The GABAAα5-selective Modulator, RO4938581, Rescues Protein Anomalies in the Ts65Dn Mouse Model of Down Syndrome.

Down syndrome (DS), trisomy of human chromosome 21 (Hsa21), is the most common genetic cause of intellectual disability (ID). There are no treatments for the cognitive deficits. The Ts65Dn is a partial trisomy mouse model of DS that shows learning and memory (LM) impairments and other abnormalities relevant to those seen in DS. Many drugs and small molecules have been shown to rescue the LM deficits, but little is known about the associated molecular responses. Here, patterns of protein expression are described in hippocampus of Ts65Dn and euploid littermate controls exposed to a battery of LM and behavior tests with and without chronic treatment with the GABAA receptor α5 subunit-selective negative allosteric modulator, RO4938581, that rescued LM deficits. Levels of 91 proteins/protein modifications, selected for relevance to LM and synaptic plasticity, were measured: 44 of 52 abnormalities present in vehicle-treated Ts65Dn were corrected by RO4938581. Superimposing protein data onto the molecular pathway defining long-term potentiation (LTP) shows that profiles are consistent with both abnormal LTP in vehicle-treated Ts65Dn and its observed rescue by RO4938581. Lastly, comparing these results with those from Ts65Dn treated, using a different protocol, with the NMDA receptor antagonist, memantine, that also rescues LM impairments, identifies common and divergent responses to the two drugs. Expansion of this approach to include additional drugs and DS models would aid in determining critical protein abnormalities and in identifying cocktails of drugs and/or new drug targets that would be effective in clinical trials for ID in DS.

The experience of living with advanced-stage cancer: a thematic synthesis of the literature.

The aim of the study was to understand the experience of people living with advanced-stage cancer through literature. The search included The Cochrane Library, PubMed, PsycInfo, CINAHL and Cuiden. Thirteen studies were included. A qualitative meta-synthesis was conducted. One thread emerged from the thematic synthesis: the desire to live as normally as possible, despite being aware of the proximity of death. Three themes also emerged: "a process that is unique" with its four sub-themes; "support network" and "health context," each of them having two sub-themes. This study concludes that living with advanced-stage cancer is a unique and complex process which has both positive and negative aspects. The review provides a comprehensive view of the experience, which considers the importance of the support network and the health context in which the person lives. In this study, "normalcy" is the adjustment to the new reality and living as closely as possible to the way one lived before the disease, while developing a new relationship with being finite and death. A better understanding of the experience of living with advanced-stage cancer will help health professionals to identify the needs of the patients in order to plan individual, high-quality care.

Immobilization of Lipases on Heterofunctional Octyl-Glyoxyl Agarose Supports: Improved Stability and Prevention of the Enzyme Desorption.

Lipases are among the most widely used enzymes in industry. Here, a novel method is described to rationally design the support matrix to retain the enzyme on the support matrix without leaching and also activate the enzyme for full activity retention. Lipases are interesting biocatalysts because they show the so-called interfacial activation, a mechanism of action that has been used to immobilize lipases on hydrophobic supports such as octyl-agarose. Thus, adsorption of lipases on hydrophobic surfaces is very useful for one step purification, immobilization, hyperactivation, and stabilization of most lipases. However, lipase molecules may be released from the support under certain conditions (high temperature, organic solvents), as there are no covalent links between the enzyme and the support matrix. A heterofunctional support has been proposed in this study to overcome this problem, such as the heterofunctional glyoxyl-octyl agarose beads. It couples the numerous advantages of the octyl-agarose support to covalent immobilization and creates the possibility of using the biocatalyst under any experimental conditions without risk of enzyme desorption and leaching. This modified support may be easily prepared from the commercially available octyl-agarose. Preparation of this useful support and enzyme immobilization on it via covalent linking is described here. The conditions are described to increase the possibility of achieving at least one covalent attachment between each enzyme molecule and the support matrix.

Changes in the brain and plasma Aß peptide levels with age and its relationship with cognitive impairment in the APPswe/PS1dE9 mouse model of Alzheimer's disease.

Double transgenic mice expressing mutant amyloid precursor protein (APPswe) and mutant presenilin 1 (PS1dE9) are a model of Alzheimer-type amyloidosis and are widely used in experimental studies. In the present work, the relationships between brain and plasma amyloid-ß peptide (Aß) levels and cognitive impairments were examined in male APPswe/PS1dE9 double transgenic mice at different ages. When compared with non-transgenic littermates, APPswe/PS1dE9 mice exhibited significant learning deficits from the age of 6months (M6), which were aggravated at later stages of life (M8 and M12). Sporadic brain amyloid plaques were observed in mice as early as M3 and progressively increased in number and size up to M12. A similar increase was observed in brain insoluble Aß levels as assessed by enzyme-linked immunosorbent assay (ELISA). In particular, the levels of brain insoluble Aß peptides rose steeply from M4 to M6. Interestingly, this pronounced amyloid deposition was accompanied by a temporary fall in the concentration of brain soluble and membrane-bound Aß peptides at M6 that rose again at M8 and M12. The plasma levels of Aß40 and Aß42 decreased with advancing age up to M8, when they stabilized at M12. This decrease in plasma Aß levels coincided with the observed increase in insoluble brain Aß levels. These results could be useful for developing plasma Aß levels as possible biomarkers of the cerebral amyloidosis and provide advances in the knowledge of the Aß peptide biochemical changes that occur in the brain of Alzheimer's disease patients.

Lack of behavioral and cognitive effects of chronic ethosuximide and gabapentin treatment in the Ts65Dn mouse model of Down syndrome.

The Ts65Dn (TS) mouse model of Down syndrome (DS) displays a number of behavioral, neuromorphological and neurochemical phenotypes of the syndrome. Altered GABAergic transmission appears to contribute to the mechanisms responsible for the cognitive impairments in TS mice. Increased functional expression of the trisomic gene encoding an inwardly rectifying potassium channel, subfamily J, member 6 (KCNJ6) has been reported in DS and TS mice, along with the consequent impairment in GAB Aergic function. Partial display of DS phenotypes in mice harboring a single trisomy of Kcnj6 provides compelling evidence for a functional role of increased channel expression in some of the abnormal neurological phenotypes found in DS. Notably, the antiepileptic drug (AED) ethosuximide (ETH), but not other AEDs such as gabapentin (GAB), is known to inhibit KCNJ6 channels in mice. Here, we report the effect of chronic ETH and GAB on the behavioral and cognitive phenotypes of TS and disomic control (CO) mice. Neither drug significantly affected sensorimotor abilities, motor coordination or spontaneous activity in TS and CO mice. Also, ETH and GAB did not induce anxiety in the open field or plus maze tests, did not alter performance in the Morris water maze, and did not affect cued - or context - fear conditioning. Our results thus suggest that KCNJ6 may not be a promising drug target candidate in DS. As a corollary, they also show that long-term use of ETH and GAB is devoid of adverse behavioral and cognitive effects.

Effects of voluntary physical exercise on adult hippocampal neurogenesis and behavior of Ts65Dn mice, a model of Down syndrome.

The Ts65Dn (TS) mouse is the most widely used model of Down syndrome (DS). This mouse shares many phenotypic characteristics with the human condition including cognitive and neuromorphological alterations. In this study the effects of physical exercise on hippocampal neurogenesis and behavior in TS mice were assessed. 10-12 month-old male TS and control (CO) mice were submitted to voluntary physical exercise for 7 weeks and the effects of this protocol on hippocampal morphology, neurogenesis and apoptosis were evaluated. Physical exercise improved performance in the acquisition sessions of the Morris water maze in TS but not in CO mice. Conversely, it did not have any effect on anxiety or depressive behavior in TS mice but it did reduce the cognitive components of anxiety in CO mice. TS mice presented a reduced dentate gyrus (DG) volume, subgranular zone area and number of granule neurons. Hippocampal neurogenesis was reduced in TS mice as shown by the reduced number of 5-bromo-2-deoxyuridine (BrdU) positive cells. Voluntary physical exercise did not rescue these alterations in TS mice but it did increase the number of doublecortin (DCX)-and phospho histone 3 (PH3)-positive neurons in CO mice. It is concluded that physical exercise produced a modest anxiolytic effect in CO mice and that this was accompanied by an increased number of immature cells in the hippocampal DG. On the other hand, voluntary physical exercise exerted a positive effect on TS mice learning of the platform position in the Morris water maze that seems to be mediated by a neurogenesis-independent mechanism.

Satisfacción de pacientes y cuidadores con el programa de rehabilitación seguido tras el ictus / Patient and caregiver satisfaction with rehabilitation services after stroke

ObjetivoEvaluar la satisfacción con el programa rehabilitador del ictus de pacientes y cuidadores. Identificar los factores dependientes del propio paciente y del proceso asistencial relacionados con mayor insatisfacción en nuestra área.Material y métodosEstudio transversal en 74 pacientes ingresados en Rehabilitación con el diagnóstico de ictus (el 70,3% eran varones, con edad media de 65,4±12,2, índice de Barthel al alta de 70,5±27) desde junio de 2005 hasta junio de 2006. La satisfacción con la rehabilitación seguida durante el ingreso y el soporte al alta hospitalaria se evaluaron mediante el cuestionario de satisfacción de Pound, administrado telefónicamente 13 meses de media después del alta hospitalaria. Se entrevistó a 85 cuidadores, de los que el 71% era familiar directo (cónyuge o relación filial) y el 80,9% era de sexo femenino.ResultadosEl 52,9% de los pacientes cumplimentó el cuestionario: más del 80% refirió estar completamente satisfecho con el trato y la información recibidos durante el ingreso. En cuanto al tratamiento, el 52,7% se mostró satisfecho; la cantidad de tratamiento recibido fue el aspecto peor valorado. La menor satisfacción correspondió al soporte recibido tras el alta hospitalaria, con menos del 25% de satisfechos. Un 83,1% de cuidadores cumplimentó el cuestionario: el 74,1% estaba satisfecho con la información recibida, el 63,5% con la formación sobre el tratamiento del paciente y el 42,4% con el soporte al alta. Sólo la depresión y el tiempo de evolución tras el ictus se relacionaron con mayor insatisfacción (p<0,05).ConclusionesAunque la satisfacción de pacientes y cuidadores con la información recibida es alta, se detectan elevados porcentajes de insatisfacción con la cantidad de tratamiento recibido y el soporte social al alta hospitalaria, por lo que es necesario incluir medidas sistemáticas de información, formación y soporte al alta en el programa de rehabilitación del ictus(AU)

ObjectivesTo assess patient and caregiver satisfaction with the regular rehabilitation care after stroke. To identify patient features or aspects of the rehabilitation programme related to lower rates of satisfaction in our area.Material and methodsCross-sectional study of 74 stroke in-patients admitted from June 2005 to June 2006 (70.3% men, age 65.4±12.2 years, Barthel discharge 70.5±27). A telephone Satisfaction questionnaire (Pound 1999) was administered at 13.6±3.1 months to assess satisfaction regarding in-patient care, therapy and recovery, and services after hospital discharge. Three items addressed to caregiver satisfaction were also included. A total of 84 caregivers were identified: 71% relatives (partner or children), of which 80.9% were women.ResultsThe satisfaction questionnaire was completed by 52.9% of patients. Over 80% of interviewed patients were completely satisfied with in-patient care, and 52.7% were satisfied with therapy and recovery during admission, but more patients were dissatisfied with the amount of therapy received. The lowest rate of satisfaction was related to the services after discharge, with less than 25% of patients satisfied. A total of 83.1% of caregivers completed the questionnaire, of which 74.1% were satisfied with the information provided. Stroke educational training was given to 63.5% of caregivers, and 42.4% were given support after discharge. Only the presence of depression during admission and time passed after stroke were significantly related to patient satisfaction. (p<0.05).ConclusionsDissatisfaction with some aspects of stroke rehabilitation is considerable in our care area. Despite general patient and caregiver satisfaction regarding information provided, high dissatisfaction rates are also detected related to the amount of therapy and the social support provided after hospital discharge...(AU)

[Patient and caregiver satisfaction with rehabilitation services after stroke]. / Satisfacción de pacientes y cuidadores con el programa de rehabilitación seguido tras el ictus.

OBJECTIVES: To assess patient and caregiver satisfaction with the regular rehabilitation care after stroke. To identify patient features or aspects of the rehabilitation programme related to lower rates of satisfaction in our area. MATERIAL AND METHODS: Cross-sectional study of 74 stroke in-patients admitted from June 2005 to June 2006 (70.3% men, age 65.4 + or - 12.2 years, Barthel discharge 70.5 + or - 27). A telephone Satisfaction questionnaire (Pound 1999) was administered at 13.6 + or - 3.1 months to assess satisfaction regarding in-patient care, therapy and recovery, and services after hospital discharge. Three items addressed to caregiver satisfaction were also included. A total of 84 caregivers were identified: 71% relatives (partner or children), of which 80.9% were women. RESULTS: The satisfaction questionnaire was completed by 52.9% of patients. Over 80% of interviewed patients were completely satisfied with in-patient care, and 52.7% were satisfied with therapy and recovery during admission, but more patients were dissatisfied with the amount of therapy received. The lowest rate of satisfaction was related to the services after discharge, with less than 25% of patients satisfied. A total of 83.1% of caregivers completed the questionnaire, of which 74.1% were satisfied with the information provided. Stroke educational training was given to 63.5% of caregivers, and 42.4% were given support after discharge. Only the presence of depression during admission and time passed after stroke were significantly related to patient satisfaction. (p<0.05). CONCLUSIONS: Dissatisfaction with some aspects of stroke rehabilitation is considerable in our care area. Despite general patient and caregiver satisfaction regarding information provided, high dissatisfaction rates are also detected related to the amount of therapy and the social support provided after hospital discharge. According to these results, systematic information and training programs for patients and caregivers should be included in stroke rehabilitation, as well as providing social support at discharge.

Chronic pentylenetetrazole but not donepezil treatment rescues spatial cognition in Ts65Dn mice, a model for Down syndrome.

The most commonly used model of Down syndrome, the Ts65Dn (TS) mouse, is trisomic for most of the region of MMU16 that is homologous to HSA21. This mouse shares many phenotypic characteristics with people with Down syndrome including behavioral and cognitive alterations. The objective of this study was to analyze the ability of two drugs that improve cognition in different experimental models, the acetylcholinesterase inhibitor donepezil and the non-competitive GABA(A) antagonist pentylenetetrazole (PTZ), to improve the cognitive deficits found in TS mice. The drugs were administered p.o. to TS and CO mice for 8 weeks and a behavioral characterization was performed. Sensorimotor abilities, including vision, hearing, strength and motor coordination, as well as locomotor activity in the home cage, were not modified by any chronic treatment in TS and CO mice. TS mice showed altered equilibrium in the aluminium rod, and this effect was larger under PTZ treatment. This result may indicate a potential adverse effect of PTZ in Ts65Dn mice. Learning and memory were evaluated in TS and CO mice after both treatments in the Morris water maze. Donepezil administration did not modify learning and memory in animals of any genotype. On the other hand, PTZ administration rescued TS performance in the Morris water maze.

Both increases in immature dentate neuron number and decreases of immobility time in the forced swim test occurred in parallel after environmental enrichment of mice.

A direct relation between the rate of adult hippocampal neurogenesis in mice and the immobility time in a forced swim test after living in an enriched environment has been suggested previously. In the present work, young adult mice living in an enriched environment for 2 months developed considerably more immature differentiating neurons (doublecortin-positive, DCX(+)) than control, non-enriched animals. Furthermore, we found that the more DCX(+) cells they possessed, the lower the immobility time they scored in the forced swim test. This DCX(+) subpopulation is composed of mostly differentiating dentate neurons independently of the birthdates of every individual cell. However, variations found in this subpopulation were not the result of a general effect on the survival of any newborn neuron in the granule cell layer, as 5-bromo-2-deoxyuridine (BrdU)-labeled cells born during a narrow time window included in the longer lifetime period of DCX(+) cells, were not significantly modified after enrichment. In contrast, the survival of the mature population of neurons in the granule cell layer of the dentate gyrus in enriched animals increased, although this did not influence their performance in the Porsolt test, nor did it influence the dentate gyrus volume or granule neuronal nuclei size. These results indicate that the population of immature, differentiating neurons in the adult hippocampus is one factor directly related to the protective effect of an enriched environment against a highly stressful event.

Anxiety and panic responses to a predator in male and female Ts65Dn mice, a model for Down syndrome.

Hyperactivity is a feature frequently reported in behavioral studies on the Ts65Dn (TS) mouse, the most widely accepted model of Down syndrome, when tested in anxiety-provoking situations such as the plus-maze and the open-field tests. Although this behavior could be considered as an expression of reduced anxiety, it has been considered as a consequence of a lack of behavioral inhibition and/or reduced attention. This study addressed anxiety and panic behavior of male and female TS mice by evaluating serum biochemical parameters and behavioral responses to a predator in the Mouse Defense Test Battery. Flight, risk assessment, defensive threat/attack and escape attempts were measured during and after rat confrontation. When confronted to a rat, male TS mice showed similar biochemical and behavioral responses as control mice. However, female control and TS mice presented lower serum adrenocorticotropic hormone (ACTH) levels under basal conditions and higher corticosterone levels after predator exposure than male mice. Thus, there was a larger increase in ACTH and corticosterone levels after predator exposure with respect to the undisturbed condition in females than in males. In addition, TS females showed some alterations in defensive behaviors after predator exposure. The results emphasize the need to consider gender as a confounding factor in the behavioral assessment of TS mice.

Sarcoma granulocítico aislado de mama. Presentación de un caso y revisión de la literatura / No disponible

Los Sarcomas Granulocíticos (S.G) son tumores sólidos y muypoco frecuentes, localizados en hueso, periostio, tejidos blandosy ganglio linfático, cuya expresión clínica está relacionada consu ubicación. Pueden presentarse en diferentes entidades clínicasy se caracterizan por escasa maduración mieloide, pobrerespuesta terapéutica y corta sobrevida, progresandohabitualmente a Leucemia Mieloide Aguda (LMA). Existendiferentes propuestas terapéuticas, la más recomendada es laQTP e.v. con protocolos para Leucemia Mieloide Aguda.Describimos una paciente de 31 años con diagnóstico de SGaislado de glándula mamaria, en ausencia de Leucemia Aguda.Fue tratada con radioterapia local, presentando buena respuestaterapéutica, cursando 24 meses de sobrevida Hbre de enfermedaden la actualidad(AU)

The Granulocytic Sarcoma (GS) are salid tumours, not veryfrequent, placed in bones, periostium, soft tissues and theIymphatic nades, which clinical express ion is related to itsplacement. There can be different clinical entitites and they havelimited myeloid maturation, a poor therapeutical answer andshort survival, habitually evolving towards an Acute MyelogenousLeukemia (AML).There are different therapeutical proposals and the mostrecommended one is with protocols for Acute Leukemia.We describe here a 31 years cid woman, with diagnosis of SGisolated gland mammary, in absence of Acute Leukemia, whowas trated with local radiotherapy, having a good therapeuticalanswer. She has survived 24 months, remains free from illness.Plasmocytomas are not common tumours, formed by plasmaticcells in different maturing stages. There are two kinds of entities:the Bony Plasmocytoma and the Extramedullar Plasmocytoma.Both occupy from 2 to 10% of all the Plasmaticas Neoplasiasand are characterized by significant absence of anemia, numerousbony destruction, not enough plasmocytary medullar infiltrationand appropriated answer to the therapy.Its main place is the head and neck; 82,8% is at an aereodigestivelevel. Only 14 of the cases published in the literatureshow lonely renallocalization, habitually having a palpable mass,hematuria or peripherical neuropathy. We present an adult patientwith diagnosis of 10 Kidney Plasmocytoma, of fast and fatalevolution, whose initial diagnosis was renal carcinoma(AU)

Apoptosis y expresión de Bcl-2 y Bax en el endometrio eutópico de pacientes con endometriosis / Apoptosis and Bcl-2 and Bax in normal endometrium of patients with endometriosis

El objetivo de este trabajo es investigar una posible predisposición de las células endometriales de pacientes con endometriosis (EDT), a ser resistentes a la muerte celular programada. Se evaluó apoptosis y expresión de las proteínas Bcl-2 y Bax en 30 cortes de tejido de endometrio eutópico, 14 de mujeres con EDT y 16 de controles (C). Para la determinación de apoptosis, se utilizó el kit Apoptag-Plus basado en la localización y tinción de los extremos 3'-OH de los fragmentos de ADN. Los resultados se expresan como nº de células apoptóticas (CA)/campo a 630x de aumento. Se detectaron CA sólo en el epitelio glandular. Se observó menor cantidad de CA en tejido endometrial proveniente de pacientes con EDT: 2,26 ñ 0,53 vs 9,37 ñ 1,69 en los C (p<0,001). Esta disminución se conservó a lo largo del ciclo menstrual. En la fase proliferativa tardía, los resultados fueron de: 7,08 ñ 0,92 vs 1,9 ñ 0,73 (p<0,05), para las muestras provenientes de mujeres C y pacientes con EDT respectivamente; mientras que en el endometrio secretorio los niveles de apoptosis detectados fueron de 11,6 ñ 1,74 en los C vs 2,7 ñ 0,82 en EDT (p<0,001). No se observaron diferencias significativas de apoptosis en endometrio de acuerdo al grado de la enfermedad. La evolución de los productos de protooncógenes, bcl-2 y bax se realizó utilizando metodologías de inmunohistoquímica. Se halló incrementada la expresión de la proteína antiapoptótica Bcl-2 en el endometrio proliferativo proveniente de pacientes con EDT comparado con el C. La expresión del antagonista de Bcl-2, Bax, aumentó durante la fase secretoria tanto en muestras provenientes de pacientes como de C, y se halló ausente durante la fase proliferativa. De los resultados se desprende que las células endometriales de pacientes con EDT poseen características apoptóticas alteradas que las harían más susceptibles a crecer en un sitio ectópico. Estas no se ven modificadas a lo largo del ciclo menstrual. La proteína Bcl-2 estaría implicada en la protección de la apoptosis de las células endometriales eutópicas de pacientes con EDT durante la fase proliferativa del ciclo menstrual. La proteína Bax estaría involucrada en la regulación de la muerte celular programada que se produce en el endometrio eutópico previo a la menstruación. La resistencia a la muerte celular programada que posee el endometrio eutópico de pacientes con EDT, estaría relacionada con la etiología y/o fisiopatología de la enfermedad

Apoptosis y expresión de Bcl-2 y Bax en el endometrio eutópico de pacientes con endometriosis / Apoptosis and Bcl-2 and Bax in normal endometrium of patients with endometriosis

El objetivo de este trabajo es investigar una posible predisposición de las células endometriales de pacientes con endometriosis (EDT), a ser resistentes a la muerte celular programada. Se evaluó apoptosis y expresión de las proteínas Bcl-2 y Bax en 30 cortes de tejido de endometrio eutópico, 14 de mujeres con EDT y 16 de controles (C). Para la determinación de apoptosis, se utilizó el kit Apoptag-Plus basado en la localización y tinción de los extremos 3-OH de los fragmentos de ADN. Los resultados se expresan como nº de células apoptóticas (CA)/campo a 630x de aumento. Se detectaron CA sólo en el epitelio glandular. Se observó menor cantidad de CA en tejido endometrial proveniente de pacientes con EDT: 2,26 ñ 0,53 vs 9,37 ñ 1,69 en los C (p<0,001). Esta disminución s

Citopunción ecoguiada de lesiones mamarias no palpables. Ventajes y limitaciones / Cytopuncture guided of nonpalpable breast lessions. Advantes and limitations

La nueva imagenología mamaria ha descubierto un grupo de lesiones no palpables que puede alcanzar hasta el treinta por ciento de los casos examinados

Citopunción ecoguiada de lesiones mamarias no palpables. Ventajes y limitaciones / Cytopuncture guided of nonpalpable breast lessions. Advantes and limitations

La nueva imagenología mamaria ha descubierto un grupo de lesiones no palpables que puede alcanzar hasta el treinta por ciento de los casos examinados

Primary hormonal treatment for early endometrial carcinoma.

Four cases of clinical Stage I endometrial carcinoma initially treated with hormonal therapy are included in this study. Three of them resulted in tumor regression and two of them permitted a subsequent three pregnancies. All patients are alive and without evidence of disease with a median follow-up of 35.7 months (range 17 to 72 months). We believe this is a promising approach through which we may be able to offer a conservative treatment maintaining high survival rates and preserving childbearing potential. Diagnostic and therapeutic data for fertility-desiring patients with endometrial carcinoma are analyzed in this study.

Long-term follow-up of the first randomized trial using neoadjuvant chemotherapy in stage Ib squamous carcinoma of the cervix: the final results.

OBJECTIVE: To determine if three courses consisting of 50 mg/m2 cis-platinum, 1 mg/m2 vincristine, and 25 mg/m2 bleomycin (day 1-3) at 10-day intervals can improve survival before Wertheim-Meigs + radiotherapy. MATERIAL: Two hundred five unselected stage Ib patients (having tumors > 2 cm in diameter) were divided into two groups at random: (1) The group control consisted of 103 patients (56 bulky, > 4 cm diameter) treated with Wertheim-Meigs (if the tumor was resectable with free surgical margins) + adjuvant radiotherapy to whole pelvis (extended field radiation was used only in patients with paraaortic lymph node metastases). When the tumor was unresectable, a surgical staging was performed and radiotherapy was the chosen treatment. (2) Neoadjuvant (102 patients, 61 bulky) had neoadjuvant chemotherapy and then the same treatment as the control patients. RESULTS: After 67 (31-102) months of follow-up, no difference was seen in tumors > 2 and < 4 cm in both groups (C = 77% vs N = 82%), but statistically significant differences were seen in survival and disease-free survival, in bulky tumors, and between patients with neoadjuvant chemotherapy + Wertheim-Meigs + radiotherapy (80%) and the control (61%). This was due to an increased operability that was substantially improved in bulky tumors in the neoadjuvant chemotherapy group (61/61, 100%) vs control (48/56, 85%; P < 0.01). After 7 years of follow-up, the outcome of the unresectable bulky control group of patients is significantly worse (14%) than that of the resectable group (69%; P < 0.001). With regard to recurrences, a significant decrease in pelvic failures in the neoadjuvant chemotherapy group was observed (P < 0.001). Survival was improved in bulky resectable cases (N = 81% vs C = 69%, P < 0.05). Pathological findings for the surgical specimens revealed differences between both groups because all the risk factors such as parametrial and lymph node metastases, tumor bulk, and vascular embolism had been decreased (P < 0.001). CONCLUSION: Neoadjuvant chemotherapy can improve survival because of increased operability with free survival margins and a decrease in pathologic risk factors in unselected, bulky (> 4 cm diameter) stage Ib patients.