Evaluation of the new advanced 15-loci MIRU-VNTR genotyping tool in Mycobacterium tuberculosis molecular epidemiology studies

Background. During the last few years, PCR-based methods have been developed to simplify and reduce the time required for genotyping Mycobacterium tuberculosis (MTB) by standard approaches based on IS6110-Restriction Fragment Length Polymorphism (RFLP). Of these, MIRU-12-VNTR (Mycobacterial interspersed repetitive units- variable number of tandem repeats) (MIRU-12) has been considered a good alternative. Nevertheless, some limitations and discrepancies with RFLP, which are minimized if the technique is complemented with spoligotyping, have been found. Recently, a new version of MIRU-VNTR targeting 15 loci (MIRU-15) has been proposed to improve the MIRU-12 format. Results. We evaluated the new MIRU-15 tool in two different samples. First, we analyzed the same convenience sample that had been used to evaluate MIRU-12 in a previous study, and the new 15-loci version offered higher discriminatory power (Hunter-Gaston discriminatory index [HGDI]: 0.995 vs 0.978; 34.4% of clustered cases vs 57.5%) and better correlation (full or high correlation with RFLP for 82% of the clusters vs 47%). Second, we evaluated MIRU-15 on a population-based sample and, once again, good correlation with the RFLP clustering data was observed (for 83% of the RFLP clusters). To understand the meaning of the discrepancies still found between MIRU-15 and RFLP, we analyzed the epidemiological data for the clustered patients. In most cases, splitting of RFLP-clustered patients by MIRU-15 occurred for those without epidemiological links, and RFLP-clustered patients with epidemiological links were also clustered by MIRU-15, suggesting a good epidemiological background for clustering defined by MIRU-15. Conclusion. The data obtained by MIRU-15 suggest that the new design is very efficient at assigning clusters confirmed by epidemiological data. If we add this to the speed with which it provides results, MIRU-15 could be considered a suitable tool for real-time genotyping.

Chemotherapy for advanced gastric cancer.

BACKGROUND: Gastric cancer currently ranks second in global cancer mortality. Most patients are either diagnosed at an advanced stage, or develop a relapse after surgery with curative intent. Apart from supportive care and palliative radiation to localized (e.g. bone) metastasis, systemic chemotherapy is the only treatment option available in this situation. OBJECTIVES: To assess the efficacy of chemotherapy versus best supportive care, combination versus single agent chemotherapy and different combination chemotherapy regimens in advanced gastric cancer. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials, MEDLINE and EMBASE up to March 2009, reference lists of studies, and contacted pharmaceutical companies and national and international experts. SELECTION CRITERIA: Randomised controlled trials on systemic intravenous chemotherapy versus best supportive care, combination versus single agent chemotherapy and different combination chemotherapies in advanced gastric cancer. DATA COLLECTION AND ANALYSIS: Two authors independently extracted data. A third investigator was consulted in case of disagreements. We contacted study authors to obtain missing information. MAIN RESULTS: Thirty five trials, with a total of 5726 patients, have been included in the meta-analysis of overall survival. The comparison of chemotherapy versus best supportive care consistently demonstrated a significant benefit in overall survival in favour of the group receiving chemotherapy (hazard ratios (HR) 0.37; 95% confidence intervals (CI) 0.24 to 0.55, 184 participants). The comparison of combination versus single-agent chemotherapy provides evidence for a survival benefit in favour of combination chemotherapy (HR 0.82; 95% CI 0.74 to 0.90, 1914 participants). The price of this benefit is increased toxicity as a result of combination chemotherapy. When comparing 5-FU/cisplatin-containing combination therapy regimens with versus without anthracyclines (HR 0.77; 95% CI 0.62 to 0.95, 501 participants) and 5-FU/anthracycline-containing combinations with versus without cisplatin (HR 0.82; 95% CI 0.73 to 0.92, 1147 participants) there was a significant survival benefit for regimens including 5-FU, anthracyclines and cisplatin. Both the comparison of irinotecan versus non-irinotecan (HR 0.86; 95% CI 0.73 to 1.02, 639 participants) and docetaxel versus non-docetaxel containing regimens (HR 0.93; 95% CI 0.75 to 1.15, 805 participants) show non-significant overall survival benefits in favour of the irinotecan and docetaxel-containing regimens. AUTHORS' CONCLUSIONS: Chemotherapy significantly improves survival in comparison to best supportive care. In addition, combination chemotherapy improves survival compared to single-agent 5-FU. All patients should be tested for their HER-2 status and trastuzumab should be added to a standard fluoropyrimidine/cisplatin regimen in patients with HER-2 positive tumours. Two and three-drug regimens including 5-FU, cisplatin, with or without an anthracycline, as well as irinotecan or docetaxel-containing regimens are reasonable treatment options for HER-2 negative patients.

Combination of trastuzumab and letrozole after resistance to sequential trastuzumab and aromatase inhibitor monotherapies in patients with estrogen receptor-positive, HER-2-positive advanced breast cancer: a proof-of-concept trial (SAKK 23/03).

A sequential treatment design was chosen in this trial to ensure complete resistance to single-agent non-steroidal aromatase inhibitor (AI) and trastuzumab both given as monotherapy before receiving the combination of a non-steroidal AI and trastuzumab. Key eligibility criteria included postmenopausal patients with advanced, measurable, human epidermal growth factor receptor-2 (HER-2)-positive disease (assessed by FISH, ratio (≥2)), hormone receptor (HR)-positive disease, and progression on prior treatment with a non-steroidal AI, e.g. letrozole or anastrozole, either in the adjuvant or in the advanced setting. Patients received standard dose trastuzumab monotherapy in step 1 and upon disease progression continued trastuzumab in combination with letrozole in step 2. The primary endpoint was clinical benefit rate (CBR) in step 2. Totally, 13 patients were enrolled. In step 1, six patients (46%) achieved CBR. Median time to progression (TTP) was 161 days (95% confidence interval (CI): 82-281). In step 2, CBR was observed in eight out of the 11 evaluable patients (73%), including one patient with partial response. Median TTP for all the 11 patients was 188 days (95% CI: 77-not reached). Results of this proof-of-concept trial suggest that complete resistance to both AI and trastuzumab can be overcome in a proportion of patients by combined treatment of AI and trastuzumab, as all patients served as their own control. Our results appear promising for a new treatment strategy that offers a chemotherapy-free option for at least a subset of patients with HR-positive, HER-2-positive breast cancer over a clinically relevant time period.

Prospective analysis of KRAS, BRAF, and PIK3CA mutations and EGFR copy number in patients (pts) with locally advanced rectal cancer: A translational substudy of a clinical trial (SAKK 41/07) evaluating the effect of neoadjuvant chemoradiation (CRT) with or without panitumumab

Background: Prognostic and predictive markers are of great importance for future study designs and essential for the interpretation of clinical trials incorporating an EGFR-inhibitor. The current study prospectively assessed and validated KRAS, BRAF and PIK3CA mutations in rectal cancer patients screened for the trial SAKK41/07 of concomitant preoperative radio-chemotherapy with or without panitumumab.Methods: Macrodissection was performed on pretreatment formalin fixed paraffin embedded biopsy tissue sections to arrive at a minimum of 50% of tumor cells. DNA was extracted with the Maxwell 16 FFPE Tissue LEV DNA purification kit. After PCR amplification, mutations were identified by pyrosequencing. We prospectively analysed pretreatment biopsy material from 149 rectal cancer pts biopsies for KRAS (exon 2 codon 12 [2-12] and 13 [2-13], exon 3 codon 59 [3-59]) and 61 [3-61], exon 4 codon 117 [4-117] and 146 [4-146]). Sixty-eight pts (KRASwt exon 2, 3 only) were further analysed for BRAF (exon 15 codon 600) and PIK3CA (exon 9 codon 542, 545 and 546, exon 20 codon 1043 [20-1043] and 1047 [20-1047]) mutations, and EGFR copy number by qPCR. For the calculation of the EGFR copy number, we used KRAS copy number as internal reference standard. The calculation was done on the basis of the two standard curves relative quantification method.Results: In 149 screened pts with rectal cancer, the prevalence of KRAS mutations was 36%. Among the 68 pts enrolled in SAKK 41/07 based on initially presumed KRASwt status (exon 2/codons 12+13), 18 pts (26%) had a total of 23 mutations in the RAS/PIK3CA-pathways upon validation analysis. Twelve pts had a KRAS mutation, 7 pts had a PIK3CA mutation, 3 pts had a NRAS mutation, 1 patient a BRAF mutation. Surprisingly, five of these pts had double- mutations, including 4 pts with KRAS plus PIK3CA mutations, and 1 pt with NRAS plus PIK3CA mutations. The median normalized EGFR copy number was 1. Neither mutations of KRAS, BRAF, and PIK3CA, nor EGFR copy number were statistically associated with the primary study endpoint pCR (pathological complete regression).Conclusions: The prevalence of KRAS mutations in rectal and in colon cancer appears to be similar. BRAF mutations are rare; PIK3CA mutations are more common (10%). EGFR copy number is not increased in rectal cancer. A considerable number or KRAS exon 2 wt tumors harbored KRAS exon 3+4 mutations. Further study is needed to determine if KRAS testing should include exons 2-4.

Correlations between imatinib pharmacokinetics, pharmacodynamics, adherence, and clinical response in advanced metastatic gastrointestinal stromal tumor (GIST): An emerging role for drug blood level testing?

Imatinib is the standard of care for patients with advanced metastatic gastrointestinal stromal tumors (GIST), and is also approved for adjuvant treatment in patients at substantial risk of relapse. Studies have shown that maximizing benefit from imatinib depends on long-term administration at recommended doses. Pharmacokinetic (PK) and pharmacodynamic factors, adherence, and drug-drug interactions can affect exposure to imatinib and impact clinical outcomes. This article reviews the relevance of these factors to imatinib's clinical activity and response in the context of what has been demonstrated in chronic myelogenous leukemia (CML), and in light of new data correlating imatinib exposure to response in patients with GIST. Because of the wide inter-patient variability in drug exposure with imatinib in both CML and GIST, blood level testing (BLT) may play a role in investigating instances of suboptimal response, unusually severe toxicities, drug-drug interactions, and suspected non-adherence. Published clinical data in CML and in GIST were considered, including data from a PK substudy of the B2222 trial correlating imatinib blood levels with clinical responses in patients with GIST. Imatinib trough plasma levels <1100ng/mL were associated with lower rates of objective response and faster development of progressive disease in patients with GIST. These findings have been supported by other analyses correlating free imatinib (unbound) levels with response. These results suggest a future application for imatinib BLT in predicting and optimizing therapeutic response. Nevertheless, early estimates of threshold imatinib blood levels must be confirmed prospectively in future studies and elaborated for different patient subgroups.

Diagnostic Performance of Magnetic Resonance Imaging and Computed Tomography for Advanced Retinoblastoma: A Systematic Review and Meta-analysis.

PURPOSE: To determine and compare the diagnostic performance of magnetic resonance imaging (MRI) and computed tomography (CT) for the diagnosis of tumor extent in advanced retinoblastoma, using histopathologic analysis as the reference standard. DESIGN: Systematic review and meta-analysis. PARTICIPANTS: Patients with advanced retinoblastoma who underwent MRI, CT, or both for the detection of tumor extent from published diagnostic accuracy studies. METHODS: Medline and Embase were searched for literature published through April 2013 assessing the diagnostic performance of MRI, CT, or both in detecting intraorbital and extraorbital tumor extension of retinoblastoma. Diagnostic accuracy data were extracted from included studies. Summary estimates were based on a random effects model. Intrastudy and interstudy heterogeneity were analyzed. MAIN OUTCOME MEASURES: Sensitivity and specificity of MRI and CT in detecting tumor extent. RESULTS: Data of the following tumor-extent parameters were extracted: anterior eye segment involvement and ciliary body, optic nerve, choroidal, and (extra)scleral invasion. Articles on MRI reported results of 591 eyes from 14 studies, and articles on CT yielded 257 eyes from 4 studies. The summary estimates with their 95% confidence intervals (CIs) of the diagnostic accuracy of conventional MRI at detecting postlaminar optic nerve, choroidal, and scleral invasion showed sensitivities of 59% (95% CI, 37%-78%), 74% (95% CI, 52%-88%), and 88% (95% CI, 20%-100%), respectively, and specificities of 94% (95% CI, 84%-98%), 72% (95% CI, 31%-94%), and 99% (95% CI, 86%-100%), respectively. Magnetic resonance imaging with a high (versus a low) image quality showed higher diagnostic accuracies for detection of prelaminar optic nerve and choroidal invasion, but these differences were not statistically significant. Studies reporting the diagnostic accuracy of CT did not provide enough data to perform any meta-analyses. CONCLUSIONS: Magnetic resonance imaging is an important diagnostic tool for the detection of local tumor extent in advanced retinoblastoma, although its diagnostic accuracy shows room for improvement, especially with regard to sensitivity. With only a few-mostly old-studies, there is very little evidence on the diagnostic accuracy of CT, and generally these studies show low diagnostic accuracy. Future studies assessing the role of MRI in clinical decision making in terms of prognostic value for advanced retinoblastoma are needed.

Chimioradiothérapie postopératoire des cancers des voies aérodigestives : vers un nouveau standard [Post-operative radiochemotherapy of the head and neck: Towards new standards?]

Head and neck squamous cell carcinomas are frequently diagnosed at an advanced stage. Their treatment remains controversial, and has to be multidisciplinary. External beam radiotherapy is a recognized treatment option after radical curative surgery in order to improve local control. Different adjuvant treatment options have been studied in order to improve the outcome of these patients. We review in this paper the different prognostic factors indicating an adjuvant treatment and the interest of treatment intensification in bad prognostic patients.

Temporary employment in advanced economies: drawing lessons from Spain

This study analyses the determinants of the rate of temporary employment in various OECD countries using both macro-level data drawn from the OECD and EUROSTAT databases, as well as micro-level data drawn from the 8th wave of the European Household Panel. Comparative analysis is set out to test different explanations originally formulated for the Spanish case. The evidence suggests that the overall distribution of temporary employment in advanced economies does not seem to be explicable by the characteristics of national productive structures. This evidence seems at odds with previous interpretations based on segmentation theories. As an alternative explanation, two types of supply-side factors are tested: crowding-out effects and educational gaps in the workforce. The former seems non significant, whilst the effects of the latter disappear after controlling for the levels of institutional protection in standard employment during the 1980s. Multivariate analysis shows that only this latter institutional variable, together with the degree of coordinated centralisation of the collective bargaining system, seem to have a significant impact on the distribution of temporary employment in the countries examined. On the basis of this observation, an explanation of the very high levels of temporary employment observed in Spain is proposed. This explanation is consistent with both country-specific and comparative evidence.

Introducing systematic dispatcher-assisted cardiopulmonary resuscitation (telephone-CPR) in a non-Advanced Medical Priority Dispatch System (AMPDS): implementation process and costs.

OBJECTIVE: In order to improve the quality of our Emergency Medical Services (EMS), to raise bystander cardiopulmonary resuscitation rates and thereby meet what is becoming a universal standard in terms of quality of emergency services, we decided to implement systematic dispatcher-assisted or telephone-CPR (T-CPR) in our medical dispatch center, a non-Advanced Medical Priority Dispatch System. The aim of this article is to describe the implementation process, costs and results following the introduction of this new "quality" procedure. METHODS: This was a prospective study. Over an 8-week period, our EMS dispatchers were given new procedures to provide T-CPR. We then collected data on all non-traumatic cardiac arrests within our state (Vaud, Switzerland) for the following 12months. For each event, the dispatchers had to record in writing the reason they either ruled out cardiac arrest (CA) or did not propose T-CPR in the event they did suspect CA. All emergency call recordings were reviewed by the medical director of the EMS. The analysis of the recordings and the dispatchers' written explanations were then compared. RESULTS: During the 12-month study period, a total of 497 patients (both adults and children) were identified as having a non-traumatic cardiac arrest. Out of this total, 203 cases were excluded and 294 cases were eligible for T-CPR. Out of these eligible cases, dispatchers proposed T-CPR on 202 occasions (or 69% of eligible cases). They also erroneously proposed T-CPR on 17 occasions when a CA was wrongly identified (false positive). This represents 7.8% of all T-CPR. No costs were incurred to implement our study protocol and procedures. CONCLUSIONS: This study demonstrates it is possible, using a brief campaign of sensitization but without any specific training, to implement systematic dispatcher-assisted cardiopulmonary resuscitation in a non-Advanced Medical Priority Dispatch System such as our EMS that had no prior experience with systematic T-CPR. The results in terms of T-CPR delivery rate and false positive are similar to those found in previous studies. We found our results satisfying the given short time frame of this study. Our results demonstrate that it is possible to improve the quality of emergency services at moderate or even no additional costs and this should be of interest to all EMS that do not presently benefit from using T-CPR procedures. EMS that currently do not offer T-CPR should consider implementing this technique as soon as possible, and we expect our experience may provide answers to those planning to incorporate T-CPR in their daily practice.

Nonanesthesiologist-administered propofol sedation: from the exception to standard practice. Sedation and monitoring trends over 20 years.

The practice of sedation, including monitoring practice for digestive endoscopy, continues to evolve throughout the world. In many countries, including Switzerland, there is a trend towards increased utilization of sedation during both routine and advanced endoscopic procedures. Sedation improves patient satisfaction with endoscopy and also improves the quality of the examination. In addition, a trend can be observed towards an increasing use of propofol as the preferred sedative drug. Here we review the latest published data from surveys describing sedation and monitoring practice in different countries and compare them with our own data from successive nationwide surveys among Swiss gastroenterologists over a period of 20 years. This development between these socioeconomically very similar Western industrialized countries, however, shows some unique and surprising differences. In Germany and Switzerland, propofol use has become increasingly widespread, in Switzerland even to the extent that during the last few years propofol has overtaken benzodiazepine sedation, with an absolute majority of Swiss gastroenterologists using it without the assistance of an anesthesiologist. In addition, the change in Switzerland reflects a successful generalization of nonanesthesiologist-administered propofol (NAAP) sedation from the hospital setting to private practice.

Prediction of difficult intubation with advanced face recognition techniques: a preliminary study

Introduction: Difficult tracheal intubation remains a constant and significant source of morbidity and mortality in anaesthetic practice. Insufficient airway assessment in the preoperative period continues to be a major cause of unanticipated difficult intubation. Although many risk factors have already been identified, preoperative airway evaluation is not always regarded as a standard procedure and the respective weight of each risk factor remains unclear. Moreover the predictive scores available are not sensitive, moderately specific and often operator-dependant. In order to improve the preoperative detection of patients at risk for difficult intubation, we developed a system for automated and objective evaluation of morphologic criteria of the face and neck using video recordings and advanced techniques borrowed from face recognition. Method and results: Frontal video sequences were recorded in 5 healthy volunteers. During the video recording, subjects were requested to perform maximal flexion-extension of the neck and to open wide the mouth with tongue pulled out. A robust and real-time face tracking system was then applied, allowing to automatically identify and map a grid of 55 control points on the face, which were tracked during head motion. These points located important features of the face, such as the eyebrows, the nose, the contours of the eyes and mouth, and the external contours, including the chin. Moreover, based on this face tracking, the orientation of the head could also be estimated at each frame of the video sequence. Thus, we could infer for each frame the pitch angle of the head pose (related to the vertical rotation of the head) and obtain the degree of head extension. Morphological criteria used in the most frequent cited predictive scores were also extracted, such as mouth opening, degree of visibility of the uvula or thyreo-mental distance. Discussion and conclusion: Preliminary results suggest the high feasibility of the technique. The next step will be the application of the same automated and objective evaluation to patients who will undergo tracheal intubation. The difficulties related to intubation will be then correlated to the biometric characteristics of the patients. The objective in mind is to analyze the biometrics data with artificial intelligence algorithms to build a highly sensitive and specific predictive test.

An EORTC phase I itudy of bortezomib in combination with oxaliplatin, leucovorin and 5-fluorouracil in patients with advanced colorectal cancer.

The combination of oxaliplatin, leucovorin and 5-fluorouracil (FOLFOX-4) is still a reference regimen in advanced colorectal cancer; however, the addition of new biologic compounds represents a significant way forward. Bortezomib is an inhibitor of proteasome, a multicatalytic enzyme complex that degrades several intracellular proteins. In this study, escalating doses of Bortezomib were administered along with the standard FOLFOX-4 doses, in order to evaluate the dose-limiting toxicity (DLT), toxicity profile and activity of the combination. Patients with advanced colorectal cancer, unpretreated for metastatic disease, were enroled in the study. Bortezomib starting dose was 1.3mg/m(2), which was to be escalated in the subsequent steps according to the toxicities observed after first cycle. Exploratory pharmacogenetics research was conducted by analysing the association between clinical outcomes and polymorphisms in candidate genes for response to each of the used drugs. Correlation between tumour marker changes and response was also investigated. One mg/m(2) (DL-1) was defined as being the maximum tolerated dose since only 1 DLT was observed in 6 patients. The main toxicities were haematologic, neuropathy, diarrhoea and fatigue. Amongst 13 evaluable patients, five had a partial response, five had a stable disease and three patients progressed. Two patients are long-term survivors after a combined chemosurgical approach. Further trials of the current combination may be justified.

Advanced age increases the failure rate of non-operative management of blunt splenic injuries

Introduction: Non-operative management (NOM) of blunt splenic injuries in hemodynamically stable patients is nowadays considered the standard treatment. Material and Methods: The aim was to clarify the criteria used for primary operative management (OM) and planned NOM. Furthermore, the study aimed to identify risk factors for failure of NOM. All adult patients with blunt splenic injuries treated from 2000-2008 were reviewed and a logistic regression analysis employed. Results: There were 206 patients (146 men, 70.9%). Mean age was 38.2 ± 19.1 years. The mean Injury Severity Score (ISS) was 30.9 ± 11.6. The American Association for the Surgery of Trauma (AAST) classification of the splenic injury was: grade I, n = 43 (20.9%); grade II, n = 52 (25.2%); grade III, n = 60 (29.1%), grade IV, n = 42 (20.4%) and grade V, n = 9 (4.4%). 47 patients (22.8%) required immediate surgery (OM). More than 5 units of red cell transfusions (odds ratio [OR] 13.72, P < 0.001), a Glasgow Coma Scale < 11 (OR 9.88, P = 0.009) and age ? 55 years (OR 3.29, P = 0.038) were associated with primary OM. 159 patients (77.2%) qualified for a non-surgical approach (NOM), which was successful in 89.9% (143/159). The overall splenic salvage rate amounted to 69.4% (143/206). Multiple logistic regression analysis found age ? 40 years to be the only factor significantly and independently related to the failure of NOM (OR 13.58, P = 0.001). Conclusion: Advanced age is associated with an increased failure rate of NOM in patients with blunt splenic injuries.

Radiochemotherapy in locally advanced squamous cell carcinomas of the head and neck.

Squamous cell carcinoma of the head and neck (SCCHN) is a common disease that develops in the upper aerodigestive epithelium. The most important risk factors are tobacco and alcohol consumption. There is also increasing evidence that human papillomavirus plays an important role in the cause of SCCHN. The complex anatomy, the vital functions of the upper aerodigestive tract and the close proximity to vital structures, explain that the goal of treatment is not only to improve survival outcomes, but also to preserve organ function. Radiotherapy and surgery are the standard modalities of treatment, reflecting the locoregional predominance of SCCHN. Chemotherapy plays an important role in the treatment of patients with locoregionally advanced disease, in conjunction with radiotherapy and surgery. Indeed, standard therapy for resectable locoregionally advanced (stage III or IV) SCCHN cancers consists either of surgery and adjuvant chemoradiotherapy or definitive concomitant chemoradiotherapy, depending upon disease site, stage and resectability of the tumour, or institutional experience. Concomitant chemoradiotherapy has been shown in several randomised trials to improve disease-free and overall survival in the postoperative setting for resected disease with poor prognostic factors. Furthermore, multiple randomised studies and meta-analyses have shown that definitive chemoradiotherapy, as well anti-epidermal growth factor receptor treatment in one randomised study, improved disease-free and overall survival when compared with radiotherapy alone. This overview reviews the most relevant published studies on the multidisciplinary management of SCCHN and discusses future strategies to reduce locoregional failures.

Phase II study of imatinib in advanced chordoma.

PURPOSE: To explore the antitumor activity of imatinib in patients with advanced platelet-derived growth factor β (PDGFB)/PDGF receptor β (PDGFRB)-positive chordomas.¦PATIENTS AND METHODS: In a collaborative Italian-Swiss, prospective, phase II clinical study conducted from November 2004 through April 2006, 56 patients with advanced PDGFB and/or PDGFRB chordoma received 800 mg/d of imatinib until progression. The primary end point was the overall tumor response rate (ORR), defined by RECIST. Secondary, exploratory end points included tissue response (ie, changes in tumor density or signal intensity/contrast enhancement, and/or [18F]-fluorodeoxyglucose positron emission tomography [PET] uptake), overall survival, progression-free survival (PFS), and pain score.¦RESULTS: Among 50 patients evaluable by RECIST, the best response was one partial response (PR) obtained at 6 months (ORR, 2%). There were 35 patients with stable disease (SD, 70%) and a 64% clinical benefit rate (ie, RECIST complete response + PR + SD ≥ 6 months). A minor dimensional response (< 20%) was detected in nine patients. A maximum standard uptake value decrease ≥ 25% was observed in 10 (39%) of 26 patients evaluable for PET response at 3 months. Changes in the Brief Pain Inventory score were consistent with the response assessment. Median PFS (intention-to-treat population, 56 patients) was 9 months. No unexpected toxicities were observed.¦CONCLUSION: This is the largest phase II study in chordoma to date. It confirms anecdotal evidence that imatinib has antitumor activity in this orphan disease, and therefore, it is worth further investigation.