Maio M., Lewis K., Demidov L., Mandalà M., Bondarenko I., Ascierto P. A., Herbert C., Mackiewicz A., Rutkowski P., Guminski A., Goodman G. R., Simmons B., Ye C., Yan Y., Schadendorf D.   mutation-positive melanoma (BRIM8): a randomised, double-blind, placebo-controlled, multicentre, phase 3 trial.  Lancet Oncol..  2018 ;19 :510-520

BACKGROUND: Systemic adjuvant treatment might mitigate the high risk of disease recurrence in patients with resected stage IIC-III melanoma. The BRIM8 study evaluated adjuvant vemurafenib monotherapy in patients with resected, BRAF(V600) mutation-positive melanoma. METHODS: BRIM8 was a phase 3, international, double-blind, randomised, placebo-controlled study that enrolled 498 adults (aged >/=18 years) with histologically confirmed stage IIC-IIIA-IIIB (cohort 1) or stage IIIC (cohort 2) BRAF(V600) mutation-positive melanoma that was fully resected. Patients were randomly assigned (1:1) by an interactive voice or web response system to receive twice-daily adjuvant oral vemurafenib 960 mg tablets or matching placebo for 52 weeks (13 x 28-day cycles). Randomisation was done by permuted blocks (block size 6) and was stratified by pathological stage and region in cohort 1 and by region in cohort 2. The investigators, patients, and sponsor were masked to treatment assignment. The primary endpoint was disease-free survival in the intention-to-treat population, evaluated separately in each cohort. Hierarchical analysis of cohort 2 before cohort 1 was prespecified. This trial is registered with ClinicalTrials.gov, number NCT01667419. FINDINGS: The study enrolled 184 patients in cohort 2 (93 were assigned to vemurafenib and 91 to placebo) and 314 patients in cohort 1 (157 were assigned to vemurafenib and 157 to placebo). At the time of data cutoff (April 17, 2017), median study follow-up was 33.5 months (IQR 25.9-41.6) in cohort 2 and 30.8 months (25.5-40.7) in cohort 1. In cohort 2 (patients with stage IIIC disease), median disease-free survival was 23.1 months (95% CI 18.6-26.5) in the vemurafenib group versus 15.4 months (11.1-35.9) in the placebo group (hazard ratio [HR] 0.80, 95% CI 0.54-1.18; log-rank p=0.026). In cohort 1 (patients with stage IIC-IIIA-IIIB disease) median disease-free survival was not reached (95% CI not estimable) in the vemurafenib group versus 36.9 months (21.4-not estimable) in the placebo group (HR 0.54 [95% CI 0.37-0.78]; log-rank p=0.0010); however, the result was not significant because of the prespecified hierarchical prerequisite for the primary disease-free survival analysis of cohort 2 to show a significant disease-free survival benefit. Grade 3-4 adverse events occurred in 141 (57%) of 247 patients in the vemurafenib group and 37 (15%) of 247 patients in the placebo group. The most common grade 3-4 adverse events in the vemurafenib group were keratoacanthoma (24 [10%] of 247 patients), arthralgia (17 [7%]), squamous cell carcinoma (17 [7%]), rash (14 [6%]), and elevated alanine aminotransferase (14 [6%]), although all keratoacanthoma events and most squamous cell carcinoma events were by default graded as grade 3. In the placebo group, grade 3-4 adverse events did not exceed 2% for any of the reported terms. Serious adverse events were reported in 40 (16%) of 247 patients in the vemurafenib group and 25 (10%) of 247 patients in the placebo group. The most common serious adverse event was basal cell carcinoma, which was reported in eight (3%) patients in each group. One patient in the vemurafenib group of cohort 2 died 2 months after admission to hospital for grade 3 hypertension; however, this death was not considered to be related to the study drug. INTERPRETATION: The primary endpoint of disease-free survival was not met in cohort 2, and therefore the analysis of cohort 1 showing a numerical benefit in disease-free survival with vemurafenib versus placebo in patients with resected stage IIC-IIIA-IIIB BRAF(V600) mutation-positive melanoma must be considered exploratory only. 1 year of adjuvant vemurafenib was well tolerated, but might not be an optimal treatment regimen in this patient population. FUNDING: F Hoffman-La Roche Ltd.

Roman H., Ballester M., Loriau J., Canis M., Bolze P. A., Niro J., Ploteau S., Rubod C., Yazbeck C., Collinet P., Rabischong B., Merlot B., Fritel X.   [Strategies and surgical management of endometriosis: CNGOF-HAS Endometriosis Guidelines].  Gynecol Obstet Fertil Senol.  2018 ;46 :326-330

The article presents French guidelines for surgical management of endometriosis. Surgical treatment is recommended for mild to moderate endometriosis, as it decreases pelvic painful complaints and increases the likelihood of postoperative conception in infertile patients (A). Surgery may be proposed in symptomatic patients with ovarian endometriomas which diameter exceeds 20mm. Cystectomy allows for better postoperative pregnancy rates when compared to ablation using bipolar current, as well as for lower recurrences rates when compared to ablation using bipolar current or CO2 laser. Ablation of ovarian endometriomas using bipolar current is not recommended (B). Surgery may be employed in patients with deep endometriosis infiltrating the colon and the rectum, with good impact on painful complaints and postoperative conception. In these patients, laparoscopic route increases the likelihood of postoperative spontaneous conception when compared to open route. When compared to conservative rectal procedures (shaving or disc excision), segmental colorectal resection increases the risk of postoperative stenosis, requiring additional endoscopic or surgical procedures. In large deep endometriosis infiltrating the rectum (>20mm length of bowel infiltration), conservative rectal procedures do not improve postoperative digestive function when compared to segmental resection. In patients with bowel anastomosis, placing anti-adhesion agents on contact with bowel suture is not recommended, due to higher risk of bowel fistula (C). Various other recommendations are proposed in the text, however, they are based on studies with low level of evidence.

Raichi A., Marcq G., Fantoni J. C., Puech P., Villers A., Ouzzane A.   [Active surveillance in prostate cancer: Assessment of MRI in the selection and follow-up of patients].  Prog. Urol..  2018 ;28 :416-424

AIM: To evaluate the contribution of multiparametric MRI (MRI) and targeted biopsies (TB) in the selection and follow-up of patients under active surveillance (AS). METHODS: A single-center, retrospective cohort study on 131 patients in AS, with following criteria:6 and/or a maximum tumor length>5mm. RESULTS: Overall, 29 patients (22.1 %) were reclassified. Reclassification free survival rate was 93 % and 70 % at 1 year and 4 years respectively. Reclassification independent risk factors were: PSA density>0.15ng/mL/cm(3) (RR=2.75), PSA doubling time<3 years (RR=9.28), suspicious lesion on MRI diagnosis (RR=2.79) and occurrence of MRI progression during follow-up (RR=2). Sensitivity, specificity, PPV and NPV of MRI to assess progression for reclassification were 61 %, 69 %, 45 % and 81 %, respectively. CONCLUSION: For patients under AS, mpMRI decreases reclassification rates over time through better initial detection of significant cancers. Its high NPV makes it an efficient monitoring tool to distinguish patients with low risk of reclassification. LEVEL OF EVIDENCE: 4.

Quidet M., Zairi F., Boyle E., Facon T., Vieillard M. H., Machuron F., Lejeune J. P., Assaker R.   Evaluation of the relevance of surgery in patients with multiple myeloma harboring symptomatic spinal involvement: a retrospective case series.  World Neurosurg.  2018 ;114 :e356-e365

BACKGROUND: Multiple myeloma spinal involvement can lead to bone fractures and neurologic impairment that can severely alter quality of life. The role of surgery is controversial, given its high morbidity, and the lack of evidence. We hereby aim to evaluate efficacy and safety of surgery in the management of symptomatic spinal lesions in patients with multiple myeloma. METHODS: We included all patients operated on for a myeloma-related spinal lesion in our institution between 2007 and 2015. Demographic, clinical, and surgical data were collected as well as hematologic profiles. We retrospectively assessed the surgical success of the procedures, if at 3 months the patient fulfilled the following 4 criteria: pain relief, ability to walk, spinal stability, and no relevant morbidity. RESULTS: Thirty-six men and 19 women, with a median age of 62 years, were included. Seventeen patients underwent an emergency intervention, whereas 38 patients underwent elective surgery. At 3 months, 88.2% and 96.1%, respectively, of patients experienced pain relief and were able to walk. Spinal stability was considered satisfactory for 94.1% of patients. We reported 8 major complications in 8 patients. Altogether, 34 patients (61.8%) fulfilled all criteria for surgical success. An International Staging System score of 1 and the absence of previous chemotherapy were significantly associated with surgical success. CONCLUSIONS: Management of myeloma-related spine lesions requires a multidisciplinary approach. Surgery rapidly provides both decompression and stabilization. Using a strict patient-specific evaluation, we reported rewarding functional results, with acceptable morbidity. Surgery for multiple myeloma vertebral lesions seems to be a valuable option for carefully selected patients.

Ploteau S., Merlot B., Roman H., Canis M., Collinet P., Fritel X.   [Minimal and mild endometriosis: Impact of the laparoscopic surgery on pelvic pain and fertility. CNGOF-HAS Endometriosis Guidelines].  Gynecol Obstet Fertil Senol.  2018 ;46 :273-277

Minimal and mild endometriosis (stage 1 and 2 AFSR) can lead to chronic pelvic pain and infertility but can also exist in asymptomatic patients. The prevalence of asymptomatic patients with minimal and mild endometriosis is not clear but typical endometriosis lesions are found in about 5 to 10% of asymptomatic women and more than 50% of painful and/or infertile women. Laparoscopic treatment of minimal and mild endometriotic lesions is justified in case of pelvic pain because their destruction decrease significatively the pain compared with diagnostic laparoscopy alone. In this context, ablation and excision give identical results in terms of pain reduction. Moreover, literature shows no interest in uterine nerve ablation in case of dysmenorrhea due to minimal and mild endometriosis. Then, it is recommended to treat these lesions during a laparoscopy realised as part of pelvic pain. On the other hand, it is not recommended to treat asymptomatic patients. With regard to treatment of minimal and mild endometriosis in infertile patients, only two studies can be selected and both show that laparoscopy with excision or ablation and ablation of adhesions is superior to diagnostic laparoscopy alone in terms of pregnancy rate. However, it is not recommended to treat these lesions when they are asymptomatic because there is no evidence that they can progress with symptomatic disease. There is no study assessing the interest to treat these lesions when they are found fortuitously. Adhesion barrier utilisation permits to reduce post-operative adhesions, however literature failed to demonstrate the clinical profit in terms of reduction of the risk of pain or infertility.

Pierot L., Spelle L., Berge J., Januel A. C., Herbreteau D., Aggour M., Piotin M., Biondi A., Barreau X., Mounayer C., Papagiannaki C., Lejeune J. P., Gauvrit J. Y., Costalat V.   Feasibility, complications, morbidity, and mortality results at 6 months for aneurysm treatment with the Flow Re-Direction Endoluminal Device: report of SAFE study.  J Neurointerv Surg.  2018 ;10 :765-770

BACKGROUND AND PURPOSE: Flow diverters are increasingly used for the treatment of intracranial aneurysms. Evaluation of the first devices available for clinical use showed high efficacy of this treatment although safety results were worse compared with coiling or balloon-assisted coiling. The Safety and Efficacy Analysis of FRED Embolic Device in Aneurysm Treatment (SAFE) trial is a single-arm, multicenter, prospective study conducted to precisely analyze the safety and efficacy of the FRED and FRED Jr devices. METHODS: Unruptured and recanalized aneurysms located in the anterior circulation treated with FRED and FRED Jr were prospectively included. Adverse events were independently evaluated by a Clinical Event Committee with a vascular neurosurgeon and an interventional neuroradiologist. Primary safety outcome measures were morbidity and mortality rates at 6 months after treatment. RESULTS: A total of 103 patients/aneurysms were included in 13 interventional neuroradiology (INR) centers. Aneurysm locations were supraclinoid internal carotid artery (ICA) in 71 (68.9%), cavernous ICA in 15 (14.6%), anterior cerebral artery or anterior communicating artery in nine (8.7%), and middle cerebral artery in eight (7.8%). Aneurysms were small (<10 mm) in 71 patients (68.9%). Treatment was successfully performed in 98/103 patients (95.1%). Thromboembolic (TE) complications occurred in 5/103 patients (4.9%), intraoperative rupture in 2/103 patients (1.9%), delayed aneurysm rupture in 1/103 patient (1.0%), and delayed hematoma occurred in 1/103 patient (1.0%). Six-months' mortality and morbidity rates were 1/102 (1.0%) and 2/102 (2.0%), respectively. CONCLUSIONS: Aneurysm treatment with the FRED device is safe with low mortality (1.0%) and morbidity (2.0%). CLINICAL TRIAL REGISTRATION: NCT02921698.

Perron E., Pissaloux D., Neub A., Hohl D., Tartar M. D., Mortier L., Alberti L., de la Fouchardiere A.   Unclassified sclerosing malignant melanomas with AKAP9-BRAF gene fusion: a report of two cases and review of BRAF fusions in melanocytic tumors.  Virchows Arch..  2018 ;472 :469-476

The current classification of melanocytic tumors includes clinical, pathological, and molecular data. A subset of lesions remains difficult to classify according to these complex multilayer schemes. We report two cases of deeply infiltrating melanomas with a sclerosing background. The first case occurred on the back of a middle-aged man appearing clinically as a dermatofibroma. The architectural and cytological aspects resembled those of a desmoplastic melanoma but the strong expression of both melanA and HMB45, two stainings usually reported as negative in this entity, raised the question of an alternate diagnosis. The second case was a large, slowly growing, perivulvar tumor in a middle-aged woman. The morphology was complex with a central junctional spitzoid pattern associating an epidermal hyperplasia with large nests of large spindled melanocytes. The dermal component was made of deeply invasive strands and nests of nevoid unpigmented melanocytes surrounded by fibrosis; a perineural invasion was present at the periphery of the lesion. In both cases, aCGH found, among many other anomalies, a chromosomal breakpoint at the BRAF locus. RNA sequencing identified in both an AKAP9-BRAF gene fusion. A complementary resection was performed and no relapses have been observed in the respectively 15 and 6 months of follow-up. Both of these melanomas remained unclassified. We further review the variety of melanocytic tumors associated with such BRAF fusions.

Orczyk C., Villers A., Rusinek H., Le Pennec V., Bazille C., Mikheev A., Bernaudin M., Fohlen A., Valable S.   PROSTATE CANCER HETEROGENEITY: TEXTURE ANALYSIS OF MULTIPLE MRI SEQUENCES FOR DETECTION AND SELECTION OF BIOPSY TARGETS.  J. Urol..  2018 ;199 :E183-E183
Olivier J., Puech P., Fantoni J. C., Drumez E., Leroy X., Villers A.   ACTIVE SURVEILLANCE IN PROSTATE CANCER FOR PATIENTS WITH NON-SUSPICIOUS MRI AT ENTRY: CAN CONFIRMATORY BIOPSIES BE AVOIDED?.  J. Urol..  2018 ;199 :E143-E143
Olivier J., Kasivisvanathan V., Drumez E., Fantoni J. C., Leroy X., Puech P., Villers A.   Low-risk prostate cancer selected for active surveillance with negative MRI at entry: can repeat biopsies at 1 year be avoided? A pilot study.  World J Urol.  2018

PURPOSE: In patients considered for active surveillance (AS), the use of MRI and targeted biopsies (TB) at entry challenges the approach of routine "per protocol" repeat systematic biopsies (SB) at 1 year. This pilot study aimed to assess whether an approach of performing repeat biopsies only if PSA kinetics are abnormal would be safe and sufficient to detect progression. METHODS: Prospective single-centre study of 149 patients on AS with low-risk PCa, a negative MRI at entry, followed for a minimum of 12 months between 01/2007 and 12/2015. Group 1 (n = 78) patients had per-protocol 12-month repeat SB; group 2 (n = 71) patients did not. Surveillance tests for tumour progression were for both groups: for cause SB and MRI-TB biopsies if PSA velocity (PSA-V) > 0.75 ng/ml/year, or PSA doubling time (PSADT) < 3 years. The main objectives are to compare the 2-year rates of tumour progression and AS discontinuation between groups. The secondary objectives are to estimate the diagnostic power of PSA-V and PSA-DT, to predict the risk of tumour progression. RESULTS: Overall, 21 out of 149 patients (14.1%) showed tumour progression, 17.1% for group 1 and 12.3% for group 2, and 31 (21.2%) discontinued AS at 2 years. There was no difference between the 2 groups (p = 0.56). The area under the PSA-V and PSADT curves to predict tumour progression was 0.92 and 0.83, respectively. CONCLUSIONS: We did not find any significant difference for progression and AS discontinuation rate between the 2 groups. The PSA kinetic seems accurate as a marker of tumour progression. These results support the conduct of a multi-centre prospective trial to confirm these findings.