Direct comparison between Grade Group assessed on systematic and MRI/ultrasound fusion targeted biopsies correlated to the radical prostatectomy specimens in patients with prostate cancer.

OBJECTIVES: To compare the correlation of Gleason score (GS) and ISUP grade determined by prostate biopsies (PBx) and radical prostatectomy (RP) specimens according to the biopsy technique: ultrasound randomised (RBx) vs. MRI/ultrasound fusion targeted (TBx). MATERIALS AND METHODS: Between March 2013 and June 2018, we retrospectively included patients who underwent RP for prostate cancer (PCa) histopathologically proven by RBx and/or TBx. All patients had a prebiopsy MRI by a single radiologist (using PI-RADS score), then transrectal RBx (12cores, blinded to MRI lesions) and TBx (2-4 cores/target) with elastic MRI/ultrasound fusion (UroStation™, Koelis, Grenoble, France). Histological findings were compared: PBx vs. RP. RESULTS: One hundred and four patients underwent RP after RBx and/or TBx. ISUP concordance rate was better with the association RBx+TBx 49% (51/104) vs. 43.3% with TBx (P=0.07) and 43.3% with RBx (P=0.13). With RBx, 50% of the patients were downgraded (52/104) against 42.3% (44/104) with TBx (P=0.088). The association RBx+TBx significantly decreased the rate of downgrading of the ISUP score compared to the ISUP score of RP 35.6% (37/104) vs. RBx (50%, P=0.0001) and vs. TBx (42.3%, P=0.016). CONCLUSION: In half of cases, the ISUP score was underestimated in RBx compared to RP specimens. Adding TBx to RBx significantly reduced downgrading. The combination of both biopsy techniques appeared to be the best protocol to get closer to ISUP score and GS of the RP specimens. LEVEL OF EVIDENCE: C.

[Morbidity of extended pelvic lymphadenectomy during robot-assisted laparoscopic prostatectomy for localized cancer prostate]. / Morbidité du curage ganglionnaire pelvien étendu au cours de la prostatectomie totale laparoscopique robot assistée.

OBJECTIVES: To assess the morbidity specific of extended pelvic lymphadenectomy during robot-assisted laparoscopic radical prostatectomy in a 8 year retrospective study. MATERIAL: We carried out a single-center, single-surgeon retrospective study on 342 consecutive patients who underwent a robot-assisted laparoscopic radical prostatectomy and extended pelvic lymphadenectomy, from July 2010 to March 2018. Postoperative complications were recorded up to 3 months after the operation. RESULTS: Thirty (8.8%) patients had at least one complication related to lymphadenectomy including 1 vascular injury (0.3%), 7 injuries of the obturator nerve (2%), 5 venous thromboembolic complications (1.5%) including 4 pulmonary embolisms, 10 symptomatic lymphoceles (2.9%) and 8 lymphoedemas (2.3%). Of these complications, 13 were classified Clavien 1 (43.3%), 8 Clavien 2 (26.7%), 7 Clavien 3a (23.3%) and 2 Clavien 3b (6.7%). In univariate analysis a high age (P=0.04), high BMI (P<0.01) and pT stage (P=0.02) were significantly associated with complication whereas in multivariate analysis, only age (P=0.02) and BMI (P<0.01) lived were. In univariate analysis high BMI (P=0.04) and lymph node involvement (P=0.04) were associated with lymphatic complication. We did not find any other specific risk factor for the other complications. CONCLUSION: With 8.8% of overall complications related to lymphadenectomy and 5% of complication classified Clavien grade 2 or higher, extended pelvic lymphadenectomy was not very morbid. Age and BMI were risk factors for a overall complication. BMI and lymph node involvement were risk factors for lymphatic complications. LEVEL OF PROOF: 4.

Overexpression of certain transient receptor potential and Orai channels in prostate cancer is associated with decreased risk of systemic recurrence after radical prostatectomy.

BACKGROUND: Several studies had suggested the potential role of calcium signaling in prostate cancer (PCa) prognosis and agressiveness. We aimed to investigate selected proteins contributing to calcium (Ca2+ ) signaling, (Orai, stromal interaction molecule (STIM), and transient receptor potential (TRP) channels) and involved in cancer hallmarks, as independent predictors of systemic recurrence after radical prostatectomy (RP). METHODS: A case-control study including 112 patients with clinically localized PCa treated by RP between 2002 and 2009 and with at least 6-years' follow-up. Patients were divided into two groups according to the absence or presence of systemic recurrence. Expression levels of 10 proteins involved in Ca2+ signaling (TRPC1, TRPC4, TRPV5, TRPV6, TRPM8, STIM1, STIM2, Orai1, Orai2, and Orai3), were assessed by immunohistochemistry using tissue microarrays (TMAs) constructed from paraffin-embedded PCa specimens. The level of expression of the various transcripts in PCa was assessed using quantitative polymerase chain reaction (qPCR) analysis. RNA samples for qPCR were obtained from fresh frozen tissue samples of PCa after laser capture microdissection on RP specimens. Relative gene expression was analyzed using the 2-▵▵Ct method. RESULTS: Multivariate analysis showed that increased expression of TRPC1, TRPC4, TRPV5, TRPV6, TRPM8, and Orai2 was significantly associated with a lower risk of systemic recurrence after RP, independently of the prostate-specific antigen (PSA) level, percentage of positive biopsies, and surgical margin (SM) status (P = .007, P = .01, P < .001, P = .0065, P = .007, and P = .01, respectively). For TRPC4, TRPV5, and TRPV6, this association was also independent of Gleason score and pT stage. Moreover, overexpression of TRPV6 and Orai2 was significantly associated with longer time to recurrence after RP (P = .048 and .023, respectively). Overexpression of TRPC4, TRPV5, TRPV6, and Orai2 transcripts was observed in group R- (3.71-, 5.7-, 1.14-, and 2.65-fold increase, respectively). CONCLUSIONS: This is the first study to suggest the independent prognostic value of certain proteins involved in Ca2+ influx in systemic recurrence after RP: overexpression of TRPC1, TRPC4, TRPV5, TRPV6, TRPM8, and Orai2 is associated with a lower risk of systemic recurrence. TRPC4, TRPV5, and TRPV6 appear to be particularly interesting, as they are independent of the five commonly used predictive factors, that is, PSA, percentage of positive biopsies, SM status, Gleason score, and pT stage.

Comprehensive molecular classification of localized prostate adenocarcinoma reveals a tumour subtype predictive of non-aggressive disease.

Background: Management of localized prostate cancer (PCa) is a major clinical challenge since most of these cancers would not evolve but a majority of patients will still undergo a life-changing radical surgery. Molecular studies have shown that PCa can be classified according to their genomic alterations but none of the published PCa molecular classifications could identify a subtype corresponding to non-evolutive tumours. Materials and methods: Multi-omics molecular profiling was carried out on post-radical prostatectomy material from a cohort of 130 patients with localized PCa. We used unsupervised classification techniques to build a comprehensive classification of prostate tumours based on three molecular levels: DNA copy number, DNA methylation, and mRNA expression. Merged data from our cohort and The Cancer Genome Atlas cohort were used to characterize the resulting tumour subtypes. We measured subtype-associated risks of biochemical relapse using Cox regression models and survival data from five cohorts including the two aforementioned. Results: We describe three PCa molecular subtypes associated with specific molecular characteristics and different clinical outcomes. Particularly, one subtype was strongly associated with the absence of biochemical recurrence. We validated this finding on 746 samples from 5 distinct cohorts (P = 3.41 × 10-8, N = 746 tumour samples), and showed that our subtyping approach outperformed the most popular prognostic molecular signatures to accurately identify a subset of patients with a non-evolutive disease. We provide a set of 36 transcriptomic biomarkers to robustly identify this subtype of non-evolutive cases whose prevalence was estimated to 22% of all localized PCa tumours. Conclusion: At least 20% of patients with localized PCa can be accurately predicted to have a non-evolutive disease on the basis of their molecular subtype. Those patients should not undergo immediate surgery and rather be placed under active surveillance.

Effect of an Early Switch to Belatacept Among Calcineurin Inhibitor-Intolerant Graft Recipients of Kidneys From Extended-Criteria Donors.

Transplant recipients receiving a kidney from an extended-criteria donor (ECD) are exposed to calcineurin inhibitor (CNI) nephrotoxicity, as demonstrated by severe delayed graft function and/or a low GFR. Belatacept is a nonnephrotoxic drug that is indicated as an alternative to CNIs. We reported 25 cases of conversion from a CNI to belatacept due to CNI intolerance within the first 6 mo after transplantation. The mean age of the recipients was 59 years, and 24 of 25 patients received ECD kidneys. At the date of the medication switch, 12 of 25 patients displayed a calculated GFR (cGFR) <15 mL/min, six patients remained on dialysis, and the biopsies showed evidence of acute tubular damage associated with severe vascular or tubulointerstitial chronic lesions. Three patients did not recover renal function, and three patients died during the follow-up period. Among the remaining patients, renal function improved: The cGFR was 18.28 ± 12.3 mL/min before the medication switch compared with 34.9 ± 14.5 mL/min at 1 year after conversion to belatacept (p = 0.002). Tolerance of and compliance with belatacept were good, and only one patient experienced acute rejection. Belatacept is an effective therapy that preserves renal function in kidney transplant patients who are intolerant of CNIs.

[Comparison of the morbidity between limited and extended pelvic lymphadenectomy during laparoscopic radical prostatectomy]. / Comparaison de la morbidité entre curage étendu et curage limité au cours de la prostatectomie radicale laparoscopique.

OBJECTIVE: To compare the morbidity of limited pelvic lymphadenectomy to extended lymphadenectomy in patients undergoing LRP (Laparoscopic Radical Prostatectomy) for clinically localized prostate cancer. PATIENTS AND METHODS: We performed a prospective monocentric study focused on 303 consecutive patients having a pelvic lymphadenectomy during LRP from June 2000 to April 2010. One hundred and seventy six patients had a limited pelvic lymphadenectomy (June 2000-June 2006, group 1). One hundred and twenty seven patients had an extended pelvis lymphadenectomy (June 2006-April 2010, group 2) including two sub-groups according to the lateral limit of the procedure i.e. with (group 2a, 60 patients) or without dissection of the lateral side of the iliac artery (group 2b, 67 patients). RESULTS: Preoperative data (age, BMI, cTNM, Gleason score and PSA) were comparable between the groups. The number of lymph nodes and the incidence of metastatic lymph nodes were lower in group 1 (6,7 lymph nodes and 5,7%) compared to group 2 (a+b) (15.6 lymph nodes and 18.9%) (P=0.001 and P=0.0004). However, there was no difference between groups 2a and 2b (15.4 and 16.7% vs 15,8 and 20.8% P=0.65 respectively). There were more complications in the extended lymphadenectomy group compared to the limited procedure (35.4% vs 14.2%, P=0.0001), in particular more lymphatic complications (27.5% vs 10.2% P=0.0001) and lymphoedema (LO) (15.7% vs 0.6% P=0.00001). However the lymphorhea (LR) and lymphocele (LC) rate was not different (P=0.11 and P=0.17). All complications were mainly of low Clavien's classification grade (1+2) whatever the group of lymphadenectomy. The hospital stay was not increased in group 2a or 2b in regard to group 1. The rate of LR and LC was higher in group 2a than in group 1 (P=0.02 and P=0.05) but not between group 2b and 1 (P=0.81 and P=0.47). CONCLUSION: Our study showed a higher rate of complications after extended pelvic lymphadenectomy but of low grade in most cases. Moreover the lateral dissection sparing the lateral side of the iliac artery reduced the risk of lymphatic complications without decreasing the number of lymph nodes removed and the rate of metastasis.

Which protocol for prostate biopsies in patients with a positive MRI? Interest of systematic biopsies by sectors.

BACKGROUND: Current prostate biopsy (PBx) protocol for prostate cancer (PCa) diagnosis is to perform systematic biopsies (SBx) combined with targeted biopsies (TBx) in case of positive MRI (i.e. PI-RADS ≥ 3). To assess the utility of performing SBx in combination with TBx, we determined the added value of SBx brought to the diagnosis of PCa according to their sextant location and MRI target characteristics. METHODS: In our local prospectively collected database, we conducted a single-center retrospective study including all patients with a suspicion of PCa, who underwent transrectal ultrasound-guided (TRUS) prostate biopsies (PBx) with a prior MRI and a single lesion classified as PI-RADS ≥ 3. We have characterized the SBx according to their location on MRI: same sextant (S-SBx), adjacent sextant (A-SBx), ipsilateral side (I-SBx) and contralateral side (C-SBx). The added value of SBx and TBx was defined as any upgrading to significant PCa (csPCa) (ISUP ≥2). RESULTS: 371 patients were included in the study. The added value of SBx was 10% overall. Regarding the lesion location and the SBx sextant, the added value of SBx was: 5.1% for S-SBx, 5.4% for A-SBx, 4.9% for I-SBx and 1.9% for C-SBx. The overall added value of SBx was 6.8% for PI-RADS 3 lesions, 14% for PI-RADS 4 lesions and 6.7% for PI-RADS 5 lesions (p = 0.063). The added value of SBx for contralateral side was 1.9% (2/103), 3.1% (5/163) and 0% (0/105) for PI-RADS 3, PI-RADS 4 and PI-RADS 5 lesions, respectively (p = 0,4). The added value of SBx was lower when the number of TBx was higher (OR 0.57; CI 95% 0.37-0.85; p = 0.007). CONCLUSIONS: Our results suggest that the utility of performing SBx in the contralateral lobe toward the MRI lesion was very low, supporting that they might be avoided.

Association between post-operative hPG80 (circulating progastrin) detectable level and worse prognosis in glioblastoma.

BACKGROUND: Patients with glioblastomas have a dismal prognosis, and there is no circulating predictive or prognostic biomarker. Circulating progastrin, hPG80, is a tumor-promoting peptide present in the blood of patients with various cancers that has been shown to have prognostic value. We evaluated the prognostic value of plasma hPG80 in patients with isocitrate dehydrogenase-wild type glioblastoma after surgery. PATIENTS AND METHODS: A multicentric retrospective study in glioblastoma patients treated with standard radio-chemotherapy was conducted. The hPG80 levels were measured in plasma EDTA samples collected after surgery with an ELISA DxPG80.lab kit (Biodena Care, Montpellier, France), which has a detection threshold of 1.2 pM. The relationship between post-operative hPG80 plasma levels, in combination with other known prognostic factors, and patients' progression-free survival (PFS) and overall survival (OS) was evaluated. RESULTS: Sixty-nine patients were assessable. Plasma samples were collected after tumor biopsy (B), partial resection (PR), and complete resection (CR) for 22, 25, and 22 patients, respectively. At a median concentration of 5.37 pM (interquartile range 0.00-13.90 pM), hPG80 was detected in 48 (70%) patients (hPG80+). CR was associated with significant lower values of hPG80 levels: the median value was 0.7 versus 9.1 pM for PR (P = 0.02) and 8.3 pM for B (P = 0.004). The hPG80 detection rate was also significantly lower: 50% (CR) versus 72% (PR) versus 86% (B) (P = 0.005). The median follow-up was 39 months [22.4 months-not reached]. hPG80 post-operative detection was associated with numerically shorter PFS (6.4 versus 9.4 months, P = 0.13) and OS (14.5 versus 20.9 months, P = 0.11). In multivariate analysis, hPG80 was a prognostic factor for OS (P = 0.034). CONCLUSIONS: Circulating hPG80 could serve as a new prognostic biomarker after surgery in patients with glioblastoma treated with radio-chemotherapy.

[Urinary continence following laparoscopic radical prostatectomy: qualitative analysis]. / Étude qualitative de la continence urinaire après prostatectomie radicale laparoscopique.

PURPOSE: The main purpose of this study was to report urinary continence after laparoscopic radical prostatectomy (LRP) for localised prostate cancer and the return to baseline rate for urinary continence. The minor purpose was to determine the risk factors, which influence return to baseline urinary continence after radical prostatectomy. METHODS: Prospective evaluation of urinary continence with self-administered questionnaire in 300 consecutive LRP for localized prostate cancer. RESULTS: After LRP, at 3, 6 and 12 months, respectively 12.5%, 23% and 33.7% of patients recover baseline urinary continence. Fifty-four percent, 72.3% and 78.4% of patients did not wear pads 3, 6 and 12 months after LRP. In patients without pad, 43 % recovered baseline continence one year after radical prostatectomy. In univariate analysis, age older than 60 years (P=0.003, P=0.003, P=0.02, 3, 6 and 12 months after LRP) and no sparing of neurovascular bundles (P=0.01, P=0.08 at 3 and 6 months after LRP) were risks factors of urinary incontinence. In multivariate analysis, only age older than 60 years (P=0.018, P=0.01 and P=0.01 at 3, 6 and 12 months after LRP) was a risk factor of urinary incontinence. CONCLUSION: One year after LRP, 66.3% of patients had urinary incontinence according to our evaluation using stringent criteria, i.e. return to baseline continence status. However, only 21.6% of patients wore pads and less than 2% wore more than two pads per day.

Early crustal processes revealed by the ejection site of the oldest martian meteorite.

The formation and differentiation of the crust of Mars in the first tens of millions of years after its accretion can only be deciphered from incredibly limited records. The martian breccia NWA 7034 and its paired stones is one of them. This meteorite contains the oldest martian igneous material ever dated: ~4.5 Ga old. However, its source and geological context have so far remained unknown. Here, we show that the meteorite was ejected 5-10 Ma ago from the north-east of the Terra Cimmeria-Sirenum province, in the southern hemisphere of Mars. More specifically, the breccia belongs to the ejecta deposits of the Khujirt crater formed 1.5 Ga ago, and it was ejected as a result of the formation of the Karratha crater 5-10 Ma ago. Our findings demonstrate that the Terra Cimmeria-Sirenum province is a relic of the differentiated primordial martian crust, formed shortly after the accretion of the planet, and that it constitutes a unique record of early crustal processes. This province is an ideal landing site for future missions aiming to unravel the first tens of millions of years of the history of Mars and, by extension, of all terrestrial planets, including the Earth.

The Tharsis mantle source of depleted shergottites revealed by 90 million impact craters.

The only martian rock samples on Earth are meteorites ejected from the surface of Mars by asteroid impacts. The locations and geological contexts of the launch sites are currently unknown. Determining the impact locations is essential to unravel the relations between the evolution of the martian interior and its surface. Here we adapt a Crater Detection Algorithm that compile a database of 90 million impact craters, allowing to determine the potential launch position of these meteorites through the observation of secondary crater fields. We show that Tooting and 09-000015 craters, both located in the Tharsis volcanic province, are the most likely source of the depleted shergottites ejected 1.1 million year ago. This implies that a major thermal anomaly deeply rooted in the mantle under Tharsis was active over most of the geological history of the planet, and has sampled a depleted mantle, that has retained until recently geochemical signatures of Mars' early history.

Management of cancer-related thrombosis in the era of direct oral anticoagulants: A comprehensive review of the 2019 ITAC-CME clinical practice guidelines. On behalf of the Groupe Francophone Thrombose et Cancer (GFTC).

Venous thromboembolism (VTE) is a common disease complication in cancer patients and the second cause of death after cancer progression. VTE management and prophylaxis are critical in cancer patients, but effective therapy can be challenging because these patients are at higher risk of VTE recurrence and bleeding under anticoagulant treatment. Numerous published studies report inconsistent implementation of existing evidence-based clinical practice guidelines (CPG), including underutilization of thromboprophylaxis, and wide variability in clinical practice patterns across different countries and various practitioners. This review aims to summarize the 2019 ITAC-CME evidence-based CPGs for treatment and prophylaxis of cancer-related VTE, which include recommendations on the use of direct oral anticoagulants specifically in cancer patients. The guidelines underscore the gravity of developing VTE in cancer and recommend the best approaches for treating and preventing cancer-associated VTE, while minimizing unnecessary or over-treatment. Greater adherence to the 2019 ITAC guidelines could substantially decrease the burden of VTE and improve survival of cancer patients.

Nivolumab-refractory patients with advanced non-small-cell lung cancer.

INTRODUCTION: Immune checkpoint inhibitors (ICIs) have revolutionised cancer care especially in lung cancer. New response patterns have been described under ICIs such as pseudo-progression or hyper-progressive disease (HPD). The definition of HPD is yet to be consensual. The aim of this study was to suggest a clinical definition of nivolumab-refractory patients and find factors associated with this entity. METHODS: We performed a multi centric retrospective study including all patients who received nivolumab for the treatment of advanced non-small cell lung cancer (NSCLC) during the French authorisation for temporary use in 2015. RESULTS: 303 patients were included in the cohort and 292 had details on the number of nivolumab injections received. 57 patients (20%) were nivolumab-refractory. These patients had worse PS at nivolumab initiation (p < 0.0001), shorter duration of treatment before nivolumab (p = 0.028) and had dramatically shorter nivolumab overall survival (p < 0.0001) than patients who did not present with refractory disease. CONCLUSION: Nivolumab-refractory disease can affect up to 20% of patients treated with nivolumab for advanced NSCLC with dramatically shortened survival rates. Further studies are needed to understand the precise mechanisms leading to refractory disease as well as its management.

Contribution of plasmid DNA to hepatotoxicity after systemic administration of lipoplexes.

Several studies have demonstrated that intravenous administration of DNA complexed with cationic lipid vectors induces the production of large quantities of proinflammatory cytokines. In this study we confirm these observations, using cationic lipid DOTAP and cationic phospholipid compounds. Moreover, we demonstrate that although intravenous administration of lipid-DNA complexes does not induce toxic effects in the lung, high transgene expression in lung correlates with histopathological lesions in liver, this fact being documented by high transaminase levels in serum of treated mice. We examine the contribution of various components of the lipoplexes in this observed liver toxicity, as well as in the increasing level of transaminases, and more particularly the role of nonmethylated CpG sequences of plasmid DNA. We show that blood samples from animals treated either with cationic lipid alone, or with cationic lipid complexed with methylated plasmid DNA, contain low levels of transaminases. The significant decrease in transaminase levels after injection of cationic lipid-methylated pDNA complexes leads us to believe that nonmethylated CpG sequences could play a major role in this hepatoxicity. Similar results were observed when using a vector that did not encode a transgene, demonstrating that the expression of luciferase in lung was not responsible for this liver toxicity. All these observations suggest that significant work should be devoted to understand more clearly the mechanism of cationic lipid-DNA complex toxicity, and to overcome the problems subsequent to administration of non-methylated CpG sequences of plasmid DNA.

Radioimmunoassay of a new angiotensin-converting enzyme inhibitor (perindopril) in human plasma and urine: advantages of coupling anion-exchange column chromatography with radioimmunoassay.

Perindopril (P) is a prodrug whose active metabolite perindoprilat (PT) is an antihypertensive agent which acts by inhibition of angiotensin-converting enzyme (ACE). Anti-PT antiserum was produced in a rabbit immunized against PT that was covalently linked to bovine serum albumin. The radioligand is an iodinated (125I) derivative of PT-glycyltyrosinamide. Both the drug (PT) and the prodrug (P) are assayed in the same sample; PT is assayed as is and P is assayed after quantitative alkaline hydrolysis into PT. Certain data obtained from such assays suggest the occurrence in plasma and urine of a third immunoreactive component. A chromatographic fractionation of samples allowed us to isolate a new immunoreactive metabolite which was further identified as a glucuronide of PT (PT-G). Therefore, the whole assay was carried out as follows: biological samples were fractionated by stepwise chromatography on a anion-exchange resin (the first fraction contained P, the second contained PT, and the third contained PT-G); and RIA was performed on fractions 2 and 3 as is, and on fraction 1 after alkaline hydrolysis. Performances and assessments of this method are presented together with an example of a pharmacokinetic profile.

Frequencies of KIT and PDGFRA mutations in the MolecGIST prospective population-based study differ from those of advanced GISTs.

Gastrointestinal stromal tumors (GISTs) are the most common human sarcoma. Most of the data available on GISTs derive from retrospective studies of patients referred to oncology centers. The MolecGIST study sought to determine and correlate clinicopathological and molecular characteristics of GISTs. Tumor samples and clinical records were prospectively obtained and reviewed for patients diagnosed in France during a 24-month period. Five hundred and ninety-six patients were included, of whom 10% had synchronous metastases. GISTs originated from the stomach, small bowel or other site in 56.4, 30.2 and 13.4% of cases, respectively. The main prognostic markers, tumor localization, size and mitotic index were not independent variables (P < 0.0001). Mutational status was determined in 492 (83%) patients, and 138 different mutations were identified. KIT and PDGFRA mutations were detected in 348 (71%) and 74 (15%) patients, respectively, contrasting with 82.8 and 2.1% in patients with advanced GIST (MetaGIST) (P < 0.0001). Further comparison of localized GISTs in the MolecGIST cohort with advanced GISTs from previous clinical trials showed that the mutations of PDGFRA exon18 (D842V and others) as well as KIT exon11 substitutions (W557R and V559D) were more likely to be seen in patients with localized GISTs (odds ratio 7.9, 3.1, 2.7 and 2.5, respectively), while KIT exon 9 502_503dup and KIT exon 11 557_559del were more frequent in metastatic GISTs (odds ratio of 0.3 and 0.5, respectively). These data suggest that KIT and PDGFRA mutations and standardized mitotic count deserve to be investigated to evaluate the relapse risk of GISTs.