RESUMO
BACKGROUND: Endometriosis affects 190 million women and those assigned female at birth worldwide. For some, it is associated with debilitating chronic pelvic pain. Diagnosis of endometriosis is often achieved through diagnostic laparoscopy. However, when isolated superficial peritoneal endometriosis (SPE), the most common endometriosis subtype, is identified during laparoscopy, limited evidence exists to support the common decision to surgically remove it via excision or ablation. Improved understanding of the impact of surgical removal of isolated SPE for the management of chronic pelvic pain in women is required. Here, we describe our protocol for a multi-centre trial to determine the effectiveness of surgical removal of isolated SPE for the management of endometriosis-associated pain. METHODS: We plan to undertake a multi-centre participant-blind parallel-group randomised controlled clinical and cost-effectiveness trial with internal pilot. We plan to randomise 400 participants from up to 70 National Health Service Hospitals in the UK. Participants with chronic pelvic pain awaiting diagnostic laparoscopy for suspected endometriosis will be consented by the clinical research team. If isolated SPE is identified at laparoscopy, and deep or ovarian endometriosis is not seen, participants will be randomised intraoperatively (1:1) to surgical removal (by excision or ablation or both, according to surgeons' preference) versus diagnostic laparoscopy alone. Randomisation with block-stratification will be used. Participants will be given a diagnosis but will not be informed of the procedure they received until 12 months post-randomisation, unless required. Post-operative medical treatment will be according to participants' preference. Participants will be asked to complete validated pain and quality of life questionnaires at 3, 6 and 12 months after randomisation. Our primary outcome is the pain domain of the Endometriosis Health Profile-30 (EHP-30), via a between randomised group comparison of adjusted means at 12 months. Assuming a standard deviation of 22 points around the pain score, 90% power, 5% significance and 20% missing data, 400 participants are required to be randomised to detect an 8-point pain score difference. DISCUSSION: This trial aims to provide high quality evidence of the clinical and cost-effectiveness of surgical removal of isolated SPE. TRIAL REGISTRATION: ISRCTN registry ISRCTN27244948. Registered 6 April 2021.
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Dor Crônica , Endometriose , Laparoscopia , Feminino , Humanos , Dor Crônica/diagnóstico , Dor Crônica/etiologia , Dor Crônica/cirurgia , Endometriose/complicações , Endometriose/diagnóstico , Endometriose/cirurgia , Laparoscopia/métodos , Estudos Multicêntricos como Assunto , Dor Pélvica/diagnóstico , Dor Pélvica/etiologia , Dor Pélvica/cirurgia , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto , Medicina EstatalRESUMO
BACKGROUND: Tubal ectopic pregnancies can cause substantial morbidity or even death. Current treatment is with methotrexate or surgery. Methotrexate treatment fails in approximately 30% of women who subsequently require rescue surgery. Gefitinib, an epidermal growth factor receptor inhibitor, might improve the effects of methotrexate. We assessed the efficacy of oral gefitinib with methotrexate, versus methotrexate alone, to treat tubal ectopic pregnancy. METHODS: We performed a multicentre, randomised, double-blind, placebo-controlled trial across 50 UK hospitals. Participants diagnosed with tubal ectopic pregnancy were administered a single dose of intramuscular methotrexate (50 mg/m2) and randomised (1:1 ratio) to 7 days of additional oral gefitinib (250 mg daily) or placebo. The primary outcome, analysed by intention to treat, was surgical intervention to resolve the ectopic pregnancy. Secondary outcomes included time to resolution of ectopic pregnancy and serious adverse events. This trial is registered at the ISRCTN registry, ISCRTN 67795930. FINDINGS: Between Nov 2, 2016, and Oct 6, 2021, 328 participants were allocated to methotrexate and gefitinib (n=165) or methotrexate and placebo (n=163). Three participants in the placebo group withdrew. Surgical intervention occurred in 50 (30%) of 165 participants in the gefitinib group and in 47 (29%) of 160 participants in the placebo group (adjusted risk ratio 1·15, 95% CI 0·85 to 1·58; adjusted risk difference -0·01, 95% CI -0·10 to 0·09; p=0·37). Without surgical intervention, median time to resolution was 28·0 days in the gefitinib group and 28·0 days in the placebo group (subdistribution hazard ratio 1·03, 95% CI 0·75 to 1·40). Serious adverse events occurred in five (3%) of 165 participants in the gefitinib group and in six (4%) of 162 participants in the placebo group. Diarrhoea and rash were more common in the gefitinib group. INTERPRETATION: In women with a tubal ectopic pregnancy, adding oral gefitinib to parenteral methotrexate does not offer clinical benefit over methotrexate and increases minor adverse reactions. FUNDING: National Institute of Health Research.
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Metotrexato , Gravidez Ectópica , Gravidez , Feminino , Humanos , Gefitinibe/uso terapêutico , Gravidez Ectópica/induzido quimicamente , Gravidez Ectópica/tratamento farmacológico , Modelos de Riscos Proporcionais , Método Duplo-CegoRESUMO
BACKGROUND: Bleeding in early pregnancy is strongly associated with pregnancy loss. Progesterone is essential for the maintenance of pregnancy. Several small trials have suggested that progesterone therapy may improve pregnancy outcomes in women who have bleeding in early pregnancy. METHODS: We conducted a multicenter, randomized, double-blind, placebo-controlled trial to evaluate progesterone, as compared with placebo, in women with vaginal bleeding in early pregnancy. Women were randomly assigned to receive vaginal suppositories containing either 400 mg of progesterone or matching placebo twice daily, from the time at which they presented with bleeding through 16 weeks of gestation. The primary outcome was the birth of a live-born baby after at least 34 weeks of gestation. The primary analysis was performed in all participants for whom data on the primary outcome were available. A sensitivity analysis of the primary outcome that included all the participants was performed with the use of multiple imputation to account for missing data. RESULTS: A total of 4153 women, recruited at 48 hospitals in the United Kingdom, were randomly assigned to receive progesterone (2079 women) or placebo (2074 women). The percentage of women with available data for the primary outcome was 97% (4038 of 4153 women). The incidence of live births after at least 34 weeks of gestation was 75% (1513 of 2025 women) in the progesterone group and 72% (1459 of 2013 women) in the placebo group (relative rate, 1.03; 95% confidence interval [CI], 1.00 to 1.07; P = 0.08). The sensitivity analysis, in which missing primary outcome data were imputed, resulted in a similar finding (relative rate, 1.03; 95% CI, 1.00 to 1.07; P = 0.08). The incidence of adverse events did not differ significantly between the groups. CONCLUSIONS: Among women with bleeding in early pregnancy, progesterone therapy administered during the first trimester did not result in a significantly higher incidence of live births than placebo. (Funded by the United Kingdom National Institute for Health Research Health Technology Assessment program; PRISM Current Controlled Trials number, ISRCTN14163439.).
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Aborto Espontâneo/prevenção & controle , Complicações na Gravidez/diagnóstico por imagem , Progesterona/administração & dosagem , Progestinas/administração & dosagem , Hemorragia Uterina/tratamento farmacológico , Administração Intravaginal , Adulto , Método Duplo-Cego , Feminino , Humanos , Nascido Vivo , Gravidez , Primeiro Trimestre da Gravidez , Falha de TratamentoRESUMO
BACKGROUND: Laparoscopic surgery is progressing rapidly is becoming the normal route for many abdominal operations, even for major complex surgery. The integrated laparoscopic theatre is a state-of-the-art system in which the laparoscopic equipment and multiple flat-screen monitors are permanently installed to be operational on demand inside the theatre. These expensive systems are being widely adopted, however very little research has been published regarding which features of these systems are desired by the surgeons who use them. The study objective was to assess the strength of preference for key attributes of integrated laparoscopic theatres and to compare these preferences between Gynaecologists and General surgeons. METHODS: This was an electronically distributed discrete choice experiment survey of British practicing Laparoscopic Gynaecologists and General Surgeons (Through The British Society of Gynaecology Endoscopy and The Association of Laparoscopic Surgeons of Great Britain and Ireland). An electronic survey was designed and pre-tested. This was then sent to practicing British Laparoscopic Gynaecologists and General-Surgeons. There were structured questions regarding the seven key attributes of integrated laparoscopic theatres in the standard form for a discrete choice experiment. RESULTS: Questionnaires from 167 respondents were analysed. One hundred three were gynaecologists and 64 were general-surgeons. Adjustable screens for height and position was the most favoured attribute and it is 4.7 times more desirable than the next most desirable attribute, which was a wire free floor. The least desirable features were piped CO2, ceiling-mounted-screens and external-transmission-of-images. CONCLUSION: Both groups favour adjustable screens for position and height above all the other features. These findings are in contrast with previous research, which showed that when asked to rank the attributes in order, gynaecologists chose ceiling mounted screens first and adjustable screens fourth. When asked to "trade off" attributes in the discrete choice experiment the adjustability of the screens became much more important than how the screens were mounted. With new wireless technology the benefits of a fully integrated theatre could be delivered with floor mounted systems at a considerably reduced cost. This information is important to manufacturers and purchasers of these systems in order to design cost effective ergonomic theatres that are fit for purpose.
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Atitude do Pessoal de Saúde , Cirurgia Geral , Ginecologia , Decoração de Interiores e Mobiliário , Laparoscopia/instrumentação , Salas Cirúrgicas , Feminino , Humanos , Irlanda , Masculino , Cirurgiões , Inquéritos e Questionários , Reino UnidoRESUMO
Our study examined the impact of adenomyosis on the chance of clinical pregnancy after IVF and embryo transfer (IVF-ET). This was a prospective multicentre study from April 2013 to October 2015. We included 375 women with history of infertility who attended for a 3D scan prior to IVF-ET. A total of 150/375 (40.0%, 95% confidence interval [CI] 35.2-45.0) women had clinical pregnancy. Women with any feature of adenomyosis had a lower clinical pregnancy rate (21/72 [29.2%, 95% CI 18.6-39.6] versus 129/303 [42.6%, 95% CI 37.1-48.2], P = 0.044, relative risk (RR) 0.68 [95% CI 0.47-1.00]). Logistic regression selected an adenomyosis score of 4 or higher as an independent predictor of clinical pregnancy (odds ratio [OR] 0.35 [95% CI 0.15-0.82]). Estimated probability of clinical pregnancy decreased from 42.7% (95% CI 37.1-48.3) for women with no adenomyosis features to 22.9% (95% CI 13.4-32.6) for those with four and 13.0% (95% CI 2.2-23.9) for those with all seven. Women with adenomyosis have lower clinical pregnancy rate after IVF-ET. Condition severity expressed as a number of morphological features on ultrasound scan increases the magnitude of the effect.
Assuntos
Adenomiose/fisiopatologia , Transferência Embrionária , Fertilização in vitro , Taxa de Gravidez , Adenomiose/diagnóstico por imagem , Adulto , Feminino , Humanos , Infertilidade Feminina , Gravidez , Estudos ProspectivosRESUMO
STUDY OBJECTIVE: To review surgical outcomes and histopathological findings after laparoscopic myomectomy by a team at a university teaching hospital. DESIGN: This was a retrospective review of consecutive cases of laparoscopic myomectomy performed by members of our minimal access surgery team between January 2004 and December 2015 (Canadian Task Force classification II-3). SETTING: A university teaching hospital. PATIENTS: Women undergoing laparoscopic myomectomy. INTERVENTIONS: Laparoscopic myomectomy. MEASUREMENTS AND MAIN RESULTS: We collected women's demographic data, clinical histories, and surgical outcomes, including complication rates and the incidence of undiagnosed uterine malignancy. Five hundred fourteen women were booked for laparoscopic myomectomy during the study period. Five hundred twelve of 514 (99.6%; 95% confidence interval [CI], 99.05-100.00) procedures were successfully completed. Two cases were converted to open surgery: one because of suspected uterine malignancy and another because of bowel injury at initial entry. The median number of myomas removed at laparoscopy was 1 (range, 1-12; mode = 1). The median size of the largest myoma removed at each procedure was 70 mm (range, 10-200 mm) as assessed subjectively by the operating surgeon. The median blood loss was 73 mL (range, 5-3000 mL). The median length of stay in the hospital was 2 nights (range, 0-24 nights). Breach of the uterine cavity occurred in 50 of 514 (9.7%; 95% CI, 7.17-12.29) cases. Electromechanical morcellation was used in 496 of 514 (96.5%; 95% CI, 94.9-98.1) patients. Eighteen of 514 (3.5%; 95% CI, 1.91-5.09) women suffered significant complications including blood loss >1000 mL (n = 15), bowel injury (n = 1), bladder injury (n = 1), and small bowel obstruction secondary to port site hernia (n = 1). There were no cases of undiagnosed uterine malignancies after myoma morcellation. CONCLUSION: Laparoscopic myomectomy can be conducted with a low rate of major complications, and, in our experience, the chance of discovering occult malignancy is very low.
Assuntos
Laparoscopia/estatística & dados numéricos , Leiomioma/cirurgia , Miomectomia Uterina/estatística & dados numéricos , Neoplasias Uterinas/cirurgia , Adolescente , Adulto , Idoso , Feminino , Humanos , Laparoscopia/efeitos adversos , Laparoscopia/métodos , Pessoa de Meia-Idade , Procedimentos Cirúrgicos Minimamente Invasivos , Estudos Retrospectivos , Miomectomia Uterina/efeitos adversos , Miomectomia Uterina/métodos , Adulto JovemRESUMO
BACKGROUND: Endometriosis is a common condition which causes pain and reduced fertility. Treatment can be difficult, especially for severe disease, and an accurate preoperative assessment would greatly help in the managment of these patients. The objective of this study is to assess the accuracy of pre-operative transvaginal ultrasound scanning (TVS) in identifying the specific features of pelvic endometriosis and pelvic adhesions in comparison with laparoscopy. METHODS: Consecutive women with clinically suspected or proven pelvic endometriosis, who were booked for laparoscopy, were invited to join the study. They all underwent a systematic transvaginal ultrasound examination in order to identify discrete endometriotic lesions and pelvic adhesions. The accuracy of ultrasound diagnosis was determined by comparing pre-operative ultrasound to laparoscopy findings. RESULTS: 198 women who underwent preoperative TVS and laparoscopy were included in the final analysis. At laparoscopy 126/198 (63.6%) women had evidence of pelvic endometriosis. 28/126 (22.8%) of them had endometriosis in a single location whilst the remaining 98/126 (77.2%) had endometriosis in two or more locations. Positive likelihood ratios (LR+) for the ultrasound diagnosis of ovarian endometriomas, moderate or severe ovarian adhesions, pouch of Douglas adhesions, and bladder deeply infiltrating endometriosis (DIE), recto-sigmoid colon DIE, rectovaginal DIE, uterovesical fold DIE and uterosacral ligament DIE were >10, whilst for pelvic side wall DIE and any ovarian adhesions the + LH was 8.421 and 9.81 respectively.The negative likelihood ratio (LR-) was: <0.1 for bladder DIE; 0.1-0.2 for ovarian endometriomas, moderate or severe ovarian adhesions, and pouch of Douglas adhesions; 0.5-1 for rectovaginal, uterovesical fold, pelvic side wall and uterosacral ligament DIE. The accuracy of TVS for the diagnosis of both total number of endometriotic lesions and DIE lesions significantly improved with increasing total number of lesions. CONCLUSIONS: Our study has shown that the TVS diagnosis of endometriotic lesion is very specific and false positive results are rare. Negative findings are less reliable and women with significant symptoms may still benefit from further investigation even if TVS findings are normal. The accuracy of ultrasound diagnosis is significantly affected by the location and number of endometriotic lesions.
Assuntos
Endometriose/diagnóstico por imagem , Pelve/diagnóstico por imagem , Anexos Uterinos/diagnóstico por imagem , Anexos Uterinos/cirurgia , Doenças dos Anexos/diagnóstico por imagem , Doenças dos Anexos/cirurgia , Adulto , Escavação Retouterina/diagnóstico por imagem , Escavação Retouterina/cirurgia , Endometriose/cirurgia , Feminino , Humanos , Laparoscopia , Funções Verossimilhança , Pessoa de Meia-Idade , Pelve/cirurgia , Doenças Peritoneais/diagnóstico por imagem , Doenças Peritoneais/cirurgia , Estudos Prospectivos , Sensibilidade e Especificidade , Aderências Teciduais/diagnóstico por imagem , Aderências Teciduais/cirurgia , Ultrassonografia , Adulto JovemRESUMO
INTRODUCTION: Telemetric measurement of intra-pleural pressure in conscious animals that are restrained in head-out plethysmography chambers enables determination of airway resistance. Originally proposed over 10 years ago, pharmacological validation of this technique is limited. Here airway resistance in conscious, instrumented rats was compared to measurement in anaesthetised rats via a fluid filled oesophageal catheter following administration of two different pharmacological agents. METHODS: Male rats were implanted with telemetry devices and were trained to accept the restraint of head-out plethysmography chambers. A separate group of male rats were anaesthetised, placed in a body-enclosed plethysmography chamber and were prepared with a tracheal, oesphageal and jugular vein cannulae. Methacholine or NECA were given intravenously and changes in ventilation and airway resistance were measured. RESULTS: The pressure signal obtained in the telemetered rats was found to be extremely variable. Variability was confounded by excessive struggling, particularly during the infusion periods. Misplacement of the pressure sensitive catheter tip and prior habituation to the chamber were not factors in signal variability. Consequently, no dose-response relationship to either pharmacological agent was established in this model. Dose-dependent increases in resistance to both methacholine and NECA were measured in anaesthetised rats using body-enclosed plethysmography. DISCUSSION: Given the variability of the pressure signal within and between rats, the feasibility of a model in conscious rats for the measurement of airway resistance is questioned. Improved restraint methods or alternative models in conscious animals should therefore be explored. In the meantime, assessment of airway resistance is best confined to the anaesthetised rat.
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Broncoconstritores/farmacologia , Telemetria/métodos , Adenosina-5'-(N-etilcarboxamida) , Resistência das Vias Respiratórias/efeitos dos fármacos , Anestesia , Animais , Cateterismo , Estado de Consciência , Masculino , Cloreto de Metacolina/farmacologia , Agonistas Muscarínicos/farmacologia , Pletismografia Total , Pleura/fisiologia , Pressão , Agonistas do Receptor Purinérgico P1 , Ratos , Ratos Wistar , Reprodutibilidade dos TestesRESUMO
AIM: To determine how accurately and confidently examiners with different levels of ultrasound experience can classify adnexal masses as benign or malignant and suggest a specific histological diagnosis when evaluating ultrasound images using pattern recognition. METHODS: Ultrasound images of selected adnexal masses were evaluated by 3 expert sonologists, 2 senior and 4 junior trainees. They were instructed to classify the masses using pattern recognition as benign or malignant, to state the level of confidence with which this classification was made and to suggest a specific histological diagnosis. Sensitivity, specificity, accuracy and positive and negative likelihood ratios (LR+ and LR-) with regard to malignancy were calculated. The area under the receiver operating characteristic curve (AUC) of pattern recognition was calculated by using six levels of diagnostic confidence. RESULTS: 166 masses were examined, of which 42% were malignant. Sensitivity with regard to malignancy ranged from 80 to 86% for the experts, was 70 and 84% for the 2 senior trainees and ranged from 70 to 86% for the junior trainees. The specificity of the experts ranged from 79 to 91%, was 77 and 89% for the senior trainees and ranged from 59 to 83% for the junior trainees. The experts were uncertain about their diagnosis in 4-13% of the cases, the senior trainees in 15-20% and the junior trainees in 67-100% of the cases. The AUCs ranged from 0.861 to 0.922 for the experts, were 0.842 and 0.855 for the senior trainees, and ranged from 0.726 to 0.795 for the junior trainees. The experts suggested a correct specific histological diagnosis in 69-77% of the cases. All 6 trainees did so significantly less often (22-42% of the cases). CONCLUSION: Expert sonologists can accurately classify adnexal masses as benign or malignant and can successfully predict the specific histological diagnosis in many cases. Whilst less experienced operators perform reasonably well when predicting the benign or malignant nature of the mass, they do so with a very low level of diagnostic confidence and are unable to state the likely histology of a mass in most cases.
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Doenças dos Anexos/diagnóstico por imagem , Ginecologia/normas , Neoplasias Ovarianas/diagnóstico por imagem , Reconhecimento Automatizado de Padrão/normas , Ultrassonografia Doppler em Cores/normas , Adenocarcinoma Mucinoso/diagnóstico por imagem , Adenocarcinoma Mucinoso/epidemiologia , Adenocarcinoma Mucinoso/patologia , Doenças dos Anexos/epidemiologia , Doenças dos Anexos/patologia , Bases de Dados Factuais , Feminino , Ginecologia/educação , Humanos , Modelos Estatísticos , Neoplasias/diagnóstico por imagem , Neoplasias/epidemiologia , Neoplasias/patologia , Neoplasias Ovarianas/epidemiologia , Neoplasias Ovarianas/patologia , Curva ROC , Reprodutibilidade dos Testes , Fatores de Risco , Sensibilidade e EspecificidadeRESUMO
BACKGROUND: The diagnostic accuracy of ultrasonography for differentiating between benign and malignant adnexal masses is proportional to the expertise of the operator. However, we do not know whether improved diagnostic accuracy will affect the management of these tumours. We assessed the effect of the quality of gynaecological ultrasonography on the management of patients with suspected ovarian cancer in a randomised controlled trial. METHODS: 165 patients who were referred to the regional gynaecological cancer centre at Guy's and St Thomas' NHS Foundation Trust (London, UK), between June 7, 2004, and April 23, 2006, with suspected adnexal tumours met the inclusion criteria. Of these, 150 patients were randomly assigned to either level II (routine) ultrasonography (n=73) or to level III (expert) ultrasonography (n=77). The primary endpoint was the number of major surgical staging procedures (including a laparotomy and at least an oophorectomy and omental biopsy) in each group of the study. Secondary endpoints were: total number of surgical procedures; number of minimally invasive procedures (eg, operative laparoscopy or ultrasonography-guided cyst aspiration); number of additional diagnostic tests (eg, CT or laparoscopy); number of follow-up scans; diagnostic accuracy of level II and level III ultrasonography; and duration of hospital stay. All analyses were by intention to treat. This study is registered on the Current Controlled Trials website http://www.controlled-trials.com/mrct/trial/230201/ISRCTN02631195. FINDINGS: More major surgical staging procedures for suspected ovarian cancer were done in the level II group than in the level III group of the study (27 of 73 [37%] vs 17 of 77 [22%], respectively; difference between groups 15% [95% CI 0-29]; RR 1.68 [1.00-2.81]; p=0.049). The total number of surgical procedures was similar between the two groups: 35 of 73 (48%) in the level II group and 33 of 77 (43%) in the level III group (RR 1.12 [0.79-1.59]; p=0.53). The median duration of hospital stay for patients who were operated on was 6 days (range 3-13) in the level II group and 5 days (range 1-9) in the level III group (p=0.01). A likely histological diagnosis was provided to clinicians after ultrasonography for 76 of 77 (99%) patients in the level III group compared with only 38 of 73 (52%) patients in the level II group. 18 of 150 (12%) patients recruited were eventually diagnosed with ovarian malignancy. The sensitivity and specificity of ultrasonography was 2 of 5 (40%; [95% CI 6.5-84.6]) and 10 of 10 (100%; [34-100]), respectively, in the level II group and 7 of 8 (88%; [47-98]) and 27 of 28 (96%; [82-99]), respectively, in the level III group. INTERPRETATION: Improved quality of ultrasonography has a measurable effect on the management of patients with suspected ovarian cancer in a tertiary gynaecology cancer centre, and results in a significant decrease in the number of major staging procedures and a shorter inpatient hospital stay.
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Neoplasias Ovarianas/diagnóstico por imagem , Qualidade da Assistência à Saúde , Ultrassonografia/normas , Feminino , Humanos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias Ovarianas/patologia , Estudos Prospectivos , Sensibilidade e EspecificidadeRESUMO
The development of the dual peroxisome proliferator-activated receptor (PPAR) alpha/gamma agonist tesaglitazar as an oral antidiabetic was recently discontinued. Here we present tumor data from a 2-year carcinogenicity study in rats given 0.3, 1, 3, and 10 micromol/kg tesaglitazar is presented with focus on the findings of subcutaneous fibrosarcomas. To investigate the mechanism for induction of fibrosarcomas, replicative DNA synthesis (immunohistochemical detection of BrdU-labeled cells) and expression of PPARgamma (immunohistochemistry and reverse transcription-polymerase chain reaction) in subcutaneous adipose tissues was assessed in rats administered 1 or 10 micromol/kg for 2 weeks or 3 months. Poorly differentiated subcutaneous mesenchymal sarcomas with a predominant spindle cell appearance occurred at the highest dose level of 10 micromol/kg in both sexes, and these tumors were diagnosed as fibrosarcomas. The 10-micromol/kg dose was at or above the maximum tolerated dose and caused considerable cardiovascular mortality. Tesaglitazar stimulated DNA synthesis mainly in subcutaneous interstitial mesenchymal cells. The percentage of BrdU-labeled interstitial cells was increased at 1 and 10 micromol/kg after 2 weeks. The increase in DNA synthesis was still significant at the end of the 12-week treatment at 10 mumol/kg, the dose producing fibrosarcoma. However, at 1 micromol/kg, a dose below the no-observed-effect level for fibrosarcoma, the level of DNA synthesis was similar to control levels at 12 weeks. Immunohistochemical analyses showed no detectable PPARgamma protein in the majority of BrdU-labeled interstitial mesenchymal cells in white and brown fat. This indicates that stimulation of DNA synthesis is not mediated via direct activation of PPARgamma in these cells. The results suggest that the induction of rat fibrosarcoma by tesaglitazar, at exposures 100-fold above the human therapeutic exposure, may involve proliferation of undifferentiated mesenchymal cells in subcutaneous tissues.