Single-cell multiomics reveals the interplay of clonal evolution and cellular plasticity in hepatoblastoma.

Hepatoblastomas (HB) display heterogeneous cellular phenotypes that influence the clinical outcome, but the underlying mechanisms are poorly understood. Here, we use a single-cell multiomic strategy to unravel the molecular determinants of this plasticity. We identify a continuum of HB cell states between hepatocytic (scH), liver progenitor (scLP) and mesenchymal (scM) differentiation poles, with an intermediate scH/LP population bordering scLP and scH areas in spatial transcriptomics. Chromatin accessibility landscapes reveal the gene regulatory networks of each differentiation pole, and the sequence of transcription factor activations underlying cell state transitions. Single-cell mapping of somatic alterations reveals the clonal architecture of each tumor, showing that each genetic subclone displays its own range of cellular plasticity across differentiation states. The most scLP subclones, overexpressing stem cell and DNA repair genes, proliferate faster after neo-adjuvant chemotherapy. These results highlight how the interplay of clonal evolution and epigenetic plasticity shapes the potential of HB subclones to respond to chemotherapy.

Mutational signature, cancer driver genes mutations and transcriptomic subgroups predict hepatoblastoma survival.

BACKGROUND: Hepatoblastoma is the most frequent pediatric liver cancer. The current treatments lead to 80% of survival rate at 5 years. In this study, we evaluated the clinical relevance of molecular features to identify patients at risk of chemoresistance, relapse and death of disease. METHODS: All the clinical data of 86 children with hepatoblastoma were retrospectively collected. Pathological slides were reviewed, tumor DNA sequencing (by whole exome, whole genome or target) and transcriptomic profiling with RNAseq or 300-genes panel were performed. Associations between the clinical, pathological, mutational and transcriptomic data were investigated. RESULTS: High-risk patients represented 44% of our series and the median age at diagnosis was 21.9 months (range: 0-208). Alterations of the WNT/ß-catenin pathway and of the 11p15.5 imprinted locus were identified in 98% and 74% of the tumors, respectively. Other cancer driver genes mutations were only found in less than 11% of tumors. After neoadjuvant chemotherapy, disease-specific survival and poor response to neoadjuvant chemotherapy were associated with 'Liver Progenitor' (p = 0.00049, p < 0.0001) and 'Immune Cold' (p = 0.0011, p < 0.0001) transcriptomic tumor subtypes, SBS35 cisplatin mutational signature (p = 0.018, p = 0.001), mutations in rare cancer driver genes (p = 0.0039, p = 0.0017) and embryonal predominant histological type (p = 0.0013, p = 0.0077), respectively. Integration of the clinical and molecular features revealed a cluster of molecular markers associated with resistance to chemotherapy and survival, enlightening transcriptomic 'Immune Cold' and Liver Progenitor' as a predictor of survival independent of the clinical features. CONCLUSIONS: Response to neoadjuvant chemotherapy and survival in children treated for hepatoblastoma are associated with genomic and pathological features independently of the clinical features.

Standardization of the management of rheumatoid purpura nephropathy in the West of France. What are the repercussions on the renal sequelae?

Introduction: Rheumatoid purpura is the most common vasculitis in children, and its renal involvement determines the prognosis. To date, no national protocol exists for its management. A protocol was drafted for the French Grand Ouest inter-region in 2011 in order to standardize practices. Objectives: The main objective is to evaluate renal sequelae with a median follow-up of 2 years since the implementation of this protocol. The secondary objectives are to evaluate the different therapeutic and diagnostic management. Method: Inclusion of all children from 2006 to 2018 with nephropathy due to rheumatoid purpura followed in the university hospitals of Rennes, Nantes, Tours, Angers and Brest. Results: 169 patients were included, of whom 104 were treated accroding to protocol and 65 differently. Sequels at 2-year follow-up concerned 27.0% of patients with no significant difference according to whether or not the protocol was followed. A significant decrease of 26.1% in the number of renal biopsies was observed in the group that followed the protocol. The latter was performed with a median delay of less than 30 days. Conclusion: The protocol allowed a standardization of practices without deleterious consequences at 2 years of follow-up and a decrease in renal biopsy punctures. It is in agreement with the recommendations of KDIGO (Kidney Disease Improving Global Outcomes) and European experts. On the other hand, in view of recent studies and the physiopathology, immunosuppressive drugs other than corticosteroids could be introduced earlier in severe forms.

Introduction: Le purpura rhumatoïde est la vascularite la plus fréquente chez l'enfant, dont l'atteinte rénale détermine le pronostic. Aucun protocole national n'existe à ce jour concernant sa prise en charge. Un protocole a été rédigé sur le Grand Ouest de la France en 2011 afin d'uniformiser les pratiques. Objectifs: L'objectif principal est d'évaluer les séquelles rénales avec une médiane de suivi de deux ans depuis la mise en place de ce protocole. Les objectifs secondaires sont d'évaluer les différentes prises en charge thérapeutiques et diagnostiques. Méthodes: Nous avons inclus tous les enfants de 2006 à 2018 ayant présenté une néphropathie due à un purpura rhumatoïde suivis dans les CHU de Rennes, Nantes, Tours, Angers et Brest. Résultats: Au total, 169 patients ont été inclus, dont 104 respectant le protocole et 65 hors protocole. Les séquelles à deux ans de suivi concernent 27 % des patients sans différence significative selon l'application ou non du protocole. Une diminution significative de 26,1 % des ponctions biopsies rénales est observée dans le groupe respectant le protocole. Cette dernière est réalisée avec un délai médian inférieur à 30 jours. Conclusion: Le protocole réalisé par le Grand Ouest a permis une uniformisation des pratiques sans conséquences délétères à deux ans de suivi et une diminution des ponctions biopsies rénales. Il est en accord avec les recommandations du KDIGO (Kidney Disease Improving Global Outcomes) et des experts européens. En revanche, au vu des études récentes et de la physiopathologie, les immunosuppresseurs hors corticothérapies pourraient être intégrés plus précocement dans les formes sévères.

Impact of newborn screening for SCID on the management of congenital athymia.

BACKGROUND: Newborn screening (NBS) programs for severe combined immunodeficiency facilitate early diagnosis of severe combined immunodeficiency and promote early treatment with hematopoietic stem cell transplantation, resulting in improved clinical outcomes. Infants with congenital athymia are also identified through NBS because of severe T-cell lymphopenia. With the expanding introduction of NBS programs, referrals of athymic patients for treatment with thymus transplantation have recently increased at Great Ormond Street Hospital (GOSH) (London, United Kingdom). OBJECTIVE: We studied the impact of NBS on timely diagnosis and treatment of athymic infants with thymus transplantation at GOSH. METHODS: We compared age at referral and complications between athymic infants diagnosed after clinical presentation (n = 25) and infants identified through NBS (n = 19) who were referred for thymus transplantation at GOSH between October 2019 and February 2023. We assessed whether age at time of treatment influences thymic output at 6 and 12 months after transplantation. RESULTS: The infants referred after identification through NBS were significantly younger and had fewer complications, in particular fewer infections. All deaths occurred in the group of those who did not undergo NBS, including 6 patients before and 2 after thymus transplantation because of preexisting infections. In the absence of significant comorbidities or diagnostic uncertainties, timely treatment was achieved more frequently after NBS. Treatment when younger than age 4 months was associated with higher thymic output at 6 and 12 months after transplantation. CONCLUSION: NBS contributes to earlier recognition of congenital athymia, promoting referral of athymic patients for thymus transplantation before they acquire infections or other complications and facilitating treatment at a younger age, thus playing an important role in improving their outcomes.

Preneoplastic liver colonization by 11p15.5 altered mosaic cells in young children with hepatoblastoma.

Pediatric liver tumors are very rare tumors with the most common diagnosis being hepatoblastoma. While hepatoblastomas are predominantly sporadic, around 15% of cases develop as part of predisposition syndromes such as Beckwith-Wiedemann (11p15.5 locus altered). Here, we identify mosaic genetic alterations of 11p15.5 locus in the liver of hepatoblastoma patients without a clinical diagnosis of Beckwith-Wiedemann syndrome. We do not retrieve these alterations in children with other types of pediatric liver tumors. We show that mosaic 11p15.5 alterations in liver FFPE sections of hepatoblastoma patients display IGF2 overexpression and H19 downregulation together with an alteration of the liver zonation. Moreover, mosaic livers' microenvironment is enriched in extracellular matrix and angiogenesis. Spatial transcriptomics and single-nucleus RNAseq analyses identify a 60-gene signature in 11p15.5 altered hepatocytes. These data provide insights for 11p15.5 mosaicism detection and its functional consequences during the early steps of carcinogenesis.

Efficacy and Safety of Eculizumab in Pediatric Patients Affected by Shiga Toxin-Related Hemolytic and Uremic Syndrome: A Randomized, Placebo-Controlled Trial.

SIGNIFICANCE STATEMENT: Shiga toxin-related hemolytic uremic syndrome (STEC-HUS) is a serious condition, characterized by multiorgan thrombotic microangiopathy, mainly affecting children. Renal involvement is severe, with approximately half of patients requiring dialysis. So far, no specific treatment has been proven efficient in STEC-HUS. The use of eculizumab, a monoclonal antibody inhibiting terminal complement complex, has demonstrated remarkable success in atypical hemolytic uremic syndrome, but its use in uncontrolled studies to treat STEC-HUS has yielded inconsistent results. In this Phase 3 randomized, placebo-controlled trial in 100 pediatric patients with STEC-HUS, the findings did not show efficacy of eculizumab during the acute phase of the disease. However, the results indicated a reduction of renal sequelae in eculizumab-treated patients at 1-year follow-up. Larger prospective studies would be needed to further explore eculizumab as a potential treatment. BACKGROUND: Shiga toxin-related hemolytic uremic syndrome (STEC-HUS) in children is a severe condition, resulting in approximately 50% of patients requiring RRT. Furthermore, at least 30% of survivors experience kidney sequelae. Recently, activation of the complement alternative pathway has been postulated as a factor in STEC-HUS pathophysiology, leading to compassionate use of eculizumab, a monoclonal antibody inhibiting the terminal complement complex, in affected patients. Given the lack of therapy for STEC-HUS, a controlled study of eculizumab efficacy in treating this condition is a priority. METHODS: We conducted a Phase 3 randomized trial of eculizumab in children with STEC-HUS. Patients were randomly assigned in a 1:1 ratio to receive either eculizumab or placebo during 4 weeks. Follow-up lasted for 1 year. The primary end point was RRT duration <48 hours after randomization. Secondary endpoints included hematologic and extrarenal involvement. RESULTS: Baseline characteristics were similar among the 100 patients who underwent randomization. The rate of RRT <48 hours did not differ significantly between the two groups (48% in the placebo versus 38% in the eculizumab group; P = 0.31) or in the course of ARF. The two groups also exhibited similar hematologic evolution and extrarenal manifestations of STEC-HUS. The proportion of patients experiencing renal sequelae at 1 year was lower in the eculizumab group than in the placebo group (43.48% and 64.44%, respectively, P = 0.04). No safety concern was reported. CONCLUSIONS: In pediatric patients with STEC-HUS, eculizumab treatment does not appear to be associated with improved renal outcome during acute phase of the disease but may reduce long-term kidney sequelae. CLINICAL TRIALS REGISTRATIONS: EUDRACT (2014-001169-28) ClinicalTrials.gov ( NCT02205541 ).

Seasonality of main childhood embryonal tumours and rhabdomyosarcoma, France, 2000-2015.

Few studies have investigated the seasonal patterns of embryonal tumours. Based on data from the French National Registry of Childhood Cancers, the present study aimed to investigate seasonal variations in embryonal tumour incidence rates by month of birth and by month of diagnosis. The study included 6635 primary embryonal tumour cases diagnosed before the age of 15 years over the period 2000-2015 in mainland France. Assuming monthly variations in incidence rates were homogeneous over 2000-2015, we used a Poisson regression model to test for overall heterogeneity in standardised incidence ratios (SIRs) by month of birth or diagnosis. The seasonal scan statistic method was used to detect monthly excesses or deficits of embryonal tumour cases over the whole study period. The annual reproducibility of the observed monthly variations was formally tested. An overall heterogeneity in incidence rates by month of birth was observed for rhabdomyosarcoma in boys only. Based on the month of diagnosis, a seasonality was evidenced for unilateral retinoblastoma, with a lower incidence rate in the summer (SIRJul-Aug  = 0.68, 95% CI = 0.52-0.87), whilst the incidence rate of rhabdomyosarcoma tended to be lower in August (SIRAug  = 0.68, 95% CI = 0.52-0.89). No seasonality was detected for the other embryonal tumour groups by month of birth or month of diagnosis. This study is one of the largest to have investigated the seasonality of childhood embryonal tumours. The study showed a seasonal variation in the incidence rates by month of diagnosis for unilateral retinoblastoma and rhabdomyosarcoma. Our findings are likely to reflect a delay in consultation during the summer months. However, the role of seasonally varying environmental exposures cannot be ruled out.

Severe hematopoietic stem cell inflammation compromises chronic granulomatous disease gene therapy.

X-linked chronic granulomatous disease (CGD) is associated with defective phagocytosis, life-threatening infections, and inflammatory complications. We performed a clinical trial of lentivirus-based gene therapy in four patients (NCT02757911). Two patients show stable engraftment and clinical benefits, whereas the other two have progressively lost gene-corrected cells. Single-cell transcriptomic analysis reveals a significantly lower frequency of hematopoietic stem cells (HSCs) in CGD patients, especially in the two patients with defective engraftment. These two present a profound change in HSC status, a high interferon score, and elevated myeloid progenitor frequency. We use elastic-net logistic regression to identify a set of 51 interferon genes and transcription factors that predict the failure of HSC engraftment. In one patient, an aberrant HSC state with elevated CEBPß expression drives HSC exhaustion, as demonstrated by low repopulation in a xenotransplantation model. Targeted treatments to protect HSCs, coupled to targeted gene expression screening, might improve clinical outcomes in CGD.

Late toxicity comparison of alkylating-based maintenance regimen with cyclophosphamide (VAC) vs ifosfamide (VAI) in Ewing sarcoma survivors treated in the randomized clinical trial Euro-EWING99-R1 in France.

In Euro-EWING99-R1 randomized trial, cyclophosphamide was shown to be noninferior to ifosfamide in the consolidation of standard-risk Ewing sarcoma (SR-EWS) after a common induction with VIDE (vincristine-ifosfamide-doxorubicin-etoposide). We present the results of the late effects analysis of VAC (vincristine-dactinomycin-cyclophoshamide) vs VAI (vincristine-dactinomycin-ifosfamide) conducted in Euro-EWING99-R1 French cohort. Of 267 French randomized patients, 204 were alive and free-of-relapse at 5-years including 172 with available long-term follow-up data concerning cardiac, renal and/or gonadal functions (sex-ratio M/F = 1.3, median age at diagnosis = 14 years): 84 randomized in VAC (median cumulative doses: cyclophosphamide = 9.7 g/m2 , ifosfamide = 59.4 g/m2 ) and 88 in VAI (ifosfamide = 97.1 g/m2 ). With a median follow-up of 10 years (range = 5-17), five late relapses and five second malignancies were recorded. The 10-year event-free survival among 5-year free-of-relapse survivors was similar between VAC and VAI (93% vs 95%, P = .63). We estimated the 10-year cumulative probabilities of cardiac and kidney toxicities at 4.4% (95% confidence interval [95% CI] = 1.1%-7.6%) and 34.8% (95% CI = 26.8%-42.0%), respectively. Cardiac toxicity cumulative probability was similar in both arms, whereas kidney toxicity was higher in VAI (at 10 years, 43.0% vs 25.7%, P = .02), resulting from significant difference in glomerular toxicity (31.1% vs 13.1%, P < .01). At 10 years, gonadal toxicity was observed in 27% and 28% of pubertal men and women, respectively, without significant difference between VAC and VAI. Kidney and gonadal toxicities represent major issues in Euro-EWING99-R1, with significantly higher risk of kidney toxicities with VAI, without significant gonadal toxicity reduction. These results support the need to limit cumulative doses of both alkylating agents and to use mixed regimen as in VIDE-VAC or VDC/IE (vincristine-doxorubicin-cyclophoshamide/ifosfamide-etoposide).

Social Deprivation Is Associated With Lower Access to Pre-emptive Kidney Transplantation and More Urgent-Start Dialysis in the Pediatric Population.

Introduction: Socioeconomic status (SES) is recognized as an important determinant of kidney health. We aimed to evaluate the association of social deprivation with different indicators at kidney replacement therapy (KRT) initiation in the French pediatric metropolitan population. Methods: All patients with end-stage kidney disease (ESKD) who started KRT before 20 years old in France between 2002 and 2015 were included. We investigated different indicators at KRT initiation, which are as follows: KRT modality (dialysis vs. pre-emptive transplantation), late referral to a nephrologist, and dialysis modality (hemodialysis [HD] vs. peritoneal dialysis [PD], urgent vs. planned start of dialysis, use of catheter vs. use of fistula for HD vascular access). An ecological index (European Deprivation Index [EDI]) was used as a proxy for social deprivation. Results: A total of 1115 patients were included (males 59%, median age at dialysis 14.4 years, glomerular/vascular diseases 36.8%). The most deprived group represented 38.7% of the patients, suggesting pediatric patients with ESKD come from a more socially deprived background. The most deprived group was more likely to initiate KRT with dialysis versus kidney transplantation. Among patients on HD, the odds of starting treatment in emergency with a catheter was >2-fold higher for the most deprived compared with the least deprived children (adjusted odds ratio [aOR] 2.35, 95% CI 1.16-4.78). Conclusion: Children from the most deprived area have lower access to pre-emptive transplantation, have lower access to PD, tend to be late referred to a nephrologist, and have more urgent initiation of HD with a catheter.

Renal Prognosis in Children With Tubulointerstitial Nephritis and Uveitis Syndrome.

INTRODUCTION: Tubulointerstitial nephritis (TIN) and uveitis (TINU) syndrome is a rare disease. The renal prognosis is generally thought to be better in children with TINU syndrome than in adults. However, data are scarce. We aimed to investigate the long-term renal prognosis in a French cohort of children with TINU syndrome. METHODS: We performed a national retrospective study including 23 French pediatric nephrology centers enrolling patients with TINU syndrome diagnosed between January 2000 and December 2018. RESULTS: A total of 46 patients were included (52% female, median age 13.8 years). At diagnosis of TIN, the median estimated glomerular filtration rate (eGFR) was 30.6 ml/min per 1.73 m2 (4.9-62.8). The median time between diagnosis of uveitis and TIN was 0.4 months (-4.1; +17.1). All patients had anterior uveitis, but 12 (29%) were asymptomatic. Nearly all patients (44 of 46) received steroid treatment, and 12 patients (26%) received a second-line therapy. At last follow-up (median 2.8 years), the median eGFR was 87.5 ml/min per 1.73 m2 (60.3-152.7) and <90 ml/min per 1.73 m2 in 20 patients. CONCLUSION: In our study, nearly half of the patients had renal sequelae at last follow-up. Given the possible progression to chronic kidney disease, long-term monitoring of children with TINU syndrome is mandatory. Approximately a quarter of the children had asymptomatic uveitis suggesting all children presenting with TIN should undergo systematic ophthalmologic screening even in the absence of ocular signs.

Childhood ovarian nonseminomatous germ cell tumors: A highly curable disease with few long-term treatment-related toxicities-Results of the French TGM95 study.

We report survival and late effects analysis of TGM95 study for childhood (≤18 years) ovarian nonseminomatous germ cell tumors (NS-GCT). Patients with localized tumors (FIGO-stage IA) had no adjuvant treatment (low-risk, LR). Patients with advanced-stage received 3-5 VBP (vinblastin-bleomycin-cisplatin) in intermediate-risk group (IR: FIGO-stage IC-II-III and AFP < 15 000 ng/mL) or 4-6 VIP (etoposide-ifosfamide-cisplatin) in high-risk group (HiR: metastatic or AFP ≥ 15 000 ng/mL). Seventy-seven patients were included (median age = 12 years): 14 LR (13 FIGO-stage IA, 1 retrospectively IC), 26 IR (12 IC, 12 II-III, 2 not-available) and 37 HiR (2 IA with AFP ≥ 15 000 ng/mL, 27 II-III, 8 IV). After a median follow-up of 13.4 years, 12 events (eight relapses) and six deaths (two GCT-related, two due to acute myeloid leukemia and two noncancer related) occurred. All relapses (6 LR, 1 IR) occurred within 2 years. Four contralateral mature teratomas were observed within 8 years. Five-year EFS and OS were 88.2% (95%CI = 79-94%) and 94.6% (95%CI = 87-98%). Seven patients (9%) had bilateral gonadectomy. Among 51 survivors at 2 years aged >15 years (median = 26 years) with remaining ovarian tissue, all had developed spontaneous puberty and 21 (41%) had at least one pregnancy (including two with infertility treatment). Among 69 patients treated with platinum-based chemotherapy, chronic-kidney-disease was diagnosed in four patients (three after VIP) and significant ototoxicity occurred in three (all grade-2). Childhood ovarian NS-GCTs have an excellent prognosis with few late effects. The low-intensive etoposide-free VBP regimen could be an alternative in children with IR disease especially in cases of tumor rupture. The risk of contralateral mature teratoma needs regular monitoring of the remaining ovary.

[Management of patients developing acute gastro-intestinal graft-versus-host-disease: Guidelines from the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC)]. / Prise en charge de la GVH digestive aiguë : recommandations de la Société francophone de greffe de moelle et de thérapie cellulaire (SFGM-TC).

Graft-versus-host disease (GVHD) is the most common complication after allogeneic hematopoietic cell transplantation (allo-HCT) with a frequency range of 30% to 50%. GVH is the leading cause of non-relapse-related deaths and a cause early mortality. Gastro-intestinal (GI) GVH results in digestive manifestations that involve the small intestine and the colon. The patient may then have diarrhea, intestinal bleeding, abdominal pain but also clinical signs such as nausea and vomiting may lead to anorexia. GI-GVHD promotes undernutrition as well as significant losses of vitamins and trace elements. In the case of post-transplant diarrhea, differential diagnosis can include GI-GVHD, infection and drug toxicity. Although, corticosteroids w/wo calcineurin inhibitors represent the standard of care in first line treatment, there is no consensus regarding salvage therapy in case of corticoresistant GI-GVH. In addition, assessment of early nutritional status would help combating undernutrition, which is an independent risk factor for mortality in patients with GI-GVHD. In this workshop of the Fancophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC) we focused on the management of patients developing GI-GVHD following allo-HCT.

Integrated Genomic Analysis Identifies Driver Genes and Cisplatin-Resistant Progenitor Phenotype in Pediatric Liver Cancer.

Pediatric liver cancers (PLC) comprise diverse diseases affecting infants, children, and adolescents. Despite overall good prognosis, PLCs display heterogeneous response to chemotherapy. Integrated genomic analysis of 126 pediatric liver tumors showed a continuum of driver mechanisms associated with patient age, including new targetable oncogenes. In 10% of patients with hepatoblastoma, all before three years old, we identified a mosaic premalignant clonal expansion of cells altered at the 11p15.5 locus. Analysis of spatial and longitudinal heterogeneity revealed an important plasticity between "hepatocytic," "liver progenitor," and "mesenchymal" molecular subgroups of hepatoblastoma. We showed that during chemotherapy, "liver progenitor" cells accumulated massive loads of cisplatin-induced mutations with a specific mutational signature, leading to the development of heavily mutated relapses and metastases. Drug screening in PLC cell lines identified promising targets for cisplatin-resistant progenitor cells, validated in mouse xenograft experiments. These data provide new insights into cisplatin resistance mechanisms in PLC and suggest alternative therapies. SIGNIFICANCE: PLCs are deadly when they resist chemotherapy, with limited alternative treatment options. Using a multiomics approach, we identified PLC driver genes and the cellular phenotype at the origin of cisplatin resistance. We validated new treatments targeting these molecular features in cell lines and xenografts.This article is highlighted in the In This Issue feature, p. 2355.

Medication non-adherence after allogeneic hematopoietic cell transplantation in adult and pediatric recipients: a cross sectional study conducted by the Francophone Society of Bone Marrow Transplantation and Cellular Therapy.

Medication non-adherence (NA) after allogeneic hematopoietic cell transplantation (allo-HCT) can lead to serious complications. This study assesses NA in French adult and pediatric recipients and identifies factors associated with NA. In accordance with the EMERGE and STROBE guidelines, a cross sectional multicentric survey was conducted. We used a self-reported questionnaire that was adapted to adults and pediatrics and that could provide a picture of all three phases of medication adherence: initiation, implementation, persistence. We enrolled 242 patients, 203 adults (mean age: 51 years old, 50.7% male) and 39 children (mean age: 9 years old, 56.4% female). Reported NA was estimated at about 75% in both populations, adults and pediatrics. In adults, the univariate analysis showed that patients less than 50 years old (P = 0.041), (i) treated with cyclosporine (P = 0.02), (ii) treated with valacyclovir/acyclovir (P = 0.016), and (iii) experiencing side effects (P = 0.009), were significantly more non-adherent. In multivariate analysis, only recipient age was significantly associated to NA (P = 0.05). The limited size of the pediatric population did not allow us to draw any statistical conclusion about this population. To the best of our knowledge, this is the first study in France on NA in allo-HCT recipients. Our results highlight the age factor as the only factor related to NA. Further studies are needed to confirm our observations and refine results in pediatric populations, currently most at risk of medication NA.

Tumor rupture in hepatoblastoma: A high risk factor?

BACKGROUND: Hepatoblastoma tumor rupture is a high-risk criterion in the SIOPEL 3/4 protocol. Little is known about the outcome of these children. METHODS: Radiological signs of possible tumor rupture, defined as peritoneal effusion, peritoneal nodules, or hepatic subcapsular hematoma, were reported in 24 of 150 patients treated for hepatoblastoma in France from January 2000 to December 2014 after central radiological expert review. RESULTS: Twenty-two patients with available clinical data were included (nine PRETEXT-I/II, six PRETEXT-III, seven PRETEXT-IV, and five had lung metastases). Five patients had a subcapsular hematoma only, and 17 patients had intraperitoneal rupture (subcapsular hematoma and peritoneal effusion). A hepatic biopsy was performed in 19 patients. Intraperitoneal rupture occurred before biopsy in 12 and after biopsy in three (including one with prebiopsy subcapsular hematoma) (missing data: two). All patients were treated with chemotherapy, with high-risk regimens including cisplatin or carboplatin and doxorubicin in 19 and cisplatin or carboplatin alone in three. Liver surgery was performed in 20 patients (including three liver transplants). Fifteen patients (68%) achieved complete remission. With a median follow-up of 5.5 years, 11 events occurred (six progressions and three relapses, including three peritoneal progressions/relapses, one surgical complication, and one second cancer) and eight patients died. One of eight patients with no other high-risk criterion had a relapse. The three-year event-free survival and overall survival rates were 49.6% (95% CI = 30-69) and 68.2% (40-84), respectively. CONCLUSIONS: Tumor rupture is predictive of poor prognosis with risk of peritoneal progression/relapse. However, it should not be a contraindication for liver transplantation.

APC germline hepatoblastomas demonstrate cisplatin-induced intratumor tertiary lymphoid structures.

Hepatoblastoma (HB) is the most common liver cancer in children. We aimed to characterize HB related to APC (Adenomatous Polyposis Coli) germline mutation (APC-HB). This French multicentric retrospective study included 12 APC-HB patients under 5 at diagnosis. Clinical features of APC-HB were compared to the French SIOPEL2-3 cohort of HB patients. Molecular and histopathological analyses of APC-HB were compared to 15 consecutive sporadic HB treated at Bicêtre hospital from 2013 to 2015 (non-APC-HB). APC-HB patients have a peculiar spectrum of germline APC mutations, with no events in the main hotspot of classical APC mutations at codon 1309 (P < .05). Compared to sporadic HB, they have similar clinical features including good prognosis since all patients are alive in complete remission at last follow-up. APC-HB are mostly well-limited tumors with fetal predominance and few mesenchymal components. All APC-HB have an activated Wnt/ß-catenin pathway without CTNNB1 mutation, confirming that germline APC and somatic CTNNB1 mutations are mutually exclusive (P < .001). Pathological reviewing identified massive intratumor tertiary lymphoid structures (TLS) containing both lymphocytes and antigen-presenting cells in all 11 APC-HB cases who received cisplatin-based neoadjuvant chemotherapy but not in five pre-chemotherapy samples (four paired biopsies and one patient resected without chemotherapy), indicating that these TLS are induced by chemotherapy (P < .001). Conclusion: APC-HB show a good prognosis, they are all infiltrated by cisplatin-induced TLS, a feature only retrieved in a minority of non-APC-HB. This suggests that APC inactivation can synergize with cisplatin to induce an immunogenic cell death that initiates an anti-tumor immune response.

Treatment and outcome of congenital nephrotic syndrome.

BACKGROUND: Recommendations for management of Finnish-type congenital nephrotic syndrome (CNS) followed by many teams include daily albumin infusions, early bilateral nephrectomy, dialysis and transplantation. We aimed to assess the treatment and outcome of patients with CNS in France. METHODS: We conducted a nationwide retrospective study on 55 consecutive children born between 2000 and 2014 treated for non-infectious CNS. RESULTS: The estimated cumulative incidence of CNS was 0.5/100 000 live births. The underlying defect was biallelic mutations in NPHS1 (36/55, 65%), NPHS2 (5/55, 7%), PLCE1 (1/55, 2%), heterozygous mutation in WT1 (4/55, 7%) and not identified in nine children (16%). Fifty-three patients (96%) received daily albumin infusions from diagnosis (median age 14 days), which were spaced and withdrawn in 10 patients. Twenty children (35%) were managed as outpatients. Thirty-nine patients reached end-stage kidney disease (ESKD) at a median age of 11 months. The overall renal survival was 64% and 45% at 1 and 2 years of age, respectively. Thirteen children died during the study period including four at diagnosis, two of nosocomial catheter-related septic shock, six on dialysis and one after transplantation. The remaining 13 patients were alive with normal renal function at last follow-up [median 32 months (range 9-52)]. Renal and patient survivals were longer in patients with NPHS1 mutations than in other patients. The invasive infection rate was 2.41/patient/year. CONCLUSIONS: Our study shows: (i) a survival free from ESKD in two-thirds of patients at 1 year and in one-half at 2 years and (ii) a significant reduction or even a discontinuation of albumin infusions allowing ambulatory care in a subset of patients. These results highlight the need for new therapeutic guidelines for CNS patients.

A Pharmacokinetic and Pharmacogenetic Analysis of Osteosarcoma Patients Treated With High-Dose Methotrexate: Data From the OS2006/Sarcoma-09 Trial.

Growing evidence suggests that polymorphisms of genes coding for transporters or enzymes may partially explain the large between subject variability reported for methotrexate (MTX) pharmacokinetics (PK). This prospective study aimed to develop a population PK-pharmacogenetic model to evaluate the part of between-subject variability due to single-nucleotide polymorphisms (SNPs) in transporters and enzyme genes implicated in MTX distribution and elimination. MTX concentrations and 54 SNPs (located in ABCB1, ABCC1, ABCC2, ABCC3, ABCC4, ABCG2, SLC19A1, SLCO1B1, and UGT1A1 genes) were analyzed in patients treated with MTX included in the OS2006/sarcoma-09 trial (a multicenter, open-label, phase III trial, ClinicalTrials.gov. Identifier: NCT00470223). PK data were analyzed using the nonlinear mixed-effect modeling software program Monolix. The influence of each SNP was evaluated using a stepwise procedure under additive, recessive, or dominant genetic model. The likelihood ratio test was used to test the effect of each SNP on PK parameters. Overall, 187 patients with 7898 MTX blood concentrations were included in the PK-pharmacogenetic analysis. A 2-compartment model adequately described the data. Although high-dose MTX dosing recommendations in pediatric patients are currently based on body surface area, body weight was more predictive of clearance between-subject variability than body surface area. The most significant polymorphism associated with MTX clearance was rs13120400 (on the ABCG2 gene) under the recessive genetic model (P < .0001). GG genotype carriers for rs13120400 appeared to have a moderate decrease in MTX exposure compared to AA or GA carriers.