muy flaco al que le tenían que apretar la nariz para que comiera, desde niño intervenía en la conversación de sus mayores, desde niño resultó molesto porque inquiría acerca de lo que sucede. “En plena sala ante la familia reunida preguntó qué es un fornicador” y la tía Socorro lo salvó de la reprobación al responderle: “Hay unas cajas de vidrio/ en que puedes meter hormigas/ para observar sus túneles y sus nidos/ Se llaman formicarios. Formicador es el hombre que estudia las hormigas.” Desde entonces en la poesía de José Emilio abundan las hormigas, las pulgas, las moscas, las chinches, los mosquitos y las termitas que tienen que compartir el aire con nosotros.
Desde joven se negó a figurar, no quiso dar entrevistas, firmó JEP (que son las iniciales de mi sangre puesto que son las de mi padre Jean Evremont Poniatowski), pidió disculpas, escribió: “Antes de que seas vieja ya me habrás olvidado./ Y si por confusión sueltas mi nombre/ a tu lado una joven dirá:/-¿Quién era ese?”
Los jóvenes lo quieren porque es uno de ellos, es la voz de la tribu. Es asombroso pensar que un hombre que no sale, no hace vida social, rechaza figurar, vive en el rigor y en la soledad demandante del trabajo creativo, tenga esa respuesta multitudinaria, esa comunicación por la palabra que de pronto estalla en un auditorio en el que ya nadie cabe. José Emilio Pacheco cuenta con la atención y el seguimiento de las comunidades estudiantiles, las públicas y las privadas, las de todo el país, las de Europa y las de Estados Unidos, las de sistemas de signos y las de elementos configuradores. Así como Jorge Luis Borges confesó no tener casi ninguna experiencia fuera de la lectura de libros, José Emilio nos lega la experiencia adquirida desde que decidió entregarse a la palabra sin tener la menor idea de cuál sería su repercusión porque en los cincuentas nadie vivía de la escritura.
HACER DE NUEVO
Los jóvenes lo quieren porque no está satisfecho, no se cree, declara una y otra vez que es un aprendiz y que “cada página es de nuevo la primera y puede ser la última”. “Si él dice eso, entonces nosotros tenemos una oportunidad”, se alientan unos a otros. No se llega nunca, nada es seguro. Los poemas de José Emilio no sólo son escritos, los cuece a fuego lento, parecen materializarse en un caldero, se acendran, hierven durante años, no son literarios, no son ilustraciones, son poemas destilados en la cueva oscura de la creatividad, sublimados. Crecen con el tiempo y de tanto cocerse vienen a formar parte de nuestro subconsciente. Jamás se conforma aunque a veces se ve muy contento y nos alegre con su sentido del humor. “No tuve más remedio, lo hice de nuevo”, se disculpa. Hacer de nuevo podría ser el ritornello de su vida. Le cuesta más trabajo reescribir cuentos y poemas que escribirlos por primera vez pero es imposible dejarlos como están. Allí sigue, revisa, coteja, lee otra vez, recorre la literatura del planeta Tierra a la que él llama “la amarga tierra”, memoriza la literatura mexicana del siglo XIX, sufre, vuelve a leer lo que ya publicó y encuentra nuevos e imaginarios errores, tiene supersticiones de torero gitano.
Ganador del Premio Internacional Alfonso Reyes, el Iberoamericano de Poesía Pablo Neruda, el José Asunción Silva de Bogotá, Colombia, el Iberoamericano de Letras José Donoso, el Octavio Paz y el Federico García Lorca de Granada (en el que superó a Gonzalo Rojas, Juan Gelman, Nicanor Parra y Mario Benedetti), el Reina Sofía, aunque lo acompañen el cielo, la luna y las estrellas, José Emilio se niega al principio del placer. Lo coronan todos los premios que puede dar nuestro continente, el Nacional, el de la Academia , el del Colegio Nacional, nuestra máxima institución cultural, el de la Universidad de Maryland que lo hizo Profesor Universitario Distinguido, el de “El poeta más joven del siglo XXI” del crítico Julio Ortega de la Universidad de Brown. Los homenajes lo desbordan, pero dentro de él está el enemigo que desde sus primeros versos editados en 1956 le dice que “no volveremos nunca a tener en las manos el instante”.
Es imposible imaginar en su casa tantas preseas, medallas, condecoraciones, tantos diplomas enmarcados, tantos premios, tantos reconocimientos, tantas estatuas, tantos libros, la vida entera de un hombre, la vida entera de un país. En “Otredad, otra edad” nos dice: “¿Qué pensaría de mí si entrara en este momento/ y me encontrase en donde estoy, como soy/ aquel que fui a los veinte años?” Como repite en “Despedida”: “Fracasé. Fue mi culpa, lo reconozco./ Pero en manera alguna pido perdón o indulgencia:/ Eso me pasa por intentar lo imposible.”
Tampoco en el poema “Conferencia” José Emilio se salva de sí mismo: “Halagué a mi auditorio. Refresqué/ su bastimento de lugares comunes,/ de ideas adecuadas a los tiempos que corren./Pude hacerlo reír una o dos veces/y terminé cuando empezaba el tedio./ En recompensa me aplaudieron./ ¿En dónde/ voy a ocultarme para expiar mi vergüenza?”
Claro, José Emilio puede alegar que no es él, que no escribe sobre sí mismo, pero ¿cómo no identificarlo con su poesía? Escribe sobre el otro, sobre Lezama Lima, sobre Cortázar, sobre Lawrence Durrel y su Cuarteto de Alejandría, sobre Alfonso Reyes, sobre López Velarde, escribe sobre Henry Miller y Edgar Allan Poe, sobre Heráclito y Eurípides, sobre Kavafis y Elytis, pero al escogerlos escribe sobre sí mismo, todos pasan por su tamiz que es su éxtasis. A diferencia de los escritores que ven al mundo desde la perspectiva de los hombres de poder, José Emilio ve del lado de las víctimas y actúa en consecuencia. De allí sus inclinaciones.
LA HISTORIA DE NUESTRO FUTURO
Los jóvenes lo siguen porque mantiene la voluntad de enseñar y de volver accesible lo que de otra manera “sólo sería el privilegio de unos cuantos”. En Inventario José Emilio es ensayista, cuentista, poeta, novelista, crítico político, crítico literario, cronista, traductor y sus traducciones dicen más que los originales porque estudió griego y latín durante varios años, hizo bien su tarea y la cultura clásica es su punto de partida. En el prólogo a la obra de Salvador Novo escribió en 1965:
Ya que el presente desengaña, sólo el futuro puede consolar, volver los ojos al pasado es asumir el riesgo de convertirse en estatua de sal –sí, pero también de conocernos, de conocer lo que fuimos o lo que fue, de aceptar que ningún tiempo pasado fue mejor-. Territorio entre lo que ya no es y lo que no es todavía, lo cotidiano nos permite recuperar, en la memoria, el tiempo irreversible; saber que decir tiempo es decir pasado y de algún modo, sólo es verdaderamente nuestro lo que perdemos, lo que ya hemos perdido para siempre.
Vuelve a decirlo en “La edad de las tinieblas” que hoy empieza a circular: “Ayer no resucita. Lo que hay atrás no cuenta. Lo que vivimos ya no está. El amanecer nos entrega la primera hora y el primer ahora de otra vida. Lo único de verdad nuestro es el día que comienza.”
Ninguno de los que llamaban a José Emilio “profeta del desastre”, se dio cuenta que escribía la historia de nuestro futuro. Quizá su abuela lo adivinó, su abuela Emilia Abreu de Berny, su Sherezada allá en Veracruz, la que le contaba en la noche todo lo que alimentó su imaginación, la que abrió las compuertas a la creatividad, la que le dio la pasión por las letras, la que intentó explicarle el mundo.
Los jóvenes lo quieren porque José Emilio es un caso de vocación literaria extraordinaria. A diferencia de su familia materna, los Berny, empresarios conservadores y muy católicos, su padre fue uno de aquellos mexicanos pobres que pudieron estudiar gracias a la Revolución mexicana en que participó desde 1910. Colaboró con Salvador Alvarado y Felipe Carrillo Puerto y alcanzó el grado de general y procurador de Justicia Militar. En 1927 se negó a hacer pasar por consejo de guerra el fusilamiento del general Francisco Serrano y sus partidarios en Huitzilac, como se lo ordenaban las autoridades. Estuvo a punto de ir al paredón por desacato y lo salvó en el último momento una orden de Álvaro Obregón. A partir de entonces quedó fuera de los regímenes revolucionarios. Practicó la abogacía y más tarde se hizo notario. Como no les cobraba a los pobres, al morir en 1964 dejó por toda herencia menos de diez mil pesos. De todos modos temió que su hijo como escritor fuera a morirse de hambre y esperó que heredara la notaría número 50. Pero no fue así. A José Emilio las carreras de abogado y notario le parecieron “horribles”. Esta es su verdadera biografía y no la de sus personajes de ficción que muchos han tomado como declaraciones autobiográficas, lo que a él le satisface porque, dice, le confiere autenticidad a sus imaginaciones.
José Emilio considera que gran parte del trabajo de un escritor se hace escuchando y se cree muy privilegiado porque las amistades que hizo su padre durante el período revolucionario le dieron de niño y adolescente la oportunidad de oír en la mesa familiar a muchos personajes grandes y pequeños de la historia de México. Él se ha empeñado en “recordar con la ayuda de la imaginación”, como decía Rodolfo Usigli, muchos de esos relatos olvidados porque raras veces llegaron a los libros. Por ejemplo, basado en lo que oyó en labios de las personas más diversas, cree que la guerra cristera fue en Ciudad de México mucho más terrible de lo que se supone: por vez primera hubo en Hispanoamérica guerrilla urbana y práctica sistemática de la tortura. El gran triunfo de Calles fue lograr que no quedara constancia de casi nada de esto en los periódicos.
Algunas de esas amistades familiares eran libertarias, como Juan de la Cabada y Héctor Pérez Martínez, y sobre todo José Vasconcelos. Carlos Monsiváis recordó que José Emilio lo invitaba a comer a su casa y ambos escuchaban muy serios y callados a Vasconcelos, personalidad absolutamente fascinante. Juntos iban a visitar también a Martín Luis Guzmán, que es una de las admiraciones de los dos, y don Julio Torri les hablaba en voz baja de la historia secreta de la pornografía mexicana.
DECIR “GRACIAS”
Los jóvenes lo quieren porque lleva dentro de la caja de su pecho a sus muertos. José Emilio les dedica sus poemas a los que se han ido: José Carlos Becerra, José Agustín Goytisolo, Paul Celan, Alaide Foppa, Eliseo Diego, Efraín Huerta, Miguel Guardia, José Durand, Rosario Castellanos, Raúl Gustavo Aguirre, Octavio Paz. “Llevamos siempre adentro la misma muerte, también el cielo fue un ave negra.” A propósito de José Carlos Becerra, cuenta que su método de trabajo era contrario al suyo, que José Carlos Becerra iba añadiendo a medida que escribía y él va quitando. JEP extraña a sus muertos y los mantiene vivos, rendirles homenaje es para él una obligación moral, practica como nadie el agradecimiento y recuerda constantemente a Fernando Benítez, con quien trabajó durante tantos años. Valora como ningún otro el aprendizaje y el martirio de hacer el suplemento. Le agradece a Reyes, le agradece a Paz, le agradece a Rubén Darío, le agradece a Albert Camus, le agradece a Jaime García Terrés, le agradece a Vicente Rojo, le agradece al Mercure de Francia, le agradece al Time, le agradece al Newsweek , le agradece a Mario Vargas Llosa, le agradece a Moreno Tagle, el maestro que se dio cuenta que le interesaba la literatura, le invitó un café y le dijo: “Muéstrame todo lo que escribes”, para llevarlo más tarde a la revista Estaciones de Elías Nandino, el médico poeta que abría la puerta de su consultorio a todos los jóvenes enfermos de literatura. JEP le agradece a Sanborns los waffles y hotcakes que desayuna después de comulgar y la venta de unos libritos de los clásicos que ya no existen. La lista es infinita: le agradece al Departamento de Investigaciones Históricas que le permitió hacer sus búsquedas incansables, le agradece a su padre, quien le dijo: “Te compro un libro por semana y otro cuando ya lo hayas leído.” Aunque alega que es muy desordenado (en reacción a su padre), José Emilio da la impresión de leer cinco libros a la vez y retenerlos todos. Sus críticas, sus reseñas, sus crónicas así lo demuestran. En estos últimos años, José Emilio, pozo de sabiduría, se disculpa por el poema a George B. Moore que Octavio Paz criticó aunque puede suscribir cada uno de estos versos con su vida. Nunca ha traicionado a lo largo del tiempo lo que le escribió al crítico George B. Moore. Fiel a sí mismo, nadie más igual a José Emilio Pacheco que José Emilio Pacheco, y esto no puede decirse de otros que van desgajándose poco a poco, dejando sus cuartos de naranja, tajadas y cicatrices a lo largo del viaje. No, José Emilio sigue siendo el mismo escritor compacto y nítido, el mismo hombre angustiado que se usa a sí mismo como vehículo de pensamiento, el mismo que escribe todo el día y lee todo el día, el mismo que se encierra y va recogiendo desde que amanece el material que da la vida. A la ciudad, al país entero lo ha inventariado y gracias a él sabemos qué tenemos y de qué carecemos.
La Ciudad de México, la pasada y la actual regresan una y otra vez a su poesía y le resultan extrañas, las desconoce, nada está en su lugar, incluso fuera de México; en Riverside Drive, por ejemplo, el padre de su amigo le dice: “Conozco tu país./ Pasé una noche en Tijuana./ Estas son las palabras que me sé de tu idioma:/ puta, ladrón, auxilio, me robaron.”
Su cuento “La catástrofe” en La sangre de Medusa se basa en el cuento que Eça de Queiroz, el novelista portugués, publicó una semana antes de su muerte en 1900. José Emilio escribe en el párrafo final a propósito de un padre que encamina a sus hijos:
Los acostumbro a amar la patria en vez de despreciarla como hicimos nosotros. Nos sentíamos tan distintos, tan superiores al resto de los mexicanos. Decíamos llenos de arrogancia: “No se puede con Mexiquito. Esto es una mierda. A este país ya se lo llevó la chingada. Aquí lo único que producimos son pendejos y ladrones. La única salvación es que nos anexen a Estados Unidos. Y en vez de esforzarnos por salvar a este país, el único que tenemos, bebíamos whisky y echábamos a andar nuestras videocaseteras. Ah generación cobarde, qué bien castigada fuiste”.
A José Emilio lo aman los jóvenes porque además de gran poeta es un poeta con vocación de servicio, el héroe moral que pide Saramago. Ya a los veintiséis años se preguntaba:
¿Quién a mi lado llama, quién susurrao gime en la pared?Si pudiera saberlo, si pudieraalguien saber que el otro lleva a solastodo el dolor del mundo, todo el miedo.
En 1970 lo fui a ver con el manuscrito de La noche de Tlatelolco y antes de empezar a leerlo, su prudencia le hizo cerrar las cortinas de su cuarto de trabajo y preguntarme por las precauciones que había tomado. Como no tengo sentido de la realidad y no sé vivir en ella le dije que ninguna. Se sentó a leer y casi no hablamos. Diez años después de la masacre de los estudiantes, José Emilio escribió “Las voces de Tlatelolco”: “Eran las seis y diez. Un helicóptero/ sobrevoló la plaza./ Sentí miedo./ Cuatro bengalas verdes./ Los soldados/ cerraron las salidas./ Vestidos de civil, los integrantes/ del Batallón Olimpia/ –mano cubierta por un guante blanco–/ iniciaron el fuego./ En todas direcciones/ se abrió fuego a mansalva./ Desde las azoteas/ dispararon los hombres de guante blanco./ Disparó también el helicóptero./ Se veían las rayas grises./ Como pinzas/ se desplegaron los soldados./ Se inició el pánico./ La multitud corrió hacia las salidas/ y encontró bayonetas./ En realidad no había salidas:/ la plaza entera se volvió una trampa./ –Aquí, aquí Batallón Olimpia./ Aquí, aquí Batallón Olimpia./ Las descargas se hicieron aún más intensas./ Sesenta y dos minutos duró el fuego./ –¿Quién ordenó todo esto?/ Los tanques arrojaron sus proyectiles./ Comenzó a arder el edificio Chihuahua./ Los cristales volaron hechos añicos./ De las ruinas saltaban piedras./ Los gritos, los aullidos, las plegarias/ bajo el continuo estruendo de las armas./ Con los dedos pegados a los gatillos/ le disparan a todo lo que se mueva./ Y muchas balas dan en el blanco./ –Quédate quieto, quédate quieto:/ si nos movemos nos disparan./ –¿Por qué no me contestas?/ ¿Estás muerto?/ –Voy a morir, voy a morir./ Me duele./ Me está saliendo mucha sangre./ Aquél también se está desangrando./ –¿Quién, quién ordenó todo esto?/ –Aquí, aquí Batallón Olimpia./ –Hay muchos muertos./ Hay muchos muertos./ –Asesinos, cobardes, asesinos./ –Son cuerpos, señor, son cuerpos./ Los iban amontonando bajo la lluvia./ Los muertos bocarriba junto a la iglesia./ Les dispararon por la espalda./ Las mujeres cosidas por las balas,/ niños con la cabeza destrozada,/ transeúntes acribillados./ Muchachas y muchachos por todas partes./ Los zapatos llenos de sangre./ Los zapatos sin nadie llenos de sangre./ Y todo Tlatelolco respira sangre./ –Vi en la pared la sangre./ –Aquí, aquí Batallón Olimpia./ –¿Quién, quién ordenó todo esto?/ –Nuestros hijos están arriba./ Nuestros hijos, queremos verlos./ –Hemos visto cómo asesinan./ Mire la sangre./ mire nuestra sangre./ En la escalera del edificio Chihuahua/ sollozaban dos niños/ junto al cadáver de su madre./ –Un daño irreparable e incalculable./ Una mancha de sangre en la pared,/ una mancha de sangre escurría sangre./ Lejos de Tlatelolco todo era/ de una tranquilidad horrible, insultante./ –¿Qué va a pasar ahora, qué va a pasar?”
Esa pregunta se la hace José Emilio a los setenta años, esa pregunta nos la hacemos nosotros hoy que le rendimos homenaje.
En cuanto a mí, siempre espero ansiosa la llegada de José Emilio. Me hace falta. En torno a él, el aire se vuelve cálido, familiar, verdadero. No hace frases solemnes, no excluye a los otros, los estudiantes lo rodean, las muchachas se enamoriscan de él, no fabrica una capilla, no trata de apantallar con su presencia, sus comentarios son caseros: “creí que iba a perder el tren”, “no encontré taxi”, “ya todos se casaron”, “no sé qué decir en el discurso”, se entreteje su erudición admirable. En medio del relato de sus pifias y desventuras, que José Emilio acentúa para rescatar a los demás y hacerlos juez y parte (siempre los demás), surgen sus prodigiosos conocimientos, su información insuperable y José Emilio agridulce acaba riéndose de sí mismo, nos vuelve cómplices de su infortunio, cualquier que éste sea. Después de conocerlo desde hace casi cincuenta años, he comprobado que su humildad, su modestia son verdaderas. Desde el fondo del alma, José Emilio es un niño bueno. Si es tan querido, es porque además de su generosidad se incorporó desde chavito a las causas de los presos políticos. No en balde en 1960 hizo una huelga de hambre en la Academia de San Carlos junto a don Filomeno Mata, que en 1959 acabaría preso en Lecumberri. Conversó toda la noche con José Revueltas, el más encantador y ocurrente de los presos que así como Gandhi en su vida comió cuatro veces, Revueltas en la suya estuvo libre como una semanita. Fue entonces cuando Pacheco empezó a concebir sus célebres “Inventarios” políticos, comprometidos, notables y radicales.

LEUCEMIA LINFOCITICA CRONICA : MECANISMOS MOLECULARES

Review
Nature Reviews Clinical Oncology 6, 405-418 (July 2009)

Subject Categories: Hematology Molecular and Cellular Signaling
Molecular and cellular mechanisms of CLL: novel therapeutic approaches
Lisa Pleyer1, Alexander Egle1, Tanja Nicole Hartmann1 & Richard Greil1

Abstract
The mainstay of therapy of chronic lymphocytic leukemia (CLL) is cytotoxic chemotherapy; however, CLL is still an incurable disease with resistance to therapy developing in the majority of patients. In recent years, our understanding of the biological basis of CLL pathogenesis has substantially improved and novel treatment strategies are emerging. Tailoring and individualizing therapy according to the molecular and cellular biology of the disease is on the horizon, and advances with targeted agents such as monoclonal antibodies combined with traditional chemotherapy have lead to improved remission rates. The proposed key role of the B-cell receptor (BCR) in CLL pathogenesis has led to a number of possible opportunities for therapeutic exploitation. We are beginning to understand that the microenviroment is of utmost importance in CLL because certain T-cell subsets and stromal cells support the outgrowth and development of the malignant clone. Furthermore, an increase in our understanding of the deregulated cell-death machinery in CLL is a prerequisite to developing new targeted strategies that might be more effective in engaging with the cell-death machinery. This Review summarizes the progress made in understanding these features of CLL biology and describes novel treatment strategies that have also been exploited in current clinical trials.
Key points
Antigenic input and B-cell receptor (BCR) signaling are important in the pathophysiology of chronic lymphocytic leukemia (CLL)
A number of relevant signals downstream of the BCR signal, or that modify its signal, have been implicated in CLL and are currently exploited as targets for therapy
The contribution of accessory immune cells and of stromal microenvironment to CLL pathophysiology is starting to be exploited in a therapeutic fashion
CLL-specific proapoptotic and antiapoptotic influences contributed by microenvironmental and immunologic cues allow for a unique opportunity to target the core cell-death machinery in various combinations
A large number of early clinical trials exploiting such rationales are currently under way and the results will need careful integration into future therapeutic concepts
Introduction
The treatment of chronic lymphocytic leukemia (CLL) is in the process of substantially changing. While treatment approaches in the past were based on disease control that achieved a chronic indolent disease, treatment goals nowadays are aimed at achieving long-term remissions, at least in a less-indolent subset of patients. Such remissions are defined by negativity for minimal residual disease (MRD), as measured by highly sensitive methods such as multicolor flow cytometry. Achievement of an MRD-negative state is associated with superior long-term outcome. This has been shown for monotherapy with the monoclonal antibody alemtuzumab in pretreated patients with CLL (improved overall and treatment-free survival for MRD-negative patients);1 the combination of fludarabine, cyclophosphamide and mitoxantrone as front-line treatment (longer response duration and overall survival for MRD-negative patients);2 and first-line sequential3 or combined therapy4 with fludarabine, cyclophosphamide and rituximab (longer response duration for MRD-negative patients). Currently, cytotoxic drugs are still the mainstay of CLL therapy, with fludarabine being the backbone of many different treatment regimens. Although it is possible to achieve complete remission rates in the range of up to 80% using combinations of fludarabine with the anti-CD20 antibody rituximab in conjunction with cyclophosphamide and/or mitoxantrone,2, 5 approximately 20% of patients with CLL do not achieve complete disease control with these conventional therapies. In this context it is important to emphasize that deactivation of the DNA damage pathway, most notably by loss of p53 function, leads to exquisite resistance to cytotoxic agents, including those mentioned above. Primary resistance to fludarabine, for instance, is almost uniformly observed in patients bearing p53-deletions6 and has devastating consequences. Such patients survive for less than 1 year despite dose-intense salvage therapies. In addition, it is currently not possible to change the underlying biology of the disease by impressive reduction of cell numbers and/or lymph-node size alone, as risk factors such as immunoglobulin heavy-chain variable region gene (IgVH) mutational status are still able to predict progression-free survival, even in patients who achieve a complete remission.7 In future it will be necessary to develop therapeutic strategies that circumvent cellular resistance mechanisms to cytotoxic agents, which are often caused by an inactive p53 pathway, in order to obtain sustained remission rates in patients with adverse prognostic factors. In an effort to address these medical needs, this Review focuses on the current knowledge of CLL disease biology, and how this increased understanding can be employed to develop therapeutic approaches that might directly modify central pathways of CLL maintenance and/or bypass cellular resistance mechanisms to cytotoxic drugs.
Role of BCR-signaling pathways
Immunoglobulin diversity and, therefore, antigen receptor binding specificity of the B-cell receptor (BCR), results from the assembly of the variable (V), diversity (D) and joining (J) gene segments of the immunoglobulin (Ig) heavy chain (IgH) and the V and J segments of the Ig light chains. Further diversity arises from antigen triggered class switching recombination and the deletion or insertion of nucleotides, as well as the usage of different open reading frames. The third heavy chain complementary determining region (HCDR3) has the major role in determining antigen binding specificity,8 and is created de novo by the VDJ recombination process.9 Somatic hypermutation following mature B-cell stimulation with antigens may occur in a T-cell-dependent or T-cell-independent manner, mainly within germinal centers, but also outside classic germinal centers,10 resulting in further antibody diversity.
In CLL, the biased heavy chain Ig repertoire in conjunction with preferential usage of distinct light chain genes, as well as the use of similar amino acid motifs in the HCDR3, have led to the hypothesis of an antigen component being involved in the pathogenesis of the disease.11 Clonal CLL selection by specific antigens is indicated by the high proportion of patients with CLL who express virtually identical Ig heavy and light chains, and the presence of precisely targeted somatic hypermutation patterns in the form of recurrent 'stereotyped' amino acid changes across the entire IgVH sequence.12, 13 Evidence for the important role of the BCR for CLL pathogenesis also stems from the fact that the mutational status observed in the BCR sequences is one of the strongest predictors of disease outcome.14, 15
Initially it was assumed that CLL might comprise two different diseases: one with cells that express unmutated IgVH genes (U-CLL) derived from naive B cells, and another with mutated CLL cells (M-CLL) thought to be derived from antigen-experienced B cells. It is now known that all CLL cells bear the surface membrane phenotype of antigen experienced (CD27) and activated (CD23, CD25, CD69, CD71) B cells and show gene-expression profiles similar to memory B cells,16, 17 irrespective of IgVH mutational status. This finding is consistent with the notion that all cases of CLL have a common cellular origin and/or common mechanism of transformation16 and a continued requirement for antigen after the transformation event in disease perpetuation.18 Comparative analysis of mutated and unmutated subgroups, however, suggests that B-CLL cells differing in IgVH phenotype may have different antigen encounter histories.18 Specific stereotyped HDCR3s are preferentially associated with molecular, cytogenetic, phenotypic and clinical features, some of which portend a considerably more-aggressive disease with shorter time-to-initial treatment and worse overall survival times, and this might be regardless of IgVH mutation status.19, 20 This striking association between stereotyped BCRs and the phenotypic and clinical features for selected subsets of patients suggests that an antigen-driven process might be critical in determining clinical features and for modulating disease outcome, irrespective of mutation status in B-CLL.21 In addition, several molecules that modify BCR signaling, such as ZAP-70 or CD38, display important prognostic power,22 thus lending further support for the prominent role of BCR signaling in CLL pathophysiology, and identifying molecules involved in BCR signaling as important potential therapeutic targets.
Downstream signaling of the BCR in CLL is dominated by the kinases Lyn and Syk, which transduce survival and antiapoptotic signals after antigenic BCR triggering (Figure 1).23 In CLL, antiapoptotic BCR signaling has been associated with prolonged activation of the MEK/ERK and PI3K/AKT pathways and with AKT-induced elevated expression of antiapoptotic Mcl-1, which leads to increased survival of malignant cells (Figure 1).24 Signal transduction via Lyn is regulated and amplified via CD19 and these signals are responsible for the establishment of baseline signaling thresholds in B cells before antigen-receptor ligation, in addition to augmenting tonic signaling (that is, BCR signaling occurring independently of antigen-ligation) following BCR engagement.25 Lyn was identified as a major contributor to antigen-independent BCR signaling as it is strongly overexpressed, constitutively active and aberrantly present in the cytosol.23 Additionally, the recruitment and subsequent activation of Syk to immunoreceptor tyrosine-based activation motifs within the cytoplasmic tails of Ig and Ig seems to be disturbed in CLL, as alternative transcripts of Ig have been described (Figure 1).26 CLL clones with proliferative response to BCR ligation have considerably higher Syk levels than nonresponsive 'anergic' CLL cells,27 and the tyrosine kinase ZAP-70 can partially restore BCR signaling when Syk is not expressed.28
Figure 1 The role of BCR signaling in the biology of CLL.The engagement of the BCR leads to complex formation of CD79alpha-beta heterodimers with several costimulatory molecules. This results in intracellular recruitment and activation of the protein tyrosine kinases Syk, ZAP-70 and Lyn at the immunoreceptor tyrosine-based activation motifs of the BCR and activation of several signal transducers and pathways such as p38, JNK, MEK/ERK and PI3K/PKC/AKT. Coligation of B cell negative regulatory molecules with the BCR results in phosphorylation of ITIMs (instead of ITAMs) and recruitment of SHP-1, which deactivates signal transduction molecules.140, 141 Positive regulators of the BCR are marked in green, while negative regulators are marked in red. The lightning bolt symbols indicate putative therapeutic targets. Abbreviations: BCR, B-cell receptor; Ig, immunoglobulin; IL, interleukin; ITAM, immunoreceptor tyrosine-based activation motif; LPA, lysophosphatidic acid; PD-1, programmed death 1; PIR-B, paired immunoglobulin-like receptor B; PKC, protein kinase C; SDF1 stromal-cell-derived factor 1; SHP, Src homology 2 domain containing protein tyrosine phosphatase; Tcl-1, T-cell leukemia 1; XIAP, X-linked inhibitor of apoptosis protein.
CLL can be distinguished in two subsets depending on the incidence of somatic mutations in the IgV genes, with a poorer clinical prognosis for U-CLL compared with M-CLL.22 ZAP-70, which is involved in T-cell-receptor signaling, is aberrantly expressed in some patients with CLL and shows partial, but not complete, overlap with overexpression of other risk factors such as the presence of CD38 or unmutated IgVH genes.29, 30 High ZAP-70 expression in B-CLL cells is associated with more-aggressive disease. While M-CLL cells are considered anergized, U-CLL cells seem to retain some capacity for competent BCR signaling, with an increased tendency to phosphorylate Syk and to recruit and phosphorylate ZAP-70.31 The presence of ZAP-70 can enhance and prolong BCR signaling in CLL independent of its tyrosine kinase function, probably by acting as an adaptor protein.28 The anergy of M-CLL cells is thought to be the result of chronic exposure to soluble (auto)antigens in the absence of co-stimulatory signals,32 and of unresponsiveness to BCR signaling owing to receptor desensitization. In addition, BCR translocation to lipid rafts (that is, cholesterol-enriched microdomains in cell membranes) and associated signaling, differs in M-CLL compared with U-CLL. A constitutive exclusion of the BCR from lipid rafts was observed in M-CLL and might be responsible for impaired interactions between the BCR and the actin cytoskeleton.33
Another potential modifier of BCR signaling is CD38, which is a molecule that affects proliferation and longevity of the neoplastic clone.34 CD38 ligation by monoclonal antibodies results in proliferation and blastic transformation of a subset of CLL cells, and engagement of CD38 as a receptor is a Lyn-dependent process.35 Dynamic localization to lipid rafts (for example, mediated by CD31 crosstalk) and lateral association of CD38 with the BCR, CD19 and CD81 (Figure 1) was reported to be a prerequisite for CD38-mediated signaling, and enhancement and fine-tuning of BCR signaling.36 Importantly, ZAP-70 represents a limiting factor in the CD38 signaling pathway, probably serving as a cross-point where BCR signals are enhanced and where migratory signals from chemokine receptors intersect with growth signals mediated via CD38 (Figure 1).37 This might be one reason why CD38+/ZAP-70+ patients have a worse prognosis than CD38+/ZAP-70- patients.30 However, functional linkage or a specific association with signaling capacity has not been proven so far, and elevated levels of CD38 and/or ZAP-70 may merely be markers of activation. In addition, the main determinant of BCR-mediated signaling may be the expression level of surface IgM, which is generally upregulated in U-CLL and downregulated to anergy in M-CLL.31 This molecular signature of anergy is characterized by constitutive activation of MEK and ERK.38 As CLL anergy primarily occurs in the mutated CLL subset, it is not surprising that ERK phosphorylation defines CLL cases with a favorable prognosis.38
Targeting the BCR pathway
Pharmacological inhibition of BCR signaling could provide a dual therapeutic benefit, as disruption of both tonic and antigen-ligation-dependent BCR signaling is expected. In this respect, targets could be signaling components of the BCR itself or modifiers of these components. Agents that target the BCR and current clinical trials are listed in Tables 1 and 2. Potential therapeutic targets in CLL are Lyn and Syk.32 Specific inhibition of Lyn and Syk induced CLL-cell apoptosis in vitro, which indicates that these kinases primarily transmit prosurvival signals.32 Inhibition of Lyn might partially 'mimic' an anergic state, as is present in M-CLL. The Abl and Src-kinase inhibitor dasatinib induces apoptosis in primary CLL cells in vitro, with a preference for the U-CLL and/or ZAP-70-bearing subgroups, at concentrations clinically achievable by oral administration.39 Preliminary data of a currently ongoing phase II clinical trial of dasatinib in heavily pretreated patients with relapsed CLL was presented at the American Society of Hematology Annual Meeting and Exposition 2008. Data from 11 evaluable patients indicates that dasatinib monotherapy produced no complete or partial responses according to National Cancer Institute Working Group (NCI-WG) criteria. However, several patients showed evidence of biologic activity of dasatinib, including partial responses in lymph nodes but worsening anemia, decline in stable disease and reductions of lymphocyte counts.40 Although ZAP-70 and Syk are highly homologous structurally and functionally, direct inhibition of ZAP-70 by dasatinib is unlikely, as the binding affinity for Syk is tenfold higher than for most Src family kinases.39 A specific targeting of ZAP-70 positive CLL, however, was suggested by inhibition of HSP-90 (heat shock protein 90).41
Table 1 Agents targeting the BCR and downstream signaling pathways in CLL
Decreased signaling via survival-signaling cascades involving AKT and ERK, reduced expression of antiapoptotic Mcl-1 and Bcl-xL, and increased p53 levels are at the basis of the antiproliferative and proapoptotic capacity of dasatinib, probably as the result of inhibition of Lyn. An additive effect can be achieved by combination with fludarabine.39 Ex vivo, CLL lymph-node samples display strong ERK activation together with high levels of Bcl-xL and Mcl-1, and this has been attributed to CD40-triggered events by interaction of CLL cells with the microenvironment.42 Dasatinib and imatinib prevented antiapoptotic CD40 signaling and restored CLL drug sensitivity to fludarabine, bortezomib and roscovitine, indicating that chemoresistant niches, such as lymph nodes, may be sensitive to c-Abl inhibitors.42 Importantly, these effects were also observed in the presence of p53 dysfunction. Thus, dasatinib can overcome chemoresistance, resulting in the re-establishment of sensitivity to p53-dependent (fludarabine) and p53-independent drugs (for example, roscovitine, bortezomib, ABT-737).42 Although limited effects of dasatinib as a single agent were observed in a phase II trial, a reduction of lymph-node size was observed in a major fraction of patients43 and at least two further phase II clinical trials are currently ongoing (NCT00364286 and NCT00438854). Histone deacetylase inhibitors seem to be potential combination partners for dasatinib as they can directly repress the transcription of Lyn and other Src tyrosine kinases.44
Protein kinase C (PKC) and phosphatidylinositol 3-kinase (PI3K)-mediated signaling pathways are centrally involved in controlling apoptosis and CLL-cell survival.45 Approaches that target several isoforms of PKC are under clinical investigation. Several PKC isoforms are constitutively active in CLL.46 Although some PKC isoforms are key mediators of BCR signaling (for example, PKCII, which is overexpressed in CLL and inversely correlates with CLL-cell response to BCR engagement),47 other isoforms induce AKT activation independently of BCR ligation and PI3K in CLL cells, but not in normal B cells, a fact that could be exploited in the future for producing a more targeted and selective therapy.48 PKC is permanently activated and downstream of the constitutively activated PI3K in CLL. Specific blockade of PKC by rottlerin induces apoptosis and synergizes with vincristine in CLL cells but not in normal B lymphocytes.49 It is possible that this synergistic effect of rottlerin is sufficient to disrupt the balance between antagonizing PKC and PKC isoforms.49, 50 The PKC modulator, bryostatin 1, increases CD20 expression via MEK1/ERK signaling in a PKC-dependent manner in CLL B-cells, and leads to a twofold increase in apoptosis induction by rituximab.51 Of interest, rituximab achieves inhibition of the Raf/MEK/ERK signaling pathway, resulting in Bcl-xL downregulation and chemosensitization.52 Intriguingly, farnesyl transferase inhibitors, known to block Ras activity and ERK phosphorylation, have been shown to induce CLL cell apoptosis in primary CLL cells derived from patients with cladribine and fludarabine refractory disease.53 Inhibition of MEK significantly enhances cytotoxicity of purine analogs in a CLL cell line.54 However, although considerable, the toxicity of specific MEK inhibition alone is low. The sensitization of MEK to various cytotoxic agents is thought to result from a lower apoptotic threshold because of downregulation of downstream ERK targets such as Bcl-2, Bcl-xL and/or inhibitor of apoptosis proteins (IAPs).
Taken together, although defining the biological role of the BCR in CLL pathogenesis still remains a challenge, BCR-targeting strategies show promise as potential therapeutic approaches. The remarkable difference in clinical behavior between U-CLL and M-CLL is likely to involve BCR signal competence; thus, BCR-targeted treatment strategies will have to be carefully tailored and individualized to the molecular state of the patient.
Impact of the microenvironment
The major relevant events in CLL pathogenesis—proliferation, survival and hematogenous spread of the malignant cells—are dependent on specific combinations of cell types and soluble factors present in microenvironmental niches.55, 56, 57, 58 Imbalances in the composition of immune system components contribute to the creation of these niches. Several aberrant cytokine networks and cell–cell interactions have been identified (Figure 2)59, 60 that result in T-cell dysregulation, which is responsible for cell-death evasion and progressive accumulation of the malignant B cells. On the basis of a better understanding of underlying molecular mechanisms, targeting the microenvironment by either changing the cytokine networks or modulating immune effector cells, or both, is being considered as a novel therapeutic concept in CLL.
Figure 2 Cellular interactions as potential therapeutic targets in the CLL microenvironment.The diagram shows the crosstalk of CLL cells with accessory cells in the bone marrow and lymph-node microenvironment, and potential therapeutic targets. Agents targeting specific crosspoints of the interactions are marked with stars. In the proliferation centers the growth of leukemic cells is favored by an advantageous T-cell help. Selective manipulation of T-cell subsets or cytokine networks involved in this interaction can be therapeutically exploited, potential agents are anti-CD200 or HCD122 antibody or lenalidomide. CLL cell interaction with stromal cells and follicular dendritic cells via chemokine receptors and integrins leads to extended survival. Chemokine receptor antagonists such as AMD3100 (targeting the CXCR4–CXCL12 interaction) and anti-CD38 antibodies possibly interrupt this survival support. Note that interactions and possible therapeutic agents displayed in a certain organ are dominantly present in this organ, but not necessarily restricted to it. Abbreviations: Ab, antibody; CLL, chronic lymphocytic leukemia; GM-CSF, granulocyte macrophage colony-stimulating factor; ICAM, intercellular adhesion molecule; IL, interleukin; TNF, tumor necrosis factor ; VCAM, vascular cell adhesion molecule.
Immune defects and the role of T cells
There is general agreement that patients with CLL are immunocompromised with defective T-cell, natural-killer-cell and dendritic-cell function, in addition to the obvious B-cell defects.55, 61 Patients with CLL typically develop hypogammaglobulinea and progressive immune deficiency, which impairs their immune response to vaccines.62 Rather surprisingly, absolute T-cell numbers are increased and the peripheral blood CD4+ and CD8+ T-cell repertoire is markedly oligoclonal.63 The increase in T-cell numbers is mainly because of an increased CD8+ subpopulation, which results in a lower CD4+:CD8+ ratio, especially in patients with progressive disease.64, 65 Remarkably, Mackus and colleagues reported that only cytomegalovirus-positive patients with CLL displayed increased numbers of CD8+ cells with a CD45RA+CD27- cytotoxic phenotype directed at cytomegalovirus, suggesting that repeated antigenic stimulation in vivo by viral infections can contribute to the disturbed immune balance in CLL.57 Nevertheless, adoptive immunotherapy experiments with cytotoxic T-cell lymphocytes (CTLs) turned out to be disappointing, as they resulted in rather weak antitumor responses despite successful CTL production.66 This gave rise to the search of additional mechanisms of how CLL cells are capable of escaping immune surveillance. Implicated in the abnormal immune function are immunosuppressive factors and an acquired functional deficiency of the CD40 ligand (CD40L).66 CLL cells are particularly inept at antigen presentation, probably because of the low expression of immune co-stimulatory and adhesion molecules.67 The capability of immune synapse formation between CLL and T cells is highly impaired, and CLL T cells display reduced synapse-related signaling and proliferative capacity.68 Most interestingly, direct-contact coculture of CLL B cells with heterologous healthy T cells induced these defects in the healthy T cells as well.68
In CLL not only are the CD4:CD8 ratios imbalanced but there is an additional shift towards activated effector/memory T cells in both CD4+ and CD8+ subpopulations.69 Furthermore, expression of CTLA-4, which has the opposite effect to the co-stimulatory molecule CD28, is reduced in CLL T cells,70 and CTLA-4 knockout mice develop a clinical and pathological syndrome similar to human CLL.71 One means by which immunogenicity could be increased in CLL is by manipulation of the CD40/CD40L pathway. Activation of CD40 by CD40L induces proliferation and rescues the cells from spontaneous and chemotherapy-induced apoptosis. CD40 activation also induces secretion of cytokines such as interleukin (IL)-6, IL-10, tumor necrosis factor (TNF)-alpha, IL-8, and granulocyte-macrophage colony-stimulating factor. HCD122, a novel anti-CD40 monoclonal antibody, was shown to inhibit CD40L-induced activation of signaling pathways, proliferation and survival, and secretion of cytokines, and turned out to be a potent mediator of antibody-dependent cellular cytotoxicity, lysing CLL cells more efficiently than rituximab in vitro.72 Conversely, CD40L expression via gene therapeutic approaches has been proposed as a therapeutic concept.73 One important downstream molecule to augment the proliferation and survival of memory CD4+ T cells is OX40L. Transfer of a combination of CD40L and OX40L molecules in a fibroblast transference technique induced a cytotoxic T-cell immune response against autologous tumor cells, which could potentially be used to generate immunogenic tumor cells for active or adoptive immunotherapy of CLL.74
A striking presence of CD4+CD40L+ T cells is observed in pseudofollicles, the hypothesized proliferative compartment and histopathologic hallmark of CLL present in lymph nodes and to a lesser extent in the bone marrow. Pseudofollicles are not only a collection of proliferating monoclonal CD5+ B lymphoctes but are also formed by a number of bystander nontumor cells. In pseudofollicles, proliferative prolymphocytes and paraimmunoblasts are found to be interspersed with T lymphocytes, which are supposed to provide short-term proliferative support to the malignant cells. Most T lymphocytes found in these centers belong to the CD4+ subset and are in close contact with proliferating Ki67+ CLL cells.75 Several CD4+ T cells within pseudofollicles express CD40L, implying that they are in an activated state. Furthermore, follicular dendritic cells (FDCs) may be detected within pseudofollicles,76 which is reminiscent of the classical copresence of FDCs and Ag-specific CD4+ cells in the germinal centers of secondary lymphoid follicles. It is unclear how CD4+ T cells in CLL pseudofollicles acquire the expression of CD40L. In individual CD38 bimodal patients (that is, patients with two distinct CLL cell populations, one CD38+ and one CD38-), the CD38+ subpopulation in bone marrow was higher than in the peripheral blood, which suggests that interaction with the bone marrow environment might influence the expression of CD38.77, 78 CD38 expression is generally higher in areas of pseudofollicles, and proliferative markers such as Ki-67 might change upon contact with activated CD4+ T cells. In addition, an important role for CD38 in CD8+ cells can be inferred from the prognostic potential CD38 expression displayed in male patients with CLL.79 Currently, a phase I/II clinical trial is underway testing an anti-CD38 antibody (HuMax-CD38™, Genmab, Copenhagen, Denmark) in patients with multiple myeloma (ClinicalTrials identifier NCT00574288). In CLL lymph nodes, Ki-67+ CLL cells were more likely to be in direct contact with CD4+ activated T-helper lymphocytes than Ki-67- cells.78 The strong implication of T-cell imbalances in CLL pathogenesis gives rise to a number of novel therapeutic targets. One potential target is CD200, which is an immunomodulatory molecule that is overexpressed in CLL and has been implicated in the induction of regulatory T cells and downregulation of Th1 immune responses.81 The combination of an immune induction paralleled by a disruption of immunosuppressive factors makes CD200 blockage, (for example, with an inhibiting antibody) a potential powerful tool for future treatment of CLL.81
Other supportive cellular networks
Apart from the activated T lymphocytes that are supposed to provide short-term proliferative support, a number of other accessory cell types can be found in the CLL microenvironment. These accessory cells are in close contact with the accumulating leukemic pool and provide long-term support and survival benefits. In vitro, CLL cells derive survival benefits from interactions with accessory cells, such as marrow stromal cells.82 Stromal cells support the survival of CLL cells not only by direct integrin-mediated adhesion to the stroma but also by the secretion of soluble factors such as chemokines. Expression of the major lymphocyte integrin ligands VCAM-1 (vascular cell adhesion molecule 1) and ICAM-1 (intercellular adhesion molecule 1) that bind the integrins VLA-4 (also known as integrin alpha-4) and LFA-1 (also known as integrin alpha-L), respectively, was also reported on FDCs (Figure 2).83 Furthermore, FDCs produce the B-cell chemokine CXCL13, which is responsible for the localization of B lymphocytes within B-cell follicles of secondary lymphoid tissues.84 CXCR5, the chemokine receptor for CXCL13, is highly expressed on CLL cells.85 Other homeostatic chemokine receptors such as CCR7 and CXCR4 are highly expressed in CLL. In addition, marrow stromal cells and extramedullary stromal cells of mesenchymal origin secrete high amounts of stromal-cell-derived factor 1 (SDF-1, CXCL12), the ligand of CXCR4. VCAM and CXCL12, secreted by marrow stromal cells, have vital roles during early, normal B-cell development and CLL cells are rescued from apoptosis by cell–cell contact with these cells.59, 86 In addition, VEGF, which is important for microvessel formation in the CLL microenvironment, has a growth promoting and survival effect on CLL cells, and the motility of CLL cells within certain niches seems to be dependent on VEGF interaction with integrin signaling.87 Targeting CXCR4, CCR7 and/or their interaction with ligands has been used as a novel tool for treatment, and is currently being explored extensively in vitro and in clinical trials (Tables 1 and 2).86, 88
Targeting the CLL microenvironment
Rapidly emerging knowledge on microenvironmental influences provides a rationale for therapeutical use of immunomodulating agents in CLL treatment. Lenalidomide, which is already approved for use for other tumors, and actimid (pomalidomid), which is not approved yet, are closely related to thalidomide, but less toxic. Lenalidomide and actimid have shown promising antineoplastic activity in various tumor types, including multiple myeloma, myelodysplastic syndrome, renal-cell carcinoma, and prostate cancer.89, 90 Our understanding of the mechanisms of action of these drugs is still in its infancy but they clearly change the angiogenesis and the cytokine micromilieu, and modulate the immune system by enhancing cytotoxic T-cell and natural-killer-cell activity. As lenalidomide does not show an antiproliferative effect in vitro but a clear antitumor effect in vivo, its efficacy seems to be directly dependent on microenvironmental factors. Interestingly, lenalidomide was recently shown to improve the above discussed impaired synapse formation between CLL and T cells.68 Furthermore, both thalidomide and lenalidomide downregulate VEGF, IL-6, and TNF-1.91 Lenalidomide is clinically active as a single agent in patients with relapsed or refractory CLL.92, 93 Although the exact lenalidomide dose is still under evaluation owing to tumor-flare reactions seen with very high doses,94 the findings nevertheless set the stage for future clinical studies of lenalidomide and related immunomodulatory drugs, not only as single agents, but also as modulators of established chemotherapy regimens or maintenance treatments.
Aberrant apoptotic signaling pathways
Multiple signals converge in CLL cells to influence cellular fate. Cell death is regulated by a network of cellular signaling cascades that are also influenced by intracellular sensor modules.59 A shortcut to cell death is present in the form of death receptors; in CLL they are CD95/Fas and TRAIL (tumor-necrosis factor-related apoptosis-inducing ligand). Upon ligation, these receptors create a platform for activation of initiator caspases that directly feed into a caspase cascade leading to cell death.95 Such 'shortcut' killing potential is tightly regulated. The intrinsic cell death pathway, or mitochondrial pathway, is regulated by the balance between antiapoptotic and proapoptotic members of the Bcl-2 family. Antiapoptotic proteins (Bcl-2, Bcl-xL, Bcl-w, A1, Mcl-1) possess the Bcl-2 homology (BH) domains BH1–4, whereas proapoptotic proteins (Bax, Bak) contain domains BH1–3, and the so-called 'BH-3 only' proteins contain exclusively the BH3 domain.
Non-death-receptor transmitted death signals derive from developmental cues (for example, Bim-dependent B-cell killing upon BCR crosslinking) or from a lack of survival signals.96 Such death signals also originate in sensor platforms, such as the DNA damage sensor network involving the ATM (ataxia telangiectasia mutated) and p53 tumor suppressors, which prominently determine survival and treatment outcomes in CLL. All these pathways modify the action of death sensory molecules, the most important of which are called "BH3-only" proteins (for example, Bim, Bid, Bmf, Puma, Bad and Noxa)—a name derived from their short homology with members of the classical Bcl-2 family of cell-death regulators. The BH3-only proteins are regulated by incoming cell death and survival signals and transmit these signals to the core machinery made up of proapoptotic effector molecules Bax and Bak as well as of antiapoptotic Bcl-2 family members (for example, Bcl-2 itself, Bcl-xL, Mcl-1 and A1). In one model, BH3-only proteins counteract the present prosurvival Bcl-2-type proteins in order to overcome this cell-death inhibition and initiate the Bax/Bak signal to initiate a caspase cascade.96 Although a few BH3-only proteins (for example, Bim) can counteract all known antiapoptotic Bcl-2 family members, others, such as Bmf or Noxa, can only counteract some of the opponents within the family (Figure 3). Thus, a complex network is formed by which the cell establishes a net signal that will determine its fate.
Figure 3 Therapeutic roads into the Bcl-2 death-signaling machinery.The core of the figure represents the interactions between BH3-only proteins with respect to their specific inhibition of antiapoptotic multidomain Bcl-2 family members. This inhibition then leads to an activation of the Bax/Bak complex, resulting in activation of the cell-death executioner machinery. The outer circle of the figure represents signals that influence cell-death machinery—either as intrinsic signals or as therapeutic approaches. Abbreviations: BCR, B-cell receptor; BH1–4, Bcl-2 homology domain 1–4; BH3, Bcl-2 homology domain 3; CD40L, CD40 ligand; CLL, chronic lymphocytic leukemia; IL, interleukin; LN, lymph node; Tcl-1, T-cell leukemia-1; TRAIL, tumor-necrosis-factor apoptosis-inducing ligand.
A number of death signaling components have been characterized in CLL. CLL cells express CD95 but are largely resistant to CD95 crosslinking.97 Overexpression of the CD95 regulator TOSO in CLL might contribute to CD95 resistance.98 Although CD40 signaling upregulated CD95 in CLL, cells remained resistant to CD95 triggering.99 This effect, however, was transient in a subset of patients where CD95 sensitivity was attained after 72 h.99 IL-15 treatment was also able to sensitize CD40-stimulated CLL cells to CD95 crosslinking.100 In addition, CD40L-stimulated CLL cells were rendered CD95-sensitive by XIAP (X-linked inhibitor of apoptosis protein) inhibition using non-SMAC (second mitochondria-derived activator of caspases) mimetic, synthetic compounds.101 Also, CD40-activated CLL cells were effectively killed by genetically engineered effector cells expressing both the CD95 ligand (CD178) and TRAIL.102 With regard to TRAIL sensitivity, the ex vivo phenotype of CLL is again one of resistance.103 However, two publications have shown that histone deacetylase inhibition is able to sensitize CLL to the effects of TRAIL and that the TRAIL receptor DR4, but not DR5, was involved in cell killing.103, 104
As mentioned above, CD40 has a prominent role in CLL pathogenesis. In terms of cell-death regulation, CD40 signaling has been suggested to trigger a major reprogramming along the Bcl-2 governed pathway to cell death.105, 106, 107 In parallel to a pattern observed in CLL from lymph-node tissue, CD40L triggered upregulation of Mcl-1 and A1, as well as Bcl-xL antiapoptotic proteins.106 In one report this triggered upregulation also led to downregulation of the BH3-only protein Noxa, while the relatively highly expressed Bim and Bmf remained (almost) unchanged;106 however, in another report Bim was reduced.105 In CLL, Noxa did not seem to be exclusively induced by p53, but regulated by extracellular signaling.108, 109 Among the other BH3-only proteins, Puma has been shown to be regulated in response to p53 stimuli,108 and Bim and Bmf seem to be constitutively expressed.110 Other upstream signals involved in regulation of Bcl-2 family member proteins in CLL include extracellular cues (such as BCR or cytokine signaling), microRNA input or conventional therapeutic intervention via cytotoxic drugs.
BCR signaling has been reported to also be able to regulate Mcl-1.24 This was suggested to be mediated via Akt signaling. Akt has also been shown to target BH3-only proteins Bad and Bim for deactivation by phosphorylation.111, 112 Interestingly the Akt signal seems to be positively modified by the overexpression of Tcl-1, which is found in a relatively large proportion of patients with CLL and has been proposed to be the consequence of a dysregulation of the microRNAs, miR-29 and miR-181.111, 113 In addition, miR-15 and miR-16 were proposed to be the basis of constitutive Bcl-2 overexpression in CLL.111, 114, 115 Another reported signal that modifies cell-death machinery is IL-21, which mediates apoptosis through upregulation of Bim.116 Increasing our understanding of the deregulated cell-death machinery in CLL is a prerequisite to developing new targeting strategies that might engage the cell-death machinery in a more-effective way.
Targeting apoptotic pathways
Currently, the mainstay of therapeutic strategies that kill CLL cells is still cytotoxic chemotherapy with alkylating agents or purine analogs. The major contribution to cell death in this respect stems from the DNA damage response via p53 that leads to a dominant cell-death signal via Puma.108, 117 A major problem encountered with these strategies is that a number of patients with CLL harbor defects in the DNA damage machinery that leads to deactivation of the pathway. Apart from the prognostically highly significant del17p6 (a surrogate marker for p53 deletion), p53 mutation,118 ATM deletion or mutation119 and changes in the MDM2 p53 signal modifier120 have been described to influence prognosis and potentially therapy sensitivity by modulating the DNA damage response. The challenge thus seems to be to bypass such resistance and produce p53-independent cell death. In CLL without deficient DNA damage response, specific microenvironmental cues may protect a small population effectively from current death-inducing treatment strategies and thus harbor the seed of therapeutic failure. In this respect, classic chemotherapy may still be part of a winning concept, if combined with modulation of the relevant cell-death pathways.
Regarding the targeting of death-receptor pathways, the exploitation of CD95 signaling seems to be restricted, as systemic CD95 triggering leads to fulminant liver toxicity.121 The role of TRAIL receptor targeting is currently under development. While recombinant TRAIL is developed, a strategy of triggering TRAIL receptors via antibody-strategies is also pursued. However, no trials in CLL have been reported to clinicaltrials.gov. Efforts to combine TRAIL receptor agonists with histone deacetylase inhibitors will be important.103, 104
Modification of the cell-death machinery along the CD40 signaling cascade seems promising. While CD154 (CD40L) has previously been used to generate relevant immune responses,73 its application was able to induce the p53-related transcription factor p73, leading to a sensitization of p53-deficient CLL cells to conventional therapeutics such as fludarabine.122 This result suggests that the CD40 signal may also have a positive effect on conventional therapy. On the other hand, inhibition of Abl and Src-like kinases by dasatinib was able to revert the complete antiapoptotic program induced by CD40 stimulation and may contribute to overcoming chemoresistance in microenvironmental niches.105
Finally, a number of approaches have been taken to directly modulate the core components of the Bcl-2 cell-death machinery. The Bcl-2 antisense molecule oblimersen is the most advanced agent in clinical testing. Encouraging phase I/II and phase III data in CLL were reported,123, 124 with longer response duration after fludarabime and cyclophosphamide plus oblimersen than fludarabime and cyclophosphamide alone. Oblimersen has been filed for FDA approval and is the first agent to change the cell-death outcome in CLL by targeting the cell-death machinery. However, given the important roles of other prosurvival Bcl-2 family members such as Mcl-1 and A1 for the pathogenesis of CLL (discussed earlier), targeting of Bcl-2 alone might be less efficient than other targeting strategies in development. New classes of substances in development are the "BH3-mimetics" and "pan-Bcl-2 family antagonists". These molecules mimic the BH3 domain of BH3-only death-inducing proteins and are thought to liberate BH3-only proteins from the inhibition by antiapoptotic Bcl-2 proteins, thus making them effective killers. A relevant therapeutic window seems to be achieved by the tumor cells themselves. Owing to oncogenic stress signals and failed checkpoint controls, tumor cells display a balance between proapoptotic and antiapoptotic signals that is much closer to the cell-death threshold than is the case in normal tissues, which makes tumors more susceptible to the effects of antiapoptotic protein signals.125
ABT-737126 (plus orally available derivative ABT-263) and GX15-070 (Obatoclax)127 were described to kill target cells using a BH3-only protein displacement strategy. While ABT-737 shows "Bmf-like" specificity (that is, it targets Bcl-2 but not Mcl1-like proteins), data presented for GX15-070 suggest a "Noxa-like" behavior (that is, it efficiently targets Mcl-1 but not Bcl-2).128 Consequently, a combination of both substances was more effective than the single substance.128 Both substances are in clinical trials in CLL, with a phase I trial in extensively pretreated disease reported for Obatoclax129 and a phase I/II study of ABT-263 published in abstract form.130 Both substances showed single agent efficacy in extensively pretreated collectives. At least one further substance with Bcl-2 binding activity, AT-101, a gossypol derivative, is in development in CLL. Preclinical data suggest that AT-101 may help to overcome stroma-mediated drug resistance;131 phase II data were reported in abstract form.41 Trials underway are listed in Table 3.
Table 3 Ongoing and currently recruiting clinical trials targeting cell-death regulatory molecules
Given the expression profile of Bcl-2 proteins in CLL cells, a number of strategies seem promising. For example, one might combine substances that selectively downregulate antiapoptotic Bcl-2, such as ABT-263, with substances that preferentially target antiapoptotic Mcl-1, such as GX15-070, to achieve additive or synergistic effects. Other strategies could be aimed at upstream signals, such as targeting CD40 using CD40 antibodies or dasatinib. GX15-070 could be used in combination with oblimersen to cover a wider range of Bcl-2 family proteins. On a more conventional note, BH3-only mimetic treatment might help counteract microenvironmentally determined chemotherapy resistance in combination with cytotoxic CLL treatment.
Conclusions
Currently, the major problem in the treatment of CLL is that, despite promising response rates in recent years, patients with high-risk disease still seem to relapse with mostly unchanged kinetics. During these relapses the disease is often refractory to conventional chemotherapeutics. Targeting the immune and microenvironmental interactions in CLL might provide the means to relieve protection of the malignant cells derived from those interactions, and may create strong synergies with conventional therapeutics, allowing control of CLL even in the 'hideaway' places where residual disease survives conventional therapeutics. In addition, chronic modulation of pathophysiologically relevant signals may modify the rate of disease progression. Such strategies may then help to maintain an MRD-negative state in CLL after intensive chemoimmunotherapy, a state that has been associated with superior long-term survival in patients with CLL. Finally, a better understanding of the ways in which CLL cells escape cell-death cues from extracellular signals as well as from cytotoxic stress will facilitate the intelligent design of strategies employing the growing number of modulators available in this field.
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