Dramatic response of vemurafenib-induced cutaneous lesions upon switch to dual BRAF/MEK inhibition in a metastatic melanoma patient.

BRAF inhibitory therapy is the mainstream treatment for BRAF mutant advanced melanoma. However vemurafenib, a type I mutant BRAF V600 inhibitor, induces an array of proliferative skin disorders from keratosis pilaris-like and keratoacanthoma-like lesions to locally aggressive cutaneous squamous cell carcinoma (cuSCC). Dual BRAF/MEK inhibition is known to lower the incidence of such manifestations, but it is not known whether it can counteract established lesions. Here we show, for the first time, a dramatic response and a restitution ad integro upon dual inhibition of a widespread proliferative affection induced by BRAF monotherapy. A 75-year-old woman was diagnosed with a BRAF V600E mutated metastatic melanoma. Following dacarbazine (DTIC) and ipilimumab, the patient was started on 960 mg twice daily vemurafenib (Zelboraf), which resulted in complete response, but the patient also developed grade IV skin toxicity. Despite dose-reduction to 720 mg twice daily the side effects persisted. We hypothesized that a switch to double inhibition of the mitogen-activated protein kinase pathway with dabrafenib and trametinib could lead to improvement of the skin lesions, while preserving tumor control. The patient was closely followed for changes in skin lesions. We witnessed a rapid regression followed by complete disappearance of all side effects of vemurafenib except for grade I fatigue. The biopsied skin lesions show regression of established keratoacanthoma-like lesions with signs of apoptosis. Switching from the current standard of care vemurafenib therapy to the double BRAF/MEK inhibition in BRAF mutant melanoma patients results in rapid disappearance of established proliferative skin disorders.

The potential of metastatic lymph nodes to predict positive resection margins in patients with resectable pancreatic cancer

Objective: Despite progress during recent decades, long-term outcome¦of patients with pancreatic cancer remains dismal. Since positive resection¦margins and metastatic lymph nodes are known risk factors for early tumor¦recurrence, patients at risk should be identified and could potentially benefit¦from preoperative radio-chemotherapy. This study aimed to assess whether the¦presence of lymph node metastasis could be used to predict positive resection¦margins in patients with pancreatic cancer.¦Methods: A series of 146 patients (82 male, 64 female, median age 68 years)¦underwent pancreatic head resection for various malignant diseases (pancreatic¦ductal adenocarcinoma, biliary cancer, periampullary cancer) at our institution¦from 2000 to 2011. Patients were identified from our prospective database¦that collects more than 60 single items of all patients undergoing pancreatic¦resection. Lymph node metastasis and positive resection margins were all¦confirmed by histological evaluation. Positive predictive value (PPV), negative¦predictive value (NPV), sensitivity and specificity were calculated to assess¦the predictive value of metastatic lymph nodes regarding tumor-free (R0) and¦tumor-involved (R1) resection margins.¦Results: There were 110 specimens (76%) with tumor-positive lymph nodes¦and 36 specimens with tumor-negative lymph nodes. Resection margins were¦positive in 47 specimens (32%) and negative in 99 specimens. Sensitivity of¦tumor-positive lymph nodes to detect positive resection margins was 96%, and¦the NPV was 94%. In contrast, specificity was 34% and the PPV was 41%.¦Conclusion: Patients with resectable pancreatic cancer, who have no lymph¦node metastasis, are at very low risk to have positive resection margins (2 of¦36 patients, NPV 94%). In contrast, more than one third of patients with¦metastatic lymph nodes are at increased risk for an incomplete tumor resection¦(sensitivity 96%). If lymph nodesmetastases are highly suspected at preoperative¦staging, a neoadjuvant treatment strategy should be considered to increase the¦R0 resection rate.

Epigenetic alterations and constitutive Wnt signaling are early events in the progression from Barrett's esophagus to esophageal adenocarcinoma

SUMMARY Barrett's esophagus (BE) is an acquired condition in which the normal squamous epithelium in the distal esophagus is replaced by a metaplastic columnar epithelium, as a complication of chronic gastroesophageal reflux. The clinical significance of this disease is its associated predisposition to esophageal adenocarcinoma (EAC). EAC is a highly lethal disease. Better understanding of the pathogenesis of columnar metaplasia and its progression to cancer might allow the identification of biomarkers that can be used for early diagnosis, which will improve the patient survival. In this study, an improved protocol for methylation-sensitive single-strand conformation analysis, which is used to analyze promoter methylation, is proposed and a methylation-sensitive dot blot assay is described, which allows a rapid, easy, and sensitive detection of promoter methylation. Both methods were applied to study the methylation pattern of the APC promoter in histologically normal appearing gastric mucosa. The APC promoter showed monoallelic methylation, and because the methylated allele differed between the different gastric cell types, this corresponded to allelic exclusion. The APC methylation pattern was frequently altered in noimal gastric mucosa associated with neoplastic lesions, indicating that changes in the pattern of promoter methylation might precede the development of neoplasia, without accompanying histological manifestations. An epigenetic profile of 10 genes important in EAC was obtained in this study; 5 promoter genes (APC, TIMP3, TERT, CDKN2A and SFRP1) were found to be hypermethylated in the tumors. Furthermore, the promoter of APC, TIMP3 and TERT was frequently methylated in BE samples from EAC patients, but rarely in BE samples that did not progress to EAC. These three biomarkers might therefore be considered as potential predictive markers for increased EAC risk. Analysis of Wnt pathway alterations indicated that WNT2 ligand is overexpressed as early as the low-grade dysplastic stage and downregulation by promoter methylation of the SFRP1 gene occurrs already in the metaplastic lesions. Moreover, loss of APC expression is not the only factor involved in the activation of the Wnt pathway. These results indicate that a variety of biologic, mostly epigenetic events occurs very early in the carcinogenesis of BE. This new information might lead to improved early diagnosis of EAC and thus open the way to a possible application of these biomarkers in the prediction of increased EAC risk progression. RESUME L'oesophage de Barrett est une lésion métaplasique définie par le remplacement de la muqueuse malpighienne du bas oesophage par une muqueuse cylindrique glandulaire, suite à une agression chronique par du reflux gastro-esophagien. La plus importante signification clinique de cette maladie est sa prédisposition au développement d'un adénocarcinome. Le pronostic de l'adénocarcinome sur oesophage de Barrett est sombre. Seule une meilleure compréhension de la pathogenèse de l'épithélium métaplasique et de sa progression néoplasique permettrait l'identification de biomarqueurs pouvant être utilisés pour un diagnostic précoce ; la survie du patient serait ainsi augmentée. Dans cette étude, un protocole amélioré pour l'analyse de la méthylation par conformation simple brin est proposé. De plus, une technique d'analyse par dot blot permettant une détection rapide, facile et sensible de la méthylation d'un promoteur est décrite. Les deux méthodes ont été appliquées à l'étude de la méthylation du promoteur du gène APC dans des muqueuses gastriques histologiquement normales. Le promoteur APC a montré une méthylation monoallélique et, parce que les allèles méthylés différaient entre les différents types de cellules gastriques, celle-ci correspondait à une méthylation allélique exclusive. La méthylation d'APC a été trouvée fréquemment altérée dans la muqueuse gastrique normale associée à des lésions néoplasiques. Ceci indique que des changements dans la méthylation d'un promoteur peuvent précéder le développement d'une tumeur, et cela sans modification histologique. Un profil épigénétique des adénocarcinomes sur oesophage de Barrett a été obtenu dans cette étude. Cinq promoteurs (APC, TIMP3, TERT, CDKN2A et SFRP1) ont été trouvés hyperméthylés dans les tumeurs. Les promoteurs d'APC, TIMP3 et TERT étaient fréquemment méthylés dans l'épithélium métaplasique proche d'un adénocarcinome et rarement dans l'épithélium sans évolution néoplasique. Ces trois biomarkers pourraient par conséquent être considérés comme marqueur prédicatif d'un risque accru de développer une tumeur. L'analyse des altérations de la voie Wnt a montré que WNT2 est surexprimé déjà dans des dysplasies de bas-grade et que la dérégulation de SFRP1 par méthylation de son promoteur intervenait dans les lésions métaplasiques. Une perte d'expression d'APC n'est pas le seul facteur impliqué dans l'activation de cette voie. Ces résultats montrent qu'une grande diversité d'événements biologiques, principalement épigénétiques, surviennent très tôt lors de la carcinogenèse de l'oesophage de Barrett. Ces nouveaux éléments pourraient améliorer le diagnostic précoce et rendre possible l'application de ces biomarqueurs dans la prédiction d'un risque accru de développer un adénocarcinome sur un oesophage de Barrett.

Dysregulated activation of the CXCR4/CXCL12 Axisand its role in the malignant phenotype of neural crest-derived neuroblastoma tumours

Résumé: Le neuroblastome (NB) est un néoplasme dévastateur de la petite enfance, pour lequel il n'existe pas encore de traitement efficace. Les chimiokines et leurs récepteurs ont été impliqués dans la croissance des tumeurs et la formation de métastases, et en particulier, il a été rapporté que l'axe CXCR4/CXCL12 dirigeait le guidage, ainsi que l'invasion des cellules cancéreuses vers des organes spécifiques. Notre étude avait pour objectif d'analyser le rôle de CxCR4 exogène dans le comportement malin du NB, en étudiant la croissance des cellules tumorales, leur capacité de survie, de migration et d'invasion in vitro et en validant ces résultats grâce à un modèle orthotopique murin de la progression tumorale du NB in vivo. La surexpression de CXCR4 dans les cellules faiblement métastatiques IGR-NB8 n'exprimant pas CXCR4, a augmenté la mobilité des cellules vers CXCL12 in vitro. De plus, les cellules surexprimant CXCR4 ont été moins affectées par la privation de sérum que les cellules contrôles. Le volume des tumeurs chez les animaux greffés de manière orthotopique avec les cellules NB8-CXCR4-C3 était significativement plus élevé que celui des tumeurs issues des cellules contrôles NB8-E6 au moment du sacrifice des animaux. Cependant, aucune induction des métastases n'a été observée. La lignée cellulaire IGR-N91, aux propriétés invasives et métastatiques in vivo, exprime constitutivement des quantités modérées de CXCR4. La surexpression du récepteur dans cette lignée a accéléré la croissance tumorale in vivo, mais n'a pas augmenté pas l'occurrence des métastases. Les cellules IGR-N91, dans lesquelles l'expression de CXCR4 a été éteinte, suite à l'introduction de shRNA stable contre CXCR4, a présenté une croissance cellulaire plus lente, in vitro et in vivo. Afin d'identifier les gènes et les voies de signalisation impliqués dans les effets dépendants de CXCR4-CXCL12 dans le NB, des analyses du profil d'expression des gènes ont été effectuées sur les lignées cellulaires transfectées ou non (contrôle). Trois clones contrôles ont été comparés à 3 clones surexprimant CXCR4 pour chacune des lignées (IGR-NB8 et IGR-N91). Les analyses biostatiques ont identifié 10 gènes induits, dont CXCR4, et 31 gènes réprimés, communs entre tous les clones surexprimant CXCR4. Ces observations démontrent que la surexpression de CXCR4 dans le NB stimule la croissance, la survie et la migration chémotactique des cellules tumorales, mais est insuffisante pour induire ou augmenter leurs capacités invasives et métastatiques. Les voies de signalisation activées suite à la surexpression de CXCR4 et identifiées à travers le profil global de l'expression des gènes pourraient être des cibles intéressantes pour le développement de drogues capables d'inhiber la croissance tumorale. Abstact: Neuroblastoma (NB) is a devastating childhood neoplasm for which there is not yet an efficient treatment. Chemokines and their receptors have been involved in tumour growth and metastasis, and in particular the CXCR4/CXCL12 axis has been reported to mediate organ-specific cancer cells homing and invasion. The purpose of the study was to investigate the role of ectopic CXCR4 in the malignant behaviour of NB by studying tumour cell growth, survival, migration, and invasion in vitro and by validating these results using a murine orthotopic model of NB tumour progression in vivo. CXCR4 overexpression in the low metastatic, CXCR4-negative IGR-NB8 cells resulted in CXCL12-mediated chemotaxis in vitro. Furthermore, CXCR4 overexpressing cells were less affected by serum deprivation than mock-transduced cells. In vivo studies revealed that, at sacrifice, volumes of tumours developing in mice with orthotopically implanted NB8-CXCR4-C3 cells, were significantly increased compared to NB8-E6 control tumours. However, no induction of metastases was observed. The in vivo invasive and metastatic cell line IGR-N91 cell line constitutively expresses moderate levels of CXCR4. Overexpression of CXCR4 enhanced in vivo tumour growth but did not increase the occurrence of metastases. IGR-N91 cells where CXCR4 has been knocked-down by stable shRNA grew slower in vitro and in vivo. To identify genes and pathways involved in the CXCR4/CXCL12-mediated effects in NB expression, profiles analyses (Affymetrix) were performed on transduced and control cell lines. Three mock-transduced clones were compared to three CXCR4 overexpressing clones of either cell line IGR-NB8 and IGR-N91. Biostatistical analysis identified 10 commonly upregulated genes (including CXCR4) and 31 downregulated genes common to all CXCR4 overexpressing clones. These observations demonstrate that overexpression of CXCR4 in NB stimulates tumour cell growth, survival, and chemotactic migration but is not sufficient to induce or enhance invasive and metastatic capacities. Activated pathways upon CXCR4 overexpression, identified through global gene expression profiling may be interesting targets for drugs inhibiting tumour growth.

Research resource: the dynamic transcriptional profile of sertoli cells during the progression of spermatogenesis.

Sertoli cells (SCs), the only somatic cells within seminiferous tubules, associate intimately with developing germ cells. They not only provide physical and nutritional support but also secrete factors essential to the complex developmental processes of germ cell proliferation and differentiation. The SC transcriptome must therefore adapt rapidly during the different stages of spermatogenesis. We report comprehensive genome-wide expression profiles of pure populations of SCs isolated at 5 distinct stages of the first wave of mouse spermatogenesis, using RNA sequencing technology. We were able to reconstruct about 13 901 high-confidence, nonredundant coding and noncoding transcripts, characterized by complex alternative splicing patterns with more than 45% comprising novel isoforms of known genes. Interestingly, roughly one-fifth (2939) of these genes exhibited a dynamic expression profile reflecting the evolving role of SCs during the progression of spermatogenesis, with stage-specific expression of genes involved in biological processes such as cell cycle regulation, metabolism and energy production, retinoic acid synthesis, and blood-testis barrier biogenesis. Finally, regulatory network analysis identified the transcription factors endothelial PAS domain-containing protein 1 (EPAS1/Hif2α), aryl hydrocarbon receptor nuclear translocator (ARNT/Hif1β), and signal transducer and activator of transcription 1 (STAT1) as potential master regulators driving the SC transcriptional program. Our results highlight the plastic transcriptional landscape of SCs during the progression of spermatogenesis and provide valuable resources to better understand SC function and spermatogenesis and its related disorders, such as male infertility.

Cerebrospinal fluid cortisol and clinical disease progression in MCI and dementia of Alzheimer's type.

Increased peripheral and central nervous system cortisol levels have been reported in Alzheimer's disease (AD) and may reflect dysfunction of cerebral components of the hypothalamic-pituitary-adrenal (HPA) axis. However, brain exposure to high cortisol concentrations may also accelerate disease progression and cognitive decline. The objectives of this study were to investigate whether HPA-axis dysregulation occurs at early clinical stages of AD and whether plasma and CSF cortisol levels are associated with clinical disease progression. Morning plasma and CSF cortisol concentrations were obtained from the subjects with AD dementia, mild cognitive impairment of AD type (MCI-AD), MCI of other type (MCI-O), and controls with normal cognition included in a multicenter study from the German Dementia Competence Network. A clinical and neuropsychological follow-up was performed in a subgroup of participants with MCI-AD, MCI-O, and AD dementia. CSF cortisol concentrations were increased in the subjects with AD dementia or MCI-AD compared with subjects with MCI-O or normal cognition. After controlling for possible confounders including CSF measures of amyloid beta1-42 and total tau, higher baseline CSF cortisol levels were associated with faster clinical worsening and cognitive decline in MCI-AD. The findings suggest that HPA-axis dysregulation occurs at the MCI stage of AD and may accelerate disease progression and cognitive decline.

René-Théophile-Hyacinthe Laennec (1781-1826) and the description of metastatic pulmonary melanoma.

In 19th century, the anatomo-clinical school of Paris linked clinical signs with anatomical lesions establishing clinical medicine. One of the most enlightened promoters of this method was the French physician René-Théophile-Hyacinthe Laennec, known as the inventor of stethoscope. In our article, we reveal his work on pulmonary melanoma.

miR-143 Interferes with ERK5 Signaling, and Abrogates Prostate Cancer Progression in Mice

Abstract Background: Micro RNAs are small, non-coding, single-stranded RNAs that negatively regulate gene expression at the post-transcriptional level. Since miR-143 was found to be down-regulated in prostate cancer cells, we wanted to analyze its expression in human prostate cancer, and test the ability of miR-43 to arrest prostate cancer cell growth in vitro and in vivo. Results: Expression of miR-143 was analyzed in human prostate cancers by quantitative PCR, and by in situ hybridization. miR-143 was introduced in cancer cells in vivo by electroporation. Bioinformatics analysis and luciferase-based assays were used to determine miR-143 targets. We show in this study that miR-143 levels are inversely correlated with advanced stages of prostate cancer. Rescue of miR-143 expression in cancer cells results in the arrest of cell proliferation and the abrogation of tumor growth in mice. Furthermore, we show that the effects of miR-143 are mediated, at least in part by the inhibition of extracellular signal-regulated kinase-5 (ERK5) activity. We show here that ERK5 is a miR-143 target in prostate cancer. Conclusions: miR-143 is as a new target for prostate cancer treatment.

Méta-analyses d'essais randomisés sur données individuelles dans le traitement des cancers ORL non métastatiques : principes, résultats, perspectives [Individual patient data meta-analyses of randomized trials for the treatment of non-metastatic head and neck squamous cell carcinomas: Principles, results and perspectives].

Meta-analyses are considered as an important pillar of evidence-based medicine. The aim of this review is to describe the main principles of a meta-analysis and to use examples of head and neck oncology to demonstrate their clinical impact and methodological interest. The major role of individual patient data is outlined, as well as the superiority of individual patient data over meta-analyses based on published summary data. The major clinical breakthrough of head and neck meta-analyses are summarized, regarding concomitant chemotherapy, altered fractionated chemotherapy, new regimens of induction chemotherapy or the use of radioprotectants. Recent methodological developments are described, including network meta-analyses, the validation of surrogate markers. Lastly, the future of meta-analyses is discussed in the context of personalized medicine.

Chemotherapy and radiotherapy in nasopharyngeal carcinoma: an update of the MAC-NPC meta-analysis.

BACKGROUND: A previous individual patient data meta-analysis by the Meta-Analysis of Chemotherapy in Nasopharynx Carcinoma (MAC-NPC) collaborative group to assess the addition of chemotherapy to radiotherapy showed that it improves overall survival in nasopharyngeal carcinoma. This benefit was restricted to patients receiving concomitant chemotherapy and radiotherapy. The aim of this study was to update the meta-analysis, include recent trials, and to analyse separately the benefit of concomitant plus adjuvant chemotherapy. METHODS: We searched PubMed, Web of Science, Cochrane Controlled Trials meta-register, ClinicalTrials.gov, and meeting proceedings to identify published or unpublished randomised trials assessing radiotherapy with or without chemotherapy in patients with non-metastatic nasopharyngeal carcinoma and obtained updated data for previously analysed studies. The primary endpoint of interest was overall survival. All trial results were combined and analysed using a fixed-effects model. The statistical analysis plan was pre-specified in a protocol. All data were analysed on an intention-to-treat basis. FINDINGS: We analysed data from 19 trials and 4806 patients. Median follow-up was 7·7 years (IQR 6·2-11·9). We found that the addition of chemotherapy to radiotherapy significantly improved overall survival (hazard ratio [HR] 0·79, 95% CI 0·73-0·86, p<0·0001; absolute benefit at 5 years 6·3%, 95% CI 3·5-9·1). The interaction between treatment effect (benefit of chemotherapy) on overall survival and the timing of chemotherapy was significant (p=0·01) in favour of concomitant plus adjuvant chemotherapy (HR 0·65, 0·56-0·76) and concomitant without adjuvant chemotherapy (0·80, 0·70-0·93) but not adjuvant chemotherapy alone (0·87, 0·68-1·12) or induction chemotherapy alone (0·96, 0·80-1·16). The benefit of the addition of chemotherapy was consistent for all endpoints analysed (all p<0·0001): progression-free survival (HR 0·75, 95% CI 0·69-0·81), locoregional control (0·73, 0·64-0·83), distant control (0·67, 0·59-0·75), and cancer mortality (0·76, 0·69-0·84). INTERPRETATION: Our results confirm that the addition of concomitant chemotherapy to radiotherapy significantly improves survival in patients with locoregionally advanced nasopharyngeal carcinoma. To our knowledge, this is the first analysis that examines the effect of concomitant chemotherapy with and without adjuvant chemotherapy as distinct groups. Further studies on the specific benefits of adjuvant chemotherapy after concomitant chemoradiotherapy are needed. FUNDING: French Ministry of Health (Programme d'actions intégrées de recherche VADS), Ligue Nationale Contre le Cancer, and Sanofi-Aventis.

Systematic analysis of factors associated with progression and regression of ulcerative colitis in 918 patients.

BACKGROUND: Studies that systematically assess change in ulcerative colitis (UC) extent over time in adult patients are scarce. AIM: To assess changes in disease extent over time and to evaluate clinical parameters associated with this change. METHODS: Data from the Swiss IBD cohort study were analysed. We used logistic regression modelling to identify factors associated with a change in disease extent. RESULTS: A total of 918 UC patients (45.3% females) were included. At diagnosis, UC patients presented with the following disease extent: proctitis [199 patients (21.7%)], left-sided colitis [338 patients (36.8%)] and extensive colitis/pancolitis [381 (41.5%)]. During a median disease duration of 9 [4-16] years, progression and regression was documented in 145 patients (15.8%) and 149 patients (16.2%) respectively. In addition, 624 patients (68.0%) had a stable disease extent. The following factors were identified to be associated with disease progression: treatment with systemic glucocorticoids [odds ratio (OR) 1.704, P = 0.025] and calcineurin inhibitors (OR: 2.716, P = 0.005). No specific factors were found to be associated with disease regression. CONCLUSIONS: Over a median disease duration of 9 [4-16] years, about two-thirds of UC patients maintained the initial disease extent; the remaining one-third had experienced either progression or regression of the disease extent.

Risk Prediction Scores for Recurrence and Progression of Non-Muscle Invasive Bladder Cancer: An International Validation in Primary Tumours

Abstract Objective: We aimed to determine the validity of two risk scores for patients with non-muscle invasive bladder cancer in different European settings, in patients with primary tumours. Methods: We included 1,892 patients with primary stage Ta or T1 non-muscle invasive bladder cancer who underwent a transurethral resection in Spain (n = 973), the Netherlands (n = 639), or Denmark (n = 280). We evaluated recurrence-free survival and progression-free survival according to the European Organisation for Research and Treatment of Cancer (EORTC) and the Spanish Urological Club for Oncological Treatment (CUETO) risk scores for each patient and used the concordance index (c-index) to indicate discriminative ability. Results: The 3 cohorts were comparable according to age and sex, but patients from Denmark had a larger proportion of patients with the high stage and grade at diagnosis (p,0.01). At least one recurrence occurred in 839 (44%) patients and 258 (14%) patients had a progression during a median follow-up of 74 months. Patients from Denmark had the highest 10- year recurrence and progression rates (75% and 24%, respectively), whereas patients from Spain had the lowest rates (34% and 10%, respectively). The EORTC and CUETO risk scores both predicted progression better than recurrence with c-indices ranging from 0.72 to 0.82 while for recurrence, those ranged from 0.55 to 0.61. Conclusion: The EORTC and CUETO risk scores can reasonably predict progression, while prediction of recurrence is more difficult. New prognostic markers are needed to better predict recurrence of tumours in primary non-muscle invasive bladder cancer patients.

Thromboxane prostaglandin receptor antagonist and carotid atherosclerosis progression in patients with cerebrovascular disease of ischemic origin: a randomized controlled trial.

BACKGROUND AND PURPOSE: Thromboxane prostaglandin receptors have been implicated to be involved in the atherosclerotic process. We assessed whether Terutroban, a thromboxane prostaglandin receptor antagonist, affects the progression of atherosclerosis, as measured by common carotid intima-media thickness and carotid plaques. METHODS: A substudy was performed among 1141 participants of the aspirin-controlled Prevention of Cerebrovascular and Cardiovascular Events of Ischemic Origin with Terutroban in Patients with a History of Ischemic Stroke or Transient Ischemic Attack (PERFORM) trial. Common carotid intima-media thickness and carotid plaque occurrence was measured during a 3-year period. RESULTS: Baseline characteristics did not differ between Terutroban (n=592) and aspirin (n=549) treated patients and were similar as in the main study. Mean study and treatment duration were similar (28 and 25 months, respectively). In the Terutroban group, the annualized rate of change in common carotid intima-media thickness was 0.006 mm per year (95% confidence interval, -0.004 to 0.016) and -0.005 mm per year (95% confidence interval, -0.015 to 0.005) in the aspirin group. There was no statistically significant difference between the groups in the annualized rate of change of common carotid intima-media thickness (0.011 mm per year; 95% confidence interval, -0.003 to 0.025). At 12 months of follow-up, 66% of Terutroban patients had no emergent plaques, 31% had 1 to 2 emergent plaques, and 3% had ≥3 emergent plaques. In the aspirin group, the corresponding percentages were 64%, 32%, and 4%. Over time, there was no statistically significant difference in the number of emergent carotid plaques between treatment modalities (rate ratio, 0.91; 95% confidence interval, 0.77-1.07). CONCLUSIONS: Compared with aspirin, Terutroban did not beneficially affect progression of carotid atherosclerosis among well-treated patients with a history of ischemic stroke or transient ischemic attacks with an internal carotid stenosis <70%. CLINICAL TRIAL REGISTRATION URL: http://www.controlled-trials.com. Unique identifier: ISRCTN66157730.