Neurofibromatosis type 1 mosaicism in patients with constitutional mismatch repair deficiency.

Differential diagnosis between constitutional mismatch repair deficiency (CMMRD) and neurofibromatosis type 1 (NF1) is crucial as treatment and surveillance differ. We report the case of a girl with a clinical diagnosis of sporadic NF1 who developed a glioblastoma. Immunohistochemistry for MMR proteins identified PMS2 loss in tumour and normal cells and WES showed the tumour had an ultra-hypermutated phenotype, supporting the diagnosis of CMMRD. Germline analyses identified two variants (one pathogenic variant and one classified as variant(s) of unknown significance) in the PMS2 gene and subsequent functional assays on blood lymphocytes confirmed the diagnosis of CMMRD. The large plexiform neurofibroma of the thigh and the freckling were however more compatible with NF1. Indeed, a NF1 PV (variant allele frequencies of 20%, 3% and 9% and in blood, skin and saliva samples, respectively) was identified confirming a mosaicism for NF1. Retrospective analysis of a French cohort identified NF1 mosaicism in blood DNA in 2 out of 22 patients with CMMRD, underlining the existence of early postzygotic PV of NF1 gene in patients with CMMRD whose tumours have been frequently reported to exhibit somatic NF1 mutations. It highlights the potential role of this pathway in the pathogenesis of CMMRD-associated gliomas and argues in favour of testing MEK inhibitors in this context.

Constitutional Microsatellite Instability, Genotype, and Phenotype Correlations in Constitutional Mismatch Repair Deficiency.

BACKGROUND & AIMS: Constitutional mismatch repair deficiency (CMMRD) is a rare recessive childhood cancer predisposition syndrome caused by germline mismatch repair variants. Constitutional microsatellite instability (cMSI) is a CMMRD diagnostic hallmark and may associate with cancer risk. We quantified cMSI in a large CMMRD patient cohort to explore genotype-phenotype correlations using novel MSI markers selected for instability in blood. METHODS: Three CMMRD, 1 Lynch syndrome, and 2 control blood samples were genome sequenced to >120× depth. A pilot cohort of 8 CMMRD and 38 control blood samples and a blinded cohort of 56 CMMRD, 8 suspected CMMRD, 40 Lynch syndrome, and 43 control blood samples were amplicon sequenced to 5000× depth. Sample cMSI score was calculated using a published method comparing microsatellite reference allele frequencies with 80 controls. RESULTS: Thirty-two mononucleotide repeats were selected from blood genome and pilot amplicon sequencing data. cMSI scoring using these MSI markers achieved 100% sensitivity (95% CI, 93.6%-100.0%) and specificity (95% CI 97.9%-100.0%), was reproducible, and was superior to an established tumor MSI marker panel. Lower cMSI scores were found in patients with CMMRD with MSH6 deficiency and patients with at least 1 mismatch repair missense variant, and patients with biallelic truncating/copy number variants had higher scores. cMSI score did not correlate with age at first tumor. CONCLUSIONS: We present an inexpensive and scalable cMSI assay that enhances CMMRD detection relative to existing methods. cMSI score is associated with mismatch repair genotype but not phenotype, suggesting it is not a useful predictor of cancer risk.

Tyrosine phosphatases regulate resistance to ALK inhibitors in ALK+ anaplastic large cell lymphoma.

Anaplastic large cell lymphomas (ALCLs) frequently carry oncogenic fusions involving the anaplastic lymphoma kinase (ALK) gene. Targeting ALK using tyrosine kinase inhibitors (TKIs) is a therapeutic option in cases relapsed after chemotherapy, but TKI resistance may develop. By applying genomic loss-of-function screens, we identified PTPN1 and PTPN2 phosphatases as consistent top hits driving resistance to ALK TKIs in ALK+ ALCL. Loss of either PTPN1 or PTPN2 induced resistance to ALK TKIs in vitro and in vivo. Mechanistically, we demonstrated that PTPN1 and PTPN2 are phosphatases that bind to and regulate ALK phosphorylation and activity. In turn, oncogenic ALK and STAT3 repress PTPN1 transcription. We found that PTPN1 is also a phosphatase for SHP2, a key mediator of oncogenic ALK signaling. Downstream signaling analysis showed that deletion of PTPN1 or PTPN2 induces resistance to crizotinib by hyperactivating SHP2, the MAPK, and JAK/STAT pathways. RNA sequencing of patient samples that developed resistance to ALK TKIs showed downregulation of PTPN1 and PTPN2 associated with upregulation of SHP2 expression. Combination of crizotinib with a SHP2 inhibitor synergistically inhibited the growth of wild-type or PTPN1/PTPN2 knock-out ALCL, where it reverted TKI resistance. Thus, we identified PTPN1 and PTPN2 as ALK phosphatases that control sensitivity to ALK TKIs in ALCL and demonstrated that a combined blockade of SHP2 potentiates the efficacy of ALK inhibition in TKI-sensitive and -resistant ALK+ ALCL.

Prognostic value of hemogram parameters in osteosarcoma: The French OS2006 experience.

BACKGROUND: Previous studies have shown that neutrophil-to-lymphocyte (NLR) ratio at diagnosis and early lymphocytes recovery on doxorubicin-based chemotherapy, may impact the outcome in patients with osteosarcoma (OST). This study aimed to evaluate the prognostic value of hemogram parameters in patients with OST treated with high-dose methotrexate and etoposide/ifosfamide (M-EI) chemotherapy. MATERIALS AND METHODS: We retrospectively analyzed the prognostic value of various hemogram parameters at diagnosis and during therapy in a large consecutive cohort of patients with OST included in the French OS2006 trial and treated with M-EI chemotherapy. RESULTS: A total of 164 patients were analyzed. The median age was 14.7 years (interquartile range [IQR]: 11.7-17). Median follow-up was 5.6 years (IQR: 3.3-7.7 years). Three-year event-free survival (EFS) and overall survival (OS) were 71.5% (95% confidence interval [CI]: 64%-78%) and 86.4% (95% CI: 80%-91%), respectively. In univariate analysis, blood count parameters at diagnosis and early lymphocyte recovery at Day 14 were not found prognostic of survival outcomes. By contrast, an increase of NLR ratio at Day 1 of the first EI chemotherapy (NLR-W4) was associated with reduced OS in univariate (p = .0044) and multivariate analysis (hazards ratio [HR] = 1.3, 95% CI: 1.1-1.5; p = .002), although not with EFS. After adjustment on histological response and metastatic status, an increase of the ratio NLR-W4 of 1 was associated with an increased risk of death of 30%. CONCLUSIONS: We identified NLR-W4 as a potential early biomarker for survival in patients with OST treated with M-EI chemotherapy. Further studies are required to confirm the prognostic value of NLR and better identify immune mechanisms involved in disease surveillance.

High yield of surveillance in patients diagnosed with constitutional mismatch repair deficiency.

BACKGROUND: Constitutional mismatch repair deficiency (CMMRD) is a rare autosomal recessively inherited syndrome that is caused by biallelic pathogenic variants of the mismatch repair genes. It is characterised by the development of multiple tumours in the first and second decade of life including brain, gastrointestinal and haematological tumours often resulting in early death. In order to improve the prognosis of these patients, the European collaborative group 'care for CMMRD' developed a surveillance programme in 2014 and established a registry of patients with CMMRD in Paris. The aim of the study was to evaluate the outcome of this programme. METHODS: Twenty-two patients with a definitive diagnosis of CMMRD and with at least one follow-up study were selected from the registry. Medical data on the outcome of surveillance were collected from these patients. RESULTS: During a mean follow-up of 4 years, the programme detected eight malignant tumours including three brain tumours, three upper gastrointestinal cancers and two colorectal cancers. Most tumours could successfully be treated. In addition, many adenomas were detected in the duodenum, and colorectum and subsequently removed. Seven patients developed a symptomatic malignancy, including two brain tumours, one small bowel cancer and four haematological malignancies. At the end of the follow-up, 16 out of 22 patients (73%) who participated in the surveillance programme were still alive. CONCLUSION: The study suggests a beneficial effect of surveillance of the digestive tract and brains.

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).

Patient-derived xenograft models of ALK+ ALCL reveal preclinical promise for therapy with brigatinib.

Anaplastic large-cell lymphoma (ALCL) is a T-cell malignancy predominantly driven by the oncogenic anaplastic lymphoma kinase (ALK), accounting for approximately 15% of all paediatric non-Hodgkin lymphoma. Patients with central nervous system (CNS) relapse are particularly difficult to treat with a 3-year overall survival of 49% and a median survival of 23.5 months. The second-generation ALK inhibitor brigatinib shows superior penetration of the blood-brain barrier unlike the first-generation drug crizotinib and has shown promising results in ALK+ non-small-cell lung cancer. However, the benefits of brigatinib in treating aggressive paediatric ALK+ ALCL are largely unknown. We established a patient-derived xenograft (PDX) resource from ALK+ ALCL patients at or before CNS relapse serving as models to facilitate the development of future therapies. We show in vivo that brigatinib is effective in inducing the remission of PDX models of crizotinib-resistant (ALK C1156Y, TP53 loss) ALCL and furthermore that it is superior to crizotinib as a second-line approach to the treatment of a standard chemotherapy relapsed/refractory ALCL PDX pointing to brigatinib as a future therapeutic option.

Pediatric Tumors and Developmental Anomalies: A French Nationwide Cohort Study.

OBJECTIVE: To assess the associations between congenital abnormalities and pediatric malignancies and evaluate the potential underlying molecular basis by collecting information on pediatric patients with cancer and congenital abnormalities. STUDY DESIGN: Tumeur Et Développement is a national, prospective, and retrospective multicenter study recording data of children with cancer and congenital abnormalities. When feasible, blood and tumoral samples are collected for virtual biobanking. RESULTS: From June 2013 to December 2019, 679 associations between pediatric cancers and congenital abnormalities were recorded. The most represented cancers were central nervous system tumors (n = 139; 20%), leukemia and myelodysplastic syndromes (n = 123; 18.1%), and renal tumors (n = 101; 15%). Congenital abnormalities were not related to any known genetic disorder in 66.5% of cases. In this group, the most common anomaly was intellectual disability (22.3%), followed by musculoskeletal (14.2%) and genitourinary anomalies (12.4%). Intellectual disability was mostly associated with hematologic malignancies. Embryonic tumors (neuroblastoma, Wilms tumor, and rhabdomyosarcoma) were associated with consistent abnormalities, sometimes with a close anatomical neighborhood between the abnormality and the neoplasm. CONCLUSIONS: In the first Tumeur Et Développement analysis, 3 major themes have been identified: (1) germline mutations with or without known cancer predisposition, (2) postzygotic events responsible for genomic mosaicism, (3) coincidental associations. New pathways involved in cancer development need to be investigated to improve our understanding of childhood cancers.

Diagnostic criteria for constitutional mismatch repair deficiency (CMMRD): recommendations from the international consensus working group.

BACKGROUND: Constitutional mismatch repair deficiency syndrome (CMMRD) is the most aggressive cancer predisposition syndrome associated with multiorgan cancers, often presenting in childhood. There is variability in age and presentation of cancers and benign manifestations mimicking neurofibromatosis type 1. Genetic testing may not be informative and is complicated by pseudogenes associated with the most commonly associated gene, PMS2. To date, no diagnostic criteria exist. Since surveillance and immune-based therapies are available, establishing a CMMRD diagnosis is key to improve survival. METHODS: In order to establish a robust diagnostic path, a multidisciplinary international working group, with representation from the two largest consortia (International Replication Repair Deficiency (IRRD) consortium and European Consortium Care for CMMRD (C4CMMRD)), was formed to establish diagnostic criteria based on expertise, literature review and consensus. RESULTS: The working group established seven diagnostic criteria for the diagnosis of CMMRD, including four definitive criteria (strong evidence) and three likely diagnostic criteria (moderate evidence). All criteria warrant CMMRD surveillance. The criteria incorporate germline mismatch repair results, ancillary tests and clinical manifestation to determine a diagnosis. Hallmark cancers for CMMRD were defined by the working group after extensive literature review and consultation with the IRRD and C4CMMRD consortia. CONCLUSIONS: This position paper summarises the evidence and rationale to provide specific guidelines for CMMRD diagnosis, which necessitates appropriate surveillance and treatment.

Cancer risk and tumour spectrum in 172 patients with a germline SUFU pathogenic variation: a collaborative study of the SIOPE Host Genome Working Group.

BACKGROUND: Little is known about risks associated with germline SUFU pathogenic variants (PVs) known as a cancer predisposition syndrome. METHODS: To study tumour risks, we have analysed data of a large cohort of 45 unpublished patients with a germline SUFU PV completed with 127 previously published patients. To reduce the ascertainment bias due to index patient selection, the risk of tumours was evaluated in relatives with SUFU PV (89 patients) using the Nelson-Aalen estimator. RESULTS: Overall, 117/172 (68%) SUFU PV carriers developed at least one tumour: medulloblastoma (MB) (86 patients), basal cell carcinoma (BCC) (25 patients), meningioma (20 patients) and gonadal tumours (11 patients). Thirty-three of them (28%) had multiple tumours. Median age at diagnosis of MB, gonadal tumour, first BCC and first meningioma were 1.5, 14, 40 and 44 years, respectively. Follow-up data were available for 160 patients (137 remained alive and 23 died). The cumulative incidence of tumours in relatives was 14.4% (95% CI 6.8 to 21.4), 18.2% (95% CI 9.7 to 25.9) and 44.1% (95% CI 29.7 to 55.5) at the age of 5, 20 and 50 years, respectively. The cumulative risk of an MB, gonadal tumour, BCC and meningioma at age 50 years was: 13.3% (95% CI 6 to 20.1), 4.6% (95% CI 0 to 9.7), 28.5% (95% CI 13.4 to 40.9) and 5.2% (95% CI 0 to 12), respectively. Sixty-four different PVs were reported across the entire SUFU gene and inherited in 73% of cases in which inheritance could be evaluated. CONCLUSION: Germline SUFU PV carriers have a life-long increased risk of tumours with a spectrum dominated by MB before the age of 5, gonadal tumours during adolescence and BCC and meningioma in adulthood, justifying fine-tuned surveillance programmes.

IL10RA modulates crizotinib sensitivity in NPM1-ALK+ anaplastic large cell lymphoma.

Anaplastic large cell lymphoma (ALCL) is a T-cell malignancy predominantly driven by a hyperactive anaplastic lymphoma kinase (ALK) fusion protein. ALK inhibitors, such as crizotinib, provide alternatives to standard chemotherapy with reduced toxicity and side effects. Children with lymphomas driven by nucleophosmin 1 (NPM1)-ALK fusion proteins achieved an objective response rate to ALK inhibition therapy of 54% to 90% in clinical trials; however, a subset of patients progressed within the first 3 months of treatment. The mechanism for the development of ALK inhibitor resistance is unknown. Through genome-wide clustered regularly interspaced short palindromic repeats (CRISPR) activation and knockout screens in ALCL cell lines, combined with RNA sequencing data derived from ALK inhibitor-relapsed patient tumors, we show that resistance to ALK inhibition by crizotinib in ALCL can be driven by aberrant upregulation of interleukin 10 receptor subunit alpha (IL10RA). Elevated IL10RA expression rewires the STAT3 signaling pathway, bypassing otherwise critical phosphorylation by NPM1-ALK. IL-10RA expression does not correlate with response to standard chemotherapy in pediatric patients, suggesting that a combination of crizotinib and chemotherapy could prevent ALK inhibitor resistance-specific relapse.

Prognostic impact of pulmonary nodules diagnosed at initial presentation in patients with osteosarcoma.

BACKGROUND: Resection of all lung metastases in patients with osteosarcoma improves survival. The increased computed tomography (CT) scan quality allows detecting smaller nodules. We aimed to evaluate the prognostic impact of those nodules that do not meet the classical criteria for lung metastases. METHODS: A central radiology review (CRR) on lung CT scans performed during the treatment of patients included in OS2006 trial and treated with a high-dose methotrexate-based chemotherapy from 2007 to 2013 was realized in three centers. RESULTS: At trial enrollment, among 77 patients, six (8%) had nodules meeting the trial's criteria for metastatic disease, 46 (60%) were classified as having localized disease, and 25 (32%) as having doubtful nodules. After CRR, 218 nodules were found at diagnosis (all in patients classified as "metastatic or doubtful" and 13 patients classified as "localized") (median two nodules per patient [1-52]). The 5-year event-free survival/overall survival (EFS/OS) of patients with at least one nodule versus no nodule were similar (67.7%/79.2% vs. 81.8%/91%). After histological analysis, two of 46 (4.3%) "localized" and eight of 25 (32.0%) "doubtful" patients were re-classified as "metastatic," whereas there was no change in patients initially "metastatic." The 5-year OS of confirmed histological metastatic versus nonmetastatic patients were different (56% vs. 92%, p < .01). CONCLUSION: Central review of lung CT scan increased the detection of nodules in osteosarcoma. Patients with small lung nodules classified as doubtful had a quite similar outcome as those with a localized disease. However, patients with confirmed metastatic nodules have a poorer prognosis, even if considered as "localized" at diagnosis.

Neuro-meningeal relapse in anaplastic large-cell lymphoma: incidence, risk factors and prognosis - a report from the European intergroup for childhood non-Hodgkin lymphoma.

Relapses involving the central nervous system (CNS) are rare in children and adolescents with ALK+ anaplastic large cell lymphoma (ALCL) treated with regimens including CNS prophylaxis. Early identification of patients at high-risk for CNS relapse would enable stratification and better adaptation of initial treatment especially in the light of the upcoming targeted therapies with limited CNS penetration. We analyzed clinical and histological data of all ALK+ALCL patients with CNS relapse registered in ALCL99-database with the aim to describe risk factors and outcome. Characteristics of patients with no relapse, relapse without CNS involvement and CNS relapse were compared. At a median follow-up of 8 years (0.05-18 years), a CNS involvement was reported at first or subsequent relapse in 26/618 patients. Median interval between initial diagnosis and first CNS relapse was 8 months (IQR 5.55-10.61/range 1.31-130.69). The 5-year cumulative risk of CNS relapse was 4% (95% CI 2.9-5.5). Bone marrow involvement, peripheral blasts and CNS involvement at diagnosis were more frequent in patients with CNS relapse than in patients with no relapse or with relapse with no CNS involvement. The treatment of CNS relapse was heterogeneous. The median survival after CNS relapse was 23.7 months. Eleven patients were alive at last follow-up. Three-year overall survival after CNS relapse was 48.70% (95% CI 30.52-67.23).

Sodium Thiosulfate for Protection from Cisplatin-Induced Hearing Loss.

BACKGROUND: Cisplatin chemotherapy and surgery are effective treatments for children with standard-risk hepatoblastoma but may cause considerable and irreversible hearing loss. This trial compared cisplatin with cisplatin plus delayed administration of sodium thiosulfate, aiming to reduce the incidence and severity of cisplatin-related ototoxic effects without jeopardizing overall and event-free survival. METHODS: We randomly assigned children older than 1 month and younger than 18 years of age who had standard-risk hepatoblastoma (≤3 involved liver sectors, no metastatic disease, and an alpha-fetoprotein level of >100 ng per milliliter) to receive cisplatin alone (at a dose of 80 mg per square meter of body-surface area, administered over a period of 6 hours) or cisplatin plus sodium thiosulfate (at a dose of 20 g per square meter, administered intravenously over a 15-minute period, 6 hours after the discontinuation of cisplatin) for four preoperative and two postoperative courses. The primary end point was the absolute hearing threshold, as measured by pure-tone audiometry, at a minimum age of 3.5 years. Hearing loss was assessed according to the Brock grade (on a scale from 0 to 4, with higher grades indicating greater hearing loss). The main secondary end points were overall survival and event-free survival at 3 years. RESULTS: A total of 109 children were randomly assigned to receive cisplatin plus sodium thiosulfate (57 children) or cisplatin alone (52) and could be evaluated. Sodium thiosulfate was associated with few high-grade toxic effects. The absolute hearing threshold was assessed in 101 children. Hearing loss of grade 1 or higher occurred in 18 of 55 children (33%) in the cisplatin-sodium thiosulfate group, as compared with 29 of 46 (63%) in the cisplatin-alone group, indicating a 48% lower incidence of hearing loss in the cisplatin-sodium thiosulfate group (relative risk, 0.52; 95% confidence interval [CI], 0.33 to 0.81; P=0.002). At a median of 52 months of follow-up, the 3-year rates of event-free survival were 82% (95% CI, 69 to 90) in the cisplatin-sodium thiosulfate group and 79% (95% CI, 65 to 88) in the cisplatin-alone group, and the 3-year rates of overall survival were 98% (95% CI, 88 to 100) and 92% (95% CI, 81 to 97), respectively. CONCLUSIONS: The addition of sodium thiosulfate, administered 6 hours after cisplatin chemotherapy, resulted in a lower incidence of cisplatin-induced hearing loss among children with standard-risk hepatoblastoma, without jeopardizing overall or event-free survival. (Funded by Cancer Research UK and others; SIOPEL 6 ClinicalTrials.gov number, NCT00652132 ; EudraCT number, 2007-002402-21 .).

Should treatment of ALK-positive anaplastic large cell lymphoma be stratified according to minimal residual disease?

In anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma (ALK+ ALCL), positive minimal residual disease (MRD+) after the first chemotherapy course was proven of strong prognostic significance. We aimed to validate these results in 138 French patients. Eighty-seven patients had a detectable minimal disseminated disease at diagnosis (MDD+). Early MRD assessment was performed in 33 of 87 patients and was positive in 18 and negative in 15 (MRD-). Three-year progression-free survival was significantly correlated with the MDD/MRD status: 81.1% in MDD-, 69.6% in MDD+/MRD-, and 15.2% in MDD+/MRD+ patients. In conclusion, we confirmed on an independent cohort that the MDD/MRD status has strong prognosis significance in ALK+ ALCL.

Adrenocortical tumours in children and adolescents: The EXPeRT/PARTNER diagnostic and therapeutic recommendations.

Adrenocortical tumours (ACTs) are rare during childhood. A complete surgical resection provides the best chance of cure, but the role and efficacy of the adjuvant therapy are still controversial. Various histologic criteria of malignancy for ACTs adopted in children do not facilitate comparative studies and are not completely shared. Therefore, a sharp demarcation between benign and malignant lesions has not been recognised, making it difficult to identify who potentially needs perioperative therapy. This manuscript presents the internationally harmonised recommendations for the diagnosis and treatment of ACTs in children and adolescents, established by the European Cooperative Study Group for Paediatric Rare Tumours (EXPeRT) group within the EU-funded project PARTNER (Paediatric Rare Tumours Network - European Registry).

Results of API-AI based regimen in osteosarcoma adult patients included in the French OS2006/Sarcome-09 study.

In the OS2006 study, patients younger than 18 years were treated with a methotrexate-based regimen (MTX), patients older than 25 years with a doxorubicin-cisplatin-ifosfamide-based regimen (API-AI), whereas patients aged 18-25 years received either API-AI or MTX. We herein report the prespecified subgroup analysis of the outcome of 106 patients treated with API-AI. Preoperative chemotherapy combined three doxorubicin-ifosfamide-cisplatin (API) and two doxorubicin-ifosfamide (AI) courses. Postoperative chemotherapy was assigned by risk group: localised patients with a good histological response (<10% viable cells) received two AI and two cisplatin-ifosfamide (PI) courses; patients with synchronous metastases, poor histological response or unresectable primary received five cycles of etoposide-ifosfamide (EI). Of the 106 patients, 61 were randomised to receive or not zoledronate. Median age was 30 years (range 18-67), 66 (62%) patients were >25 years. The primary tumours were axial in 28 patients (26%), and 28 (26%) presented with metastases. Ninety-six patients (91%) had surgery, conservative in 82 (85%); 36 patients (38%, 95% CI 28-48%) were good responders. Toxicity was manageable, with no significant difference in severe acute toxicity between patients aged >25 years and those younger. With a median follow-up of 4.8 years, the 5-year event-free survival and overall survival rates were 46% (95% CI 36-56) and 57% (95% CI 47-67), respectively. The primary tumour size and initial metastases correlated with a higher risk of event. In these 106 osteosarcoma adult patients, API-AI proved feasible with no excess of toxicity, and favourable activity despite poor-prognosis factors.

Rhabdomyosarcoma associated with germline TP53 alteration in children and adolescents: The French experience.

OBJECTIVE: To describe the clinical characteristics and outcome of patients with Li-Fraumeni-associated rhabdomyosarcoma (RMS). METHOD: Retrospective analysis of data from 31 French patients with RMS diagnosed before the age of 20 years associated with a TP53 pathogenic germline variant. Cases were identified through the French Li-Fraumeni database. Central histologic review was performed in 16 cases. RESULTS: The median age at diagnosis was 2.3 years, and the median follow-up was 9.1 years (0.3-34.8). The main tumor sites were head and neck (n = 13), extremities (n = 8), and trunk (n = 8). The local pathology report classified the 31 tumors in embryonal (n = 26), alveolar (n = 1), pleomorphic (n = 1), and spindle-cell (n = 1) RMS (missing = 2). After histological review, anaplasia (diffuse or focal) was reported in 12/16 patients. Twenty-five patients had localized disease, three had lymph node involvement, and three distant metastases. First-line therapy combined surgery (n = 27), chemotherapy (n = 30), and radiotherapy (n = 14) and led to RMS control in all, but one patient. Eleven patients relapsed, and 18 patients had second malignancies. The 10-year event-free, progression-free, and overall survival rates were 36% (95% CI: 20-56), 62% (95% CI: 43-77) and 76% (95% CI: 56-88), respectively. The 10-year cumulative risk of second malignancies was 40% (95% CI: 22-60). CONCLUSION: The high incidence of multiple primary tumors strongly influences the long-term prognosis of RMS associated with TP53 pathogenic germline variants. Anaplastic RMS in childhood, independently of the familial history, should lead to TP53 analysis at treatment initiation to reduce, whenever possible, the burden of genotoxic drugs and radiotherapy in carriers and to ensure the early detection of second malignancies.

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.

Rare non-Hodgkin lymphoma of childhood and adolescence: A consensus diagnostic and therapeutic approach to pediatric-type follicular lymphoma, marginal zone lymphoma, and nonanaplastic peripheral T-cell lymphoma.

Pediatric-type follicular (PTFL), marginal zone (MZL), and peripheral T-cell lymphoma (PTCL) account each for <2% of childhood non-Hodgkin lymphoma. We present clinical and histopathological features of PTFL, MZL, and few subtypes of PTCL and provide treatment recommendations. For localized PTFL and MZL, watchful waiting after complete resection is the therapy of choice. For PTCL, therapy is subtype-dependent and ranges from a block-like anaplastic large cell lymphoma (ALCL)-derived and, alternatively, leukemia-derived therapy in PTCL not otherwise specified and subcutaneous panniculitis-like T-cell lymphoma to a block-like mature B-NHL-derived or, preferentially, ALCL-derived treatment followed by hematopoietic stem cell transplantation in first remission in hepatosplenic and angioimmunoblastic T-cell lymphoma.