Le Rhun E., Duhamel M., Wisztorski M., Gimeno J. P., Zairi F., Escande F., Reyns N., Kobeissy F., Maurage C. A., Salzet M., Fournier I.   Evaluation of non-supervised MALDI mass spectrometry imaging combined with microproteomics for glioma grade III classification.  BBA-Proteins Proteomics.  2017 ;1865 :875-890

An integrated diagnosis using molecular features is recommended in the 2016 World Health Organization (WHO) classification. Our aim was to explore non-targeted molecular classification using MALDI mass spectrometry imaging (MALDI MSI) associated to microproteomics in order to classify anaplastic glioma by integration of clinical data. We used fresh-frozen tissue sections to perform MALDI MSI of proteins based on their digestion peptides after in-situ trypsin digestion of the tissue sections and matrix deposition by micro-spraying. The generated 70mum spatial resolution image datasets were further processed by individual or global segmentation in order to cluster the tissues according to their molecular protein signature. The clustering gives 3 main distinct groups. Within the tissues the ROIs (regions of interest) defined by these groups were used for microproteomics by micro-extraction of the tryptic peptides after on-tissue enzymatic digestion. More than 2500 proteins including 22 alternative proteins (AltProt) are identified by the Shotgun microproteomics. Statistical analysis on the basis of the label free quantification of the proteins shows a similar classification to the MALDI MSI segmentation into 3 groups. Functional analysis performed on each group reveals sub-networks related to neoplasia for group 1, glioma with inflammation for group 2 and neurogenesis for group 3. This demonstrates the interest on these new non-targeted large molecular data combining both MALDI MSI and microproteomics data, for tumor classification. This analysis provides new insights into grade III glioma organization. This specific information could allow a more accurate classification of the biopsies according to the prognosis and the identification of potential new targeted therapeutic options. This article is part of a Special Issue entitled: MALDI Imaging, edited by Dr. Corinna Henkel and Prof. Peter Hoffmann.

Adens A., Landy P., Terriou L., Baillet C., Beron A., Lambert M., Launay D., Huglo D.   Usefulness of nuclear medicine in Erdheim-Chester disease: A Lille experience.  Rev. Med. Interne.  2017 ;38 :235-242

INTRODUCTION: Erdheim-Chester disease is a rare form of non-langerhans histiocytosis and its etiology is still not well established. The aims of the study were to assess the value of the bone scintigraphy and the (18)F-FDG PET/CT for the diagnostic and for the latter in the therapeutic evaluation. METHODS: We retrospectively reviewed 49 patients suspected of Erdheim-Chester disease between 2004 and 2016. Bone scintigraphy was compared with histopathology and PET-CT to conventional morphological examinations and bone scintigraphy. For therapeutic evaluation, thresholds similar to PERCIST 1.0 were used. RESULTS: Forty-nine bone scintigraphy were evaluated with a sensitivity of 100%, a specificity 97%, a positive predictive value 90% and a negative predictive value of 100%. Eight patients had at least an initial PET-CT. The sensitivity compared to conventional morphological examinations differed from the location but was excellent for orbital, bone and vascular involvements. Specificity was comparable between the different examinations. Six patients treated with interferon((R)) and three with vemurafenib((R)) were followed by PET-CT. PET-CT, in agreement to clinicobiological data, identified 4 partial responses and one complete response with interferon((R)) et two partial responses and one complete response with vemurafenib((R)). CONCLUSION: Our retrospective study suggests that bone scintigraphy and 18F-FDG PET/CT could be useful in the initial assessment of Erdheim-Chester disease but also for the latter in the therapeutic evaluation.

Vickers A., Vertosick E. A., Sjoberg D. D., Roobol M. J., Hamdy F., Neal D., Bjartell A., Hugosson J., Donovan J. L., Villers A., Zappala S., Lilja H.   Properties of the 4-Kallikrein Panel Outside the Diagnostic Gray Zone: Meta-Analysis of Patients with Positive Digital Rectal Examination or Prostate Specific Antigen 10 ng/ml and Above.  J. Urol..  2017 ;197 :607-612

PURPOSE: The 4-kallikrein panel, commercially available as the 4Kscore, is a reflex test for prostate cancer early detection that has been extensively validated in multiple international cohorts. It has been suggested that use of such reflex tests be limited to those with prostate specific antigen less than 10 ng/ml and negative digital rectal examination. We aimed to determine the value of the panel in men outside this "diagnostic gray zone." MATERIALS AND METHODS: We performed an individual patient data meta-analysis using data from prior studies on the 4-kallikrein panel. We calculated the properties of the panel for predicting high grade (Gleason 7+) cancer in a subgroup of men with either positive digital rectal examination or prostate specific antigen 10 to 25 ng/ml. RESULTS: A total 2,891 men from 8 cohorts were included. An important proportion of patients, including 32% in the United States validation study, had prostate specific antigen 10 to 25 ng/ml or a positive digital rectal examination. For men with prostate specific antigen 10 to 25 ng/ml the fixed-effects estimate for the discrimination of the kallikrein model was 0.84 vs 0.69 for the base model (difference 0.128, 95% CI 0.098-0.159). In the positive digital rectal examination group discrimination was 0.82 vs 0.72 (difference 0.092, 95% CI 0.069-0.115). Decision analysis showed a clinical net benefit for use of the panel in this subgroup with a reduction in biopsy rates of about 20% and only a small number of high grade cancers missed, or fewer than 3% of those not biopsied. CONCLUSIONS: The use of the kallikrein panel in men with a positive digital rectal examination or prostate specific antigen 10 to 25 ng/ml is justified.

Ouldamer L., Bendifallah S., Body G., Canlorbe G., Touboul C., Graesslin O., Raimond E., Collinet P., Coutant C., Lavoué V., Lévêque J., Daraï E., Ballester M.   Call for Surgical Nodal Staging in Women with ESMO/ESGO/ESTRO High-Intermediate Risk Endometrial Cancer: A Multicentre Cohort Analysis from the FRANCOGYN Study Group.  Ann. Surg. Oncol..  2017 ;24 :1660-1666

BACKGROUND: The European Society of Medical Oncology (ESMO)/European Society of Gynaecological Oncology (ESGO)/European Society for Radiotherapy & Oncology (ESTRO) classification for endometrial cancer (EC) now includes a high-intermediate risk (HIR) group of recurrence due to the adverse prognostic role of lymphovascular space involvement (LVSI) and grade 3 for women at intermediate risk. However, optimal surgical staging, and especially the place of lymphadenectomy, remains to be elucidated. We aimed to establish whether systematic nodal staging should be part of surgical staging for women with HIR EC. METHODS: We abstracted from a prospectively maintained multicentre database the data of 181 women with HIR EC based on uterine factors (endometrioid type 1, grade 1-2 tumors with deep (>/=50%) myometrial invasion and unequivocally positive LVSI, and those with grade 3 tumors with <50% myometrial invasion regardless of LVSI status), who received primary surgical treatment between January 2001 and December 2013. We recorded frequency of lymph node (LN) metastases in those who underwent nodal staging. The secondary outcomes were overall survival and recurrence patterns. RESULTS: Overall, 145 (80.1%) women underwent nodal staging consisting of at least pelvic lymphadenectomy. Of these, 62 (42.7%) had LN disease (9.7% with micrometastases). The respective 5-year overall survival rates according to LN status were 85.0% (95% confidence interval [CI] 76.5-91.4), 71.8% (95% CI 61.9-80.4) and 36.0% (95% CI 26.6-46.2) for women with negative LN, positive LN, and unstaged (p = 0.047). Unstaged women were more likely to experience nodal recurrence than surgically staged/LN negative women (p = 0.05). CONCLUSIONS: Systematic nodal staging should be part of surgical staging for women with apparent ESMO/ESGO/ESTRO HIR EC. Sentinel LN biopsy (SLNB) could be an option in this specific setting that may possibly substitute comprehensive staging, for the identification of patients with lymphatic dissemination.

Soudet S., Lambert M., Lefèvre G., Maillard H., Huglo D., Hatron P. Y.   Long term use of metformin in idiopathic cyclic edema, report of thirteen cases and review of the literature.  Pharmacol. Res..  2017 ;119 :237-239

INTRODUCTION: Idiopathic cyclic edema (ICE) is a rare cause of edema. To date, there is no standard of care. The physiopathology of ICE could be explained by an impairment of capillary permeability. In 1995, a study demonstrated the efficacy of metformin on symptoms and capillary permeability. We evaluated ICE-patients who were treated with metformin in our department. METHODS: We retrospectively included patients diagnosed for ICE between January 1997 and October 2013. ICE was diagnosed in the presence of edema after excluding other etiologies. LANDIS test was used to support ICE diagnosis in all patients. The absence of edema at follow-up was considered as complete response (CR), partial decreased was considered as partial response (PR). Adverse events were recorded. RESULTS: Thirteen patients have accepted to use metformin. The median treatment duration was 28.5 months [8-167] and the median follow-up of treated patients was 40.5 months [14-167]. CR was reached in 10 patients (77%), and PR in 2 patients (15%). Two patients reported side-effects as diarrheas and one of them stopped the treatment due to mild diarrhea. CONCLUSION: We report the interest and tolerance of the long-term use of metformin in ICE. No severe adverse events were noticed. A prospective study is needed to confirm the efficacy of metformin in ICE-patients.

Vignion-Dewalle A. S., Baert G., Devos L., Thecua E., Vicentini C., Mortier L., Mordon S.   Red Light Photodynamic Therapy for Actinic Keratosis Using 37 J/cm(2): Fractionated Irradiation With 12.3mW/cm(2) After 30 Minutes Incubation Time Compared to Standard Continuous Irradiation With 75mW/cm(2) After 3 Hours Incubation Time Using a Mathematic.  Lasers Surg. Med..  2017 ;49 :686-697

OBJECTIVE AND STUDY DESIGN: Photodynamic therapy (PDT) is an emerging treatment modality for various diseases, especially for dermatological conditions. Although, the standard PDT protocol for the treatment of actinic keratoses in Europe has shown to be effective, treatment-associated pain is often observed in patients. Different modifications to this protocol attempted to decrease pain have been investigated. The decrease in fluence rate seems to be a promising solution. Moreover, it has been suggested that light fractionation significantly increases the efficacy of PDT. Based on a flexible light-emitting textile, the FLEXITHERALIGHT device specifically provides a fractionated illumination at a fluence rate more than six times lower than that of the standard protocol. In a recently completed clinical trial of PDT for the treatment of actinic keratosis, the non-inferiority of a protocol involving illumination with the FLEXITHERALIGHT device after a short incubation time and referred to as the FLEXITHERALIGHT protocol has been assessed compared to the standard protocol. In this paper, we propose a comparison of the two above mentioned 635 nm red light protocols with 37 J/cm(2) in the PDT treatment of actinic keratosis: the standard protocol and the FLEXITHERALIGHT one through a mathematical modeling. METHODS: This mathematical modeling, which slightly differs from the one we have already published, enables the local damage induced by the therapy to be estimated. RESULTS: The comparison performed in terms of the local damage induced by the therapy demonstrates that the FLEXITHERALIGHT protocol with lower fluence rate, light fractionation and shorter incubation time is somewhat less efficient than the standard protocol. Nevertheless, from the clinical trial results, the FLEXITHERALIGHT protocol results in non-inferior response rates compared to the standard protocol. CONCLUSION: This finding raises the question of whether the PDT local damage achieved by the FLEXITHERALIGHT protocol (respectively, the standard protocol) is sufficient (respectively, excessive) to destroy actinic keratosis cells. Lasers Surg. Med. 49:686-697, 2017. (c) 2017 Wiley Periodicals, Inc.

Chenoz L., Phelippeau J., Barranger E., Bourdel N., Brun J. L., Chereau E., Collinet P., Coutant C., Darai E., Deffieux X., Gautier T., Golfier F., Huchon C., Ouldamer L., Rouzier R., Koskas M.   Evaluation and Selection of Quality Indicators for the Management of Endometrial Cancer.  Int. J. Gynecol. Cancer.  2017 ;27 :979-986

OBJECTIVE: The aim of this study was to evaluate 36 quality indicators (QIs) for monitoring the quality of care of uterine cancer to be implemented in the EFFECT (effectiveness of endometrial cancer treatment) project. METHODS: The 36 QIs were evaluated in the first 10 patients diagnosed with endometrial cancer and managed in 14 French hospitals in 2011. To assess the status of each QI, a questionnaire detailing the 36 QIs was sent to each hospital, and the information was cross-checked with information from the multidisciplinary staff meeting, surgical reports, and pathological reports. The QIs were evaluated in terms of measurability and improvability. The remaining QIs were evaluated with a multiple correspondence analysis to highlight the interrelationships between qualitative variables describing a population. RESULTS: Thirteen of the 14 institutions responded to the survey for a total of 130 patients. Twenty-five of the 36 QIs affected less than 80% of the patients. Thirteen QIs were found not to be improvable because they reached more than 95% of the theoretical target. Finally, 5 QIs concerning more than 80% of the patients were found to be improvable. The multiple correspondence analysis finally identified 3 dimensions-outcome, safety, and perioperative management-that included the 5 QIs. CONCLUSIONS: In the present study, 5 of the 36 QIs suggested by the EFFECT project seem to be sufficient to report on the quality of endometrial cancer management. Further studies are needed to correlate the information provided by those 5 questions and the relevant outcomes reflecting quality of care in endometrial cancer.

Azais H., Canlorbe G., Belghiti J., Nikpayam M., Mergui J. L., Uzan C.   How I do... a cylindrical excision for in situ adenocarcinoma of the cervix.  Gynecol. Obstet. Fertil. Senol..  2017 ;45 :439-440
Azaïs H., Mordon S., Collinet P.   Intraperitoneal photodynamic therapy for peritoneal metastasis of epithelial ovarian cancer. Limits and future prospects.  Gynecol. Obstet. Fertil. Senol..  2017 ;45 :249-256

High peritoneal recurrence rate in advanced epithelial ovarian cancer after complete macroscopic cytoreductive surgery and platinum-based chemotherapy, raises the issue of peritoneal microscopic disease management and requires the development of additional locoregional treatment strategies. Photodynamic therapy is an effective treatment already applied in other medical and surgical indications. After administration of a photosensitizer which accumulates in cancer cells, illumination with a light of adequate wavelength may induce photochemical reaction between photosensitizer and tissue oxygen which lead to reactive oxygen species production and cytotoxic phenomenon. Photodynamic therapy's ability to treat superficial lesions disseminated on large area makes it an excellent candidate to insure destruction of microscopic peritoneal metastases in addition to macroscopic cytoreductive surgery in order to decrease peritoneal recurrence rate. Development of intraperitoneal photodynamic therapy has been limited by its poor tolerance related to the lack of specificity of photosensitizers and the location of the metastases in proximity to adjacent intraperitoneal organs. Our aim is to review clinical data concerning intraperitoneal photodynamic therapy and epithelial ovarian cancer to identify the limits of this strategy and to provide solutions which may be applied to solve these barriers and enable safe and effective treatment. Targeted photosensitizers and innovative illumination solutions are mandatory to continue research in this field and to consider the feasibility of clinical trials.

Villers A., Puech P., Flamand V., Haber G. P., Desai M. M., Crouzet S., Leroy X., Chopra S., Lemaitre L., Ouzzane A., Gill I. S.   Partial Prostatectomy for Anterior Cancer: Short-term Oncologic and Functional Outcomes.  Eur. Urol..  2017 ;72 :333-342

BACKGROUND: Focal ablative therapy may be a suboptimal option for anterior prostate cancers (APCs) reaching the prostate apex due to concerns for thermal injury to the external sphincter. OBJECTIVE: To explore the technical feasibility of anterior partial prostatectomy (APP) for isolated APCs detected by magnetic resonance imaging (MRI), and to report short-term oncologic and functional outcomes. DESIGN, SETTING, AND PARTICIPANTS: Following institutional review board approval, over an 8-yr period (2008-2015) 17 consenting patients were enrolled in a prospective single-arm single-center Innovation, Development, Exploration, Assessment, Long-term (IDEAL) phase 2a study. Inclusion criteria comprised preurethral, low- to intermediate-risk APC diagnosed by MRI, and targeted biopsies. Robotic template APP was performed; posterolateral aspect of the submontanal urethra, peripheral zone, and periprostatic tissues were preserved intact. Median follow-up was 30 mo (interquartile range [IQR]: 25-70). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We noted the incidence of perioperative complications and examined reports of pathology, prostate-specific antigen (PSA), imaging, biopsies, and questionnaires. RESULTS AND LIMITATIONS: Preoperatively, median PSA was 9.8 ng/ml, Gleason score was 6-7 (3 + 4), and cancer volume was 3.7cm(3) (IQR: 1.7-4.6). The technique was feasible in all cases. Perioperative complications included anastomotic leak (12%; G2), urinary tract infection (6%; G2), and transient intestinal ileus in one case (6%; G2). At 3 mo, continence and potency rates were 100% and 83%, respectively. Median nadir PSA was 0.4 ng/ml (IQR: 0.3-0.7). All margins and posterolateral margins rates were 55% and 35%, respectively. APC recurrence-free survival at 2 yr was 0.86 (95% confidence interval [CI], 0.55-0.96). Four patients (24%) who recurred underwent an uncomplicated completion of robot-assisted prostatectomy. Regarding limitations, CIs are quite wide for reported outcomes. CONCLUSIONS: Robotic partial prostatectomy for isolated APC is feasible with good functional results. While promising, much more research is needed to verify our initial outcomes and appropriately position APP in the treatment paradigms for APC. PATIENT SUMMARY: We explored a novel approach for partial prostatic surgical ablation for prostate cancer located in the anterior part of the prostate as an alternative to other focal ablative techniques.