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Background: This systematic review and meta-analysis assessed the effectiveness of robotic surgery compared to laparoscopy or open surgery for inguinal (IHR) and ventral (VHR) hernia repair., Methods: PubMed and EMBASE were searched up to July 2022. Meta-analyses were performed for postoperative complications, surgical site infections (SSI), seroma/hematoma, hernia recurrence, operating time (OT), intraoperative blood loss, intraoperative bowel injury, conversion to open surgery, length of stay (LOS), mortality, reoperation rate, readmission rate, use of opioids, time to return to work and time to return to normal activities., Results: Overall, 64 studies were selected and 58 were used for pooled data analyses: 35 studies (227 242 patients) deal with IHR and 32 (158 384 patients) with VHR. Robotic IHR was associated with lower hernia recurrence (OR 0.54; 95%CI 0.29, 0.99; I 2 : 0%) compared to laparoscopic IHR, and lower use of opioids compared to open IHR (OR 0.46; 95%CI 0.25, 0.84; I 2 : 55.8%). Robotic VHR was associated with lower bowel injuries (OR 0.59; 95%CI 0.42, 0.85; I 2 : 0%) and less conversions to open surgery (OR 0.51; 95%CI 0.43, 0.60; I 2 : 0%) compared to laparoscopy. Compared to open surgery, robotic VHR was associated with lower postoperative complications (OR 0.61; 95%CI 0.39, 0.96; I 2 : 68%), less SSI (OR 0.47; 95%CI 0.31, 0.72; I 2 : 0%), less intraoperative blood loss (- 95 mL), shorter LOS (- 3.4 day), and less hospital readmissions (OR 0.66; 95%CI 0.44, 0.99; I 2 : 24.7%). However, both robotic IHR and VHR were associated with significantly longer OT compared to laparoscopy and open surgery., Conclusion: These results support robotic surgery as a safe, effective, and viable alternative for IHR and VHR as it can brings several intraoperative and postoperative advantages over laparoscopy and open surgery., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Long-term follow-up (LTFU) clinics have been developed but only some childhood cancer survivors (CCS) attend long-term follow-up (LTFU)., Objective: To identify factors that influence LTFU attendance., Methods: Five-year CCS treated for a solid tumor or lymphoma in Gustave Roussy before 2000, included in the FCCSS cohort (French Childhood Cancer Survivor Study), aged >18 years and alive at the date of the LTFU Clinic opening (January 2012) were invited to a LTFU visit. Factors associated with attendance at the LTFU clinic between 2012 and 2020 were estimated using logistic regression analyses. Analyses included different types of factors: clinical (tumor characteristics, cancer treatments, late effects), medical (medical expenses were used as a proxy of survivor's health status), social (deprivation index based on census-tract data relating to income, educational level, proportion of blue-collar workers, and unemployed people living in the area of residence), and spatial (distance to the LTFU clinic)., Results: Among 2341 CCS contacted (55% males, mean age at study, 45 years; SD ± 10 years; mean age at diagnosis, 6 years; SD ± 5 years), 779 (33%) attended at least one LTFU visit. Initial cancer-related factors associated with LTFU visit attendance were: treatment with both radiotherapy and chemotherapy (odds ratio [OR], 4.02; 95% CI, 2.11-7.70), bone sarcoma (OR, 2.43; 95% CI, 1.56-3.78), central nervous system primitive tumor (OR, 1.65; 95% CI, 1.02-2.67), and autologous hematopoietic cell transplant (OR, 2.07; 95% CI, 1.34-3.20). Late effects (OR, 1.70; 95% CI, 1.31-2.20), highest medical expenses (OR, 1.65; 95% CI, 1.22-2.22), living in the most advantaged area (OR vs. the most deprived area = 1.60; 95% CI, 1.15-2.22), and shorter distance from LTFU care center (<12 miles) also increased attendance., Conclusions: Patients who are apparently healthy as well as socially disadvantaged and living far away from the center are less likely to attend LTFU care., Plain Language Summary: Among 2341 adult childhood cancer survivors contacted between 2012 and 2020, 33% attended at least one long-term follow-up visit. Clinical factors related to attendance were multimodal treatment of first cancer (combining chemotherapy and radiotherapy), stem cell transplant, type of diagnosis (bone tumor and central nervous system primitive tumor), late effects (at least one disease among second malignancy, heart disease, or stroke), and highest medical expenses. In addition, the study identified social and spatial inequalities related to attendance, with independent negative effects of distance and social deprivation on attendance, even though the medical costs related to the long-term follow-up examinations are covered by the French social security system., (© 2023 The Authors. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.)

Background: Although minimally invasive rectal surgery (MIRS) for cancer provides better recovery for similar oncologic outcomes over open approach, conversion is still required in 10% and its impact on short-term and long-term outcomes remains unclear. The aim of our study was to evaluate the impact of conversion on postoperative and oncologic outcomes in patients undergoing MIRS for cancer., Methods: From June 2011 to March 2020, we reviewed 257 minimally invasive rectal resections for cancer recorded in a prospectively maintained database, with 192 robotic and 65 laparoscopic approaches. Patients who required conversion to open (Conversion group) were compared to those who did not have conversion (No conversion group) in terms of short-term, histologic, and oncologic outcomes. Univariate and multivariate analyses of the risk factors for postoperative morbidity were performed., Results: Eighteen patients (7%) required conversion. The conversion rate was significantly higher in the laparoscopic approach than in the robotic approach (16.9% vs 3.6%, p < 0.01). Among the 4 reactive conversions, 3 (75%) were required during robotic resections. Patients in the Conversion group had a higher morbidity rate (83.3% vs 43.1%, p = 0.01) and more severe complications (38.9%, vs 18.8%, p = 0.041). Male sex [HR = 2.46, 95%CI (1.41-4.26)], total mesorectal excision [HR = 2.89, 95%CI (1.57-5.320)], and conversion (HR = 4.87, 95%CI [1.34-17.73]) were independently associated with a higher risk of overall 30-day morbidity. R1 resections were more frequent in the Conversion group (22.2% vs 5.4%, p = 0.023) without differences in the overall (82.7 ± 7.0 months vs 79.4 ± 3.3 months, p = 0.448) and disease-free survivals (49.0 ± 8.6 months vs 70.2 ± 4.1 months, p = 0.362)., Conclusion: Conversion to laparotomy during MIRS for cancer was associated with poorer postoperative results without impairing oncologic outcomes. The high frequency of reactive conversion due to intraoperative complications in robotic resections confirmed that MIRS for cancer is a technically challenging procedure., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background and Aim: The establishment of an international hospital-based register (HBR) for the French African Pediatric Oncology Group (GFAOP) was a necessary step in the group's clinical research program. With help from the Sanofi Espoir Foundation's "My Child Matters" program, the GFAOP resolved to develop an international HBR network to collect quality data on children attending the Pediatric Oncology Units (POUs)., Methods: All children entering POUs from January 2016 to December 2018 were registered using an online questionnaire. Data collection included information on diagnosis, disease stage, demographics, socioeconomic status, and outcome. An intensive training program was developed to improve both data quality and quantity., Results: Among the 3348 children registered, 3230 had a suspected cancer, 681 were not confirmed. A diagnosis was confirmed on radiological, clinical, or histological examination for 2549 children including Burkitt lymphoma (516: 20%)-the most frequent diagnosis, Wilms' tumor (459: 18%), retinoblastoma (357: 14%), and acute lymphoblastic leukemia (345: 13%). Of these, 2187 children were treated. Early deaths, abandonment, economic difficulties, and lack of equipment were some of the reasons offered to explain the numbers of undiagnosed and untreated children. Vital status is known for 1994 children: 1187 died and 807 were alive, 551 of these with a follow-up > 12 months., Conclusion: This work has provided reliable data on children attending the POUs, especially clarifying reasons and occasions for care rupture. The data will help to identify material, human resources, and staff training needs, to evaluate progress, and to encourage consideration of pediatric cancer in national cancer plans., (© 2021 The Authors. Pediatric Blood & Cancer published by Wiley Periodicals LLC.)

Background: Unhealthy behaviors among childhood cancer survivors increase the risks for cancer treatment adverse effects. We aimed to assess tobacco and cannabis use prevalence in this population and to identify factors associated with these consumptions., Methods: This study involved 2,887 5-year survivors from the French childhood cancer survivor study (FCCSS) cohort. Data on health behaviors were compared with those of controls from the general population. Associations of current smoking and cannabis use with clinical features, sociodemographic characteristics, and health-related quality of life (QOL) were investigated using multivariable logistic regressions., Results: Prevalence for tobacco use was lower in survivors (26%) than in controls (41%, P < 0.001). Among current smokers, survivors smoked more cigarettes per day and started at a younger age than controls. Women, college graduates, older, married, and CNS tumor survivors, as well as those who received chemotherapy and thoracic radiation therapy, were less likely to be smokers and/or cannabis consumers than others. Participants with a poor mental QOL were more likely to smoke., Conclusions: Preventive interventions and cessation programs must be carried out as early as possible in survivors' life, especially among young males with low educational level and poor mental health., Impact: This study brings new insights to health behaviors among childhood cancer survivors from a population with high rates of smoking and cannabis use., (©2021 American Association for Cancer Research.)

Aims . Minimally invasive liver resection is a complex and challenging operation. Although authors have reported robotic liver resection shows improved safety and efficacy compared with open liver resection, robotic major liver resections for malignant liver lesions treatment remain inadequately evaluated. The aims of the present study were to evaluate the feasibility and safety of transitioning from open to robotic liver resection in a nonuniversity hospital. Patients and Methods. From December 2015 to March 2020, 46 patients underwent totally robotic-assisted liver resections out of 446 robotic procedures. Also, we retrospectively reviewed the last 27 open right hepatectomies (ORHs) and compared then with the first 25 anatomic robotic-assisted right hepatectomies (RRHs). Results . Mean operative time, mean blood lost, rate of complications, and mean hospital stay were associated with the complexity of the procedure. The comparison between ORH and RRH showed that intraoperative complications were less frequently observed during ORH whereas RRH showed a trend in favor of less blood loss. ORH had a trend toward smaller surgical margins and higher rate of R1 resections. Recurrence occurred in 31 (59%) patients and was more frequently observed after ORH. However, the mean follow-up was significantly shorter after RRH. Conclusion . Our study demonstrated the technical feasibility and safety of transitioning from open to robotic liver resection (including major hepatectomies) in a nonuniversity setting. Higher costs remain an important drawback for robotic surgery.

Objective: Health risk behaviors (HRB) of childhood cancer survivors (CCS) are generally studied separately, despite the evidence suggesting that HRB are not independent. To our knowledge, few studies have examined HRB profiles in the former pediatric cancer patients. In this study, we identified HRB profiles and examined predictors engaging in unhealthy behaviors in CCS., Methods: We used data from a French cohort of CCS that includes five-year survivors diagnosed between 1945 and 2000 and treated before reaching age 18, in five centers in France. A total of 2961 adult CCS answered a self-reported questionnaire pertaining to HRB. Latent class analysis was used to identify HRB profiles combining physical activity, smoking, cannabis use, and alcohol drinking. Multinomial logistic analyses examined predictors for engaging in unhealthy behaviors., Results: Three HRB patterns emerged: "Low-risk" (n = 1846, 62.3%) included CCS who exhibited the highest frequency for usual physical activity and the lowest probabilities for current smoking or cannabis use, but most drank at least moderately; "Moderate-risk behaviors" (n = 291, 9.8%), and "High-risk behaviors" (n = 824, 27.8%) for CCS who exhibited the highest frequencies for current smoking, cannabis use, and heavy drinking. The multivariable regression revealed that male CCS, less educated or not married were significantly more likely to be in the high-risk behaviors group than the low-risk group., Conclusions: As CCS remain a vulnerable population, screening for HRB should be routinized in long-term follow-up care and interventions targeting multiple HRB simultaneously among survivors should be developed., (© 2020 John Wiley & Sons Ltd.)

Background: Surgery demonstration (SD) is considered to be a mainstay of surgical education, but controversy exists concerning the patient's safety. Indeed, the presence of visiting surgeons is a source of distraction and may have an impact on surgeon's performance. This study's objective was to evaluate possible differences in outcomes between robotic sphincter-saving rectal cancer surgery (RRCS) performed during routine surgical practice versus in the presence of visiting surgeons in the operating room (OR) with direct access to the surgeon., Methods: Retrospective case-matched studies were conducted from a prospectively collected database. 114 patients (38 with the presence of visiting surgeons) who underwent RRCS between January 2013 and September 2018 were included. Patients were matched in a 1:2 basis after propensity score analysis using five criteria: gender, body mass index, preoperative chemoradiation, type of mesorectum excision, and synchronous liver metastasis., Results: There was no difference between the two groups with regard to mean operating time, estimated blood loss, conversion, and hospital stay. Also, overall (44% vs. 40%; P = 0.6), major morbidity (26% vs. 19%; P = 0.5), and unplanned reoperation (17% vs. 15%; P = 1.0) rates were not statistically different. No difference was noted with regard to the quality of mesorectum excision, or positive rate of circumferential and distal longitudinal resection margins. The mean number of harvested lymph nodes (17 vs. 14.5; P = 0.04) was lower in the SD group and the number of patients with < 12 harvested lymph nodes (31% vs. 16%; P = 0.09) was greater after SD although it did not reach statistical significance. No differences were observed in disease-free or overall survival., Conclusions: The presence of visiting surgeons in the OR seems not to interfere in the quality of rectal resection and does not compromise patient's short-term outcome and survival. However, mild differences in the extent of lymphadenectomy were observed and the surgeons performing SD may be aware of this.

Purpose: The R2Pulm trial was conducted to evaluate the effect of busulfan-melphalan high-dose chemotherapy with autologous stem-cell rescue (BuMel) without whole-lung irradiation (WLI) on event-free survival (main end point) and overall survival, compared with standard chemotherapy with WLI in Ewing sarcoma (ES) presenting with pulmonary and/or pleural metastases., Methods: From 2000 to 2015, we enrolled patients younger than 50 years of age with newly diagnosed ES and with only pulmonary or pleural metastases. Patients received chemotherapy with six courses of vincristine, ifosfamide, doxorubicin, and etoposide (VIDE) and one course of vincristine, dactinomycin, and ifosfamide (VAI) before either BuMel or seven courses of VAI and WLI (VAI plus WLI) by randomized assignment. The analysis was conducted as intention to treat. The estimates of the hazard ratio (HR), 95% CI, and P value were corrected for the three previous interim analyses by the inverse normal method., Results: Of 543 potentially eligible patients, 287 were randomly assigned to VAI plus WLI (n = 143) or BuMel (n = 144). Selected patients requiring radiotherapy to an axial primary site were excluded from randomization to avoid excess organ toxicity from interaction between radiotherapy and busulfan. Median follow-up was 8.1 years. We did not observe any significant difference in survival outcomes between treatment groups. Event-free survival was 50.6% versus 56.6% at 3 years and 43.1% versus 52.9% at 8 years, for VAI plus WLI and BuMel patients, respectively, resulting in an HR of 0.79 (95% CI, 0.56 to 1.10; P = .16). For overall survival, the HR was 1.00 (95% CI, 0.70 to 1.44; P = .99). Four patients died as a result of BuMel-related toxicity, and none died after VAI plus WLI. Significantly more patients in the BuMel arm experienced severe acute toxicities than in the VAI plus WLI arm., Conclusion: In ES with pulmonary or pleural metastases, there is no clear benefit from BuMel compared with conventional VAI plus WLI.

Background and Objectives: The number of robotic colorectal procedures performed has rapidly increased, but there are only sparse data available about the robotic learning curve of expert laparoscopic colorectal surgeons., Methods: In this retrospective study, we reviewed 101 minimally invasive right colectomies consecutively performed by a single surgeon with 20 years of clinical practice fully dedicated to laparoscopic surgery. Thus, the last 59 laparoscopic resections were compared with the first 42 robotic resections., Results: The duration of the procedure was longer in the robotic group, but the conversion rate was the same in both groups. There was no difference between groups in rates of overall and severe postoperative complications, reoperation, hospital length of stay, and readmission. Number of harvested lymph nodes and oncological quality of resection defined by the pathologist were the same., Conclusions: This study suggests that the transition from the right laparoscopic colectomy with extracorporeal anastomosis to the robot-assisted right colectomy with intracorporeal anastomosis when performed by a surgeon with experience in laparoscopic colorectal surgery may not entail any increase on the morbidity rate or reduce the oncologic quality of the resection., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest directly relevant to the content of this article., (© 2019 by JSLS, Journal of the Society of Laparoendoscopic Surgeons.)

Pupose: Medulloblastoma is the most common primary malignant central nervous system tumor in childhood, accounting for 16-25% of cases (1). New treatment approaches have led to improved survival rates; however toxicities are still a major concern., Patients and Methods: Participants were selected from the records of patients who were treated with craniospinal irradiation for medulloblastoma. Between January 2008 and December 2012, 62 patients were diagnosed with medulloblastoma at the national institute of oncology Rabat, 27 patients were still alive at the time of the study, of which n=16 patients were included in the study. The mean age of patients at the time of the study was 9.6 years. All children were treated with radiation therapy and chemotherapy, according to standard protocols. Median follow-up between treatment and evaluation was 4 years. All the children were assessed with the Wechsler Intelligence Scale for Children - fourth Edition (WISC-IV) three to five years after completion of radiotherapy. The test was administered by two well-trained psychologists in a distraction-free environment. The scoring was then reviewed by a psychologist from Brooklyn College., Results: The mean standard score Full-Scale Intelligence Quotient (FSIQ) (M=63, SD=12.6) was found to be in the extremely low range and in the 1st percentile rank (PR), compared to the general population. All the measured primary index scales were below typical performance: verbal comprehension (M=67.7, SD=13.1), perceptual reasoning (M=63.5, SD=13.8) and processing speed (M=62.7, SD=15.5) were all found to be in the extremely low range, while xorking memory (M=75.5, SD=10.8) was found to be in the borderline range compared to the general population. To identify factors influencing the results, we performed both univariate and multivariate analyses. Age at the time of radiotherapy, initial clinical stage, total cranial radiotherapy dose, socioeconomic status, and the time of evaluation were identified as significantly impacting cognitive scores in the univariate analysis. In the multivariate analysis, only age at the time of radiotherapy and initial clinical stage remained factors significantly impacting cognitive outcomes with P=0.001 and P<0.001 respectively., Conclusion: Our study is evidence that tremendous efforts are still to be made in low-income countries to correctly measure neurocognitive dysfunction in medulloblastoma survivors and to prepare those patients to a typical life after the completion of treatment., (Copyright © 2019. Published by Elsevier Masson SAS.)

Renal tubulointerstitial fibrosis is the final common pathway in end-stage renal disease and is characterized by aberrant accumulation of extracellular matrix (ECM) components secreted by myofibroblasts. Tubular type 2 EMT, induced by TGF- β , plays an important role in renal fibrosis, by participating directly or indirectly in myofibroblasts generation. TGF- β 1-induced apoptosis and fibrosis in experimental chronic murine kidney diseases are concomitantly associated with an intrarenal decreased expression of the IL-15 survival factor. Since IL-15 counteracts TGF- β 1 effects in different cell models, we analyzed whether (1) human chronic inflammatory nephropathies evolving towards fibrosis could be also characterized by a weak intrarenal IL-15 expression and (2) IL-15 could inhibit epithelial-mesenchymal transition (EMT) and excess matrix deposition in human renal proximal tubular epithelial cells (RPTEC). Our data show that different human chronic kidney diseases are characterized by a strong decreased expression of intrarenal IL-15, which is particularly relevant in diabetic nephropathy, in which type 2 tubular EMT plays an important role in fibrosis. Moreover, primary epithelial tubular cultures deprived of growth supplements rapidly produce active TGF- β 1 inducing a "spontaneous" EMT process characterized by the loss of membrane-bound IL-15 (mbIL-15) expression. Both "spontaneous" EMT and recombinant human (rh) TGF- β 1-induced EMT models can be inhibited by treating RPTEC and HK2 cells with rhIL-15. Through a long-lasting phospho-c-jun activation, IL-15 inhibits rhTGF- β 1-induced Snail1 expression, the master inducer of EMT, and blocks TGF- β 1-induced tubular EMT and downstream collagen synthesis. In conclusion, our data suggest that intrarenal IL-15 could be a natural inhibitor of TGF- β in human kidney able to guarantee epithelial homeostasis and to prevent EMT process. Thus, both in vivo and in vitro an unbalance in intrarenal IL-15 and TGF- β 1 levels could render RPTEC cells more prone to undergo EMT process. Exogenous IL-15 treatment could be beneficial in some human nephropathies such as diabetic nephropathy.

Introduction: Timing of major elective operations is a potentially important outcome variable. This study examined the impact of operative start time (OST) on pathologic and short-term outcomes of minimally invasive rectal surgery (MIRS)., Methods: All rectal tumors patients who underwent MIRS from May 2012 to April 2016 were identified. Peroperative outcomes and the oncological quality of surgical excision were compared between patients with OST before 13.00h and after., Results: A total of 137 patients were included in the study (71 Romarobot-assisted and 66 conventional laparoscopic). Ninety-nine (72%) patients were operated before 13.00h and 38 after 13.00h. The majority of cases were low/middle rectal tumors (69%). Patient's baseline characteristics were quite similar in both groups. The rate of severe complication (p=0.460) or reoperation (p=0.614) was the same. Pathologic criteria (T or N stage, number of harvested lymph nodes, and presence of any positive margin) were the same between groups except for the quality of mesorectal excision (ME) that was significantly poorer for cases beginning after 13.00h (complete 91% vs 74%; p=0.016). The OST was found to be the only parameter associated with a poor quality of ME [OR 2.55 (1.08 - 6.36)]., Conclusion: Perioperative outcome after MIRS does not appear to be influenced by OST. Poorer quality of ME was observed and may thus raise important questions about the timing and sequence of case scheduling.

Background: Survivors of Hodgkin lymphoma (HL) in childhood have an increased risk of subsequent malignant neoplasms (SMNs). Herein, the authors extended the follow-up of a previously reported Late Effects Study Group cohort and identified patients at highest risk for SMNs to create evidence for risk-based screening recommendations., Methods: The standardized incidence ratio was calculated using rates from the Surveillance, Epidemiology, and End Results program as a reference. The risk of SMN was estimated using proportional subdistribution hazards regression. The cohort included 1136 patients who were diagnosed with HL before age 17 years between 1955 and 1986. The median length of follow-up was 26.6 years., Results: In 162 patients, a total of 196 solid SMNs (sSMNs) were identified. Compared with the general population, the cohort was found to be at a 14-fold increased risk of developing an sSMN (95% confidence interval, 12.0-fold to 16.3-fold). The cumulative incidence of any sSMN was 26.4% at 40 years after a diagnosis of HL. Risk factors for breast cancer among females were an HL diagnosis between ages 10 years and 16 years and receipt of chest radiotherapy. Males treated with chest radiotherapy at age <10 years were found to be at highest risk of developing lung cancer. Survivors of HL who were treated with abdominal/pelvic radiotherapy and high-dose alkylating agents were found to be at highest risk of developing colorectal cancer and females exposed to neck radiotherapy at age <10 years were at highest risk of thyroid cancer. By age 50 years, the cumulative incidence of breast, lung, colorectal, and thyroid cancer was 45.3%, 4.2%, 9.5%, and 17.3%, respectively, among those at highest risk., Conclusions: Survivors of childhood HL remain at an increased risk of developing sSMNs. In the current study, subgroups of survivors of HL at highest risk of specific sSMNs were identified, and evidence for screening provided., (© 2018 American Cancer Society.)

Background: Paediatric cancer survivors have a high risk of developing cardiac diseases, and the most frequent cardiac disease is heart failure (HF). The radiation dose-volume effects in the heart and cardiac substructures have not been explored in childhood cancer survivors (CCS). Therefore, the role of irradiated heart volume in the occurrence of HF among this population remains unclear. The aims of this study were to determine the doses and irradiated volumes of the heart and left ventricle (LV) related to the risk of HF in CCS and to investigate the impact of anthracycline exposure on this risk., Methods and Results: A case-control study nested in the French Childhood Cancer Survivors Study cohort. The mean heart and left ventricular doses and volumes indicators were estimated by reconstruction of individual treatments. A total of 239 HF cases and 1042 matched controls were included. The median age of HF diagnosis was 25.1 years. The median volume of the heart that received ≥ 30 Gy was 61.1% for cases and 16.9% for controls. In patients who did not receive anthracycline, the risk of HF was increased 3.6-fold when less than 10% of the LV received ≥ 30 Gy when compared to patients who were not exposed to any cardiac radiation and anthracycline., Conclusions: Small irradiated volumes of the heart or LV were significantly associated with HF risk. To the author's knowledge, this is the first study to report a dose-response relationship based on dose-volume indicators in CCS, which can be translated efficiently into current clinical practice., (© 2018 The Authors. European Journal of Heart Failure © 2018 European Society of Cardiology.)

Introduction: Although several studies have compared totally robot-assisted gastric bypass (RA-GB) to laparoscopic gastric bypass (L-GB), the clinical benefit of the robotic approach remains unclear., Materials and Methods: We compared perioperative outcomes of 82 consecutive patients undergoing RA-GB between 2013 and 2016 to 169 consecutive patients having undergone L-GB between 2009 and 2016. Secondary endpoints included duration of hospitalization, readmission rate, weight loss at 1 year, and the learning curve of RA-GB, assessed by operation times and complication rates., Results: There were no statistically significant differences between groups concerning age (43.5 ± 11.2 vs. 42.2 ± 12.4 years), body mass index (42.4 ± 5.0 vs. 43.6 ± 7.2 kg/m 2 ), or comorbidities. The rate of revision surgery was higher in L-GB group without reaching statistical significance. No statistically significant difference was observed for duration of operation (134 ± 35 vs. 135 ± 37 min), readmission rate at 90 days (4.9% vs. 8.9%), or percentage of excess weight loss at 1 year (RA-GB vs. L-GB) (76.8% ± 20.5 vs. 73.1% ± 23.5). There were fewer statistically significant complications overall in RA-GB (9.8% vs. 21.9%, p = 0.019). Median duration of hospital stay was shorter for RA-GB (3 vs. 4 days, p < 0.0001). The mean duration of operation for RA-GB decreased from 153 min in 2014 to 122 min in 2016; p = 0.004., Conclusion: In our experience, the robotic approach for gastric bypass was associated with fewer postoperative complications compared to traditional laparoscopic gastric bypass. Cost increment associated with RA-GB remains an important drawback that hampers its widespread.

Background: Very few previous studies have addressed the question of colorectal cancer (CRC) after childhood cancer treatment. We aimed to quantify the roles of radiation therapy and chemotherapy agents in the occurrence of subsequent CRC., Methods: A nested case-control study was conducted using 36 CRC cases and 140 controls selected from 7032 five-year survivors of the French Childhood Cancer Survivor Study (FCCSS) cohort, treated from 1945 to 2000 in France. The radiation dose-distribution metrics at the site of CRC and doses of individual chemotherapeutic agents were calculated. Conditional logistic regressions were performed to calculate odds ratios (ORs)., Results: Overall, patients who received radiotherapy with estimated dose to colon had a 4.3-fold (95% CI, 1.3-17.6) increased risk for CRC compared with patients who did not receive radiotherapy, after adjustment for chemotherapy. This risk increased to 8.9-fold and 19.3-fold among patients who received radiation doses ranging from 20 to 29.99 Gy and ≥30 Gy, respectively. Our data reported a significantly elevated OR for anthracyclines, after controlling for radiotherapy and MOPP regimen. But, restricted analyses excluding patients who had received ≥30 Gy showed that only radiation doses ranging from 20 to 29.99 Gy produced a significant increase in subsequent CRC risk (OR = 7.8; 95% CI, 1.3-56.0), after controlling for anthracyclines and MOPP regimen., Conclusions: The risk of subsequent CRC was significantly increased after radiation dose (even < 30 Gy). This novel finding supports the need to update monitoring guidelines for CRC to optimize the long-term follow-up for subsequent CRC in survivors of childhood cancer., (© 2018 Wiley Periodicals, Inc.)

Purpose For over 30 years, the place of consolidation high-dose chemotherapy in Ewing sarcoma (ES) has been controversial. A randomized study was conducted to determine whether consolidation high-dose chemotherapy improved survival in patients with localized ES at high risk for relapse. Methods Randomization between busulfan and melphalan (BuMel) or standard chemotherapy (vincristine, dactinomycin, and ifosfamide [VAI], seven courses) was offered to patients if they were younger than 50 years of age with poor histologic response (≥ 10% viable cells) after receiving vincristine, ifosfamide, doxorubicin, and etoposide (six courses); or had a tumor volume at diagnosis ≥ 200 mL if unresected, or initially resected, or resected after radiotherapy. A 15% improvement in 3-year event-free survival (EFS) was sought (hazard ratio [HR], 0.60). Results Between 2000 and 2015, 240 patients classified as high risk (median age, 17.1 years) were randomly assigned to VAI (n = 118) or BuMel (n = 122). Seventy-eight percent entered the trial because of poor histologic response after chemotherapy alone. Median follow-up was 7.8 years. In an intent-to-treat analysis, the risk of event was significantly decreased by BuMel compared with VAI: HR, 0.64 (95% CI, 0.43 to 0.95; P = .026); 3- and 8-year EFS were, respectively, 69.0% (95% CI, 60.2% to 76.6%) versus 56.7% (95% CI, 47.6% to 65.4%) and 60.7% (95% CI, 51.1% to 69.6%) versus 47.1% (95% CI, 37.7% to 56.8%). Overall survival (OS) also favored BuMel: HR, 0.63 (95% CI, 0.41 to 0.95; P = .028); 3- and 8-year OS were, respectively, 78.0% (95% CI, 69.6% to 84.5%) versus 72.2% (95% CI, 63.3% to 79.6%) and 64.5% (95% CI, 54.4% to 73.5%) versus 55.6% (95% CI, 45.8% to 65.1%). Results were consistent in the sensitivity analysis. Two patients died as a result of BuMel-related toxicity, one after standard chemotherapy. Significantly more BuMel patients experienced severe acute toxicities from this course of chemotherapy compared with multiple VAI courses. Conclusion BuMel improved EFS and OS when given after vincristine, ifosfamide, doxorubicin, and etoposide induction in localized ES with predefined high-risk factors. For this group of patients, BuMel may be an important addition to the standard of care.

Background: Vaginal/uterine rhabdomyosarcoma (VU RMS) is one of the most favorable RMS sites. To determine the optimal therapy, the experience of four cooperative groups (Children's Oncology Group [COG], International Society of Pediatric Oncology (SIOP) Malignant Mesenchymal Tumor Group [MMT], Italian Cooperative Soft Tissue Sarcoma Group [ICG], and European pediatric Soft tissue sarcoma Study Group [EpSSG]) was analyzed., Procedure: From 1981 to 2009, 237 patients were identified. Median age (years) at diagnosis differed by tumor location; it was 1.9 for vagina (n = 160), 2.7 for uterus corpus (n = 26), and 13.5 for uterus cervix (n = 51). Twenty-eight percent of patients received radiation therapy (RT) as part of primary therapy (23% COG, 27% MMT, 46% ICG, and 42% EpSSG), with significant differences in the use of brachytherapy between the cooperative groups (23% COG, 76% MMT, 64% ICG, and 88% EpSSG)., Results: Ten-year event-free (EFS) and overall survival (OS) were 74% (95% CI, 67-79%) and 92% (95% CI, 88-96%), respectively. In univariate analysis, OS was inferior for patients with uterine RMS and for those with regional lymph node involvement. Although EFS was slightly lower in patients without initial RT (71% without RT vs. 81% with RT; P = 0.08), there was no difference in OS (94% without RT vs. 89% with RT; P = 0.18). Local control using brachytherapy was excellent (93%). Fifty-one (51.5%) of the 99 survivors with known primary therapy and treatment for relapse were cured with chemotherapy with or without conservative surgery., Conclusions: About half of all patients with VU RMS can be cured without systematic RT or radical surgery. When RT is indicated, modalities that limit sequelae should be considered, such as brachytherapy., (© 2018 Wiley Periodicals, Inc.)

Background: Rhabdomyosarcoma is an aggressive tumour that can develop in almost any part of the body. Doxorubicin is an effective drug against rhabdomyosarcoma, but its role in combination with an established multidrug regimen remains controversial. Therefore, we aimed to evaluate the possible benefit of early dose intensification with doxorubicin in patients with non-metastatic rhabdomyosarcoma., Methods: We did a multicentre, open-label, randomised controlled, phase 3 trial involving 108 hospitals from 14 countries. We included patients older than 6 months but younger than 21 years with a pathologically proven diagnosis of rhabdomyosarcoma. We assigned each patient to a specific subgroup according to the EpSSG stratification system. Those with embryonal rhabdomyosarcoma incompletely resected and localised at unfavourable sites with or without nodal involvement, or those with alveolar rhabdomyosarcoma without nodal involvement were considered at high risk of relapse. These high-risk patients were randomly assigned (1:1) to receive either nine cycles of IVA (ifosfamide 3 g/m 2 given as a 3-h intravenous infusion on days 1 and 2, vincristine 1·5 mg/m 2 weekly during the first 7 weeks then only on day 1 of each cycle [given as a single intravenous injection], and dactinomycin 1·5 mg/m 2 on day 1 given as a single intravenous injection) or four cycles of IVA with doxorubicin 30 mg/m 2 given as a 4-h intravenous infusion on days 1 and 2 followed by five cycles of IVA. The interval between cycles was 3 weeks. Randomisation was done using a web-based system and was stratified (block sizes of four) by enrolling country and risk subgroup. Neither investigators nor patients were masked to treatment allocation. The primary endpoint was 3-year event-free survival assessed by the investigator at each centre in the intention-to-treat population. Patients who received at least one dose of study treatment were considered in the safety analysis. In agreement with the independent data monitoring committee, the study was closed to patient entry on Dec 16, 2013, after futility analysis. This trial is registered with EudraCT, number 2005-000217-35, and is currently in follow-up., Findings: Between Oct 1, 2005, and Dec 16, 2013, 484 patients were randomly assigned to receive each chemotherapy regimen (242 in the IVA group and 242 in the IVA plus doxorubicin group). Median follow-up was 63·9 months (IQR 44·6-78·9). The 3-year event-free survival was 67·5% (95% CI 61·2-73·1) in the IVA plus doxorubicin group and 63·3% (56·8-69·0) in the IVA group (hazard ratio 0·87, 95% CI 0·65-1·16; p=0·33). Grade 3-4 leucopenia (232 [93%] of 249 patients in the IVA plus doxorubicin group vs 194 [85%] of 227 in the IVA group; p=0·0061), anaemia (195 [78%] vs 111 [49%]; p<0·0001), thrombocytopenia (168 [67%] vs 59 [26%]; p<0.0001), and gastrointestinal adverse events (78 [31%] vs 19 [8%]; p<0·0001) were significantly more common in the IVA plus doxorubicin group than in the IVA group. Grade 3-5 infections (198 [79%] vs 128 [56%]; p<0·0001) were also significantly more common in the IVA plus doxorubicin group than in the IVA group, in which one patient had grade 5 infection. Two treatment-related deaths were reported (one patient developed septic shock and one affected by Goldenhar syndrome developed intractable seizures) in the IVA plus doxorubicin group, both occurring after the first cycle of treatment, and none were reported in the IVA group., Interpretations: The addition of dose-intensified doxorubicin to standard IVA chemotherapy did not show a significant improvement in the outcome of patients with high-risk non-metastatic rhabdomyosarcoma. Therefore, the IVA chemotherapy regimen should remain the standard of care for patients with localised rhabdomyosarcoma in Europe., Funding: Fondazione Città della Speranza, Italy, and the Association Léon Berard Enfant Cancéreux, France., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Purpose: To describe fecundity in female survivors of childhood cancer and consider the correlation with quality of life (QOL)., Materials and Methods: Of 1744 women treated for childhood cancer before the age of 15 years at one of eight French cancer treatment centers between 1948 and 1992, 1187 who were alive in 2005 were sent a self-administered questionnaire, including questions about health status, QOL (MOS SF-36), and fecundity. A standardized fecundity ratio (SFR) was calculated (SFR: observed/expected number of children) for each individual based on a national reference., Results: Of the 972 individuals (82%) who responded, 53% had at least 1 child. The overall SFR, 0.65, was dependent upon the initial diagnosis, more decreased in Central Nervous System tumors (0.24; p < 10 -3 ) than in Germ cell (0.46; p = 0.03) or Sympathetic Nervous System tumors (0.79; p = 0.02). The average QOL motor score was 72.5 ± 19.5, and the average mental score was 61.4 ± 16.7. After adjusting for age, pathology, and self-reported sequelae in the questionnaires, it was determined that SF-36 mental (p = 0.002) and motor (p < 0.0002) scores correlated positively with fecundity, and SF-36 scores correlated negatively with locomotor late effects (p < 0.0001), growth insufficiency (p = 0.002), and psychological disorders (p < 0.001). Gonadal insufficiency was correlated with neither motor nor mental scores., Conclusion: Women treated for childhood cancer demonstrated impaired fecundity that correlated with poor QOL, as registered by the SF-36. Patients should be warned of the risk of impaired fecundity early during the follow-up. If possible, preservation of fertility should be prioritized at initiation of therapy.

Objective: The purpose of this study was to determine the characteristics of early second breast cancer (SBC) among survivors of childhood and young adult malignancy treated with irradiation., Methods: We conducted a multicenter retrospective study of women who presented with breast cancer aged 50 years or younger in nine French centers., Results: 121 patients and 141 SBC were analyzed (invasive = 130; non-invasive = 11). The mean age at first cancer diagnosis was 15 years and at initial SBC diagnosis was 38 years. Bilateral disease before the age of 51 years was diagnosed in 16% of the females. The majority of SBC were invasive carcinomas (92%). Among the invasive carcinomas, 39% had a histoprognostic score of III, 3.1% overexpressed HER2 and 29% were triple negative. The proportion of triple negative phenotype SBC was higher in patients older at first cancer diagnosis [RR = 1.2, 95% CI (1.1-1.3)]. 94% of triple negative SBCs developed in breast tissue which had received >20 Gy., Conclusion: We found a high proportion of aggressive SBC following thoracic radiotherapy in childhood or early adulthood. Advances in knowledge: SBC screening is recommended by scientific societies for these child/young-adulthood cancer survivors in the same way as the one for high risk women because of constitutional mutations. Our results support these recommendations, not only because of a similar cumulative risk, but also because of the aggressive histological characteristics.

Background: Early response to induction chemotherapy is used in current European guidelines to evaluate the efficacy of chemotherapy and subsequently to adapt treatment in pediatric patients with rhabdomyosarcoma (RMS). However, existing literature on the prognostic value of early radiologic response on survival is contradictory; here the prognostic value is analyzed with data from the International Society of Pediatric Oncology (SIOP) Malignant Mesenchymal Tumor 95 (MMT-95) study., Methods: This study examined 432 Intergroup Rhabdomyosarcoma Study Grouping III (macroscopic residue) patients enrolled in the SIOP MMT-95 study with a response assessment after 3 courses of chemotherapy (a 2-dimensional assessment). Patients with progressive disease (PD) after 3 courses of chemotherapy were excluded (n = 7). Failure-free survival (FFS) and overall survival (OS), calculated with the Kaplan-Meier method, were compared for 3 groups (complete response [CR]/partial response [PR], objective response [OR], and no response [NR]). The prognostic impact of early response was assessed through the calculation of Cox proportional hazards., Results: After 3 courses of chemotherapy, 85.2% of the patients had CR/PR, 8.6% had OR, and 6.3% had NR. For all patients, the 5-year FFS and OS rates were 60% (95% confidence interval [CI], 56%-65%) and 74% (95% CI, 70%-78%), respectively. However, a Cox proportional hazards regression analysis revealed no significant difference in FFS or OS between the response groups. The adjusted hazard ratios for an OR and NR were 1.09 (95% CI, 0.63-1.88) and 0.81 (95% CI, 0.39-1.67), respectively, for FFS and 0.91 (95% CI, 0.47-1.76) and 1.27 (95% CI, 0.61-2.64), respectively, for OS., Conclusions: No evidence was found for the idea that early radiologic response to chemotherapy is prognostic for survival for patients with RMS. Treatment adaptation based on early response (except for patients with PD) should, therefore, no longer be incorporated into future studies. Cancer 2018;124:1016-24. © 2017 American Cancer Society., (© 2017 American Cancer Society.)

Background: Minimally invasive sphincter-saving rectal resection represents a challenging procedure. Robotic surgery for rectal cancer has several advantages over conventional surgery in performing precise dissection and was proved to be safe and effective in previous studies. However, comparison between laparoscopic and robotic rectal resection has drawn contradictory results. The aim of the present study was to compare robotic and laparoscopic sphincter-saving rectal resections for short-term and pathological outcomes., Methods: Between January 2013 and May 2016, we performed a total of 258 robotic surgeries, including 146 colorectal resections (56%). For this study, we included the first 65 sphincter-saving robotic resections and compared them to the last 65 consecutive laparoscopic resections. The laparoscopic group was constituted by the last 65 consecutively operated patients who matched the inclusion criteria., Results: Patients' baseline characteristics were similar in both the groups. Conversion rate was greater in the laparoscopic group (17 vs. 5%, p=0.044). Reoperation rate, overall and severe morbidity, and median hospital stay were similar in both the groups. Quality of mesorectal excision specimen was considered complete or near complete in 97 and 96% in the laparoscopic and robotic groups, respectively. There was no difference in the rates of negative circumferential radial margin, distal margin, and surgical success measured by composite criteria., Conclusion: The main finding of this study was that robotic proctectomy for sphincter-saving procedures offers similar quality of TME with a statistically significant lower rate of conversion when compared to laparoscopic proctectomy.

Purpose: To report the results from International Society of Pediatric Oncology (SIOP) Malignant Mesenchymal Tumors studies (MMT 89 and 95) of males with nonmetastatic paratesticular rhabdomyosarcoma., Methods: From 1989 to 2003, 159 patients were included. Radical inguinal orchidectomy was recommended, but retroperitoneal lymph node (LN) assessment was based on imaging alone. The treatment was stratified by stage (SIOP tumor-node-metastasis staging system) and histology., Results: Median age at presentation was 5.6 years (range 0.3-17.6) and 120 patients were of <10 years (75%). Patients ≥10 years had tumors of >5 cm more frequently compared to patients of <10 years (54% vs. 22%, P = 0.0004). The 5- year overall and progression-free survivals were 94% and 83%, respectively. Seventy-eight percent of relapses occurred in the retroperitoneal LN. Thirty-one percent of stage N0 patients of age ≥10 years developed node relapse, compared with 8% of N0 patients aged <10 years (P = 0.0005)., Conclusions: Older patients with paratesticular rhabdomyosarcoma have a significant risk of LN relapse. These results support a surgical approach to LN staging in this subgroup of patients., (© 2017 Wiley Periodicals, Inc.)

Purpose: We evaluated the role of bevacizumab as part of the multi-modality treatment of children and adolescents with metastatic rhabdomyosarcoma (RMS) or non-rhabdomyosarcoma soft tissue sarcoma (NRSTS)., Patients and Methods: Eligible patients aged ≥6 months to <18 years were randomised to receive induction chemotherapy (four cycles of IVADo + five cycles of IVA, ±bevacizumab), surgery and/or radiotherapy, followed by maintenance chemotherapy (12 cycles of low-dose cyclophosphamide + vinorelbine, ±bevacizumab). The primary objective was event-free survival (EFS) evaluated by an independent radiological review committee., Results: One hundred and fifty-four patients were randomised to receive chemotherapy alone (n = 80) or with bevacizumab (n = 74). At the data cut-off for the primary efficacy analysis, median EFS was 14.9 months (95% confidence interval [CI]: 10.8-35.9) with chemotherapy and 20.6 months (95% CI: 15.2-24.9) with bevacizumab plus chemotherapy (stratified hazard ratio [HR] = 0.93; 95% CI: 0.61-1.41; P = 0.72). The HR for EFS in patients with RMS (n = 103) was 1.24 (95% CI: 0.73-2.09) versus 0.64 (95% CI: 0.32-1.26) for those with NRSTS (n = 49). Objective response rate was 36.0% (95% CI: 25.2-47.9) with chemotherapy and 54.0% (95% CI: 40.9-66.6) with bevacizumab plus chemotherapy (difference of 18.0%; 95% CI: 0.6-35.3). There were no treatment-related deaths and no increased incidence of grade 3/4 toxicities with bevacizumab., Conclusion: The addition of bevacizumab to chemotherapy appeared tolerable in children and adolescents with metastatic RMS/NRSTS, but the primary end-point of EFS did not show statistically significant improvement., Trial Registration: ClinicalTrials.gov, NCT00643565., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Purpose: Irradiation (>3Gy) to the breast or axillae before 30years of age increases the risk of secondary breast cancer (SBC). The purpose of this article is to describe the clinical characteristics of SBC and the way of diagnosis in young women (before the age of national screening) in France who had received previous radiotherapy for a childhood or a young adulthood cancer., Patients and Methods: This retrospective, multicentre study reviewed the medical records of women with SBC before the age of the national screening who had received irradiation (≥3Gy) on part or all of the breast before 30years of age, for any type of tumour except BC., Results: A total of 121 SBC were detected in 104 women with previous radiotherapy. Twenty percent of SBC were detected during regular breast screening and 16% of the women had a regular radiological follow-up., Conclusion: Our results points out that the main proportion of childhood cancer survivors did not benefit from the recommended breast cancer screening. This result is comparable to other previously published studies in other countries. A national screening programme is necessary and should take into account the patient's age, family history, personal medical history and previous radiotherapy to reduce the number of SBC diagnosed at an advanced stage., (Copyright © 2017. Published by Elsevier B.V.)

Purpose: Access to insurance for a loan or a mortgage is an important issue for childhood cancer survivors. The aim of this study was to describe difficulties experienced by adult survivors., Methods: A total of 1920 survivors treated before the age of 18 in five French cancer centers responded to a questionnaire in 2010. Survivors who had tried to obtain a loan were asked if they had experienced difficulties, which were defined as experiencing rejection, higher premiums, or exclusions. The questionnaire investigated health problems related to the circulatory, respiratory, digestive, urinary, endocrine, hormonal, and nervous systems. Second tumors, diabetes mellitus, cardiac disease, and stroke were ascertained from a physician's report or medical records. Multivariable analyses were conducted to identify the characteristics of survivors reporting difficulties., Results: Difficulties were experienced by 10.4% of those who had tried to obtain a small loan (n = 787) and by 30.1% of those who had tried to obtain a home loan (n = 909). Disclosure of childhood cancer to the insurer and amputation surgery were negatively associated with insurance accessibility, even when controlling for age, gender, education, health-related unemployment, familial situation, and severe or life-threatening conditions such as cardiovascular diseases, second cancers, or diabetes., Conclusion: This study showed that the financial burden of cancer can extend decades after diagnosis., Implications for Cancer Survivors: Thanks to a 2016 law, French cancer survivors no longer have to disclose their cancer to insurers after a fixed number of years. This law will probably lessen the socioeconomic burden of cancer.

Purpose: To report the results of a conservative strategy based on partial surgery combined with brachytherapy in a prospective cohort of children with bladder-prostate rhabdomyosarcoma (BP RMS)., Methods and Materials: We prospectively documented the outcome of children treated in our department between 1991 and 2015 for BP RMS and undergoing a multimodal approach combining conservative surgery (partial cystectomy and/or partial prostatectomy) and perioperative interstitial low-dose-rate or pulse-dose-rate brachytherapy. Before brachytherapy, children had received chemotherapy with modalities depending on their risk group of treatment., Results: A total of 100 patients were identified, with a median age of 28 months (range, 5.6 months-14 years). According to the Intergroup Rhabdomyosarcoma Study (IRS) group, 84 were IRS-III, and 12 were IRS-IV tumors. Four patients were treated at relapse. The median number of chemotherapy cycles before local therapy was 6 (range, 4-13). After surgery, 63 patients had a macroscopic tumor residuum. Five patients underwent a brachytherapy boost before pelvic external beam radiation therapy because of nodal involvement, and 95 had exclusive brachytherapy. Median follow-up was 64 months (range, 6 months-24.5 years). Five-year disease-free and overall survival rates were 84% (95% confidence interval 80%-88%) and 91% (95% confidence interval 87%-95%), respectively. At last follow-up most survivors presented with only mild to moderate genitourinary sequelae and a normal diurnal urinary continence. Five patients required a secondary total cystectomy: 3 for a nonfunctional bladder and 2 for relapse., Conclusion: Brachytherapy is effective as part of a conservative strategy for BP RMS, with a relatively low delayed toxicity as compared with previously published studies using external beam radiation therapy. Longer follow-up is required to ensure that the functional results are maintained over time., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background and Purpose: The aim of this study was to investigate the role of radiation dose received to the circle of Willis (WC) during radiation therapy (RT) and of potential dose-response modifiers on the risk of stroke after treatment of childhood cancer., Methods: We evaluated the risk factors for stroke in a cohort of 3172 5-year survivors of childhood cancer who were followed up for a median time of 26 years. Radiation doses to the WC and brain structures were estimated for each of the 2202 children who received RT., Results: Fifty-four patients experienced a confirmed stroke; 39 were ischemic. Patients not receiving RT had a stroke risk similar to that of the general population, whereas those who received RT had an 8.5-fold increased risk (95% confidence interval [CI]: 6.3-11.0). The excess of incidence of stroke increased yearly. The dose of radiation to the WC, rather than to other brain structures, was found to be the best predictor of stroke. The relative risk was 15.7 (95% CI: 4.9-50.2) for doses of 40 Gy or more. At 45 years of age, the cumulative stroke incidence was 11.3% (95% CI: 7.1%-17.7%) in patients who received 10 Gy or more to the WC, compared with 1% expected from general population data. Radiation doses received to the heart and neck also increased the risk. Surgery for childhood brain cancer was linked to hemorrhagic strokes in these patients., Conclusion: The WC should be considered as a major organ at risk during RT for childhood brain cancers. The incidence of radiation-induced ischemic stroke strongly increases with long-term follow-up., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Hodgkin's lymphoma (HL) in children and adolescents is highly curable, but children are at risk of long-term toxicity. The MDH-03 guidelines were established in order to decrease the burden of treatment in good-responder patients, and this report should be considered a step toward further optimization of treatment within large collaborative trials. We report the therapy and long-term outcomes of 417 children and adolescents treated according to the national guidelines, which were applied between 2003 and 2007 in France. The patients were stratified into three groups according to disease extension. Chemotherapy consisted of four cycles of VBVP (vinblastine, bleomycin, VP16, prednisone) in localized stages (G1/95 pts/23%), four cycles of COPP/ABV (cyclophosphamide, vincristine, procarbazine, prednisone, adriamycin, bleomycin, vinblastine) cycles in intermediate stages (G2/184 pts/44%) and three cycles of OPPA (vincristine, procarbazine, prednisone, adriamycin) plus three cycles of COPP in advanced stages (G3/138 pts/33%). Radiation therapy of the involved field was given to 97% of the patients, with the dose limited to 20 Gy in good responders (88%). With a median follow-up of 6.6 years, the 5-year event-free survival (EFS) and overall survival (OS) were 86.7% (83.1-89.7%) and 97% (94.5-98.1%), respectively. EFS and OS for G1, G2, and G3 were 98% and 100%, 81% and 97%, and 87% and 95%, respectively. Low-risk patients treated without alkylating agents and anthracycline had excellent outcomes and a low expected incidence of late effects. Intensification with a third OPPA cycle in high-risk group patients, including stage IV patients, allowed for very good outcomes, without increased toxicity.

This study evaluated the prevalence of psychological distress (PD) in a cohort of 348 adult childhood cancer survivors with a very long-term follow-up and assessed the characteristics associated with this distress (cancer type, treatment, sex, age at diagnosis, self-reported late effects, social support, type of remembrance, time since the diagnosis, age at evaluation), assuming that with time since the diagnosis, the PD of survivors will approximate that of the general population. Before attending a long-term follow-up consultation, survivors were sent 3 questionnaires: the Brief Symptom Inventory-18, the Impact of Event Scale, and the Illness Worry Scale (IWS). During the visit, they were administered the Mini-International Neuropsychiatric Interview (MINI) by a psychologist. The mean age of the survivors was 38.5 years (18.1-65.8) at consultation, 7 years (0.0-18.0) at cancer diagnosis, and mean time since diagnosis was 31.5 years (8.8-56.1). Multiple regression analyses of the data collected from self-administered questionnaires confirmed that being female, living alone, and self-reported late effects were associated with the high scores for all scales. Negative remembrances and being accompanied to the clinic were associated with higher IWS scores. Unlike the initial hypothesis, the MINI showed that, compared with controls, survivors experienced a higher prevalence of anxiety and mood disorders even after a very long time since the diagnosis. These findings show that a substantial subset of survivors experiment a high prevalence of PD, higher than the general population, and should be screened for PD whatever the time since the diagnosis.

Background: The role of postoperative radiotherapy (PORT) in Ewing sarcoma (ES) is unclear. We assessed the impact of PORT on local control in patients with localised ES and good histological response to chemotherapy (<10% cells)., Patients and Methods: All randomised patients in the EE99-R1 trial (comparing two consolidation chemotherapy regimens) undergoing surgery after induction chemotherapy were included. Local relapse (LR) cumulative incidence was estimated using a competing risk approach. Impact of PORT was assessed in multivariable models, adjusted for country, age, tumour site and volume, quality of resection and histological response. We also evaluated the heterogeneity of PORT effect by patient and tumour characteristics., Results: One hundred forty-two (24%) of the 599 patients included from 1999 to 2009 received PORT (median dose: 45 Grays). With median follow-up of 6.2 years, 67 patients had an LR (with concomitant metastases in 28), leading to an 8-year LR-incidence = 11.9% (standard error [se] = 1.4%). Overall survival (OS) = 21% (se = 5%) 3 years after LR (31% in isolated LR). Controlling for possible confounders, we observed a statistically significant reduction of LR in patients treated by surgery + PORT compared to surgery alone (subdistribution-hazard ratio = 0.43, 95% confidence interval, 0.21-0.88, p = 0.02). The benefit of PORT was particularly marked for tumours larger than 200 ml at diagnosis and 100% necrosis. We observed a non-significant trend for benefit associated with PORT for disease-free, event-free and OS., Conclusion: Radiotherapy appears to improve local control. We now recommend PORT in case of incomplete removal of the tissues involved by the pre-chemotherapy tumour volume. Further studies are required to assess the balance between benefit and risks., (Copyright © 2016. Published by Elsevier Ltd.)

Background: Although survival from childhood cancer has increased, little is known on the long-term impact of treatment late effects on occupational attainment or work ability., Methods: A total of 3512 five-year survivors treated before the age of 19 years in 10 French cancer centres between 1948 and 2000 were identified. Educational level, employment status and occupational class of survivors were assessed by a self-reported questionnaire. These outcome measures were compared with sex-age rates recorded in the French population, using indirect standardisation. Paternal occupational class was also considered to control for the role of survivors' socioeconomic background on their achievement. Multivariable analyses were conducted to explore clinical characteristics associated with the outcomes., Results: A total of 2406 survivors responded to the questionnaire and survivors aged below 25 years were included in the current analysis. Compared with national statistics adjusted on age and sex, male survivors were more likely to be college graduates (39.2% vs 30.9% expected; P<0.001). This higher achievement was not observed either for leukaemia or central nervous system (CNS) tumour survivors. Health-related unemployment was higher for survivors of CNS tumour (28.1% vs 4.3%; P<0.001) but not for survivors of other diagnoses. Survivors of non-CNS childhood cancer had a similar or a higher occupational class than expected., Conclusions: Survivors treated for CNS tumour or leukaemia, especially when treatment included cranial irradiation, might need support throughout their lifespan.

Importance: Few studies have been published on the association of the radiation dose received to the eyes during radiotherapy (RT) for childhood cancer and the risk for later cataract., Objective: To investigate the risk for cataract after treatment of nonretinoblastoma solid cancer in childhood., Design, Setting, and Participants: The study used data from the Euro2K cohort that includes 4389 5-year survivors of solid tumors treated from January 1, 1945, to December 31, 1985; of these, 3172 patients were treated in France. A self-reported questionnaire was sent to French survivors from September 1, 2005, to December 31, 2012, when follow-up was considered completed for this study. However, 619 patients died before the beginning of the study and 128 patients treated for a retinoblastoma or who underwent enucleation were excluded. Likewise, 429 patients with unknown addresses or who did not return the consent form and 163 nonresponders did not participate. The remaining 1833 patients who completed the questionnaire underwent analysis for this study from June 1, 2014, to December 7, 2015., Main Outcomes and Measures: Radiation doses in both eyes for individuals were estimated for all patients who had received RT. The role of the radiation dose in cataract risk was investigated using the Cox proportional hazard regression model and the excess relative or the absolute risk model. The role of ctytotoxic chemotherapy was also investigated., Results: The 1833 patients (961 men [52.4%]; 872 women [47.6%]; mean [SD] age, 37.0 [8.5]) who returned the questionnaire were included in the analysis. After a mean follow-up of 32 years, 33 patients with unilateral or bilateral cataract were identified, for a total of 47 cataract events. The 47 events were validated by medical record review and by contacting the patients and the corresponding medical physician or ophthalmologist to obtain copies of diagnostic examinations or surgical reports. Overall, in a multivariable Cox proportional hazard regression analysis, patients who received RT had a 4.4-fold (95% CI, 1.5- to 13.0-fold) increased risk for cataract compared with patients who did not receive RT. Exposure to radiation doses of at least 10 Gy to the eyes increased the hazard ratio 39-fold (95% CI, 12.0- to 127.9-fold), relative to no radiation exposure. Although based on few patients, a strong increase in cataract risk (hazard ratio, 26.3; 95% CI, 7.1-96.6) was observed in patients treated with melphalan hydrochloride., Conclusions and Relevance: This study can inform guideline-based recommendations for long-term follow-up for cataract.

Background: Cardiac disease (CD) is one of the major side effects of childhood cancer therapy, but until now little has been known about the relationship between the heart radiation dose (HRD) received during childhood and the risk of CD., Methods and Results: The cohort comprised 3162 5-year survivors of childhood cancer. Chemotherapy information was collected and HRD was estimated. There were 347 CDs in 234 patients, 156 of them were rated grade ≥3. Cox and Poisson regression models were used. The cumulative incidence of any type of CD at 40 years of age was 11.0% (95% confidence interval [CI], 9.5-12.7) and 7·4% (95% CI, 6.2-8.9) when only the CDs of grade ≥3 were considered. In comparison with patients who received no anthracycline and either no radiotherapy or an HRD<0·1Gy, the risk was multiplied by 18·4 (95% CI, 7.1-48.0) in patients who had received anthracycline and no radiotherapy or a HRD <0.1Gy, by 60.4 (95% CI, 22.4-163.0) in those who had received no anthracycline and an HRD≥30Gy, and 61.5 (95% CI, 19.6-192.8) in those who had received both anthracycline and an HRD≥30Gy., Conclusions: Survivors of childhood cancers treated with radiotherapy and anthracycline run a high dose-dependent risk of developing CD. CDs develop earlier in patients treated with anthracycline than in those treated without it., (© 2015 American Heart Association, Inc.)

Background: Extremity rhabdomyosarcomas do not always show satisfactory outcomes. We analyzed data from 643 patients treated in 14 studies conducted by European and North American groups between 1983 and 2004 to identify factors predictive of outcome., Procedure: Clinical factors, including age; histology; site of primary (hand and foot vs. other); size; invasiveness (T stage); nodal involvement (N stage); and treatment factors, including post-surgical group; chemotherapy type and duration; radiotherapy; and treatment (before or after 1995); were evaluated for impact on overall survival (OS)., Results: 5-year OS were 67% (se 1.8). Multivariate analysis showed that lower OS correlated with age >3 years, T2 and N1 stage, incomplete initial surgery, treatment before 1995, and European cooperative group treatment. Patients with gross residual disease after initial incomplete resection/biopsy had similar outcomes in both continental groups. The better global survival of patients treated in American studies was accounted for by differences in outcome in the subset of those with grossly resected tumors (OS 86% [se 3] for COG patients vs. 68% [se 4] for European patients (P = 0.004)). When excluding chemotherapy duration from the model, analysis in this subset of patients showed that cooperative group (P = 0.001), site (P = 0.001), and T stage (P = 0.05) were all significant. However, after adding duration of chemotherapy (≥27 weeks) to the model, only primary site remained significant (P = 0.006)., Conclusion: This meta-analysis confirms the role of many established prognostic factors but identifies for the first time that chemotherapy duration may have an impact on outcome in patients with grossly resected tumors., (© 2015 Wiley Periodicals, Inc.)

Context: Thyroid carcinoma is a frequent complication of childhood cancer radiotherapy. The dose response to thyroid radiation dose is now well established, but the potential modifier effect of other factors requires additional investigation., Objective: This study aimed to investigate the role of potential modifiers of the dose response., Design: We followed a cohort of 4338 5-year survivors of solid childhood cancer treated before 1986 over an average of 27 years. The dose received by the thyroid gland and some other anatomical sites during radiotherapy was estimated after reconstruction of the actual conditions in which irradiation was delivered., Results: Fifty-five patients developed thyroid carcinoma. The risk of thyroid carcinoma increased with a radiation dose to the thyroid of up to two tenths of Gy, then leveled off for higher doses. When taking into account the thyroid radiation dose, a surgical or radiological splenectomy (>20 Gy to the spleen) increased thyroid cancer risk (relative risk [RR] = 2.3; 95% confidence interval [CI], 1.3-4.0), high radiation doses (>5 Gy) to pituitary gland lowered this risk (RR = 0.2; 95% CI, 0.1-0.6). Patients who received nitrosourea chemotherapy had a 6.6-fold (95% CI, 2.5-15.7) higher risk than those who did not. The excess RR per Gy of radiation to the thyroid was 4.7 (95% CI, 1.7-22.6). It was 7.6 (95% CI, 1.6-33.3) if body mass index at time of interview was equal or higher than 25 kg/m(2), and 4.1 (95% CI, 0.9-17.7) if not (P for interaction = .1)., Conclusion: Predicting thyroid cancer risk following childhood cancer radiation therapy probably requires the assessment of more than just the radiation dose to the thyroid. Chemotherapy, splenectomy, radiation dose to pituitary gland, and obesity also play a role.

Purpose: To investigate the roles of radiation therapy and chemotherapy in the occurrence of subsequent leukemia after childhood cancer., Methods and Materials: We analyzed data from a case-control study with 35 cases and 140 controls. The active bone marrow (ABM) was segmented into 19 compartments, and the radiation dose was estimated in each. The chemotherapy drug doses were also estimated to enable adjustments. Models capable of accounting for radiation dose heterogeneity were implemented for analysis., Results: Univariate analysis showed a significant trend in the increase of secondary leukemia risk with radiation dose, after accounting for dose heterogeneity (P=.046). This trend became nonsignificant after adjustment for doses of epipodophyllotoxins, alkylating agents, and platinum compounds and the first cancer on multivariate analysis (P=.388). The role of the radiation dose appeared to be dwarfed, mostly by the alkylating agents (odds ratio 6.9, 95% confidence interval 1.9-25.0). Among the patients who have received >16 Gy to the ABM, the radiogenic risk of secondary leukemia was about 4 times greater in the subgroup with no alkylating agents than in the subgroup receiving ≥10 g/m(2)., Conclusions: Notwithstanding the limitations resulting from the size of our study population and the quite systematic co-treatment with chemotherapy, the use of detailed information on the radiation dose distribution to ABM enabled consideration of the role of radiation therapy in secondary leukemia induction after childhood cancer., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Purpose: To prospectively assess the long-term toxicities of brachytherapy in female survivors with localized genital tract tumors., Patients and Methods: The data concerning 42 patients treated at Gustave Roussy between 1971 and 2004, were both retrospectively and prospectively analyzed. Strictly confidential constructed surveys based on the LENT SOMA/SF-36v2 questionnaires were mailed and 51% were completed. Complications were recorded throughout the follow-up period and graded according to CTCAE, version 4.0., Results: The median age at diagnosis was 1.7 years (range, 0.6-16.6) and most patients (69%) had rhabdomyosarcomas. Treatments included brachytherapy delivered in all patients, chemotherapy (88%), surgery (31%), and external beam radiotherapy (5%). At a median follow-up of 15.5 years, 41/42 patients were alive. A total of 160 late effects were identified in 32/42 (76%) patients: 72% G1-2, and 28% G3-4 (the mean number of all grade late effects per patient: 4 [median: 2.5; range, 0-16] and the mean number of G3-4 late effects per patient: 1[median: 0; range, 0-8]). The most common all grade late toxicities were gynecological (75/160; 47%) and G3-4 were urinary (24/45; 53%). Sixteen patients (38%) required surgical treatment of late complications. The 15-year actuarial incidence rate of G3-4 late effects was 51%. The total number of all grade and G3-4 late effects was significantly increased in patients treated before 1990 (p=0.005 and p=0.008), when the cumulative dose was higher (p=0.03 and p=0.02), when the maximal dose was delivered to the ovaries (p=0.002 and p=0.04), and when the brachytherapy volume was larger (p=0.03 and p=0.02). Quality of life was good or very good in 91% of patients who completed the surveys., Conclusion: Long-term effects decreased with advances in treatment. Stringently controlled brachytherapy parameters should allow us to pursue improvements in order to prevent or minimize long-term sequelae., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Ewing sarcoma (ES) is an aggressive sarcoma of bone and soft tissue occurring at any age with a peak incidence in adolescents and young adults. The treatment of ES relies on a multidisciplinary approach, coupling risk-adapted intensive neoadjuvant and adjuvant chemotherapies with surgery and/or radiotherapy for control of the primary site and possible metastatic disease. The optimization of ES multimodality therapeutic strategies has resulted from the efforts of several national and international groups in Europe and North America and from cooperation between pediatric and medical oncologists. Successive first-line trials addressed the efficacy of various cyclic combinations of drugs incorporating doxorubicin, vincristine, cyclophosphamide, ifosfamide, etoposide, and dactinomycin and identified prognostic factors now used to tailor therapies. The role of high-dose chemotherapy is still debated. Current 5-year overall survival for patients with localized disease is 65% to 75%. Patients with metastases have a 5-year overall survival < 30%, except for those with isolated pulmonary metastasis (approximately 50%). Patients with recurrence have a dismal prognosis. The many insights into the biology of the EWS-FLI1 protein in the initiation and progression of ES remain to be translated into novel therapeutic strategies. Current options and future approaches will be discussed., (© 2015 by American Society of Clinical Oncology.)

Deciphering the ways in which somatic mutations and germline susceptibility variants cooperate to promote cancer is challenging. Ewing sarcoma is characterized by fusions between EWSR1 and members of the ETS gene family, usually EWSR1-FLI1, leading to the generation of oncogenic transcription factors that bind DNA at GGAA motifs. A recent genome-wide association study identified susceptibility variants near EGR2. Here we found that EGR2 knockdown inhibited proliferation, clonogenicity and spheroidal growth in vitro and induced regression of Ewing sarcoma xenografts. Targeted germline deep sequencing of the EGR2 locus in affected subjects and controls identified 291 Ewing-associated SNPs. At rs79965208, the A risk allele connected adjacent GGAA repeats by converting an interspaced GGAT motif into a GGAA motif, thereby increasing the number of consecutive GGAA motifs and thus the EWSR1-FLI1-dependent enhancer activity of this sequence, with epigenetic characteristics of an active regulatory element. EWSR1-FLI1 preferentially bound to the A risk allele, which increased global and allele-specific EGR2 expression. Collectively, our findings establish cooperation between a dominant oncogene and a susceptibility variant that regulates a major driver of Ewing sarcomagenesis.

Background: Primary cutaneous/subcutaneous Ewing sarcoma (scEWS) is extremely rare. We describe clinical features, treatment, and outcome of this Ewing localization., Procedure: Retrospective study (1996-2012) on 56 patients., Results: Most primary scEWS occurred in late adolescent/young adult females (F/M = 1.9; median age 21.5 years), with primary tumor in the extremity/trunk (48.5%/39%). Only 35/56 samples had Real-Time-Polymerase-Chain-Reaction/Fluorescent-In-Situ-Hybridization analysis, 32/35 had EWS-translocation. Most of them exhibited known favorable prognostic factors: localized disease (54/56), initial tumor volume < 200 ml (51/53). Thirty and 25 patients received chemotherapy according to Euro-Ewing99 or a shorter/less intense chemotherapy regimen associated with milder toxicity. One patient had not received chemotherapy. Surgery was performed at diagnosis in 37 patients (18/37 marginal/intra-lesional resections) followed by secondary surgery in 8/37 (three remained marginal). Nineteen other patients had an initial biopsy followed by chemotherapy, 15/19 underwent late surgery (4/15 marginal/intra-lesional resections). Overall, 27/56 patients received radiotherapy. Median follow-up was six years (1-15). Two patients with metastatic disease progressed at metastatic sites. Four patients with localized disease experienced progression/relapse (local n = 3, metastatic n = 1). Survival was excellent: 5y-OS and 5y-EFS were 93.8% (95%CI = 83-98%) and 88.5% (95%CI-= 77-95), respectively., Conclusions: Unplanned primary surgery should be avoided to try to minimize potential long term sequels due to secondary surgery or radiotherapy. Biopsy with molecular analysis and staging should be performed at diagnosis to inform treatment recommendations. Patients with metastases should be treated aggressively as for other metastatic EWS. Further studies are necessary to clarify whether a less intensive chemotherapy regimen could be safely used in localized disease to minimize acute/late toxicities., (© 2015 Wiley Periodicals, Inc.)

The prognosis of primary disseminated multifocal metastatic Ewing's sarcoma (PDMES) is poor even if a slight improvement has been achieved with high-dose alkylating agent-containing chemotherapy. To enhance treatment efficacy, we assessed the feasibility, safety and efficacy of a tandem high-dose chemotherapy (HDC) regimen. In a single institution, patients with PDMES received six courses of vincristine/ifosfamide/doxorubicin/etoposide induction therapy, followed by high-dose thiotepa, and then melphalan-busulfan, 8 weeks apart. Surgical resection of primary tumour was carried out between the two HDC regimens and 70 days after the last HDC regimen for post-operative radiotherapy or irradiation alone. From October 2002 to 2009, 13 of the 18 consecutive patients with PDMES (72%) received the full treatment programme. The other five patients experienced early progression and died. Among the 13 patients, 11 relapsed after the end of the treatment programme within 6 months (2.2-11.9) from end of therapy. Only two patients are still alive in first complete remission after 9 years. The 3-year event-free survival (EFS) and overall survival (OS) rates were 11 and 22%, respectively. The median EFS and OS duration from the diagnosis were 13.4 and 17.3 months, respectively. Neither major complications nor treatment-related death occurred. The tandem-HDC regimen was feasible, with expected side effects, but it did not improve the outcome of patients with PDMES.

Study Question: What is the effect of different alkylating agents used without pelvic radiation to treat childhood cancer in girls on the ovarian reserve in survivors?, Summary Answer: Ovarian reserve seems to be particularly reduced in survivors who received procarbazine (in most cases for Hodgkin lymphoma) or high-dose chemotherapy; procarbazine but not cyclophosphamide dose is associated with diminished ovarian reserve., What Is Known Already: A few studies have demonstrated diminished ovarian reserve in survivors after various combination therapies, but the individual role of each treatment is difficult to assess., Study Design: Prospective cross-sectional study, involving 105 survivors and 20 controls., Participants/materials, Setting, Methods: One hundred and five survivors aged 17-40 years and 20 controls investigated on Days 2-5 of a menstrual cycle or Day 7 of an oral contraceptive pill-free interval., Main Outcome Measures: ovarian surface area (OS), total number of antral follicles (AFC), serum levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol and anti-Müllerian hormone (AMH)., Main Results and the Role of Chance: Survivors had a lower OS than controls: 3.5 versus 4.4 cm(2) per ovary (P = 0.0004), and lower AMH levels: 10.7 versus 22 pmol/l (P = 0.003). Ovarian markers (OS, AMH, AFC) were worse in patients who received high-dose compared with conventional-dose alkylating agents (P = 0.01 for OS, P = 0.002 for AMH, P < 0.0001 for AFC). Hodgkin lymphoma survivors seemed to have a greater reduction in ovarian reserve than survivors of leukaemia (P = 0.04 for AMH, P = 0.01 for AFC), sarcoma (P = 0.04 for AMH, P = 0.04 for AFC) and other lymphomas (P = 0.04 for AFC). A multiple linear regression analysis showed that procarbazine but not cyclophosphamide nor ifosfamide dose was associated with reduced OS (P = 0.0003), AFC (P = 0.0007), AMH (P < 0.0001) and higher FSH levels (P < 0.0001)., Limitations, Reasons for Caution: The small percentage of participating survivors (28%) from the total cohort does not allow conclusion on fertility issues because of possible response bias. The association between procarbazine and HL makes it impossible to dissociate their individual impacts on ovarian reserve. The number of controls is small, but ovarian volume and AMH levels in survivors were compared with published normal values and results were unchanged., Wider Implications of the Findings: Early detection and follow-up of compromised ovarian function after cancer therapy should help physicians to counsel young survivors about their fertility window. However, longitudinal follow-up is required to determine the rate of progression from low ovarian reserve to premature ovarian failure., Study Funding/competing Interests: La Ligue contre le Cancer (grant no., PRAYN7497). The authors have no competing interests to disclose., (© The Author 2015. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)