Khamari R., Trinh A., Gabert P. E., Corazao-Rozas P., Riveros-Cruz S., Balayssac S., Malet-Martino M., Dekiouk S., Curt M. J. C., Maboudou P., Garcon G., Ravasi L., Guerreschi P., Mortier L., Quesnel B., Marchetti P., Kluza J.   Glucose metabolism and NRF2 coordinate the antioxidant response in melanoma resistant to MAPK inhibitors.  Cell Death Dis..  2018 ;9 :325

Targeted therapies as BRAF and MEK inhibitor combination have been approved as first-line treatment for BRAF-mutant melanoma. However, disease progression occurs in most of the patients within few months of therapy. Metabolic adaptations have been described in the context of acquired resistance to BRAF inhibitors (BRAFi). BRAFi-resistant melanomas are characterized by an increase of mitochondrial oxidative phosphorylation and are more prone to cell death induced by mitochondrial-targeting drugs. BRAFi-resistant melanomas also exhibit an enhancement of oxidative stress due to mitochondrial oxygen consumption increase. To understand the mechanisms responsible for survival of BRAFi-resistant melanoma cells in the context of oxidative stress, we have established a preclinical murine model that accurately recapitulates in vivo the acquisition of resistance to MAPK inhibitors including several BRAF or MEK inhibitors alone and in combination. Using mice model and melanoma cell lines generated from mice tumors, we have confirmed that the acquisition of resistance is associated with an increase in mitochondrial oxidative phosphorylation as well as the importance of glutamine metabolism. Moreover, we have demonstrated that BRAFi-resistant melanoma can adapt mitochondrial metabolism to support glucose-derived glutamate synthesis leading to increase in glutathione content. Besides, BRAFi-resistant melanoma exhibits a strong activation of NRF-2 pathway leading to increase in the pentose phosphate pathway, which is involved in the regeneration of reduced glutathione, and to increase in xCT expression, a component of the xc-amino acid transporter essential for the uptake of cystine required for intracellular glutathione synthesis. All these metabolic modifications sustain glutathione level and contribute to the intracellular redox balance to allow survival of BRAFi-resistant melanoma cells.

Kerbage Y., Canlorbe G., Estevez J. P., Grabarz A., Mordon S., Uzan C., Collinet P., Azaïs H.   [Microscopic peritoneal metastases of epithelial ovarian cancers. Clinical relevance, diagnostic and therapeutic tools].  Gynecol Obstet Fertil Senol.  2018 ;46 :497-502

Understanding the biology and progression mechanisms of peritoneal metastases in ovarian epithelial cancers (EOC) is important because peritoneal carcinomatosis is present or will occur during surveillance of a majority of patients. Despite the clinical remission achieved after complete macroscopic cytoreductive surgery and platinum-based chemotherapy, 60% of patients will develop peritoneal recurrence. This suggests that microscopic lesions, which are not eradicated by surgery may be present and may participate in the mechanisms leading to peritoneal recurrence. This paper discusses current available data on microscopic peritoneal metastases, their diagnosis and their treatment. We reviewed all publications dealing with microscopic peritoneal metastases of EOC between 1980 and 2017. The most recent and most relevant publications dealing with the treatment modalities of these metastases were selected. Peritoneal and epiploic microscopic localizations would occur in 1.2 to 15.1% of cases at early-stage and are not treated during conventional surgery. They could represent a potential therapeutic target. Local treatments (intraperitoneal chemotherapy, photodynamic therapy, fluorescence-guided surgery) seem to be necessary in addition to surgery and chemotherapy and may help reduce the risk of peritoneal recurrence. The place of these treatments in the management of EOC remains to be defined by subsequent researches.

Kasivisvanathan V., Rannikko A. S., Borghi M., Panebianco V., Mynderse L. A., Vaarala M. H., Briganti A., Budäus L., Hellawell G., Hindley R. G., Roobol M. J., Eggener S., Ghei M., Villers A., Bladou F., Villeirs G. M., Virdi J., Boxler S., Robert G., Singh P. B., Venderink W., Hadaschik B. A., Ruffion A., Hu J. C., Margolis D., Crouzet S., Klotz L., Taneja S. S., Pinto P., Gill I., Allen C., Giganti F., Freeman A., Morris S., Punwani S., Williams N. R., Brew-Graves C., Deeks J., Takwoingi Y., Emberton M., Moore C. M.   MRI-Targeted or Standard Biopsy for Prostate-Cancer Diagnosis.  N. Engl. J. Med..  2018 ;378 :1767-1777

BACKGROUND: Multiparametric magnetic resonance imaging (MRI), with or without targeted biopsy, is an alternative to standard transrectal ultrasonography-guided biopsy for prostate-cancer detection in men with a raised prostate-specific antigen level who have not undergone biopsy. However, comparative evidence is limited. METHODS: In a multicenter, randomized, noninferiority trial, we assigned men with a clinical suspicion of prostate cancer who had not undergone biopsy previously to undergo MRI, with or without targeted biopsy, or standard transrectal ultrasonography-guided biopsy. Men in the MRI-targeted biopsy group underwent a targeted biopsy (without standard biopsy cores) if the MRI was suggestive of prostate cancer; men whose MRI results were not suggestive of prostate cancer were not offered biopsy. Standard biopsy was a 10-to-12-core, transrectal ultrasonography-guided biopsy. The primary outcome was the proportion of men who received a diagnosis of clinically significant cancer. Secondary outcomes included the proportion of men who received a diagnosis of clinically insignificant cancer. RESULTS: A total of 500 men underwent randomization. In the MRI-targeted biopsy group, 71 of 252 men (28%) had MRI results that were not suggestive of prostate cancer, so they did not undergo biopsy. Clinically significant cancer was detected in 95 men (38%) in the MRI-targeted biopsy group, as compared with 64 of 248 (26%) in the standard-biopsy group (adjusted difference, 12 percentage points; 95% confidence interval [CI], 4 to 20; P=0.005). MRI, with or without targeted biopsy, was noninferior to standard biopsy, and the 95% confidence interval indicated the superiority of this strategy over standard biopsy. Fewer men in the MRI-targeted biopsy group than in the standard-biopsy group received a diagnosis of clinically insignificant cancer (adjusted difference, -13 percentage points; 95% CI, -19 to -7; P<0.001). CONCLUSIONS: The use of risk assessment with MRI before biopsy and MRI-targeted biopsy was superior to standard transrectal ultrasonography-guided biopsy in men at clinical risk for prostate cancer who had not undergone biopsy previously. (Funded by the National Institute for Health Research and the European Association of Urology Research Foundation; PRECISION ClinicalTrials.gov number, NCT02380027 .).

Kasivisvanathan V., Rannikko A., Borghi M., Panebianco V., Mynderse L., Vaarala M., Briganti A., Budaus L., Hellawell G., Hindley R., Roobol M., Eggener S., Ghei M., Villers A., Bladou F., Villeirs G., Virdi J., Boxler S., Robert G., Singh P., Venderink W., Hadaschik B., Ruffion A., Hu J., Margolis D., Crouzet S., Klotz L., Taneja S., Pinto P., Gill I., Allen C., Giganti F., Freeman A., Morris S., Punwani S., Williams N., Brew-Graves C., Takwoingi Y., Emberton M., Moore C.   A MULTI-CENTRE RANDOMISED CONTROLLED TRIAL ASSESSING WHETHER MRI-TARGETED BIOPSY IS NON-INFERIOR TO STANDARD TRANS-RECTAL ULTRASOUND GUIDED BIOPSY FOR THE DIAGNOSIS OF CLINICALLY SIGNIFICANT PROSTATE CANCER IN MEN WITHOUT PRIOR BIOPSY - THE PRECISION STUD.  J. Urol..  2018 ;199 :E1033-E1033
Jannin A., Espiard S., Benomar K., Do Cao C., Mycinski B., Porte H., D''Herbomez M., Penel N., Vantyghem M. C.   Non-islet-cell tumour hypoglycaemia (NICTH): About a series of 6 cases.  Ann. Endocrinol. (Paris).  2018

The purpose of this study was to analyse the characteristics of 6 patients managed in a university hospital between 1996 and 2016 for non-islet cell tumor hypoglycemia (NICTH), a form of hypoglycaemia due to the paraneoplastic secretion of IGF-2 or its related substances. RESULTS: Three of these 6 patients (50%), aged over 69 years, including 2 with acromegaloid phenotype, presented with a pleural solitary fibrous tumor (SFT), with median diameter 20 cm (interquartile range, 12.5-20.5) with a low median SUV (3.3 g/mL (QR, 2-7.5)) on 18F-FDG PET. The other 3 patients presented respectively neuroendocrine carcinoma (NEC) of the palate (70-year-old woman), retroperitoneal myxofibrosarcoma (66-year-old man) and meningeal hemangiopericytoma (36-year-old woman). All 3 were inoperable and did not respond to any therapy other than glucose solution. Corticosteroid therapy was effective in the 3 SFTs and the NEC. One of the SFTs recurred 10 years later with asymptomatic hypoglycemia, which resolved after reintervention. Median (IQR) blood glucose levels of the 6 patients was 0.4g/L (QR, 0.31-0.41), with hypoinsulinemia at 0.7mIU/L (QR 0.7-2.0), undetectable GH, low IGF-1, normal IGF-2 level in 5/6 cases, a high IGF-2:IGF-1 ratio at 26.9 (QR, 20.8-37.8), hypokalemia and hypomagnesemia. CONCLUSION: NICTH is a rare syndrome, which should be considered in the presence of hypoinsulinemic hypoglycemia with low GH and IGF-1, and a IGF-2:IGF-1 ratio>10. Corticosteroid therapy was effective in elderly subjects, particularly with solitary fibrous tumor, which was generally operable. Hemangiopericytoma and myxofibrosarcoma had poor prognosis in younger patients.

Castus P., Heymans O., Melin P., Renwart L., Henrist C., Hayton E., Mordon S., Leclere F. M.   Is Salvage of Recently Infected Breast Implant After Breast Augmentation or Reconstruction Possible? An Experimental Study.  Aesthet. Plast. Surg..  2018 ;42 :362-368

INTRODUCTION: The reinsertion of an infected implant when peri-prosthetic infection occurs early after breast augmentation or breast reconstruction remains controversial. In this experimental study, the authors tried to remove bacteria, and their biofilm, from the colonized surface of breast prostheses, without damaging their integrity. MATERIALS AND METHODS: A total of 112 shell samples of silicone breast prostheses, smooth (SPSS) and textured (TPSS), were colonized by S. epidermidis (SE) or S. aureus (SA) strains, all able to produce biofilms. After 15 days, all the samples were removed from the contaminated culture broth and constituted 4 groups of 20 contaminated samples: SPSS/SE (group I), SPSS/SA (group II), TPSS/SE (group III), TPSS/SE (group IV). In another group-group SEM-, 16 colonized samples were used for documentation with scanning electron microscopy (SEM). The remaining 16 samples were used to test the limits of detection of the sterility test. All samples of groups I-IV and 8 samples of group SEM were << washed >> with a smooth brush in a povidone-iodine bath and rinsed with saline solution. A subset of the washed samples was sent for SEM and the others were immersed in sterile broth and were incubated at 35 degrees C for 3 weeks (groups I-IV). RESULTS: Fifteen days after contamination, all the samples in groups I-IV were colonized. In the SEM group, SEM images attested to the presence of bacteria in biofilm attached to the shells. After cleaning, SEM did not reveal any bacteria and there was no visible alteration in the outer structure of the shell. Sterility tests performed after decontamination in groups I-IV remained negative for all the samples. CONCLUSION: Breast prostheses recently contaminated with Staphylococci, frequently involved in peri-prosthetic breast implant infection and capable of producing biofilms, can be efficiently decontaminated by the procedure used in this study. Our decontamination procedure did not alter the surface structure of the prostheses. This decontamination procedure could allow reinsertion of an infected implant when peri-prosthetic infection occurs early after breast augmentation or breast reconstruction and when a salvage procedure is indicated. NO LEVEL ASSIGNED: This journal requires that authors assign a level of evidence to each submission to which Evidence-Based Medicine rankings are applicable. This excludes Review Articles, Book Reviews, and manuscripts that concern Basic Science, Animal Studies, Cadaver Studies, and Experimental Studies. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Vannimenus C., Bricout H., Le Rouzic O., Mouawad F., Chevalier D., Dansin E., Rotsaert L., Lefebvre G., Cottencin O., Porte H., Scherpereel A., El Fahsi A., Richard F., Rolland B.   Compared characteristics of current vs. past smokers at the time of diagnosis of a first-time lung or head and neck cancer: a cross-sectional study.  BMC Cancer.  2018 ;18 :372

BACKGROUND: Active smoking at the time of diagnosis of a first head & neck (H&N) or lung cancer is associated with a worse cancer outcome and increased mortality. However, the compared characteristics of active vs. former smokers at cancer diagnosis are poorly known. METHODS: In 371 subjects with a first H&N or lung cancer, we assessed: 1) socio-demographic features; 2) lifelong types of smoking; 3) alcohol use disorder identification test (AUDIT); 4) cannabis abuse screening test (CAST); and 5) Mini International Neuropsychiatric Interview (MINI). Using a multivariable regression model, we compared the profile of current smokers and past smokers. RESULTS: Current smokers more frequently exhibited H&N cancer (OR 3.91; 95% CI [2.00-6.51]; p < 0.0001) and ever smoking of hand-rolled cigarettes (OR 2.2; 95% CI [1.25-3.88]; p = 0.007). Among subjects with lung cancer (n = 177), current smoking was primarily associated with ever smoking of hand-rolled cigarettes (OR 2.88; 95% CI [1.32-6.30]; p = 0.008) and negatively associated with age (OR 0.92; 95% CI [0.89-0.96]; p < 0.001). Among subjects with H&N cancer (n = 163), current smokers exhibited a significantly greater AUDIT score (OR = 1.08; 95% CI [1.01-1.16]; p = 0.03). CONCLUSION: At the time of diagnosis of the first lung or H&N cancer, current smoking is highly associated with previous type of smoking and alcohol drinking patterns. TRIAL REGISTRATION: NCT01647425 ; Registration date: July 23, 2012.

Sophie D., Latxague C., Bensalah K., Bigot P., Paparel P., Beauval J. B., Salomon L., Bessede T., Lang H., Nouhaud F. X., Dariane C., Baumert H., Roupret M., Long J. A., Villers A., Patard J. J., Soulie M., Mejean A., Videau M. N., Bernhard J. C.   POSTOPERATIVE OUTCOMES OF ELDERLY PATIENTS UNDERGOING PARTIAL NEPHRECTOMY: A MULTICENTRIC-STUDY OF THE FRENCH RESEARCH NETWORK ON KIDNEY CANCER UROCCR.  J. Urol..  2018 ;199 :E538-E539
Smith M. R., Saad F., Chowdhury S., Oudard S., Hadaschik B. A., Graff J. N., Olmos D., Mainwaring P. N., Lee J. Y., Uemura H., Lopez-Gitlitz A., Trudel G. C., Espina B. M., Shu Y., Park Y. C., Rackoff W. R., Yu M. K., Small E. J.   Apalutamide Treatment and Metastasis-free Survival in Prostate Cancer.  N. Engl. J. Med..  2018 ;378 :1408-1418

BACKGROUND: Apalutamide, a competitive inhibitor of the androgen receptor, is under development for the treatment of prostate cancer. We evaluated the efficacy of apalutamide in men with nonmetastatic castration-resistant prostate cancer who were at high risk for the development of metastasis. METHODS: We conducted a double-blind, placebo-controlled, phase 3 trial involving men with nonmetastatic castration-resistant prostate cancer and a prostate-specific antigen doubling time of 10 months or less. Patients were randomly assigned, in a 2:1 ratio, to receive apalutamide (240 mg per day) or placebo. All the patients continued to receive androgen-deprivation therapy. The primary end point was metastasis-free survival, which was defined as the time from randomization to the first detection of distant metastasis on imaging or death. RESULTS: A total of 1207 men underwent randomization (806 to the apalutamide group and 401 to the placebo group). In the planned primary analysis, which was performed after 378 events had occurred, median metastasis-free survival was 40.5 months in the apalutamide group as compared with 16.2 months in the placebo group (hazard ratio for metastasis or death, 0.28; 95% confidence interval [CI], 0.23 to 0.35; P<0.001). Time to symptomatic progression was significantly longer with apalutamide than with placebo (hazard ratio, 0.45; 95% CI, 0.32 to 0.63; P<0.001). The rate of adverse events leading to discontinuation of the trial regimen was 10.6% in the apalutamide group and 7.0% in the placebo group. The following adverse events occurred at a higher rate with apalutamide than with placebo: rash (23.8% vs. 5.5%), hypothyroidism (8.1% vs. 2.0%), and fracture (11.7% vs. 6.5%). CONCLUSIONS: Among men with nonmetastatic castration-resistant prostate cancer, metastasis-free survival and time to symptomatic progression were significantly longer with apalutamide than with placebo. (Funded by Janssen Research and Development; SPARTAN ClinicalTrials.gov number, NCT01946204 .).

Sauvan M., Chabbert-Buffet N., Canis M., Collinet P., Fritel X., Geoffron S., Legendre G., Wattier J. M., Fernandez H.   [Medical treatment for the management of painful endometriosis without infertility: CNGOF-HAS Endometriosis Guidelines].  Gynecol Obstet Fertil Senol.  2018 ;46 :267-272

OBJECTIVE: To provide clinical practice guidelines for the management of painful endometriosis in women without infertility. METHODS: Systematic review of the literature literature since 2006, level of evidence rating, external proofreading and grading of the recommendation grade by an expert group according to HAS methodology. RESULTS: Combined hormonal contraceptives (COP) and the levonorgestrel-releasing intra-uterin system (LNG-IUS) are recommended as first-line hormonal therapies for the treatment of painful endometriosis (grade B). Second-line therapy relies on oral desogestrel microprogestative, etonogestrel-releasing implant, GnRH analogs (GnRHa) and dienogest (grade C). It is recommended to use add-back therapy containing estrogen in association with GnRHa (grade B). After endometriosis surgery, hormonal treatment relying on COP or LNG-IUS is recommended to prevent pain recurrence (grade B). COP is recommended to reduce the risk of endometrioma recurrence after surgery (grade B) but the prescription of GnRHa is not recommended (grade C). Continuous COP is recommended in case of dysmenorrhea (grade B). GnRHa is not recommended as first line endometriosis treatment for adolescent girl because of the risk of bone demineralization (grade B). The management of endometriosis-induced chronic pain requires an interdisciplinary evaluation. Physical therapies improving the quality of life such as yoga, relaxation or osteopathy can be proposed (expert agreement). Promising medical alternatives are currently under preclinical and clinical evaluation.