Publications by authors named "Claire Berger"

104 Publications

Surgery with emicizumab prophylaxis for two paediatric patients with severe haemophilia A with inhibitors.

Pediatr Blood Cancer 2021 Apr 13:e29041. Epub 2021 Apr 13.

Hematology and Oncology Pediatric Unit, Haemophilia CRC Hospital of Saint-Etienne, Saint-Etienne, France.

Emicizumab is a prophylaxis for patients with severe haemophilia A with and without inhibitor. Despite weekly administration of emicizumab, coagulation states stay below normal value and cannot be assessed by standard haemostasis tests. In our two patients, we used the thrombin-generation assay (endogenous thrombin potential and Peak) to monitor the patient's clotting status. Under emicizumab, it is necessary to add a bypassing agent (BPA) such as rFVIIa (Novoseven) to avoid bleeding before surgery. The BPA dosage was based on a thrombin-generation assay and collegial consultation.
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http://dx.doi.org/10.1002/pbc.29041DOI Listing
April 2021

Personalized Massive Open Online Course for Childhood Cancer Survivors: Behind the Scenes.

Appl Clin Inform 2021 03 24;12(2):237-244. Epub 2021 Mar 24.

Inserm U 1018, CESP, Cancer and Radiation Team, University of Paris-Saclay, Paris-Sud University, Villejuif, France.

Background: Today, in France, it is estimated that 1 in 850 people aged between 20 and 45 years has been treated for childhood cancer, which equals 40,000 to 50,000 people. As late effects of the cancer and its treatment affect a large number of childhood cancer survivors (CCS) and only 30% of them benefit from an efficient long-term follow-up care for prevention, early detection, and treatment of late effects, health education of CCS represents a challenge of public health.

Objectives: Massive open online courses (MOOCs) are a recent innovative addition to the online learning landscape. This entertaining and practical tool could easily allow a deployment at a national level and make reliable information available for all the CCS in the country, wherever they live.

Methods: The MOOC team brings together a large range of specialists involved in the long-term follow-up care, but also associations of CCS, video producers, a communication consultant, a pedagogical designer, a cartoonist and a musician. We have designed three modules addressing transversal issues (lifestyle, importance of psychological support, risks of fertility problems) and eight modules covering organ-specific problems. Detailed data on childhood cancer treatments received were used to allocate the specific modules to each participant.

Results: This paper presents the design of the MOOC entitled "Childhood Cancer, Living Well, After," and how its feasibility and its impact on CCS knowledge will be measured. The MOOC about long-term follow-up after childhood cancer, divided into 11 modules, involved 130 participants in its process, and resulted in a 170-minute film. The feasibility study included 98 CCS (31 males vs. 67 females;  < 0.0001).

Conclusion: Such personalized, free, and online courses with an online forum and a possible psychologist consultation based on unique characteristics and needs of each survivor population could improve adherence to long-term follow-up without alarming them unnecessarily.
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http://dx.doi.org/10.1055/s-0041-1725185DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7990573PMC
March 2021

Compliance with Early Long-Term Prophylaxis Guidelines for Severe Hemophilia A.

J Pediatr 2021 Mar 4. Epub 2021 Mar 4.

APHM, La Timone Children's Hospital, Department of Pediatric Hematology, Immunology and Oncology, Marseille, France; Aix Marseille Univ, INSERM, INRAe, C2VN, Marseille, France.

Objectives: To evaluate the applicability and compliance with guidelines for early initiation of long-term prophylaxis in infants with severe hemophilia A and to identify factors associated with guideline compliance.

Study Design: This real-world, prospective, multicenter, population-based FranceCoag study included almost all French boys with severe hemophilia A, born between 2000 and 2009 (ie, after guideline implementation).

Results: We included 333 boys in the study cohort. The cumulative incidence of long-term prophylaxis use was 61.2% at 3 years of age vs 9.5% in a historical cohort of 39 boys born in 1996 (ie, before guideline implementation). The guidelines were not applicable in 23.1% of patients due to an early intracranial bleeding or inhibitor development. Long-term prophylaxis was delayed in 10.8% of patients. In the multivariate analysis, 2 variables were significantly associated with "timely long-term prophylaxis" as compared with "delayed long-term prophylaxis": hemophilia treating center location in the southern regions of France (OR 23.6, 95% CI 1.9-286.7, P = .013 vs Paris area) and older age at long-term prophylaxis indication (OR 7.2 for each additional year, 95% CI 1.2-43.2, P = .031). Long-term prophylaxis anticipation was observed in 39.0% of patients. Earlier birth year (OR 0.5, 95% CI 0.3-0.8, P = .010 for birth years 2005-2009 vs 2000-2004) and age at first factor replacement (OR 1.9 for each additional year, 95% CI 1.2-3.0, P = .005) were significantly associated with "long-term prophylaxis guideline compliance" vs "long-term prophylaxis anticipation."

Conclusions: This study suggests that long-term prophylaxis guidelines are associated with increased long-term prophylaxis use. However, early initiation of long-term prophylaxis remains a challenge.
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http://dx.doi.org/10.1016/j.jpeds.2021.02.071DOI Listing
March 2021

Possible modification of BRSK1 on the risk of alkylating chemotherapy-related reduced ovarian function.

Hum Reprod 2021 Mar;36(4):1120-1133

German Childhood Cancer Registry, Institute of Medical Biostatistics, Epidemiology and Informatics, University Medical Center, Mainz, Germany.

Study Question: Do genetic variations in the DNA damage response pathway modify the adverse effect of alkylating agents on ovarian function in female childhood cancer survivors (CCS)?

Summary Answer: Female CCS carrying a common BR serine/threonine kinase 1 (BRSK1) gene variant appear to be at 2.5-fold increased odds of reduced ovarian function after treatment with high doses of alkylating chemotherapy.

What Is Known Already: Female CCS show large inter-individual variability in the impact of DNA-damaging alkylating chemotherapy, given as treatment of childhood cancer, on adult ovarian function. Genetic variants in DNA repair genes affecting ovarian function might explain this variability.

Study Design, Size, Duration: CCS for the discovery cohort were identified from the Dutch Childhood Oncology Group (DCOG) LATER VEVO-study, a multi-centre retrospective cohort study evaluating fertility, ovarian reserve and risk of premature menopause among adult female 5-year survivors of childhood cancer. Female 5-year CCS, diagnosed with cancer and treated with chemotherapy before the age of 25 years, and aged 18 years or older at time of study were enrolled in the current study. Results from the discovery Dutch DCOG-LATER VEVO cohort (n = 285) were validated in the pan-European PanCareLIFE (n = 465) and the USA-based St. Jude Lifetime Cohort (n = 391).

Participants/materials, Setting, Methods: To evaluate ovarian function, anti-Müllerian hormone (AMH) levels were assessed in both the discovery cohort and the replication cohorts. Using additive genetic models in linear and logistic regression, five genetic variants involved in DNA damage response were analysed in relation to cyclophosphamide equivalent dose (CED) score and their impact on ovarian function. Results were then examined using fixed-effect meta-analysis.

Main Results And The Role Of Chance: Meta-analysis across the three independent cohorts showed a significant interaction effect (P = 3.0 × 10-4) between rs11668344 of BRSK1 (allele frequency = 0.34) among CCS treated with high-dose alkylating agents (CED score ≥8000 mg/m2), resulting in a 2.5-fold increased odds of a reduced ovarian function (lowest AMH tertile) for CCS carrying one G allele compared to CCS without this allele (odds ratio genotype AA: 2.01 vs AG: 5.00).

Limitations, Reasons For Caution: While low AMH levels can also identify poor responders in assisted reproductive technology, it needs to be emphasized that AMH remains a surrogate marker of ovarian function.

Wider Implications Of The Findings: Further research, validating our findings and identifying additional risk-contributing genetic variants, may enable individualized counselling regarding treatment-related risks and necessity of fertility preservation procedures in girls with cancer.

Study Funding/competing Interest(s): This work was supported by the PanCareLIFE project that has received funding from the European Union's Seventh Framework Programme for research, technological development and demonstration under grant agreement no 602030. In addition, the DCOG-LATER VEVO study was funded by the Dutch Cancer Society (Grant no. VU 2006-3622) and by the Children Cancer Free Foundation (Project no. 20) and the St Jude Lifetime cohort study by NCI U01 CA195547. The authors declare no competing interests.

Trial Registration Number: N/A.
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http://dx.doi.org/10.1093/humrep/deaa342DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7970730PMC
March 2021

Communication and ethical considerations for fertility preservation for patients with childhood, adolescent, and young adult cancer: recommendations from the PanCareLIFE Consortium and the International Late Effects of Childhood Cancer Guideline Harmonization Group.

Lancet Oncol 2021 02;22(2):e68-e80

Division of Gynecology and Reproduction, Department of Reproductive Medicine, Karolinska University Hospital, Stockholm, Sweden; Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.

Patients with childhood, adolescent, and young adult cancer who will be treated with gonadotoxic therapies are at increased risk for infertility. Many patients and their families desire biological children but effective communication about treatment-related infertility risk and procedures for fertility preservation does not always happen. The PanCareLIFE Consortium and the International Late Effects of Childhood Cancer Guideline Harmonization Group reviewed the literature and developed a clinical practice guideline that provides recommendations for ongoing communication methods for fertility preservation for patients who were diagnosed with childhood, adolescent, and young adult cancer at age 25 years or younger and their families. Moreover, the guideline panel formulated considerations of the ethical implications that are associated with these procedures. Grading of Recommendations Assessment, Development and Evaluation methodology was used to grade the evidence and recommendations. In this clinical practice guideline, existing evidence and international expertise are combined to develop transparent recommendations that are easy to use to facilitate ongoing communication between health-care providers and patients with childhood, adolescent, and young adult cancer who might be at high risk for fertility impairment and their families.
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http://dx.doi.org/10.1016/S1470-2045(20)30595-7DOI Listing
February 2021

Health-Related Quality of Life in European Childhood Cancer Survivors: Protocol for a Study Within PanCareLIFE.

JMIR Res Protoc 2021 Jan 25;10(1):e21851. Epub 2021 Jan 25.

Swiss Childhood Cancer Registry, Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland.

Background: Survival after childhood cancer has improved to more than 80% during the last few years, leading to an increased number of childhood cancer survivors. Cancer itself, or its treatment, may cause chronic health conditions, including somatic and mental sequelae, which may affect survivors' health-related quality of life (HRQoL).

Objective: The project PanCareLIFE aims to establish a large database with comprehensive data on childhood cancer survivors from different European countries, including data on HRQoL. Within PanCareLIFE, this study aims to describe HRQoL in survivors, investigate predictors of HRQoL, and describe the association of HRQoL with hearing and female fertility impairment. This paper describes the design of the HRQoL study, the origin of data, strategies for data collection, and sampling characteristics of survivors from each contributing country.

Methods: A total of 6 institutions from 5 European countries (the Czech Republic, France, Germany, the Netherlands, and Switzerland) provided data on HRQoL assessed with the Short Form 36 and on relevant predictors. The central PanCareLIFE data center aggregated the data and harmonized the variables between the institutions. Survivors were eligible if they received a diagnosis of cancer according to the 12 main groups of the International Classification of Childhood Cancer, 3rd edition, or Langerhans cell histiocytosis; were aged ≤18 years at the time of diagnosis; were residents of the respective country at the time of diagnosis; had survived ≥5 years after cancer diagnosis; were aged ≥18 years at the time of the questionnaire survey; and did not refuse to registration in the national or local childhood cancer cohort.

Results: We identified 24,993 eligible survivors. Of those, 19,268 survivors received a questionnaire and 9871 survivors participated, resulting in response rates of 9871/24,993 (39.50%) of eligible survivors and of 9871/19,268 (51.23%) invited survivors. Most participants were diagnosed with cancer between the ages of 10 and 14 years (3448/9871, 34.93%) or <5 years (3201/9871, 32.43%). The median age was 8 years. Of the 9871 participants, 3157 (31.97%) were survivors of leukemia, 2075 (21.02%) lymphoma, and 1356 (13.7%) central nervous system (CNS) tumors. Most participants (9225/9871, 93.46%) had no history of a subsequent tumor; 77.45% (7645/9871) received chemotherapy with or without other treatments. More than half (5460/9871, 55.31%) were aged 25 to 34 years at the time of the HRQoL study. Participating survivors differed from nonparticipants; participants were more often women, survivors of leukemia or lymphoma, and less frequently, survivors of CNS tumors than nonparticipants.

Conclusions: PanCareLIFE successfully assessed HRQoL and its predictors in 9871 European survivors of childhood cancer. This large population will permit detailed investigations of HRQoL after childhood cancer, particularly the impact of hearing and female fertility impairment on HRQoL.

International Registered Report Identifier (irrid): RR1-10.2196/21851.
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http://dx.doi.org/10.2196/21851DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7870350PMC
January 2021

Prognostic relevance of clinical and molecular risk factors in children with high-risk medulloblastoma treated in the phase 2 trial PNET HR+5.

Neuro Oncol 2020 Dec 30. Epub 2020 Dec 30.

Departments of Pathology, Toulouse University Hospital, Toulouse III university, Toulouse, France.

Background: High-risk medulloblastoma are defined by the presence of metastatic disease and/or incomplete resection and/or unfavorable histopathology and/or tumors with MYC amplification. We aimed to assess the 3-year progression-free survival (PFS) and define the molecular characteristics associated with PFS in patients aged 5 to 19 years with newly diagnosed high-risk medulloblastoma treated according to the phase 2 trial PNET HR+5.

Methods: All children received postoperative induction chemotherapy (etoposide and carboplatin), followed by 2 high-dose thiotepa courses (600 mg/m 2) with hematological stem cell support. At the latest 45 days after the last stem cell rescue, patients received risk-adapted craniospinal radiation therapy. Maintenance treatment with temozolomide was planned to start between 1-3 months after the end of radiotherapy. The primary endpoint was PFS. Outcome and safety analyses were per protocol (all patients who received at least one dose of induction chemotherapy).

Results: Fifty-one patients (median age, 8 years; range, 5-19) were enrolled. The median follow-up was 7.1 years (range: 3.4-9.0). The 3 and 5-year PFS with their 95% confidence intervals (95%CI) were 78% (65-88) and 76% (63-86), and the 3 and 5-year OS were 84% (72-92) and 76% (63-86), respectively. Medulloblastoma subtype was a statistically significant prognostic factor (p-value=0.039) with large-cell/anaplastic being of worse prognosis, as well as molecular subgroup (p-value=0.012) with SHH and group 3 being of worse prognosis than WNT and group 4. Therapy was well tolerated.

Conclusions: This treatment based on high-dose chemotherapy and conventional radiotherapy resulted in a high survival rate in children with newly diagnosed high-risk medulloblastoma.
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http://dx.doi.org/10.1093/neuonc/noaa301DOI Listing
December 2020

Gastrointestinal bleeding from angiodysplasia in von Willebrand disease: Improved diagnosis and outcome prediction using videocapsule on top of conventional endoscopy.

J Thromb Haemost 2021 02 29;19(2):380-386. Epub 2020 Nov 29.

Department of Hematology and Transfusion, CHU Lille, Institut d'Hématologie Transfusion, Lille, France.

Background: Despite a high prevalence of angiodysplasia, no specific guidelines are available for the modalities of endoscopic exploration of gastrointestinal (GI) bleeding in von Willebrand disease (VWD). Whether VWD patients could benefit from video capsule endoscopy (VCE) looking for angiodysplasia eligible to endoscopic treatment or at high risk of bleeding is unknown.

Objectives: To assess the diagnostic efficacy for angiodysplasia and the prognostic value of VCE on top of conventional endoscopy in VWD patients with GI bleeding.

Patients/methods: A survey was sent to the 30 centers of the French-network on inherited bleeding disorders to identify VWD patients referred for endoscopic exploration of GI bleeding from January 2015 to December 2017. Data obtained included patient characteristics, VWD phenotype/genotype, GI bleeding pattern, results of endoscopic investigations, and medical management applied including endoscopic therapy. We assessed by Kaplan-Meier analysis the recurrence-free survival after the first GI bleeding event according to endoscopic categorization and, in patients with angiodysplasia, to the presence of small-bowel localizations on VCE exploration.

Results: GI bleeding source localization was significantly improved when including VCE exploration (P < .01), even in patients without history of angiodysplasia (P < .05). Patients with angiodysplasia had more GI bleeding recurrences (P < .01). A lower recurrence-free survival was observed in patients with angiodysplasia (log-rank test, P = .02), and especially when lesions were located in the small bowel (log-rank test, P < .01), even after endoscopic treatment with argon plasma coagulation (log-rank test, P < .01).

Conclusion: VCE should be more systematically used in VWD patients with unexplained or recurrent GI bleeding looking for angiodysplasia eligible to endoscopic treatment or at high risk of relapse.
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http://dx.doi.org/10.1111/jth.15155DOI Listing
February 2021

Guidance regarding COVID-19 for survivors of childhood, adolescent, and young adult cancer: A statement from the International Late Effects of Childhood Cancer Guideline Harmonization Group.

Pediatr Blood Cancer 2020 12 23;67(12):e28702. Epub 2020 Sep 23.

Department of Malignant Haematology, Great Ormond Street Hospital for Children NHS Trust, London, UK.

Childhood, adolescent, and young adult (CAYA) cancer survivors may be at risk for a severe course of COVID-19. Little is known about the clinical course of COVID-19 in CAYA cancer survivors, or if additional preventive measures are warranted. We established a working group within the International Late Effects of Childhood Cancer Guideline Harmonization Group (IGHG) to summarize existing evidence and worldwide recommendations regarding evidence about factors/conditions associated with risk for a severe course of COVID-19 in CAYA cancer survivors, and to develop a consensus statement to provide guidance for healthcare practitioners and CAYA cancer survivors regarding COVID-19.
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http://dx.doi.org/10.1002/pbc.28702DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7537044PMC
December 2020

Highly Ordered Boron Nitride/Epigraphene Epitaxial Films on Silicon Carbide by Lateral Epitaxial Deposition.

ACS Nano 2020 Oct 1;14(10):12962-12971. Epub 2020 Oct 1.

School of Physics, Georgia Institute of Technology, Atlanta, Georgia 30332, United States.

The realization of high-performance nanoelectronics requires control of materials at the nanoscale. Methods to produce high quality epitaxial graphene (EG) nanostructures on silicon carbide are known. The next step is to grow van der Waals semiconductors on top of EG nanostructures. Hexagonal boron nitride (h-BN) is a wide bandgap semiconductor with a honeycomb lattice structure that matches that of graphene, making it ideally suited for graphene-based nanoelectronics. Here, we describe the preparation and characterization of multilayer h-BN grown epitaxially on EG using a migration-enhanced metalorganic vapor phase epitaxy process. As a result of the lateral epitaxial deposition (LED) mechanism, the grown h-BN/EG heterostructures have highly ordered epitaxial interfaces, as desired in order to preserve the transport properties of pristine graphene. Atomic scale structural and energetic details of the observed row-by-row growth mechanism of the two-dimensional (2D) epitaxial h-BN film are analyzed through first-principles simulations, demonstrating one-dimensional nucleation-free-energy-barrierless growth. This industrially relevant LED process can be applied to a wide variety of van der Waals materials.
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http://dx.doi.org/10.1021/acsnano.0c04164DOI Listing
October 2020

Phase I study of vinblastine in combination with nilotinib in children, adolescents, and young adults with refractory or recurrent low-grade glioma.

Neurooncol Adv 2020 Jan-Dec;2(1):vdaa075. Epub 2020 Jun 9.

Department of Pediatric and Adolescent Oncology, Gustave Roussy, Villejuif, France.

Background: New rescue regimens are needed for pediatric refractory/recurrent low-grade glioma. Nilotinib is a tyrosine kinase inhibitor that has potential synergistic effects with vinblastine on angiogenesis, tumor cell growth, and immunomodulation.

Methods: This phase I trial aimed to determine the recommended doses of this combination for phase II trials (RP2D) using the dual-agent Bayesian continual reassessment method. Nilotinib was given orally twice daily (BID) in combination with once-weekly vinblastine injections for a maximum of 12 cycles of 28 days (clinicaltrials.gov, NCT01884922).

Results: Thirty-five pediatric patients were enrolled across 4 dose levels. The median age was 7 years and 10 had neurofibromatosis type 1. Patients had received a median of 3 prior treatment lines and 25% had received more than 4 previous treatment lines. Dose-limiting toxicity (DLT) during cycle 1 was hematologic, dermatologic, and cardiovascular. The RP2D was identified at 3 mg/m weekly for vinblastine with 230 mg/m BID for nilotinib (estimated probability of DLT = 18%; 95% credibility interval, 7-29%). Fifteen patients completed the 12 cycles; 2 stopped therapy prematurely due to toxicity and 18 due to disease progression. Three patients achieved a partial response leading to an objective response rate of 8.8% (95% confidence interval [CI], 1.9-23.7), and the disease control rate was 85.3% (95% CI, 68.9-95.1). The 12-month progression-free survival was 37.1% (95% CI, 23.2-53.67).

Conclusions: Vinblastine and nilotinib combination was mostly limited by myelosuppression and dermatologic toxicity. The efficacy of the combination at the RP2D is currently evaluated in a randomized phase II trial comparing this regimen to vinblastine alone.
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http://dx.doi.org/10.1093/noajnl/vdaa075DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7344116PMC
June 2020

Data Resource Profile: The French Childhood Cancer Observation Platform (CCOP).

Int J Epidemiol 2020 10;49(5):1434-1435k

Epidémiologie des Cancers des Enfants et des Adolescents (EPICEA), Centre de Recherche en Epidémiologie et Statistiques (CRESS), INSERM, UMR 1153, Université de Paris, Paris, France.

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http://dx.doi.org/10.1093/ije/dyaa048DOI Listing
October 2020

Real Life Population Pharmacokinetics Modelling of Eight Factors VIII in Patients with Severe Haemophilia A: Is It Always Relevant to Switch to an Extended Half-Life?

Pharmaceutics 2020 Apr 21;12(4). Epub 2020 Apr 21.

Department of Medical Pharmacology, University Hospital of Reims, EA3801, SFR Cap-Santé, University of Reims, 51100 Reims, France.

We retrospectively analysed the data files of 171 adults and 87 children/adolescents with severe haemophilia, except for 14 patients (moderate; minor) (1), to develop a global population pharmacokinetic (PK) model for eight factors VIII (FVIII) that could estimate individual PK parameters for targeting the desired level of FVIII activity (FVIII:C); and (2) to compare half-life (HL) in patients switching from a standard half-life (SHL) to an extended half-life (EHL) and evaluate the relevance of the switch. One-stage clotting assay for the measurement of FVIII activity (FVIII:C, IU/mL) was used for population PK modelling. The software, Monolix version 2019R1, was used for non-linear mixed-effects modelling. A linear two-compartment model best described FVIII:C. The estimated PK parameters (between-subject variability) were: 2640 mL (23.2%) for volume of central compartment (V1), 339 mL (46.8%) for volume of peripheral compartment (V2), 135 mL/h for Q (fixed random effect), and 204 mL/h (34.9%) for clearance (Cl). Weight, age, and categorical covariate EHL were found to influence Cl and only weight for V1. This model can be used for all of the FVIII cited in the study. Moreover, we demonstrated, in accordance with previous studies, that Elocta had longer half-life (EHL) than SHL (mean ratio: 1.48) as compared to Advate, Factane, Kogenate, Novoeight, and Refacto.
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http://dx.doi.org/10.3390/pharmaceutics12040380DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7238177PMC
April 2020

Multicystic and diffuse malignant peritoneal mesothelioma in children.

Pediatr Blood Cancer 2020 06 11;67(6):e28286. Epub 2020 Apr 11.

Department of Pediatric Surgery, University Hospital of Saint-Etienne, Saint-Priest-en-Jarez, France.

Background: Malignant and multicystic peritoneal mesotheliomas are extremely rare tumors in children, developing from mesothelial cells. No specific guidelines are available at this age.

Methods: We performed a retrospective analysis of all identified children (< 18-year-old) treated in France from 1987 to 2017 for a diffuse malignant peritoneal mesothelioma (DMPM) or a multicystic peritoneal mesothelioma (MCPM).

Results: Fourteen patients (5 males and nine females), aged 2.2 to 17.5 years, were included. The most frequent presenting symptoms were abdominal pain, ascitis, and alteration in the general condition. Eight patients had epithelioid mesothelioma, three had biphasic mesothelioma, and three had MCPM. Eight patients with DMPM diagnosis received cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC). Among them, six patients had neoadjuvant systemic chemotherapy, one patient, post-operative chemotherapy, and one patient CRS and HIPEC only. Three patients received only systemic chemotherapy. All patients with MCPM had only surgery. After a median follow-up of seven years (2-15), six patients (6/11; one death) with DMPM and two patients (two/three) with MCPM had a local and distant recurrences.

Conclusion: Peritoneal mesothelioma in children is a rare condition with difficult diagnosis and high risk of recurrence. Worldwide interdisciplinary collaboration and networking are mandatory to help diagnosis and provide harmonious treatment guidelines.
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http://dx.doi.org/10.1002/pbc.28286DOI Listing
June 2020

Non-Invasive Nanoscale Potentiometry and Ballistic Transport in Epigraphene Nanoribbons.

Nano Lett 2020 May 15;20(5):3786-3790. Epub 2020 Apr 15.

Université Grenoble Alpes, CNRS, Grenoble INP, Institut Néel, Grenoble 38042, France.

The recent observation of non-classical electron transport regimes in two-dimensional materials has called for new high-resolution non-invasive techniques to locally probe electronic properties. We introduce a novel hybrid scanning probe technique to map the local resistance and electrochemical potential with nm- and μV resolution, and we apply it to study epigraphene nanoribbons grown on the sidewalls of SiC substrate steps. Remarkably, the potential drop is non-uniform along the ribbons, and μm-long segments show no potential variation with distance. The potential maps are in excellent agreement with measurements of the local resistance. This reveals ballistic transport, compatible with μm-long room-temperature electronic mean-free paths.
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http://dx.doi.org/10.1021/acs.nanolett.0c00838DOI Listing
May 2020

Flat and safe under the graphene sheet.

Nat Mater 2020 06;19(6):583-584

School of Physics, Georgia Institute of Technology, Atlanta, GA, USA.

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http://dx.doi.org/10.1038/s41563-020-0666-zDOI Listing
June 2020

Infant cancers in France: Incidence and survival (2000-2014).

Cancer Epidemiol 2020 04 7;65:101697. Epub 2020 Mar 7.

Centre de Recherche en Epidémiologie et en Statistique Sorbonne-Paris Cité (CRESS), UMR 1153, INSERM, Université Paris, 75014, Paris, France; Registre National des cancers de l'Enfant, Registre National des hémopathies malignes de l'Enfant, AP-HP, Hôpital Paul Brousse, GHU Paris-Sud, Villejuif, F-94000, France.

Background: On average 185 children are diagnosed each year in France with a cancer in their first year of life, representing 11 % of cancers diagnosed in children less than 15 years.

Methods: A retrospective population-based observational study was conducted between 2000 and 2014 of all infants with a diagnosis of cancer using the National Registry of Childhood Cancers Database.

Results: Out of 2760 cases of primary cancers in infancy, there were mainly neuroblastomas 30.1 %), central nervous system (CNS) tumors (16.1 %), leukemias (15.3 %), retinoblastomas (11.6 %), and Wilms tumors (6.9 %). Embryonal malignancies accounted for 55.2 % of cases. Most diagnoses showed a male excess, particularly for malignant gonadal germ-cell tumors (GCT) with a 17.5 sex-ratio. The annual incidence rate, 242.9 per million infants overall, was stable over the study period for all types of cancer. Most deaths occurred within the first month of life (70.8 % of deaths). The 5-year overall survival (5-y OS) was 81.0 % (95 %CI, 79.4-82.4) with large contrasts between diagnoses. The best 5-y OS (>85 %) were observed for retinoblastomas, carcinomas, nephroblastomas, GCT, neuroblastomas, and hepatoblastomas. Conversely, the lowest 5-y OS (<65 %) were observed for acute myeloid leukemias, CNS tumors, and lymphoid leukemias. We observed no substantial change over time (80.5 % [95 %CI, 77.7-82.9] in 2000-2004 and 82.6 % [95 %CI, 80.0-84.9] in 2010-2014) for all cancers combined. The same result has been found whatever the diagnostic group.

Conclusion: Our results contribute to better understand these tumors by quantifying their impact on the French population and assessing the burden of some devastating infant cancers.
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http://dx.doi.org/10.1016/j.canep.2020.101697DOI Listing
April 2020

Prevalence of Psychiatric Complications in Young Adults After Childhood Cancer Treatment: Results of the Long-Term Follow-Up Studies in Oncology.

J Adolesc Young Adult Oncol 2020 04 29;9(2):247-255. Epub 2019 Oct 29.

Department of Pediatric Hematology and Oncology Unit, University Hospital of Saint-Etienne, Saint-Etienne, France.

This study evaluated the long-term psychological impact of childhood cancer and also sought to identify the risk factors in the development of psychological issues. Young adult (18-38 years) survivors of a childhood cancer (except leukemia), diagnosed younger than 15 years between 1987 and 1999 in the Rhône-Alpes region of France, were invited to a semistandardized psychological interview after a medical follow-up consultation during two successive long-term follow-up studies in Oncology (SALTO-1 and -2). Psychiatric issues from the DSM-IV were diagnosed and compared with the general French population (GFP) through interviews based on the Mini-International Neuropsychiatric Interview (MINI). Of the 288 childhood cancer survivors (CCSs) who attended the consultations, 247 completed the MINI interview. Fifty-five percent indicated they had suffered from psychiatric issues after their cancer compared to 31.9% of the GFP ( < 0.0001). These issues were generally anxiety problems (40.5%), mood disorders (28.7%), and substance dependency (10.5%;  < 0.0001). The risk of suicide was, however, less for the CCS group (8.9% vs. 13.6%,  = 0.03). Unemployment was a significant risk factor for mood disorders ( = 0.009). Men were 4.1 times more likely than women to be addicted during their lifetime ( = 0.0004), while adults cured of bone tumors were 14.3 times more likely to be at risk of drug dependence than adults cured of central nervous system tumors ( = 0.01). CCSs are particularly vulnerable to psychiatric disorders throughout their life. Systematic and long-term psychological monitoring of these patients will enable their psychiatric issues to be detected sooner.
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http://dx.doi.org/10.1089/jayao.2019.0056DOI Listing
April 2020

Medulloblastomas associated with an APC germline pathogenic variant share the good prognosis of CTNNB1-mutated medulloblastomas.

Neuro Oncol 2020 01;22(1):128-138

Curie Institute, SIREDO Cancer Center (Care, Innovation and Research in Pediatric, Adolescents, and Young Adults Oncology), Paris, France.

Background: Medulloblastomas may occur in a predisposition context, including familial adenomatosis polyposis. Medulloblastomas related to a germline pathogenic variant of adenomatous polyposis coli (APC) remain rare and poorly described. Their similarities with sporadic WNT medulloblastomas still require description.

Methods: We performed a multicentric retrospective review of 12 patients treated between 1988 and 2018 for medulloblastoma with an identified or highly suspected (personal or familial history) APC germline pathogenic variant. We report personal and familial history APC gene pathogenic variants whenever available: clinical and histologic characteristics of the medulloblastoma, treatments, and long-term outcome, including second tumor and late sequelae.

Results: Medulloblastomas associated with APC pathogenic variants are mainly classic (11/11 patients, 1 not available), nonmetastatic (10/12 patients) medulloblastomas, with nuclear immunoreactivity for ß-catenin (9/9 tested cases). Ten of 11 assessable patients are disease free with a median follow-up of 10.7 years (range, 1-28 y). Secondary tumors included desmoid tumors in 7 patients (9 tumors), 1 thyroid carcinoma, 2 pilomatricomas, 1 osteoma, 1 vertebral hemangioma, and 1 malignant triton in the radiation field, which caused the only cancer-related death in our series.

Conclusions: Medulloblastomas associated with an APC pathogenic variant have an overall favorable outcome, even for metastatic tumors. Yet, long-term survival is clouded by second tumor occurrence; treatment may play some role in some of these second malignancies. Our findings raise the question of applying a de-escalation therapeutic protocol to treat patients with APC germline pathogenic variants given the excellent outcome, and reduced intensity of craniospinal irradiation may be further evaluated.
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http://dx.doi.org/10.1093/neuonc/noz154DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6954432PMC
January 2020

Valley and Zeeman Splittings in Multilayer Epitaxial Graphene Revealed by Circular Polarization Resolved Magneto-infrared Spectroscopy.

Nano Lett 2019 10 3;19(10):7043-7049. Epub 2019 Sep 3.

School of Physics , Georgia Institute of Technology , Atlanta , Georgia 30332 , United States.

Circular-polarization-resolved magneto-infrared studies of multilayer epitaxial graphene (MEG) are performed using tunable quantum cascade lasers in high magnetic fields up to 17.5 T. Landau level (LL) transitions in the monolayer and bilayer graphene inclusions of MEG are resolved, and considerable electron-hole asymmetry is observed in the extracted electronic band structure. For monolayer graphene, a four-fold splitting of the = 0 to = 1 LL transition is evidenced and attributed to the lifting of the valley and spin degeneracy of the zeroth LL and the broken electron-hole symmetry. The magnetic field dependence of the splitting further reveals its possible mechanisms. The best fit to experimental data yields effective -factors, = 6.7 and = 4.8, for the valley and Zeeman splittings, respectively.
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http://dx.doi.org/10.1021/acs.nanolett.9b02505DOI Listing
October 2019

Anatomo-functional study of the cerebellum in working memory in children treated for medulloblastoma.

J Neuroradiol 2019 May 5;46(3):207-213. Epub 2019 Feb 5.

Grenoble institute of neurosciences, Inserm U836, 38000 Grenoble, France; University Grenoble Alps, 38000 Grenoble, France; UMS IRMaGe, 38000 Grenoble, France; Department of pediatrics, Bordeaux university hospital, 38000 Bordeaux, France; Department of neuroradiology and MRI, Grenoble university hospital, 38000 Grenoble, France. Electronic address:

Introduction: Medulloblastoma is the most common malignant cerebral tumor during childhood, arising in the posterior fossa. Children treated for medulloblastoma often experience working memory (WM) deficits, affecting their quality of life and school performance. The aim of the present study undertaken to describe the cerebellar involvement in WM deficits observed in these children.

Material And Methods: 23 healthy children and 11 children treated for medulloblastoma were included into study. All subjects performed a detailed neuropsychological examination, an anatomical and functional MRI. Stimuli were presented to the participants with alternating sensory modality and nature of communication in a block design during functional magnetic resonance imaging acquisitions. Non-parametric tests were used for analyzing neuropsychological and behavioral data. SPM8 and SUIT (Spatially Unbiased Atlas Template) were used for anatomical and functional MRI data analyses.

Results: Patients had cerebellar resections mainly located in the left posterior lobe. Patients had significantly reduced intelligence quotient, central executive and visuospatial WM. In healthy children group, fMRI showed activations for non-verbal and visuospatial WM in the left posterior cerebellar lobe.

Conclusion: This study provides further evidence that left posterior cerebellar lobe plays a critical role in WM. Indeed, lesions of left posterior cerebellar lobe were associated with WM impairment in children treated for cerebellar medulloblastoma. Additionally, fMRI using WM tasks showed activation in the left posterior cerebellar lobe in healthy children. Taken together, these findings may help for improving treatment and rehabilitation of children referred for cerebellar tumor.
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http://dx.doi.org/10.1016/j.neurad.2019.01.093DOI Listing
May 2019

Clinical and biological features in -hereditary xerocytosis and Gardos channelopathy: a retrospective series of 126 patients.

Haematologica 2019 08 17;104(8):1554-1564. Epub 2019 Jan 17.

Laboratoire d'Hématologie, Center Hospitalier Universitaire (CHU) Bicêtre, Assistance publique - Hôpitaux de Paris (AP-HP), Le Kremlin-Bicêtre

We describe the clinical, hematologic and genetic characteristics of a retrospective series of 126 subjects from 64 families with hereditary xerocytosis. Twelve patients from six families carried a mutation, five had the recurrent p.Arg352His mutation and one had a new deletion at the exon 7-intron 7 junction. Forty-nine families carried a mutation, which was a known recurrent mutation in only one-third of the cases and private sequence variation in others; 12 new probably pathogenic missense mutations were identified. The two dominant features leading to diagnosis were hemolysis that persisted after splenectomy and hyperferritinemia, with an inconstant correlation with liver iron content assessed by magnetic resonance imaging. -hereditary xerocytosis was characterized by compensated hemolysis in most cases, perinatal edema of heterogeneous severity in more than 20% of families and a major risk of post-splenectomy thrombotic events, including a high frequency of portal thrombosis. In -related disease, the main symptoms were more severe anemia, hemolysis and iron overload, with no clear sign of red cell dehydration; therefore, this disorder would be better described as a 'Gardos channelopathy'. These data on the largest series to date indicate that -hereditary xerocytosis and Gardos channelopathy are not the same disease although they share hemolysis, a high rate of iron overload and inefficient splenectomy. They demonstrate the high variability in clinical expression as well as genetic bases of -hereditary xerocytosis. These results will help to improve the diagnosis of hereditary xerocytosis and to provide recommendations on the clinical management in terms of splenectomy, iron overload and pregnancy follow-up.
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http://dx.doi.org/10.3324/haematol.2018.205328DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6669138PMC
August 2019

Perflubron Distribution During Transition From Gas to Total Liquid Ventilation.

Front Physiol 2018 30;9:1723. Epub 2018 Nov 30.

Departments of Pediatrics and Pharmacology/Physiology, Université de Sherbrooke, Sherbrooke, QC, Canada.

Total liquid ventilation (TLV) using perfluorocarbons has shown promising results for the management of neonatal respiratory distress. However, one important safety consideration for TLV is a better understanding of the early events during the transition to TLV, especially regarding the fate of residual air in the non-dependent-lung regions. Our objective was to assess perflubron distribution during transition to TLV using electrical impedance tomography, complemented by fluoroscopy, in a neonatal lamb model of induced surfactant deficiency. Eight lambs were anesthetized and ventilated in supine position. Surfactant deficit was induced by saline lung lavage. After deflation, lungs were filled with 25 ml/kg perflubron over 18 s, and TLV was initiated. Electrical impedance tomography data was recorded from electrodes placed around the chest, during the first 10 and at 120 min of TLV. Lung perfusion was also assessed using hypertonic saline injection during apnea. In addition, fluoroscopic sequences were recorded during initial lung filling with perfluorocarbons, then at 10 and 60 min of TLV. Twelve lambs were used as controls for histological comparisons. Transition to TLV involved a short period of increased total lung volume ( = 0.01) secondary to recruitment of the dependent lung regions. Histological analysis shows that TLV was protective of these same regions when compared to gas-ventilated lambs ( = 0.03). The non-dependent lung regions filled with perflubron over at least 10 min, without showing signs of overdistention. Tidal volume distribution was more homogenous in TLV than during the preceding gas ventilation. Perflubron filling was associated with a non-significant increase in the anterior distribution of the blood perfusion signal, from 46 ± 17% to 53 ± 6% ( = 0.4). However, combined to the effects on ventilation, TLV had an instantaneous effect on ventilation-perfusion relationship ( = 0.03), suggesting better coupling. Conclusion: transition to TLV requires at least 10 min, and involves air evacuation or dissolution in perflubron, dependent lung recruitment and rapid ventilation-perfusion coupling modifications. During that time interval, the total lung volume transiently increases. Considering the potential deleterious effect of high lung volumes, one must manage this transition phase with care and, we suggest using a real-time monitoring system such as electrical impedance tomography.
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http://dx.doi.org/10.3389/fphys.2018.01723DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6283896PMC
November 2018

PanCareLIFE: The scientific basis for a European project to improve long-term care regarding fertility, ototoxicity and health-related quality of life after cancer occurring among children and adolescents.

Eur J Cancer 2018 11 29;103:227-237. Epub 2018 Sep 29.

Department of Paediatrics &- Oncology, Hematology and Immunology, Centre for Paediatric, Adolescent and Women's Medicine, Klinikum Stuttgart - Olgahospital, Stuttgart, Germany.

Aims: Survival after cancer diagnosed during childhood or adolescence continues to improve with new treatments and supportive therapies. Optimal long-term care requires that risks to vulnerable organs are clearly defined and translated into guidelines that are implemented into practice. PanCareLIFE is a pan-European consortium that addresses survivorship issues comprising fertility, hearing impairment and quality of life. This article describes the scientific basis of PanCareLIFE's studies.

Methods: PanCareLIFE involves 17 partner institutions from eight European countries, with additional 11 data providers from five other countries. Study designs and methods include molecular genetic, cohort and case-control studies, a longitudinal study and an intervention study. Ethics and data protection issues have been taken into account from the beginning.

Results: PanCareLIFE will investigate the way that treatment impairs female fertility, by evaluating anti-Müllerian hormone levels and the underlying genetic susceptibility to loss of fertility. For our fertility studies, more than 6000 survivors have completed questionnaires, more than 1500 provided serum samples and more than 400 case-control triads have been identified. Fertility preservation guidelines for boys and girls will be developed. More than 2000 survivors have contributed audiograms for the ototoxicity study. Almost 1000 samples were sent for genetic analysis related to ototoxicity and gonadal reserve. The SF-36 questionnaire will measure quality of life in more than 10,000 survivors.

Conclusions: The large number of subjects enrolled in PanCareLIFE and the detailed information accumulated will allow in-depth evaluation of important outcomes. Fertility preservation guidelines will help patients and their families make informed decisions and contribute to their long-term well-being.
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http://dx.doi.org/10.1016/j.ejca.2018.08.007DOI Listing
November 2018

Genetic variation in gonadal impairment in female survivors of childhood cancer: a PanCareLIFE study protocol.

BMC Cancer 2018 Sep 26;18(1):930. Epub 2018 Sep 26.

Princess Máxima Center for Pediatric Oncology, Lundlaan 6, 3584, EA, Utrecht, The Netherlands.

Background: Improved risk stratification, more effective therapy and better supportive care have resulted in survival rates after childhood cancer of around 80% in developed countries. Treatment however can be harsh, and three in every four childhood cancer survivors (CCS) develop at least one late effect, such as gonadal impairment. Gonadal impairment can cause involuntary childlessness, with serious consequences for the well-being of CCS. In addition, early menopause increases the risk of comorbidities such as cardiovascular disease and osteoporosis. Inter-individual variability in susceptibility to therapy related gonadal impairment suggests a role for genetic variation. Currently, only one candidate gene study investigated genetic determinants in relation to gonadal impairment in female CCS; it yielded one single nucleotide polymorphism (SNP) that was previously linked with the predicted age at menopause in the general population of women, now associated with gonadal impairment in CCS. Additionally, one genome wide association study (GWAS) evaluated an association with premature menopause, but no GWAS has been performed using endocrine measurements for gonadal impairment  as the primary outcome in CCS.

Methods: As part of the PanCareLIFE study, the genetic variability of chemotherapy induced gonadal impairment among CCS will be addressed. Gonadal impairment will be determined by anti-Müllerian hormone (AMH) levels or alternatively by fertility and reproductive medical history retrieved by questionnaire. Clinical and genetic data from 837 non-brain or non-bilateral gonadal irradiated long-term CCS will result in the largest clinical European cohort assembled for this late-effect study to date. A candidate gene study will examine SNPs that have already been associated with age at natural menopause and DNA maintenance in the general population. In addition, a GWAS will be performed to identify novel allelic variants. The results will be validated in an independent CCS cohort.

Discussion: This international collaboration aims to enhance knowledge of genetic variation which may be included in risk prediction models for gonadal impairment in CCS.
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http://dx.doi.org/10.1186/s12885-018-4834-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6158859PMC
September 2018

Fertility Among Female Survivors of Childhood, Adolescent, and Young Adult Cancer: Protocol for Two Pan-European Studies (PanCareLIFE).

JMIR Res Protoc 2018 Sep 14;7(9):e10824. Epub 2018 Sep 14.

Department of Pediatrics, Amsterdam UMC, Vrije Universiteit, Amsterdam, Netherlands.

Background: Despite a significant number of studies on female fertility following childhood, adolescent, and young adult (CAYA) cancer, studies establishing precise (dose-related) estimates of treatment-related risks are still scarce. Previous studies have been underpowered, did not include detailed treatment information, or were based on self-report only without any hormonal assessments. More precise assessments of who is at risk for sub- or infertility are needed.

Objective: The objective of our study is to describe the design and methods of 2 studies on female fertility (a cohort study and a nested case-control study) among female survivors of CAYA cancer performed within the European PanCareLIFE project.

Methods: For the cohort study, which aims to evaluate the overall risk of fertility impairment, as well as the risk for specific subgroups of female CAYA cancer survivors, 13 institutions from 9 countries provide data on fertility impairment. Survivors are defined as being fertility impaired if they meet at least one of 8 different criteria based on self-reported and hormonal data. For the nested case-control study, which aims to identify specific treatment-related risk factors associated with fertility impairment in addition to possible dose-response relationships, cases (fertility impaired survivors) are selected from the cohort study and matched to controls (survivors without fertility impairment) on a 1:2 basis.

Results: Of the 10,964 survivors invited for the cohort study, data are available from 6619 survivors, either questionnaire-based only (n=4979), hormonal-based only (n=72), or both (n=1568). For the nested case-control study, a total of 450 cases and 882 controls are identified.

Conclusions: Results of both PanCareLIFE fertility studies will provide detailed insight into the risk of fertility impairment following CAYA cancer and diagnostic- or treatment-related factors associated with an increased risk. This will help clinicians to adequately counsel both girls and young women, who are about to start anticancer treatment, as well as adult female CAYA cancer survivors, concerning future parenthood and to timely refer them for fertility preservation. Ultimately, we aim to empower patients and survivors and improve their quality of life.

Registered Report Identifier: RR1-10.2196/10824.
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http://dx.doi.org/10.2196/10824DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6231763PMC
September 2018

Dysautonomia in Childhood Cancer Survivors: A Widely Underestimated Risk.

J Adolesc Young Adult Oncol 2019 02 23;8(1):9-17. Epub 2018 Aug 23.

4 Host Research Team EA4607 SNA-EPIS (Autonomic Nervous System, Epidemiology, Physiology, Exercise, and Health), Jean Monnet University of Saint-Etienne, PRES (Education and Research Cluster) Lyon, Saint-Etienne, France.

Purpose: Survival rate of childhood cancers is now reaching 80% overall. However, early or late complications related to surgery, chemotherapy, and radiotherapy remain at a high rate and greatly increase the risk of late mortality. The objective of this study is to assess the autonomic nervous system (ANS) activity, measured through heart rate variability indices in childhood cancer survivors compared with healthy controls.

Methods: This prospective study included 51 long-term childhood cancer survivors diagnosed before 15 years of age between 1987 and 1992 and controlled for age and sex with healthy volunteers.

Results: We observed a significant increase in spontaneous heart rate (beats per minute) (67 ± 10 vs. 60 ± 10, p = 0.001), and all the studied parameters showed a significantly altered ANS activity in cases compared with healthy controls. In both groups, the main cofactors of dysautonomia (tobacco, drugs, cannabis, estro-progestative pills, alcohol, limited physical activity) were analyzed without any significant difference. The effect of cancer treatments received was not analyzed due to the small number of participants.

Conclusion: The results showed a significant ANS dysfunction in childhood cancer survivors compared with healthy controls and suggested the value of autonomic screening to underscore and possibly quantify the effect of the cancer treatments in a larger cohort. This evaluation could lead to the recommendation to increase physical activity, the most efficient way known to improve ANS activity, as already shown in other pathologies (breast cancer).
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http://dx.doi.org/10.1089/jayao.2018.0021DOI Listing
February 2019

Determinants of adherence and consequences of the transition from adolescence to adulthood among young people with severe haemophilia (TRANSHEMO): study protocol for a multicentric French national observational cross-sectional study.

BMJ Open 2018 07 25;8(7):e022409. Epub 2018 Jul 25.

Haemophilia Treatment Centre, Hospital Edouard Herriot, University Hospital of Lyon, Lyon, France.

Introduction: Severe haemophilia is a rare disease characterised by spontaneous bleeding from early childhood, which may lead to various complications, especially in joints. It is nowadays possible to avoid these complications thanks to substitutive therapies for which the issue of adherence is major. The transition from adolescence to adulthood in young people with severe haemophilia is a critical period as it is associated with a high risk of lack of adherence to healthcare, which might have serious consequences on daily activities and on quality of life.

Methods And Analysis: We present the protocol for a cross-sectional, observational, multicentric study to assess the differences between adolescents and young adults with severe haemophilia in France through the transition process, especially on adherence to healthcare. This study is based on a mixed methods design, with two complementary and consecutive phases, comparing data from a group of adolescents (aged 14-17 years) with those from a group of young adults (aged 20-29 years). The quantitative phase focuses on the determinants (medical, organisational, sociodemographic and social and psychosocial and behavioural factors) of adherence to healthcare (considered as a marker of the success of transition). The qualitative phase explores participants' views in more depth to explain and refine the results from the quantitative phase. Eligible patients are contacted by the various Haemophilia Treatment Centres participating in the French national registry FranceCoag.

Ethics And Dissemination: The study was approved by the French Ethics Committee and by the French National Agency for Medicines and Health Products Safety (number: 2016-A01034-47). Study findings will be disseminated to the scientific and medical community in peer-reviewed journals and presented at scientific meetings. Results will be popularised to be communicated via the French association for people with haemophilia to participants and to the general public.

Trial Registration Number: NCT02866526; Pre-results.
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http://dx.doi.org/10.1136/bmjopen-2018-022409DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6067371PMC
July 2018

Mutations in the gene cause severe congenital neutropenia as well as Shwachman-Diamond-like syndrome.

Blood 2018 09 18;132(12):1318-1331. Epub 2018 Jun 18.

Department of Clinical Immunology, Saint-Louis Hospital, AP-HP, Paris, France.

Congenital neutropenias (CNs) are rare heterogeneous genetic disorders, with about 25% of patients without known genetic defects. Using whole-exome sequencing, we identified a heterozygous mutation in the gene, encoding the signal recognition particle (SRP) 54 GTPase protein, in 3 sporadic cases and 1 autosomal dominant family. We subsequently sequenced the gene in 66 probands from the French CN registry. In total, we identified 23 mutated cases (16 sporadic, 7 familial) with 7 distinct germ line mutations including a recurrent in-frame deletion (Thr117del) in 14 cases. In nearly all patients, neutropenia was chronic and profound with promyelocytic maturation arrest, occurring within the first months of life, and required long-term granulocyte colony-stimulating factor therapy with a poor response. Neutropenia was sometimes associated with a severe neurodevelopmental delay (n = 5) and/or an exocrine pancreatic insufficiency requiring enzyme supplementation (n = 3). The SRP54 protein is a key component of the ribonucleoprotein complex that mediates the co-translational targeting of secretory and membrane proteins to the endoplasmic reticulum (ER). We showed that SRP54 was specifically upregulated during the in vitro granulocytic differentiation, and that mutations or knockdown led to a drastically reduced proliferation of granulocytic cells associated with an enhanced P53-dependent apoptosis. Bone marrow examination of -mutated patients revealed a major dysgranulopoiesis and features of cellular ER stress and autophagy that were confirmed using -mutated primary cells and knockdown cells. In conclusion, we characterized a pathological pathway, which represents the second most common cause of CN with maturation arrest in the French CN registry.
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http://dx.doi.org/10.1182/blood-2017-12-820308DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6536700PMC
September 2018