Bendifallah S., Canlorbe G., Laas E., Huguet F., Coutant C., Hudry D., Graesslin O., Raimond E., Touboul C., Collinet P., Cortez A., Bleu G., Daraï E., Ballester M.   A Predictive Model Using Histopathologic Characteristics of Early-Stage Type 1 Endometrial Cancer to Identify Patients at High Risk for Lymph Node Metastasis.  Ann. Surg. Oncol..  2015 ;22 :4224-4232

BACKGROUND: This study aimed to develop a predictive model using histopathologic characteristics of early-stage type 1 endometrial cancer (EC) to identify patients at high risk for lymph node (LN) metastases. METHODS: The data of 523 patients who received primary surgical treatment between January 2001 and December 2012 were abstracted from a prospective multicenter database (training set). A multivariate logistic regression analysis of selected prognostic features was performed to develop a nomogram predicting LN metastases. To assess its accuracy, an internal validation technique with a bootstrap approach was adopted. The optimal threshold in terms of clinical utility, sensitivity, specificity, negative predictive values (NPVs), and positive predictive values (PPVs) was evaluated by the receiver-operating characteristics (ROC) curve area and the Youden Index. RESULTS: Overall, the LN metastasis rate was 12.4 % (65/523). Lymph node metastases were associated with histologic grade, tumor diameter, depth of myometrial invasion, and lymphovascular space involvement status. These variables were included in the nomogram. Discrimination of the model was 0.83 [95 % confidence interval (CI) 0.80-0.85] in the training set. The area under the curve ROC for predicting LN metastases after internal validation was 0.82 (95 % CI 0.80-0.84). The Youden Index provided a value of 0.2, corresponding to a cutoff of 140 points (total score in the algorithm). At this threshold, the model had a sensitivity of 0.73 (95 % CI 0.62-0.83), a specificity of 0.84 (95 % CI 0.82-0.85), a PPV of 0.40 (95 % CI 0.34-0.45), and an NPV of 0.95 (95 % CI 0.94-0.97). CONCLUSION: The results show that the risk of LN metastases can be predicted correctly so that patients at high risk can benefit from adapted surgical treatment.

Bendifallah S., Canlorbe G., Collinet P., Arsene E., Huguet F., Coutant C., Hudry D., Graesslin O., Raimond E., Touboul C., Darai E., Ballester M.   Just how accurate are the major risk stratification systems for early-stage endometrial cancer?.  Br. J. Cancer.  2015 ;112 :793-801

BACKGROUND: To compare the accuracy of five major risk stratification systems (RSS) in classifying the risk of recurrence and nodal metastases in early-stage endometrial cancer (EC). METHODS: Data of 553 patients with early-stage EC were abstracted from a prospective multicentre database between January 2001 and December 2012. The following RSS were identified in a PubMed literature search and included the Post Operative Radiation Therapy in Endometrial Carcinoma (PORTEC-1), the Gynecologic Oncology Group (GOG)-99, the Survival effect of para-aortic lymphadenectomy (SEPAL), the ESMO and the ESMO-modified classifications. The accuracy of each RSS was evaluated in terms of recurrence-free survival (RFS) and nodal metastases according to discrimination. RESULTS: Overall, the ESMO -modified RSS provided the highest discrimination for both RFS and for nodal metastases with a concordance index (C-index) of 0.73 (95% CI, 0.70-0.76) and an area under the curve (AUC) of 0.80 (0.78-0.72), respectively. The other RSS performed as follows: the PORTEC1, GOG-99, SEPAL, ESMO classifications gave a C-index of 0.68 (0.66-0.70), 0.65 (0.63-0.67), 0.66 (0.63-0.69), 0.71 (0.68-0.74), respectively, for RFS and an AUC of 0.69 (0.66-0.72), 0.69 (0.67-0.71), 0.68 (0.66-0.70), 0.70 (0.68-0.72), respectively, for node metastases. CONCLUSIONS: None of the five major RSS showed high accuracy in stratifying the risk of recurrence or nodal metastases in patients with early-stage EC, although the ESMO-modified classification emerged as having the highest power of discrimination for both parameters. Therefore, there is a need to revisit existing RSS using additional tools such as biological markers to better stratify risk for these patients.

Bendifallah S., Canlorbe G., Arsène E., Collinet P., Huguet F., Coutant C., Hudry D., Graesslin O., Raimond E., Touboul C., Daraï E., Ballester M.   French Multicenter Study Evaluating the Risk of Lymph Node Metastases in Early-Stage Endometrial Cancer: Contribution of a Risk Scoring System.  Ann. Surg. Oncol..  2015 ;22 :2722-2728

BACKGROUND: This study was designed to develop a risk scoring system (RSS) for predicting lymph node (LN) metastases in patients with early-stage endometrial cancer (EC). METHODS: Data of 457 patients with early-stage EC who received primary surgical treatment between January 2001 and December 2012 were abstracted from a prospective, multicentre database (training set). A risk model based on factors impacting LN metastases was developed. To assess the discrimination of the RSS, both internal by the bootstrap approach and external validation (validation set) were adopted. RESULTS: Overall the LN metastasis rate was 11.8 % (54/457). LN metastases were associated with five variables: age >/=60 years, histological grade 3 and/or type 2, primary tumor diameter >/=1.5 cm, depth of myometrial invasion >/=50 %, and the positive lymphovascular space involvement status. These variables were included in the RSS and assigned scores ranging from 0 to 9. The discrimination of the RSS was 0.81 [95 % confidence interval (CI) 0.78-0.84] in the training set. The area under the curve of the receiver-operating characteristics for predicting LN metastases after internal and external validation was 0.80 (95 % CI 0.77-0.83) and 0.85 (95 % CI 0.81-0.89), respectively. A total score of 6 points corresponded to the optimal threshold of the RSS with a rate of LN metastases of 7.5 % (29/385) and 34.7 % (25/72) for low-risk (6 points), respectively. At this threshold, the diagnostic accuracy was 83 %. CONCLUSIONS: This RSS could be useful in clinical practice to determine which patients with early-stage EC should benefit from secondary surgical staging including complete lymphadenectomy.

Bechet D., Auger F., Couleaud P., Marty E., Ravasi L., Durieux N., Bonnet C., Plenat F., Frochot C., Mordon S., Tillement O., Vanderesse R., Lux F., Perriat P., Guillemin F., Barberi-Heyob M.   Multifunctional ultrasmall nanoplatforms for vascular-targeted interstitial photodynamic therapy of brain tumors guided by real-time MRI.  Nanomed.-Nanotechnol. Biol. Med..  2015 ;11 :657-670

Photodynamic therapy (PDT) for brain tumors appears to be complementary to conventional treatments. A number of studies show the major role of the vascular effect in the tumor eradication by PDT. For interstitial PDT (iPDT) of brain tumors guided by real-time imaging, multifunctional nanoparticles consisting of a surface-localized tumor vasculature targeting neuropilin-1 (NRP-1) peptide and encapsulated photosensitizer and magnetic resonance imaging (MRI) contrast agents, have been designed. Nanoplatforms confer photosensitivity to cells and demonstrate a molecular affinity to NRP-1. Intravenous injection into rats bearing intracranial glioma exhibited a dynamic contrast-enhanced MRI for angiogenic endothelial cells lining the neovessels mainly located in the peripheral tumor. By using MRI completed by NRP-1 protein expression of the tumor and brain adjacent to tumor tissues, we checked the selectivity of the nanoparticles. This study represents the first in vivo proof of concept of closed-head iPDT guided by real-time MRI using targeted ultrasmall nanoplatforms. From the clinical editor: The authors constructed tumor vascular peptide targeting multifunctional silica-based nanoparticles, with encapsulated gadolinium oxide as MRI contrast agent and chlorin as a photosensitizer, as a proof of concept novel treatment for glioblastoma in an animal model.

Bayoud Y., de la Taille A., Ouzzane A., Ploussard G., Allory Y., Yiou R., Vordos D., Hoznek A., Salomon L.   International Prostate Symptom Score is a predictive factor of lower urinary tract symptoms after radical prostatectomy.  Int. J. Urol..  2015 ;22 :283-287

OBJECTIVE: To evaluate the impact of radical prostatectomy on lower urinary tract symptoms by using the International Prostate Symptom Score and International Prostate Symptom Score quality of life. METHODS: The present prospective study comprised 804 patients having localized prostate cancer who underwent radical prostatectomy. International Prostate Symptom Score and International Prostate Symptom Score quality of life were recorded preoperatively, and at 1, 3, 6, 12 and 24 months. Two study groups were considered: group 1 included patients with International Prostate Symptom Score /=8 (moderate to severe). Student's t-test and logistic regression were carried out to detect a predictive factor of International Prostate Symptom Score /=8 at 24 months, 15 of them (32%) having a QoL score >/=3. CONCLUSIONS: The present study shows the beneficial impact of radical prostatectomy on lower urinary tract symptoms. However, a proportion of patients with a baseline International Prostate Symptom Score >/=8 maintain the same score at 24 months, with worsening in quality of life score in one-third of them.

Basset-Seguin N., Hauschild A., Grob J. J., Kunstfeld R., Dreno B., Mortier L., Ascierto P. A., Licitra L., Dutriaux C., Thomas L., Jouary T., Meyer N., Guillot B., Dummer R., Fife K., Ernst D. S., Williams S., Fittipaldo A., Xynos I., Hansson J.   Vismodegib in patients with advanced basal cell carcinoma (STEVIE): a pre-planned interim analysis of an international, open-label trial.  Lancet Oncol..  2015 ;16 :729-736

BACKGROUND: The Hedgehog pathway inhibitor vismodegib has shown clinical benefit in patients with advanced basal cell carcinoma and is approved for treatment of patients with advanced basal cell carcinoma for whom surgery is inappropriate. STEVIE was designed to assess the safety of vismodegib in a situation similar to routine practice, with a long follow-up. METHODS: In this multicentre, open-label trial, adult patients with histologically confirmed locally advanced basal cell carcinoma or metastatic basal cell carcinoma were recruited from regional referral centres or specialist clinics. Eligible patients were aged 18 years or older with an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, and adequate organ function. Patients with locally advanced basal cell carcinoma had to have been deemed ineligible for surgery. All patients received 150 mg oral vismodegib capsules once a day on a continuous basis in 28-day cycles. The primary objective was safety (incidence of adverse events until disease progression or unacceptable toxic effects), with assessments on day 1 of each treatment cycle (28 days) by principal investigator and coinvestigators at the site. Efficacy variables were assessed as secondary endpoints. The safety evaluable population included all patients who received at least one dose of study drug. Patients with histologically confirmed basal cell carcinoma who received at least one dose of study drug were included in the efficacy analysis. An interim analysis was pre-planned after 500 patients achieved 1 year of follow-up. This trial is registered with, number NCT01367665. The study is still ongoing. FINDINGS: Between June 30, 2011, and Nov 6, 2014, we enrolled 1227 patients. At clinical cutoff (Nov 6, 2013), 499 patients (468 with locally advanced basal cell carcinoma and 31 with metastatic basal cell carcinoma) had received study drug and had the potential to be followed up for 12 months or longer. Treatment was discontinued in 400 (80%) patients; 180 (36%) had adverse events, 70 (14%) had progressive disease, and 51 (10%) requested to stop treatment. Median duration of vismodegib exposure was 36.4 weeks (IQR 17.7-62.0). Adverse events happened in 491 (98%) patients; the most common were muscle spasms (317 [64%]), alopecia (307 [62%]), dysgeusia (269 [54%]), weight loss (162 [33%]), asthenia (141 [28%]), decreased appetite (126 [25%]), ageusia (112 [22%]), diarrhoea (83 [17%]), nausea (80 [16%]), and fatigue (80 [16%]). Most adverse events were grade 1 or 2. We recorded serious adverse events in 108 (22%) of 499 patients. Of the 31 patients who died, 21 were the result of adverse events. As assessed by investigators, 302 (66.7%, 62.1-71.0) of 453 patients with locally advanced basal cell carcinoma had an overall response (153 complete responses and 149 partial responses); 11 (37.9%; 20.7-57.7) of 29 patients with metastatic basal cell carcinoma had an overall response (two complete responses, nine partial responses). INTERPRETATION: This study assessed the use of vismodegib in a setting representative of routine clinical practice for patients with advanced basal cell carcinoma. Our results show that treatment with vismodegib adds a novel therapeutic modality from which patients with advanced basal cell carcinoma can benefit substantially. FUNDING: F Hoffmann-La Roche.

Balossier A., Blond S., Touzet G., Sarrazin T., Lartigau E., Reyns N.   Role of radiosurgery in the management of pineal region tumours: indications, method, outcome.  Neurochirurgie.  2015 ;61 :216-222

Numerous tumour types can occur in the pineal region. Because these tumours are uncommon and heterogeneous, it is often difficult to establish optimal treatment strategies based on comparative clinical trials. To date, the role of radiosurgery for the treatment of pineal region tumours remains controversial. This report of a 10-year single-department experience and review of the literature focuses on the spectrum of pathologic features found in these pineal parenchymal tumours and on the interest of radiosurgery in their management. Considering pineocytomas, although these tumours have been considered to be radioresistant to fractionated radiotherapy, our results are in agreement with similar results reported in the literature in suggesting that radiosurgery may be an alternative to surgical resection or an adjuvant therapy when the resection is not optimal. When dissemination occurs after radiosurgery, however, craniospinal radiation and chemotherapy are necessary. Radiosurgery has also proven its interest in the treatment of germinomas as an alternative to encephalic radiotherapy with limited long-term damage. Regarding the other pathologies, radiosurgery can be considered as part of a multimodal treatment including surgery, chemo-radiotherapy and its role still has to be clearly defined.

Balossier A., Blond S., Touzet G., Lefranc M., de St-Denis T., Maurage C. A., Reyns N.   Endoscopic versus stereotactic procedure for pineal tumour biopsies: Comparative review of the literature and learning from a 25-year experience.  Neurochirurgie.  2015 ;61 :146-154

BACKGROUND AND PURPOSE: Pineal tumours account for 1% to 4% of brain tumours in adults and for around 10% in children. Except in a few cases where germ cell markers are elevated, accurate histological samples are mandatory to initiate the treatment. Open surgery still has a high morbidity and is often needless. Biopsies can either be obtained by endoscopic or stereotactic procedures. METHODS: Following an extensive review of the literature (PubMed 1970-2013; keywords pineal tumour, biopsy; English and French), 33 studies were analysed and relevant data compared regarding the type of procedure, diagnosis rate, cerebrospinal fluid diversion type and rate, perioperative mortality, morbidity. RESULTS: Endoscopic and stereotactic biopsies showed a diagnosis rate of 81.1% (20%-100%) and 93.7% (82%-100%), respectively. Endoscopic biopsies involved 21.0% of minor and 2.0% of major complications whereas stereotactic biopsies involved 6.4% of minor and 1.6% of major complications. The most frequently reported complication was haemorrhage for both endoscopic and stereotactic procedures, accounting for 4.8% and 4.3%, respectively. Mortality rate was low for both endoscopic and stereotactic procedures, equal to 0.4% and 1.3%, respectively. Local experience of stereotactic biopsies was also reported and corroborated the previous data. CONCLUSIONS: The difference between both procedures is not statistically significant (p>0.05) across large series (>/=20patients). Nevertheless, tissue diagnosis appears less accurate with endoscopic procedures than with stereotactic procedures (81.1% versus 93.7%, weighted mean across all series). In our opinion, the neuroendoscopic approach is the best tool for managing hydrocephalus, whereas stereotactic biopsies remain the best way to obtain a tissue diagnosis with accuracy and low morbidity.

Azzouzi A. R., Barret E., Bennet J., Moore C., Taneja S., Muir G., Villers A., Coleman J., Allen C., Scherz A., Emberton M.   TOOKAD (R) Soluble focal therapy: pooled analysis of three phase II studies assessing the minimally invasive ablation of localized prostate cancer.  World J. Urol..  2015 ;33 :945-953

PURPOSE: To evaluate the 6-month effects of the recommended drug and light dosage in focal vascular-targeted photodynamic therapy (VTP) using TOOKAD((R)) Soluble in patients with localized prostate cancer (LPCa). METHODS: We performed a pooled analysis of 117 men with LPCa, PSA <10 ng/mL, and Gleason score /= 1 (N = 67). Mean prostate necroses at week-1 were 76.5 and 86.3 %, respectively. In both groups, PSA levels at month 6 decreased by 2.0 ng/mL. Small changes from baseline for IPSS and IIEF-5 indicated a slight improvement in urinary function and a slight deterioration in sexual function. CONCLUSIONS: Focal VTP treatment with TOOKAD((R)) Soluble at 4 mg/kg and 200 J/cm resulted in a negative 6-month biopsy rate of 68.4 % for the whole population and 80.6 % for patients treated by hemiablation with LDI >/= 1. The treatment was well tolerated. Two phase III studies will reach completion in early 2015.

Azais H., Rubod C., Ghoneim T., Vassilieff M., Bailly E., Boileau L., Villet R., Collinet P.   Persistent urinary retention after surgery for deep infiltrating endometriosis: a multi-center series of 16 cases.  Arch. Gynecol. Obstet..  2015 ;291 :1333-1339

PURPOSE: Persistent urinary retention (UR) is a complication of 3.5-14.3% of patients having undergone deep pelvic endometriosis (DPE) surgery of posterior compartment, and it is prone to persist. The purpose of this study is to identify surgical procedures and clinical circumstances associated with persistent UR, and consider its treatment. METHODS: We undertook a multi-center retrospective study studying medical records of patients who had surgery for DPE between January 2005 and December 2012. Patients who suffered from UR defined as a post-void residual (PVR) volume >100 mL needing intermittent self-catheterizations more than 30 days after surgery were included. Preoperative data (functional complaints, clinical examination, imaging, medical treatment) were recorded. Types of surgery and detailed postoperative urinary symptoms were noted. RESULTS: 881 patients had surgery for DPE and 16 patients were included (1.8%). In 93.8% of cases, a lesion of posterior compartment was clinically significant. Mean lesion size was 28.8 +/- 7.3 mm. Colorectal resection and colpectomy were necessary in 93.8 and 87.5% of cases, respectively. Loss of bladder sensation and straining during urination were the two most common post-operative symptoms. 11 patients still required self-catheterization up to 1 year after the intervention. CONCLUSIONS: Patients with increased risks of UR present with a symptomatic and clinically palpable deep pelvic endometriotic lesion of the posterior compartment. Treatment implies surgery with colorectal resection. Bilateral resection of utero-sacral ligaments and posterior colpectomy tend to increase that risk. Complications due to PVR volume and straining during urination may be prevented by self-catheterization.