Publications by authors named "Frédérique Dijoud"

67 Publications

Testicular Sertoli cell tumour and potentially testicular Leydig cell tumour are features of syndrome.

J Med Genet 2021 Mar 29. Epub 2021 Mar 29.

Pediatric Oncology and Hematology Department, University Hospital Centre Montpellier, Montpellier, France.

syndrome is a rare paediatric autosomal dominant inherited disorder predisposing to various benign and malignant tumours. It is caused by a germline pathogenic variant in , and the second hit for tumour development is usually a missense hotspot pathogenic variant in the DICER1 ribonuclease IIIb domain. While predisposing variants account for about 60% of ovarian Sertoli-Leydig cell tumours, no -related testicular stromal tumours have been described. Here we report the first two cases of testicular stromal tumours in children carrying a germline pathogenic variant: a case of Sertoli cell tumour and a case of Leydig cell tumour diagnosed at 2 and 12 years of age, respectively. A somatic hotspot pathogenic variant was detected in the Sertoli cell tumour. This report extends the spectrum of -related tumours to include testicular Sertoli cell tumour and potentially testicular Leydig cell tumour. Diagnosis of a testicular Sertoli cell tumour should prompt genetic testing so that patients with a germline pathogenic variant can benefit from established surveillance guidelines. genetic evaluation may be considered for testicular Leydig cell tumour. Our findings suggest that miRNA dysregulation underlies the aetiology of some testicular stromal tumours.
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http://dx.doi.org/10.1136/jmedgenet-2020-107434DOI Listing
March 2021

Missing Self-Induced Activation of NK Cells Combines with Non-Complement-Fixing Donor-Specific Antibodies to Accelerate Kidney Transplant Loss in Chronic Antibody-Mediated Rejection.

J Am Soc Nephrol 2021 Feb 25;32(2):479-494. Epub 2020 Nov 25.

International Center of Infectiology research (CIRI), French Institute of Health and Medical Research (INSERM) Unit 1111, Claude Bernard University Lyon I, National Center for Scientific Research (CNRS) Mixed University Unit (UMR) 5308, Ecole Normale Supérieure de Lyon, University of Lyon, Lyon, France

Background: Binding of donor-specific antibodies (DSAs) to kidney allograft endothelial cells that does not activate the classic complement cascade can trigger the recruitment of innate immune effectors, including NK cells. Activated NK cells contribute to microvascular inflammation leading to chronic antibody-mediated rejection (AMR). Recipient NK cells can also trigger antibody-independent microvascular inflammation by sensing the absence of self HLA class I molecules ("missing self") on allograft endothelial cells. This translational study investigated whether the condition of missing self amplifies DSA-dependent NK cell activation to worsen chronic AMR.

Methods And Results: Among 1682 kidney transplant recipients who underwent an allograft biopsy at Lyon University Hospital between 2004 and 2017, 135 fulfilled the diagnostic criteria for AMR and were enrolled in the study. Patients with complement-fixing DSAs identified by a positive C3d binding assay (=73, 54%) had a higher risk of transplant failure (=0.002). Among the remaining patients with complement-independent chronic AMR (=62, 46%), those in whom missing self was identified through donor and recipient genotyping exhibited worse allograft survival (=0.02). In multivariable analysis, only proteinuria (HR: 7.24; =0.01) and the presence of missing self (HR: 3.57; =0.04) were independent predictors for transplant failure following diagnosis of chronic AMR. Cocultures of human NK cells and endothelial cells confirmed that addition of missing self to DSA-induced NK cell activation increased endothelial damage.

Conclusions: The assessment of missing self at the time of diagnosis of chronic AMR identifies patients at higher risk for kidney transplant failure.
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http://dx.doi.org/10.1681/ASN.2020040433DOI Listing
February 2021

Tumoral and pseusotumoral processes of the vagina in the pediatric population: A 26-YEAR retrospective study.

J Pediatr Urol 2020 Dec 13;16(6):831.e1-831.e7. Epub 2020 Sep 13.

Institut de Pathologie Multisite, Groupement Hospitalier Est, Hospices Civils de Lyon, France; Université Claude Bernard Lyon 1, France.

Background: Vaginal lesions are rare and of various types in children. Clinical presentation is generally undifferenciated. Histological examination is fundamental to ascertain the nature of the lesion. Regarding tumoral lesions, histological subtypes encountered are radically different from those seen in adults, dominated by stromal benign lesions.

Objective: The aim of this retrospective study was to describe characteristics and pathological aspects of pediatric vaginal lesions, diagnosed in a single pediatric experienced center.

Study Design: A database analysis was performed on all vaginal samples of patients under 18 years old received in a pediatric-specialized pathology laboratory of an academic hospital, over a 26-year period.

Results: Among 36 vaginal tissue samples reported, a total of 15 tumoral or pseudotumoral processes was recorded. Primitive malignant tumors included embryonal rhabdomyosarcoma (n = 3) and germ-cell tumors, yolk-sac type (n = 2). Benign tumoral or pseudotumoral processes included inflammatory stromal polyps (n = 8), epidermic cyst (n = 1), and benign Müllerian papilloma (n = 1).

Discussion: Over 15 primitive vaginal tumors, 1/3 was malignant with embryonal rhabdomyosarcoma being the most common. The remaining 2/3 specimens were benign, with stromal inflammatory lesions being the most commonly observed. Fibro-epithelial polyp is a debated entity, which covers a wide histological spectrum, with varying inflammation and stromal cellularity, raising sometimes the question of the differential diagnosis with rhabdomyosarcoma. Stromal cells morphology along with their immunohistochemical profile suggest their reactive myofibroblastic nature. Pseudotumoral inflammatory lesions display very similar histological findings with these entities. A common pathogenesis beginning with an inflammatory process, potentially accelerated by chronic traumatic factors, could be discussed.

Conclusion: We confirmed the rarity and the diversity of vaginal lesions in children. Vaginoscopy and biopsy sample should be systematic, given the non-specific presentation of tumoral processes. Myogenin immunostain must be systematic in case of vaginal polypoid mass, in order to rule out malignancy.
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http://dx.doi.org/10.1016/j.jpurol.2020.09.010DOI Listing
December 2020

Various Genital and Reproductive Phenotypes in 46,XX/46,XY Chimeras.

Sex Dev 2019 19;13(5-6):271-277. Epub 2020 Sep 19.

Tetragametic chimeras are due to the fusion of 2 different zygotes after fertilization. When occurring between embryos of different chromosomal sex, the phenotype ranges from fertile individuals to infertile patients and even to patients with variations in sex development. Here, we report 3 new cases of XX/XY chimeras, one in a young boy carrying an abnormal gonad which turned out to be an ovary and 2 in phenotypically normal infertile men, one of whom had been diagnosed previously as a XX-SRY negative male. These cases highlight the importance of combining several cytogenetic and molecular techniques on different tissues for a proper diagnosis and an appropriate prognosis.
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http://dx.doi.org/10.1159/000510532DOI Listing
September 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

Liver metastasis at diagnosis in children with nephroblastoma enrolled in SIOP2001 protocol: A French multicentric study.

Pediatr Blood Cancer 2020 06 24;67(6):e28201. Epub 2020 Mar 24.

Children and Adolescents Oncology Department, Gustave Roussy, Villejuif, France.

Background: Liver metastases are rare in children with Wilms tumor (WT), and their impact on the outcome is unclear.

Patients And Methods: The French cohort of patients with WT presenting liver metastases at diagnosis and enrolled in the International Society of Pediatric Oncology (SIOP) 2001 study was reviewed.

Results: From 2002 to 2012, 906 French patients were enrolled in the SIOP2001 trial. Among them, 131 (14%) presented with stage IV WT and 18 (1.9%) had liver metastases at diagnosis. Isolated liver metastases were displayed in four of them. After preoperative chemotherapy, persistent liver disease was reported in 14/18 patients, and 13 of them underwent metastasectomy after nephrectomy. In resected liver lesions, the same histology of the primary tumor was reported for three patients, blastemal cells without anaplasia were identified in one patient with DA-WT, and post-chemotherapy necrosis/fibrosis was identified for the other 10 patients. For the four patients who had liver and lung surgery, both sites had nonviable cells with post-chemotherapy necrosis/fibrosis. Six patients had hepatic radiotherapy. Sixteen patients achieved primary complete remission and were alive at the last follow-up (median follow-up: 6.4 years). The only two deceased patients presented diffuse anaplasia histology. The five-year EFS and OS were 83% (60%-94%) and 88% (66%-97%), respectively.

Conclusion: Liver involvement does not appear to be an adverse prognostic factor in metastatic WT. The role of hepatic surgery and radiotherapy remains unclear, and should be carefully considered in case of persistent liver metastases, according to histology and radiological response to other metastatic sites.
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http://dx.doi.org/10.1002/pbc.28201DOI Listing
June 2020

A new expression of immune checkpoint inhibitors' renal toxicity: when distal tubular acidosis precedes creatinine elevation.

Clin Kidney J 2020 Feb 14;13(1):42-45. Epub 2019 May 14.

Department of Nephrology, Hospices Civils de Lyon, Centre Hospitalier Lyon Sud, Pierre-Bénite, France.

The main manifestation of acute interstitial nephritis (AIN) due to immune checkpoint inhibitors is acute kidney injury. We report here a biopsy-proven AIN revealed by tubular acidosis. This case highlights that immune checkpoint inhibitor prescribers must be aware of electrolytic disorders since tubular dysfunction can precede serum creatinine increase and reveal renal toxicity.
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http://dx.doi.org/10.1093/ckj/sfz051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7025331PMC
February 2020

Disorder of sex development with germ cell tumors: Which is uncovered first?

Pediatr Blood Cancer 2020 04 4;67(4):e28169. Epub 2020 Feb 4.

Institut de Pathologie Multisite, Groupement hospitalier Est, Hospices Civils de Lyon, UCBL Lyon 1 University, Lyon, France.

Background: Disorders of sex development (DSD) are rare conditions. Although they are known to predispose to germ cell tumors (GCT), there is a paucity of information regarding the circumstances of DSD discovery.

Design/methods: All patients with DSD registered in two French pediatric GCT protocols (TGM95 and 13) were analyzed.

Results: Sixteen patients were identified among 276 ovarian, 160 testicular, and 24 mediastinal GCT. Eleven phenotypic females (median age 15 years) exhibited gonadal GCT, including 10 with a 46,XY karyotype and gonadal dysgenesis and one with 46XX,45X0 mosaicism. None had genital anomalies, seven had spontaneous pubertal changes, and one had spontaneous menarche. The tumors were bilateral in four cases. DSD was diagnosed after the GCT diagnosis in seven cases. The reasons for karyotyping were bilateral tumors (3), gonadoblastoma/streak gonad/absence of egg follicles (3), or systematic for GCT (1). The karyotyping was performed before the GCT diagnosis in four cases: for polymalformative syndrome (2) or primary amenorrhea (2). Four males (median age 14 years) exhibited mediastinal GCT (metastatic in two cases) indicative of Klinefelter syndrome, despite typical phenotypes in all cases. The remaining patient had severe hypospadias, leading to the discovery of 46,XY/45,X0 mosaicism before the diagnosis of testicular nonseminomatous GCT at 16 years of age.

Conclusion: DSD are often uncovered at the time of GCT diagnosis (11/16 cases). This should prompt oncologists to rule out a DSD in patients with GCT, even in case of pubertal development. Earlier recognition of Klinefelter syndrome could potentially lead to GCT detection at an earlier stage.
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http://dx.doi.org/10.1002/pbc.28169DOI Listing
April 2020

Pure pediatric ovarian immature teratomas: The French experience.

Pediatr Blood Cancer 2020 04 25;67(4):e28186. Epub 2020 Jan 25.

Institut d'Hemato-Oncologie Pediatrique, Lyon, France.

Objective: To describe characteristics and outcome of pediatric ovarian immature teratomas (IT) to better define the place of chemotherapy.

Methods: Children with ovarian IT enrolled in TGM95 and TGM2013 studies were analyzed. Norris grading and International Federation of Gynecology and Obstetrics staging system were used.

Results: Thirty-six cases were identified with a median age of 11 years (range = 1-18): 35 of 36 stage I (17 stage IA, 13 stage IC, and 5 stage IX), including seven patients with gliomatosis peritonei (GP), and 1 stage IIIB (IT peritoneal implants). Centrally reviewed Norris grading was performed in 31 cases: 14 grade I and 17 grade II/III tumors. All patients underwent upfront surgery: 19 unilateral oophorectomy, 14 unilateral adnexectomy, 2 unilateral cystectomy, and 1 bilateral cystectomy. No extensive GP surgery was performed. Six patients received adjuvant vinblastin, bleomycin, and cisplatinum because of tumor rupture (n = 5, including two patients with GP) or stage III (n = 1). After a median follow-up of 39.5 months (range = 6-238), two events occurred 10 and 11 months after diagnosis: one bilateralization (initial stage IX, grade I) and one IT peritoneal relapse (initial stage IA, grade II), respectively. Both were successfully rescued by platinum-based chemotherapy and delayed surgery. No stage IC patients treated without adjuvant chemotherapy relapsed (four grade I and three grade III). None of the seven patients with GP progressed. Five-year event-free survival and overall survival were 94% (95% CI = 81-98%) and 100%.

Conclusions: The current series confirms the excellent prognosis of pediatric ovarian IT, arguing for conservative surgical approach in GP and against systematic adjuvant chemotherapy, even in ruptured tumors.
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http://dx.doi.org/10.1002/pbc.28186DOI Listing
April 2020

Exploring heterogeneity of adrenal cortical tumors in children: The French pediatric rare tumor group (Fracture) experience.

Pediatr Blood Cancer 2020 02 18;67(2):e28086. Epub 2019 Nov 18.

SIREDO Oncology Center, Institut Curie, PSL University, Paris, France.

Introduction: Pediatric adrenal cortical tumors are characterized by a wide spectrum of behavior. Questions remain regarding intermediate disease stages with isolated tumor rupture or relapse.

Objectives: To describe clinical characteristics, treatment strategy, and outcome of patients depending on disease stage, tumor rupture, or in case of a refractory tumor, to discuss optimal management.

Material And Methods: Pediatric patients with histological material reviewed and treated between 2000 and 2018 in 23 French oncology centers were included.

Results: Among 95 cases, 59% of patients had stage I tumors (n = 55), 16% had stage II tumors (n = 16), 19% had stage III tumors (n = 17), and 5% had stage IV tumors (n = 5) (missing data: 2). Overall, 27% of patients (n = 25) had an unfavorable histology. Initial tumor resection was performed for 90% of patients (n = 86). Systemic therapies included mitotane in 20 cases and chemotherapy in 13 cases. Among 17 stage III patients, 12 had microscopic residual tumor due to an initial biopsy (n = 5), intraoperative rupture (n = 8), or surgical resection with microscopic residue or tumor spillage surgery (n = 1) (two patients with two modalities). After a median follow-up of 96 months (25-119), four early progressions and two relapses occurred. A total of seven patients died, including five of disease. Stage III diseases due to microscopic residual disease correlated with a worse prognosis: 5-year progression-free survival 44% (95% CI, 22-87%) versus 82% (95% CI, 73-91%) for the whole cohort (P < .0001). Among the 14 patients with refractory disease, only 3 were alive and free of disease after multimodal second-line therapy.

Conclusions: Stage III diseases due to a microscopic residual tumor have a dismal prognosis, arguing for the systematic use of adjuvant therapy. Patients with a relapsed disease should be included in experimental studies.
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http://dx.doi.org/10.1002/pbc.28086DOI Listing
February 2020

Phenotypic and genetic spectrum of alveolar capillary dysplasia: a retrospective cohort study.

Arch Dis Child Fetal Neonatal Ed 2020 Jul 22;105(4):387-392. Epub 2019 Oct 22.

Clinical Genetics, CHU Nancy, Nancy, France.

Objective: Alveolar capillary dysplasia (ACD) is one of the causes of pulmonary hypertension. Its diagnosis is histological but new pathogenetic data have emerged. The aim of this study was to describe a French cohort of patients with ACD to improve the comprehension and the diagnosis of this pathology which is probably underdiagnosed.

Methods: A retrospective observational study was conducted in French hospitals. Patients born between 2005 and 2017, whose biological samples were sent to the French genetic reference centres, were included. Clinical, histological and genetic data were retrospectively collected.

Results: We presented a series of 21 patients. The mean of postmenstrual age at birth was 37.6 weeks. The first symptoms appeared on the median of 2.5 hours. Pulmonary hypertension was diagnosed in 20 patients out of 21. Two cases had prolonged survival (3.3 and 14 months). Histological analysis was done on lung tissue from autopsy (57.1% of cases) or from percutaneous biopsy (28.6%). was found abnormal in 15 patients (71.4%): 8 deletions and 7 point mutations. Two deletions were found by chromosomal microarray.

Conclusion: This study is one of the largest clinically described series in literature. It seems crucial to integrate genetics early into diagnostic support. We propose a diagnostic algorithm for helping medical teams to improve diagnosis of this pathology.
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http://dx.doi.org/10.1136/archdischild-2019-317121DOI Listing
July 2020

Reversion SAMD9 Mutations Modifying Phenotypic Expression of MIRAGE Syndrome and Allowing Inheritance in a Usually Disorder.

Front Endocrinol (Lausanne) 2019 11;10:625. Epub 2019 Sep 11.

Laboratoire de Biochimie et Biologie Moléculaire Grand Est, UM Pathologies Endocriniennes Rénales Musculaires et Mucoviscidose, Groupement Hospitalier Est, Hospices Civils de Lyon, Bron, France.

MIRAGE (Myelodysplasia, Infection, Restriction of growth, Adrenal hypoplasia, Genital phenotypes, Enteropathy) syndrome is a severe multisystem disorder with high mortality. It is caused by a heterozygous gain of function mutation in the growth repressor gene . The increasing number of reported cases displays a spectrum of phenotypes that may be explained by an adaptation mechanism, with appearance of a somatic second hit mutation with revertant effects. To determine the genetic basis of the MIRAGE syndrome rapidly corrected in a living and healthy 46,XY patient. A 46,XY patient born with growth restriction and disorders of sex development had thrombocytopenia and necrotizing enterocolitis during the neonatal period suggestive of the syndrome. Faced with the rapid improvement of the patient's phenotype, an adaptation mechanism was sought by repeating genetic analysis at different ages; her parents also underwent genetic analysis. The previously described p.(Thr778Ile) mutation was identified and surprisingly transmitted by the asymptomatic mother in this usually syndrome. To explain the rapid improvement of the patient's phenotype and absence of symptoms in the mother, an adaptation mechanism was sought. For the mother, a non-sense mutation was found (p.(Arg221)) in , and most likely appeared . It was not transmitted to her child. The child harbored a different non-sense mutation (p.(Arg285)) that most likely appeared near day 20. We show that pathogenic variants can be inherited from a healthy parent as the adaptation mechanism may arise early in life and mask symptoms. Presence of revertant mosaicism mutations could explain "incomplete penetrance" in other disease. For a better management and outcomes in patients, appearance of this natural gene therapy should be sought by repeating genetic analysis.
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http://dx.doi.org/10.3389/fendo.2019.00625DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6749008PMC
September 2019

Neonatal Soft Tissue Sarcoma with YWHAE-NUTM2B Fusion.

Case Rep Oncol 2019 May-Aug;12(2):631-638. Epub 2019 Aug 8.

Department of Pediatric and Adolescent Oncology, Centre Leon Berard, Lyon, France.

Neonatal soft tissues sarcoma is a rare entity that comprises heterogeneous types of tumors. In this article we describe a neonatal case of round-cell sarcoma with an YWHAE-NUTM2B fusion gene. The patient was treated just after birth with neoadjuvant chemotherapy, then surgical resection, but evolution was quickly fatal. This fusion transcript has been reported in endometrial stromal sarcomas and clear cells renal sarcomas but its description in small round-cell sarcomas is recent. To our knowledge, this is the first case report describing this translocation in a newborn patient with soft tissues sarcoma and its clinical tumoral evolution.
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http://dx.doi.org/10.1159/000502227DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6738155PMC
August 2019

Aggressive large B-cell lymphoma triggered by a parvovirus B19 infection in a previously healthy child.

Hematol Oncol 2019 Oct 25;37(4):483-486. Epub 2019 Aug 25.

Institute of Pediatric Hematology and Oncology, Hospices Civils de Lyon, Claude Bernard Lyon I University, Lyon, France.

In absence of red blood cells disease or immune defect, parvovirus B19 (PVB-19) is usually considered as a benign condition. Here, we report the case of a 10-year-old boy, previously healthy, presenting with a PVB-19 infection revealed by a bicytopenia and a voluminous axillary adenopathy. Pathophysiology examination showed reactional lymphoid population. Nine months later and in the absence of remission, a new biopsy of the same adenopathy revealed a Hodgkin lymphoma with area of T-cell rich aggressive large B-cell lymphoma. This case suggests PVB-19 as potential trigger of this malignant childhood hemopathy. Although no definitive conclusion can be drawn, our clinical case questions the role of PVB-19 in lymphomagenesis.
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http://dx.doi.org/10.1002/hon.2665DOI Listing
October 2019

Denosumab for treating aneurysmal bone cysts in children.

Orthop Traumatol Surg Res 2019 10 26;105(6):1181-1185. Epub 2019 Jul 26.

IHOP, 1, place Professeur Joseph-Renaut, 69008 Lyon, France.

Background: Aneurysmal bone cyst (ABC) is a benign tumour whose progression involves the RANK/RANKL signalling pathway. Surgery is the reference standard treatment but carries risks that vary with the site of the tumour. Denosumab is a human monoclonal IgG2 antibody that targets the RANK/RANKL pathway and may therefore hold promise for inhibiting ABC progression. The objective of this study was to evaluate denosumab use in paediatric patients (younger than 18 years) with ABC and to describe the clinical and radiological outcomes, as well as the side effect profile.

Hypothesis: Denosumab is a viable option in children with ABC refractory to standard treatments.

Material And Methods: We retrospectively reviewed the medical files of paediatric patients given denosumab to treat ABC in any of 32 centres affiliated with the French Paediatric Cancer Society (Société Française du Cancer de l'Enfant, SFCE) and French Sarcoma Group (Groupe Sarcome Français, GSF-GETO). We identified 5 patients treated between March 2015 and June 2018. Median age was 8 years (range, 7-17 years). Pain was a symptom in all 5 patients and neurological deficits were present in 3 patients. Surgery was performed in 4 patients, either before (n=3) or after (n=1) denosumab therapy; the remaining patient had no surgery. Denosumab was given as monthly injections in a dosage of 70mg/m for a median of 12 months (range, 4-23 months). The clinical outcomes and changes in computed tomography and/or magnetic resonance imaging findings were evaluated.

Results: Abnormalities in calcium and phosphate levels secondary to the ABC occurred in 2 patients. At median of 24 months (range, 0-28 months) after denosumab initiation, all 5 patients were free of pain, and the neurological deficits in 3 patients had improved. Central remineralisation and cortical reconstitution were demonstrated consistently by the imaging studies.

Discussion: Denosumab is a viable treatment option in selected paediatric patients with inoperable ABC. The immediate adverse effect profile is acceptable. A larger study with a longer follow-up would be welcome to further assess the contribution of denosumab to the treatment of ABC.

Level Of Evidence: IV.
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http://dx.doi.org/10.1016/j.otsr.2019.04.028DOI Listing
October 2019

[Atypical genital development and tumor risk].

Bull Cancer 2019 May 23;106(5):461-467. Epub 2019 Mar 23.

Groupement hospitalier Est, hospices Civils de Lyon, institut Multisite de pathologie, 69500 Bron, France.

Atypical genital development (AGD), also called disorders of sex development are a set of miscellaneous pathologies who have in common a morphological and/or functional abnormality of the internal and/or external genital organs. The Chicago classification identifies 3 major groups based on karyotype, hormone balance and genetic studies. Some AGD predispose to the occurrence of tumors, mainly malignant germ cell tumors. The tumor risk depends on many factors: the type of AGD, the position of the gonad, the age of the patient, the phenotype, the function of the gonad and the presence of germ cells in the gonad. AGD with the highest tumor risk are those with gonadal dysgenesis, implying an incomplete differentiation of the bipotential gonad (dysplasia). Monitoring of patients with AGD and indication of prophylactic gonadectomies should be individualized according to tumor risk.
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http://dx.doi.org/10.1016/j.bulcan.2019.01.018DOI Listing
May 2019

Reply to "Pathological prognostication of pediatric adrenocortical tumors: Is a gold standard emerging?"

Pediatr Blood Cancer 2019 06 13;66(6):e27710. Epub 2019 Mar 13.

Institut de Pathology Multisite, Groupement hospitalier Est, Hospices Civils de Lyon, UCBL Lyon 1 University, Lyon, France.

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http://dx.doi.org/10.1002/pbc.27710DOI Listing
June 2019

Revisiting the role of the pathological grading in pediatric adrenal cortical tumors: results from a national cohort study with pathological review.

Mod Pathol 2019 04 6;32(4):546-559. Epub 2018 Nov 6.

Department of Pathology, Groupement Hospitalier Est, Hospices Civils de Lyon, UCBL Lyon 1 University, Lyon, France.

The prognosis of malignant pediatric adrenocortical tumors is closely related to disease stage, which is used to guide perioperative treatment recommendations. However, current scoring systems are inadequate to distinguish between benign and malignant adrenocortical tumors. Robust microscopic prognostic features that could help determine perioperative therapy are also lacking. The aim of this national study was to review the prognostic value of the Wieneke scoring criteria and Ki67 labeling index in unselected pediatric adrenocortical tumors. Using strict definitions previously defined by expert pathologists, a Wieneke score was re-attributed to each tumor after an independent and centralized review. In addition, Ki67 proliferation index was performed and reviewed for each case. A total of 95 cases were selected; all were treated between 2000 and 2018 and had histopathologic material and sufficient outcome-related information available. Localized disease was found in 88% of patients. Among those with advanced disease, 6% had tumor extension into adjacent organs and 5% had metastases at diagnosis. Median follow-up was 5 years and 3 months. The 5-year PFS was 82%, 95% CI [73%-91%]. Tumor stage significantly correlated with PFS (p < 0.0001). Tumor weight up to 200 g, extra-adrenal extension and initial non-complete surgical resection were statistically associated with worse outcomes. No recurrences nor metastases occurred when the Ki67 index was < 15%. Up to two of the following five factors including tumor necrosis, adrenal capsular invasion, venous invasion, mitotic count > 15/20 high-power fields, and Ki67 index > 15%, significantly correlated with worse outcomes. We propose a pathological scoring system incorporating the Ki67 index as part of a two-step approach after disease staging to guide adjuvant treatment in pediatric adrenocortical tumors, especially after incomplete resection. These results should be validated in an independent cohort.
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http://dx.doi.org/10.1038/s41379-018-0174-8DOI Listing
April 2019

Hyperphosphatemic tumoral calcinosis caused by FGF23 compound heterozygous mutations: what are the therapeutic options for a better control of phosphatemia?

Pediatr Nephrol 2018 07 28;33(7):1263-1267. Epub 2018 Mar 28.

Centre de Référence des Maladies Rénales Rares, Centre de Référence des Maladies Rares du Calcium et du Phosphate, Hospices Civils de Lyon, Hôpital Femme Mère Enfant, 59 boulevard Pinel, 69677, Bron cedex, France.

Background: Hyperphosphatemic familial tumoral calcinosis (HFTC) is a rare autosomal recessive disease caused by mutations in genes encoding FGF23 or its regulators, and leading to functional deficiency or resistance to fibroblast growth factor 23 (FGF23). Subsequent biochemical features include hyperphosphatemia due to increased renal phosphate reabsorption, and increased or inappropriately normal 1,25-dihydroxyvitamin D (1,25-D) levels.

Case-diagnosis/treatment: A 15-year-old girl was referred for a 1.2-kg-calcified mass of the thigh, with hyperphosphatemia (2.8 mmol/L); vascular impairment and soft tissue calcifications were already present. DNA sequencing identified compound heterozygous mutations in the FGF23 gene. Management with phosphate dietary restriction, phosphate binders (sevelamer, aluminum, nicotinamide), and acetazolamide moderately decreased serum phosphate levels; oral ketoconazole was secondary administered, leading to significantly decreased 1,25-D levels albeit only moderate additionally decreased phosphate levels. However, therapeutic compliance was questionable. Serum phosphate levels always remained far above the upper normal limit for age. The patient presented with two relapses of the thigh mass, requiring further surgery.

Conclusions: We suggest that control of phosphate metabolism is crucial to prevent recurrences and vascular complications in HFTC; however, the medical management remains challenging.
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http://dx.doi.org/10.1007/s00467-018-3945-zDOI Listing
July 2018

Mutiple DICER1-related lesions associated with a germline deep intronic mutation.

Pediatr Blood Cancer 2018 06 22;65(6):e27005. Epub 2018 Feb 22.

Service de Génétique, Institut Curie, Paris, France.

Germline DICER1 pathogenic variants predispose to numerous benign and malignant tumors. In this report, we describe DICER1 gene analysis in an adolescent diagnosed with multinodular goiter, ovarian Sertoli-Leydig cell tumor, and lung cyst. DICER1 mutational screening at the DNA level failed to detect any pathogenic variant. Subsequent messenger RNA (mRNA) analysis revealed a 132 nucleotide intronic sequence exonization. This truncating event was caused by a deep intronic mutation generating a de novo acceptor splice site. This study demonstrates that some undetected DICER1 mutations should be investigated at the mRNA level.
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http://dx.doi.org/10.1002/pbc.27005DOI Listing
June 2018

[A giant cell arteritis revealing a Goodpasture's syndrome].

Nephrol Ther 2018 Apr 28;14(2):105-108. Epub 2017 Dec 28.

Service de médecine interne, centre hospitalier Saint-Joseph-Saint-Luc, 20, quai Claude-Bernard, 69007 Lyon, France.

Goodpasture's syndrome is a triad of anti-glomerular basement membrane (anti-GBM) circulating antibodies, glomerulonephritis and pulmonary hemorrhage. We reported a 65-year-old woman with headaches, asthenia and weight loss. Giant cell arteritis was confirmed by temporal artery biopsy. The patient had associated renal condition with moderate acute renal failure, proteinuria and haematuria. Renal biopsy showed extracapillary glomerulonephritis and linear staining of immunoglobulins G along glomerular basement membrane. There was no clinical pulmonary involvement. Anti-MBG antibody was positive and allowed Goodpasture's syndrome diagnosis. The patient was treated with corticoids and cyclophosphamide. Patient's condition and renal function improved quickly and anti-MBG antibodies became negative. Goodpasture's syndrome may be characterized by isolated renal expression without pulmonary involvement. We described for the first time association of Goodpasture's syndrome with giant cell arteritis.
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http://dx.doi.org/10.1016/j.nephro.2017.09.004DOI Listing
April 2018

[Distinct symptoms and important implications in a 42-year-old man].

Nephrol Ther 2018 05 1;14(3):175-177. Epub 2017 Dec 1.

Département d'anatomie et cytologie pathologiques, unité des maladies métaboliques, groupement hospitalier Est, 59, boulevard Pinel, 69500 Bron, France.

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http://dx.doi.org/10.1016/j.nephro.2017.09.003DOI Listing
May 2018

Acute interstitial nephritis after sequential ipilumumab - nivolumab therapy of metastatic melanoma.

J Immunother Cancer 2017 07 18;5(1):57. Epub 2017 Jul 18.

Service de Dermatologie, ImmuCare, Hospices Civils de Lyon, Centre Hospitalier Lyon-Sud, Pierre-Bénite cedex, France.

Background: The anti-Programmed Death receptor 1 (anti-PD-1) antibodies nivolumab and pembrolizumab are new treatments in metastatic melanoma. Immunotherapies are best known to be responsible for thrombotic microangiopathy. However, immune interstitial nephritis has been described in a patient treated by nivolumab and ipilimumab concomitantly, and three cases of granulomatous interstitial nephritis have been reported with ipilimumab monotherapy. We report herein a case of acute interstitial immune nephritis in a patient treated with nivolumab after ipilimumab for pulmonary metastatic melanoma.

Case Presentation: Interstitial nephritis was diagnosed after acute kidney injury following three cycles and was confirmed by kidney biopsy. Kidney injury responded rapidly to prednisolone, which was then gradually reduced. As a follow-up computed tomography scan indicated mixed response, with minimal size progression of a pulmonary nodule, but a significant reduction in the size of the other nodules, nivolumab was reintroduced after renal function improvement. Low-dose corticosteroids were first maintained during nivolumab treatment and subsequently discontinued. Only one month after prednisolone discontinuation, creatinine levels increased. A second kidney biopsy confirmed relapse of acute interstitial nephritis.

Conclusions: To our knowledge, this is the first case of nivolumab-induced acute interstitial immune nephritis. This case highlights that anti-PD-1 immunotherapy may be continued when renal function is adequate, and this requires close interaction between dermatologists and nephrologists. This adverse effect should be made known to prescribers as nivolumab is associated with significant improvement of survival in metastatic melanoma and may be used in many different types of cancer.
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http://dx.doi.org/10.1186/s40425-017-0261-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5514510PMC
July 2017

Two Tumors in 1: What Should be the Therapeutic Target? Pediatric Germ Cell Tumor With Somatic Malignant Transformation.

J Pediatr Hematol Oncol 2017 07;39(5):388-394

*Institute of Pediatric Hematology and Oncology §Department of Pathology, Women and Children's Hospital, Lyon †Department of Child and Adolescent Cancer, Gustave Roussy Cancer Institute, Villejuif ‡Department of Pediatric Oncology, University Hospital Center of Nantes, Nantes ∥Department of Pediatric Oncology of Timone Children's Hospital, Marseille ¶Department of Pediatric Oncology, University Hospital Center of Rouen, Rouen #Department of Pediatric Oncology, Children's Hospital, Toulouse ††Department of Pediatric, Adolescents, Young Adults, Institut Curie, Paris, France **Department of Pediatric Hematology and Oncology, Lebanese Hospital, University Medical Center, Beirut, Lebanon.

Background: Germ cell tumors with somatic malignant transformation (GCT with SMT) are rare in children and poorly described. Data are missing to determine if therapies should target the GCT, the SMT compound, or both simultaneously.

Patients And Methods: A retrospective national study was conducted in the Société Française des cancers de l'Enfant (SFCE) Centers. Medical records from patients aged 0 to 18 years diagnosed with GCT with SMT between 2000 and 2015 were analyzed. Any stages and primary sites were considered as well as synchronous and metachronous cases.

Results: Fifteen patients were identified. Thirteen patients had synchronous GCT with SMT. In the latter cases, primaries were ovary (5), mediastinum (3), pineal gland (3), sacrococcyx (1), and parametrium (1). SMT histologies were central primitive neuroectodermal tumor (5), embryonal rhabdomyosarcomas (3) or thyroid papillary adenocarcinoma, leukemia, poorly differentiated carcinoma, mixed sarcomas, and miscellaneous histology (1 case each). Chemotherapy was targeted against the GCT (3), the SMT (6), or both components (3). The last patient received surgery exclusively. Partial or complete response to chemotherapy was observed in 5/10 assessable cases: 2/3 patients treated with GCT-dedicated chemotherapy, 3/6 patients treated with SMT-dedicated therapy, and 0/1 treated with combined therapy. In addition, 2 patients with mediastinal GCT primary had metachronous SMT, with acute myeloid leukemia and thyroid papillary adenocarcinoma, 8 months and 8 years, respectively, after the diagnoses of GCT. Two patients (1 synchronous and 1 metachronous) were cured with surgery exclusively. At the end of follow-up, 6 patients died of their disease including all 4 with postsurgical macroscopic residue.

Conclusions: GCT with SMT constitutes a very rare entity in children and adolescents. Surgical removal of the tumor is the cornerstone of the treatment and might be sufficient in selected cases. In the remaining cases, the best management is still unknown and should take into account both components and their respective chemosensitivity. Long-term surveillance is advised for patient with unresected teratoma as late transformation can occur.
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http://dx.doi.org/10.1097/MPH.0000000000000823DOI Listing
July 2017

Computer-assisted topological analysis of renal allograft inflammation adds to risk evaluation at diagnosis of humoral rejection.

Kidney Int 2017 07 18;92(1):214-226. Epub 2017 Mar 18.

Hospices Civils de Lyon, Hôpital Edouard Herriot, Service de Transplantation, Néphrologie et Immunologie Clinique, Lyon, France; INSERM U1111, Centre International de Recherche en Infectiologie (CIRI), Ecole Normale Supérieure de Lyon, Lyon, France; Université Lyon 1, Faculté de medecine Lyon-Est, Lyon, France. Electronic address:

Antibody-mediated rejection is associated with heterogeneous kidney allograft outcomes. Accurate evaluation of risk for graft loss at time of diagnosis is necessary to offer personalized treatment. In contrast with serological and molecular assessment, morpho-histological evaluation of antibody-mediated rejection lesions has not significantly evolved. This relies on Banff classifications designed to be of diagnostic discriminatory power rather than prognostic and face quantitative and qualitative limitations. Here we developed a method of Computer-assisted Analysis of Graft Inflammation (CAGI) to improve the classification of allograft inflammation. Digitization of immunostained biopsy sections, image processing and algorithm-driven analysis allowed quantification of macrophages, T cells, B cells, and granulocytes per unit surface of interstitium, capillaries or glomeruli. CAGI was performed on biopsy specimens of 52 patients with extensively phenotyped antibody-mediated rejection. Macrophage numbers in capillaries and interstitium, but not Banff scores or the amount of other immune cell subsets, correlated with donor-specific antibody (DSA) mean fluorescence intensity and DSA-C3d status. The quantity of macrophages in the interstitium and DSA-C3d status were the only independent predictors for significant allograft loss at the time of antibody-mediated rejection diagnosis (hazard ratio 3.71 and 2.34, respectively). A significant strategy integrating the DSA-C3d assay and the quantification of interstitial macrophages allowed identification of three groups with distinct renal prognosis: DSA-C3d, DSA-C3d/macrophages-low and DSAC3d/macrophages-high. Thus, CAGI brings a missing piece to the antibody-mediated rejection puzzle by identifying morpho-histological processes that bridge in vitro parameters of DSA pathogenicity and graft loss. Hence, this approach could be useful in future integrated strategies of risk evaluation.
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http://dx.doi.org/10.1016/j.kint.2017.01.011DOI Listing
July 2017

C3 glomerulopathy and eculizumab: a report on four paediatric cases.

Pediatr Nephrol 2017 06 24;32(6):1023-1028. Epub 2017 Feb 24.

Service de Néphrologie Rhumatologie Dermatologie Pédiatriques, Centre de Référence des Maladies Rénales Rares Hôpital Femme Mère Enfant, Hospices Civils de Lyon, 59 boulevard Pinel, 69677, Bron, France.

Background: Eculizumab may be used to treat C3-glomerulopathy (C3G), a rare but severe glomerular disease.

Diagnosis And Treatment: Patients 1, 2 and 3 were diagnosed with nephritic syndrome with alternative complement pathway activation (low C3, C3Nef-positive) and C3G at the age of 9, 13 and 12 years, respectively. Treatment with eculizumab normalized proteinuria within 1, 2 and 7 months, respectively. Proteinuria relapsed when eculizumab was withdrawn, but the re-introduction of eculizumab normalized proteinuria. Patient 4 was diagnosed with C3G at 9 years of age, with progression to end-stage renal disease within 2 years, followed by a first renal transplantation (R-Tx) with early disease recurrence and graft loss within 39 months. After a second R-Tx, she rapidly presented with biological and histological recurrence: therapy with eculizumab was started, with no effect on proteinuria after 5 months, in a complex clinical setting (i.e. association of C3G recurrence, humoral rejection and BK nephritis). Eculizumab was withdrawn due to multiple viral reactivations, but the re-introduction of the drug a few months later enabled a moderate decrease in proteinuria.

Conclusion: These cases illustrate the efficacy of eculizumab, at least on native kidneys, in paediatric C3G. However, larger international studies are warranted to confirm the benefit and safety of eculizumab therapy.
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http://dx.doi.org/10.1007/s00467-017-3619-2DOI Listing
June 2017

A novel disorder of sex development, characterized by progressive regression of testicular function and cystic leukoencephalopathy.

Am J Med Genet A 2017 Mar 4;173(3):654-660. Epub 2017 Feb 4.

Service d'Endocrinologie Moléculaire et Maladies Rares, Hospices Civils de Lyon, Bron, France.

We report a novel syndromic disorder of sex development observed in three male siblings, presenting with the association of micropenis without hypospadias, cryptorchidism, very low level of antimüllerian hormone in the neonatal period, and no persistent müllerian duct structures, suggesting a progressive regression of testicular function. The patients described here showed a striking neurological involvement including bilateral periventricular cysts observed in the anterior part of the frontal horns prenatally and increasing in size and number over time, associated with infra and supratentorial parenchymal atrophy, dilated ventricular system, corpus callosum hypoplasia, severe intellectual disability, and epilepsy. Associated features included a distinctive facies, joint contractures, retinopathy, and hearing loss. Pathological examination was consistent with testicular dysgenesis and leukoencephalopathy with spongiosis and microcalcifications. To the best of our knowledge, this disease, characterized by a recognizable pattern of malformations, has not been previously reported. An exhaustive genetic and metabolic evaluation was normal. Autosomal recessive inheritance was considered to be likely, on the basis of SNP studies. We hope that the detailed description provided here of the clinical, radiological, and pathological findings observed in this family will help to identify further unrelated patients, and ultimately, to clarify the genetic basis of this condition. © 2017 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/ajmg.a.38093DOI Listing
March 2017

Donor-Related Coccidioidomycosis Transmitted Through Left-Liver Transplant to a Child Recipient in a Nonendemic Area.

Pediatr Infect Dis J 2017 08;36(8):805-808

From the *Service d'Hépatologie, Gastroentérologie et Nutrition Pédiatriques, Hôpital Femme-Mère-Enfant, and †Service de Pathologie, Groupement Hospitalier Est, Hospices Civils de Lyon, Bron, France; ‡Université Claude Bernard Lyon 1, §Institut de Parasitologie et Mycologie Médicale, Hôpital de la Croix-Rousse, Hospices Civils de Lyon, Lyon, France; ¶Service d'Urgences et de Réanimation Pédiatrique, Hôpital Femme-Mère-Enfant, and ‖Service de Chirurgie Pédiatrique Uro-viscérale et Transplantation, Hôpital Femme-Mère-Enfant, Hospices Civils de Lyon, Bron, France; and **Unité de Transplantation Hépatique, Hôpital Edouard Herriot, Hospices Civils de Lyon, Lyon, France.

This first observation of donor-transmitted coccidioidomycosis in a pediatric liver-transplant recipient underlines a rare condition in transplanted patients in a nonendemic area. This transmission was observed after a liver split, the patient being contaminated by the left liver while the right-liver recipient was not.
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http://dx.doi.org/10.1097/INF.0000000000001560DOI Listing
August 2017

A novel morphological approach to gonads in disorders of sex development.

Mod Pathol 2016 11 29;29(11):1399-1414. Epub 2016 Jul 29.

Service d'Anatomie Pathologique, Centre de Biologie et de Pathologie Est, Bron, France.

Disorders of sex development are defined as congenital conditions with discordance between the phenotype, the genotype, the karyotype, and the hormonal profile. The disorders of sex development consensus classification established in 2005 are mainly based on chromosomal and biological data. However, histological anomalies are not considered. The aims of this study were to define the specific pathological features of gonads in various groups of disorders of sex development in order to clarify the nosology of histological findings and to evaluate the tumor risk in case of a conservative approach. One hundred and seventy-five samples from 86 patients with disorders of sex development were analyzed following a strict histological reading protocol. The term 'gonadal dysgenesis' for the histological analysis was found confusing and therefore excluded. The concept of 'dysplasia' was subsequently introduced in order to describe the architectural disorganization of the gonad (various degrees of irregular seminiferous tubules, thin albuginea, fibrous interstitium). Five histological types were identified: normal gonad, hypoplastic testis, dysplastic testis, streak gonad, and ovotestis. The analysis showed an association between undifferentiated gonadal tissue, a potential precursor of gonadoblastoma, and dysplasia. Dysplasia and undifferentiated gonadal tissue were only encountered in cases of genetic or chromosomal abnormality ('dysgenesis' groups in the disorders of sex development consensus classification). 'Dysgenetic testes', related to an embryonic malformation of the gonad, have variable histological presentations, from normal to streak. Conversely, gonads associated with hormonal deficiencies always display a normal architecture. A loss of expression of AMH and α-inhibin was identified in dysplastic areas. Foci of abnormal expression of the CD117 and OCT4 immature germ cells markers in dysplasia and undifferentiated gonadal tissue were associated with an increased risk of neoplasia. This morphological analysis aims at clarifying the histological classification and gives an indication of tumor risk of gonads in disorders of sex development.
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http://dx.doi.org/10.1038/modpathol.2016.123DOI Listing
November 2016

BRAF Mutation Correlates With High-Risk Langerhans Cell Histiocytosis and Increased Resistance to First-Line Therapy.

J Clin Oncol 2016 09 5;34(25):3023-30. Epub 2016 Jul 5.

Sébastien Héritier, Mohamed-Aziz Barkaoui, Jean Miron, and Jean Donadieu, French Reference Center for Langerhans Cell Histiocytosis, Trousseau Hospital; Sébastien Héritier, Sabah Boudjemaa, Guy Leverger, and Jean Donadieu, Trousseau Hospital, Assistance Publique-Hôpitaux de Paris; Sylvie Fraitag, Despina Moshous, and Christine Bodemer, Necker Hospital, Assistance Publique-Hôpitaux de Paris; Michel Peuchmaur and Brigitte Lescoeur, Robert Debré Hospital, Assistance Publique-Hôpitaux de Paris; Michel Peuchmaur, Université Paris Diderot, Sorbonne Paris Cité; Hélène Pacquement, Institut Curie Medical Center; Guy Leverger, Université Pierre et Marie Curie; Fleur Cohen-Aubart and Julien Haroche, Pitié-Salpêtrière Hospital, Assistance Publique-Hôpitaux de Paris; Roger Lacave, Tenon Hospital, Assistance Publique-Hôpitaux de Paris; Valérie Taly, Institut National de la Santé et de la Recherche Médicale, Unités Mixte de Recherche S1147, Centre National de la Recherche Scientifique SNC 5014, Université Paris Sorbonne Cité, Paris; Sébastien Héritier, Jean-François Emile, Zofia Hélias-Rodzewicz, and Jean Donadieu, Université de Versailles Saint-Quentin-en-Yvelines, Université Paris-Saclay; Jean-François Emile, Ambroise Paré Hospital, Assistance Publique-Hôpitaux de Paris, Boulogne-Billancourt; Caroline Thomas and Anne Moreau, Centre Hospitalo-Universitaire de Nantes, Nantes; Florence Renaud, Centre Hospitalier Régional Universitaire, Université de Lille; Anne Lambilliotte and Françoise Mazingue, Centre Hospitalo-Universitaire de Lille, Lille; Catherine Chassagne-Clément, Centre Léon Bérard; Frédérique Dijoud, Hôpital Femme-Mère-Enfant, Hospices Civils de Lyon; Kamila Kebaili, Institut d'Hémato-Oncologie Pediatrique, Lyon; Valérie Rigau, Gui de Chauliac Hospital; Eric Jeziorski, Hôpital Arnaud de Villeneuve, Montpellier; Geneviève Plat, Centre Hospitalo-Universitaire de Toulouse, Toulouse; Nathalie Aladjidi, Centre Hospitalo-Universit

Purpose: Langerhans cell histiocytosis (LCH) is an inflammatory myeloid neoplasia with a broad spectrum of clinical manifestations and outcomes in children. The somatic BRAF(V600E) mutation occurs frequently, but clinical significance remains to be determined.

Patients And Methods: BRAF(V600E) mutation was investigated in a French LCH cohort. We analyzed associations between mutation status and clinical presentation, extent of disease, reactivation rate, response to therapy, and long-term permanent sequelae.

Results: Among 315 patients with successfully determined BRAF status, 173 (54.6%) carried a BRAF(V600E) mutation. Patients with BRAF(V600E) manifested more severe disease than did those with wild-type BRAF. Patients with BRAF(V600E) comprised 87.8% of patients (43 of 49) with multisystem LCH with risk organ involvement (liver, spleen, hematology), 68.6% of patients (35 of 51) with multisystem LCH without risk organ involvement, 43.9% of patients (86 of 196) with single-system LCH, and 42.1% of patients (8 of 19) with lung-involved LCH (P < .001). BRAF(V600E) mutation was also associated with organ involvement that could lead to permanent, irreversible damage, such as neurologic (75%) and pituitary (72.9%) injuries. Compared with patients with wild-type BRAF, patients with BRAF(V600E) more commonly displayed resistance to combined vinblastine and corticosteroid therapy (21.9% v 3.3%; P = .001), showed a higher reactivation rate (5-year reactivation rate, 42.8% v 28.1%; P = .006), and had more permanent, long-term consequences from disease or treatment (27.9% v 12.6%; P = .001).

Conclusion: In children with LCH, BRAF(V600E) mutation was associated with high-risk features, permanent injury, and poor short-term response to chemotherapy. Further population-based studies should be undertaken to confirm our observations and to assess the impact of BRAF inhibitors for this subgroup of patients who may benefit from targeted therapy.
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http://dx.doi.org/10.1200/JCO.2015.65.9508DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5321082PMC
September 2016