Targeted therapies in children with renal cell carcinoma (RCC): An International Society of Pediatric Oncology-Renal Tumor Study Group (SIOP-RTSG)-related retrospective descriptive study.

INTRODUCTION: Introduction: Renal cell carcinoma (RCC) is a very rare pediatric renal tumor. Robust evidence to guide treatment is lacking and knowledge on targeted therapies and immunotherapy is mainly based on adult studies. Currently, the International Society of Pediatric Oncology-Renal Tumor Study Group (SIOP-RTSG) 2016 UMBRELLA protocol recommends sunitinib for metastatic or unresectable RCC. METHODS: This retrospective study describes the effects of tyrosine kinase inhibitors (TKI), anti-programmed cell death 1 (PD-(L)1) monoclonal antibodies, and immunotherapeutic regimens in advanced-stage and relapsed pediatric RCC. RESULTS: Of the 31 identified patients (0-18 years) with histologically proven RCC, 3/31 presented with TNM stage I/II, 8/31 with TNM stage III, and 20/31 with TNM stage IV at diagnosis. The majority were diagnosed with translocation type RCC (MiT-RCC) (21/31) and the remaining patients mainly presented with papillary or clear-cell RCC. Treatment in a neoadjuvant or adjuvant setting, or upon relapse or progression, included mono- or combination therapy with a large variety of drugs, illustrating center specific choices in most patients. Sunitinib was often administered as first choice and predominantly resulted in stable disease (53%). Other frequently used drugs included axitinib, cabozantinib, sorafenib, and nivolumab; however, no treatment seemed more promising than sunitinib. Overall, 15/31 patients died of disease, 12/31 are alive with active disease, and only four patients had a complete response. The sample size and heterogeneity of this cohort only allowed descriptive statistical analysis. CONCLUSION: This study provides an overview of a unique series of clinical and treatment characteristics of pediatric patients with RCC treated with targeted therapies.

Surgical Management of Wilms Tumors with Intravenous Extension: A Multicenter Analysis of Clinical Management with Technical Insights.

BACKGROUND: About 5% of Wilms tumors present with vascular extension, which sometimes extends to the right atrium. Vascular extension does not affect the prognosis, but impacts the surgical strategy, which is complex and not fully standardized. Our goal is to identify elements of successful surgical management of Wilms tumors with vascular extensions. PATIENTS AND METHODS: A retrospective study of pediatric Wilms tumors treated at three sites (January 1999-June 2019) was conducted. The inclusion criterion was the presence of a renal vein and vena cava thrombus at diagnosis. Tumor stage, pre and postoperative treatment, preoperative imaging, operative report, pathology, operative complications, and follow-up data were reviewed. RESULTS: Of the 696 pediatric patients with Wilms tumors, 69 (9.9%) met the inclusion criterion. In total, 24 patients (37.5%) had a right atrial extension and two presented with Budd-Chiari syndrome at diagnosis. Two died at diagnosis owing to pulmonary embolism. All patients received neoadjuvant chemotherapy and thrombus regressed in 35.6% of cases. Overall, 14 patients had persistent intra-atrial thrombus extension (58%) and underwent cardiopulmonary bypass. Most thrombi (72%) were removed intact with nephrectomy. Massive intraoperative bleeding occurred during three procedures. Postoperative renal insufficiency was identified as a risk factor for patient survival (p = 0.01). With a median follow-up of 9 years (range: 0.5-20 years), overall survival was 89% and event-free survival was 78%. CONCLUSIONS: Neoadjuvant chemotherapy with proper surgical strategy resulted in a survival rate comparable to that of children with Wilms tumors without intravascular extension. Clinicians should be aware that postoperative renal insufficiency is associated with worse survival outcomes.

Imaging characterization of paediatric tumours with the neurotrophic tyrosine receptor kinase fusion transcript.

OBJECTIVES: The neurotrophic tyrosine receptor kinase (NTRK) fusion transcript (FT) is a major genetic landmark of infantile fibrosarcoma (IFS) and cellular congenital mesoblastic nephroma (cCMN) but is also described in other tumours. The recent availability of NTRK-targeted drugs enhances the need for better identification. We aimed to describe the anatomic locations and imaging features of tumours with NTRK-FT in children. CASE SERIES: Imaging characteristics of NTRK-FT tumours of 41 children (median age: 4 months; 63% <1 year old; range: 0-188) managed between 2001 and 2019 were retrospectively analysed. The tumours were located in the soft tissues (n = 24, including 19 IFS), kidneys (n = 9, including 8 cCMN), central nervous system (CNS) (n = 5), lung (n = 2), and bone (n = 1). The tumours were frequently deep-located (93%) and heterogeneous (71%) with necrotic (53%) or haemorrhagic components (29%). Although inconstant, enlarged intratumoural vessels were a recurrent finding (70%) with an irregular distribution (63%) in the most frequent anatomical locations. CONCLUSION: Paediatric NTRK-FT tumours mainly occur in infants with very variable histotypes and locations. Rich and irregular intra-tumoural vascularization are recurrent findings. ADVANCES IN KNOWLEDGE: Apart from IFS of soft tissues and cCMN of the kidneys, others NTRK-FT tumours locations have to be known, as CNS tumours. Better knowledge of the imaging characteristics may help guide the pathological and biological identification.

A 10-year experience in testicular tissue cryopreservation for boys under 18 years of age: What can be learned from 350 cases?

BACKGROUND: A growing number of centers worldwide are preserving testicular tissue (TT) of young boys at risk of fertility loss to preserve their fertility. Data in this regard are scarce and experience sharing is essential to the optimization of the process. OBJECTIVES: This report of our 10-year activity of pediatric fertility preservation (FP) has the objective to (1) improve knowledge regarding the feasibility, acceptability, safety, and potential usefulness of the procedure; (2) analyze the impact of chemotherapy on spermatogonia in the cryopreserved TT. MATERIALS AND METHODS: For this retrospective study of data prospectively recorded, we included all boys under 18 years of age referred to the FP consultation of our academic network between October 2009 and December 2019. Characteristics of patients and cryopreservation of testicular tissue (CTT) were extracted from the clinical database. Univariate and multivariate analyses were used to assess factors associated with the risk of absence of spermatogonia in the TT. RESULTS: Three hundred and sixty-nine patients (7.2 years; 0.5-17.0) were referred to the FP consultation for malignant (70%) or non-malignant (30%) disease, of whom 88% were candidates for CTT, after a previous chemotherapy exposure (78%). The rate of recorded immediate adverse events was 3.5%, with painful episodes dominating. Spermatogonia were detected in the majority of TTs: 91.1% of those exposed to chemotherapy and 92.3% of those not exposed (p = 0.962). In multivariate analysis, the risk of absence of spermatogonia was almost three-fold higher in boys > 10 years of age ([OR] 2.74, 95% CI 1.09-7.26, p = 0.035) and four-fold higher in boys exposed to alkylating agents prior to CTT ([OR] 4.09, 95% CI 1.32-17.94, p = 0.028). DISCUSSION/CONCLUSION: This large series of pediatric FP shows that this procedure is well accepted, feasible, and safe in the short term, strengthening its place in the clinical care pathway of young patients requiring a highly gonadotoxic treatment. Our results demonstrate that CTT post-chemotherapy does not impair the chance to preserve spermatogonia in the TT except when the treatment includes alkylating agents. More data on post-CTT follow-up are still required to ensure the long-term safety and usefulness of the procedure.

Neurotrophic tropomyosin receptor kinase (NTRK) fusion positive tumors: a historical cohort analysis.

BACKGROUND: NTRK gene fusions have been identified in various tumors; some requiring aggressive therapy and sometimes new TRK inhibitors (TRKi). We aimed to describe a national, unselected, retrospective, multicenter cohort. RESEARCH DESIGN AND METHODS: Patients were identified through the French sarcoma diagnostic laboratory at Institut Curie through samples analyzed by RT-qPCR or whole-transcriptome sequencing. RESULTS: From 2001 to 2019, 65 NTRK fusion tumors were identified within 2120 analyses (3.1%): 58 by RNA sequencing (including 20 after RT-qPCR analysis) and 7 exclusively by RT-qPCR. Of the 61 patients identified, 37 patients had infantile soft tissue or kidney fibrosarcomas (IFS), 15 other mesenchymal (Other-MT) and nine central nervous system (CNS) tumors. They encompassed 14 different tumor types with variable behaviors. Overall, 53 patients had surgery (3 mutilating), 38 chemotherapy (20 alkylating agents/anthracycline), 11 radiotherapy, two 'observation strategy' and 13 received TRKi. After a median follow-up of 61.0 months [range, 2.5-226.0], 10 patients died. Five-year overall survival is, respectively, 91.9% [95%CI, 83.5-100.0], 61.1% [95%CI, 34.2-100.0] and 64.8% [95%CI, 39.3-100.0] for IFS, Other-MT, and CNS groups. CONCLUSIONS: NTRK-fusion positive tumors are rare but detection is improved through RNA sequencing. TRKi could be considered at diagnosis for CNS NTRK-fusion positive tumors, some IFS, and Other-MT. TRIAL REGISTRATION: Not adapted.

Assessment of Puberty and Hypothalamic-Pituitary-Gonadal Axis Function After Childhood Brain Tumor Treatment.

CONTEXT: Endocrine complications are common in pediatric brain tumor patients. OBJECTIVE: To describe hypothalamic-pituitary-gonadal axis (HPGA) function in patients treated in childhood for a primary brain tumor more than 5 years earlier, in order to identify risk factors for HPGA impairment. METHODS: We retrospectively included 204 patients diagnosed with a primary brain tumor before 18 years of age and monitored at the pediatric endocrinology unit of the Necker Enfants-Malades University Hospital (Paris, France) between January 2010 and December 2015. Patients with pituitary adenoma or untreated glioma were excluded. RESULTS: Among patients with suprasellar glioma not treated by radiotherapy, the prevalence of advanced puberty was 65% overall and 70% when the diagnosis occurred before 5 years of age. Medulloblastoma chemotherapy caused gonadal toxicity in 70% of all patients and in 87.5% of those younger than 5 years at diagnosis. In the group with craniopharyngioma, 70% of patients had hypogonadotropic hypogonadism, which was consistently accompanied by growth hormone deficiency. CONCLUSION: Tumor type, location, and treatment were the risk main factors for HPGA impairment. Awareness that onset can be delayed is essential to guide information of parents and patients, patient monitoring, and timely hormone replacement therapy.

NUT Carcinoma in Children and Adolescents: The Expert European Standard Clinical Practice Harmonized Recommendations.

BACKGROUND AND AIMS: Nuclear protein of the testis ( NUT ) carcinoma (NC) is a rare and highly aggressive tumor mainly occurring in adolescents and young adults, defined by the presence of a somatic NUTM1 rearrangement. The aim is to establish internationally harmonized consensus recommendations for the diagnosis and treatment of adolescents and young adults with NC in the framework of the European Reference Network for Paediatric Oncology. METHODS: The European Cooperative Study Group for Pediatric Rare Tumors developed recommendations according to the Consensus Conference Standard Operating procedure methodology and reviewed by external "experts." No evidence of level I to II exists. Recommendations were developed based on published prospective (level III), but more frequently retrospective series (level IV), case reports (level V), and personal expertise (level V). In addition, "strength" of recommendations were categorized by grading (grade A to E). RESULTS: Histology is mandatory for the diagnosis of NC, including immunolabeling with anti-NUT antibodies and molecular biology ( NUTM1 rearrangement) (level V; grade A). Treatment of NC usually combines aggressive approaches in multimodal regimens. Chemotherapy should be considered as first-line treatment (neoadjuvant vincristine-adriamycin-ifosfamide/cisplatin-adriamycin-ifsofamide or vincristine-doxorubicin-cyclophosphamide/ifosfamide-etoposide) for unresectable or metastatic tumor (ie, 3 courses), rapidly followed by local treatment (level IV; grade B). Referral to a specialized surgical oncology center is highly recommended (level V; grade A). In localized NC, a complete microscopic surgical resection should be attempted whenever and as soon as possible, followed by primary irradiation (60 to 70 Gy) and involved lymph nodes area (level IV; grade B). For head and neck tumors, a systematic neck dissection might be considered, even if N0 (level V; grade C). Adjuvant postirradiation chemotherapy is recommended, for a total of 9 to 12 courses (level IV; grade B). For first-line resected tumors, concomitant adjuvant chemotherapy to radiotherapy may be discussed (level IV; grade B). Targeted therapies and immunotherapeutic regimens should be delivered in the setting of prospective trials (level V; grade B). CONCLUSIONS: This project leads to a consensus strategy based on international experience with this very rare disease.

NUT carcinoma in children, adolescents and young adults.

BACKGROUND: NUT carcinoma (NC), defined by the presence of the NUTM1 rearrangement, is an aggressive tumour associated with poor prognosis. This rare cancer is underdiagnosed and difficult to treat. OBJECTIVE AND METHODS: The primary objective of this review is to describe the clinical, radiological and laboratory features of NC in young patients. The secondary objective is to propose a consensual strategy for the French very Rare Tumour group (FRACTURE group). RESULTS: NUT-specific antibody immunostaining in cases of undifferentiated or poorly differentiated carcinoma may demonstrate the specific NUT gene rearrangement. NCs are frequently advanced stage at diagnosis and the outcome remains poor despite a global strategy that generally includes conventional combination chemotherapy with wide local therapy (surgery, radiotherapy). Chemosensitivity is frequently only transient. CONCLUSION: Recent data have shown that new targeted drugs (histone deacetylase and bromodomain and extra-terminal protein inhibitors) are promising, but their role has yet to be evaluated in NC. Centralized data review is necessary to improve our knowledge of paediatric NC. We propose a multimodal strategy based on published data and their personal experience.

High Prevalence of Early Endocrine Disorders After Childhood Brain Tumors in a Large Cohort.

CONTEXT: Endocrine complications are common in pediatric brain tumor patients. OBJECTIVE: We aimed to describe the endocrine follow-up of patients with primary brain tumors. METHODS: This is a noninterventional observational study based on data collection from medical records of 221 patients followed at a Pediatric Endocrinology Department. RESULTS: Median age at diagnosis was 6.7 years (range, 0-15.9), median follow-up 6.7 years (0.3-26.6), 48.9% female. Main tumor types were medulloblastoma (37.6%), craniopharyngioma (29.0%), and glioma (20.4%). By anatomic location, 48% were suprasellar (SS) and 52% non-suprasellar (NSS). Growth hormone deficiency (GHD) prevalence was similar in both groups (SS: 83.0%, NSS: 76.5%; P = 0.338), appearing at median 1.8 years (-0.8 to 12.4) after diagnosis; postradiotherapy GHD appeared median 1.6 years after radiotherapy (0.2-10.7). Hypothyroidism was more prevalent in SS (76.4%), than NSS (33.9%) (P < 0.001), as well as ACTH deficiency (SS: 69.8%, NSS: 6.1%; P < 0.001). Early puberty was similar in SS (16%) and NSS (12.2%). Hypogonadotropic hypogonadism was predominant in SS (63.1%) vs NSS (1.3%), P < 0.001, and postchemotherapy gonadal toxicity in NSS (29.6%) vs SS (2.8%), P < 0.001. Adult height was lower for NSS compared to target height (-1.0 SD, P < 0.0001) and to SS patients (P < 0.0001). Thyroid nodules were found in 13/45 patients (28.8%), including 4 cancers (4.8-11.5 years after radiotherapy). Last follow-up visit BMI was higher in both groups (P = 0.0001), and obesity incidence was higher for SS (46.2%) than NSS (17.4%). CONCLUSION: We found a high incidence of early-onset endocrine disorders. An endocrine consultation and nutritional evaluation should be mandatory for all patients with a brain tumor, especially when the tumor is suprasellar or after hypothalamus/pituitary irradiation.

Subcutaneous implantable pleural port catheter in the management of malignant pleural effusions in young patients with solid tumors: A new option in the armamentarium of symptomatic treatment.

The contribution of subcutaneous implantable pleural port catheter (SIPP) for malignant pleural effusions (MPE) management in young patients with cancer, in a palliative care setting is not well explored. This monocentric series analyzed 38 patients, median age 18 years (range 3-25) with significant pleural effusion. SIPP were considered efficient for eight of 12 evaluable patients (67%) and allowed MPE outpatient management in five cases. SIPPs are safe and efficient device to manage MPE patients with solid tumors, in the palliative care setting. This original tool could help health care providers for thoracic symptom management in alternative to iterative pleural punctures.

Recurrent Somatic Chromosomal Abnormalities in Relapsed Extraocular Retinoblastoma.

Most reports about copy number alterations (CNA) in retinoblastoma relate to patients with intraocular disease and features of children with extraocular relapse remain unknown, so we aimed to describe the CNA in this population. We evaluated 23 patients and 27 specimens from 4 centers. Seventeen cases had extraocular relapse after initial enucleation and six cases after an initial preservation attempt. We performed an analysis of CNA and BCOR gene alteration by SNP array (Single Nucleotide Polymorfism array), whole-exome sequencing, IMPACT panel and CGH array (Array-based comparative genomic hybridization). All cases presented CNA at a higher prevalence than those reported in previously published studies for intraocular cases. CNA previously reported for intraocular retinoblastoma were found at a high frequency in our cohort: gains in 1q (69.5%), 2p (60.9%) and 6p (86.9%), and 16q loss (78.2%). Other, previously less-recognized, CNA were found including loss of 11q (34.8%), gain of 17q (56.5%), loss of 19q (30.4%) and BCOR alterations were present in 72.7% of our cases. A high number of CNA including 11q deletions, 17q gains, 19q loss, and BCOR alterations, are more common in extraocular retinoblastoma. Identification of these features may be correlated with a more aggressive tumor warranting consideration for patient management.

[Diagnostic strategy in pediatrics soft tissue sarcomas]. / Stratégie diagnostique des sarcomes des tissus mous de l'enfant et adolescent.

Soft tissue sarcomas in children are rare tumor, representing around 6 to 7% of children cancer. They spread mostly sporadically (90%) and therefore are rarely associated to an underlying constitutional genetic disease (10%). About half of those sarcomas are rhabdomyosarcomas and the others are a very heterogenous histologic group with various bio-pathologies and prognosis. Clinical presentation is mainly a soft tissue lump often difficult to distinguish from more frequent benign causes (malformative, infectious, benign, or pseudotumor). Inappropriate initial diagnosis work-up has a strong impact on soft tissue sarcomas' prognosis. Adapted complementary investigations (first ultrasound and MRI) are important to compile arguments for a malign origin and to indicate a biopsy. However, predictive value of imaging exams still remains imperfect, and histological analysis by percutaneous image-guided biopsy and sometimes by surgical biopsy is often necessary. Authors realize an update on optimal diagnostic pathway including molecular tests in presence of a soft tissue mass in a child.

Esthesioneuroblastoma in children, adolescents and young adults.

The esthesioneuroblastoma (ENB) is characterized as a rare malignant sinonasal tumor of neuroectodermal origin. Its starting point is the olfactory epithelium located in the upper part of the nasal cavities. Different nomenclatures have been proposed, but the most common are "esthesioneuroblastoma" and "olfactory neuroblastoma". ENBs have a bimodal distribution and mainly occur in teenagers, young adults and people aged 50-60. It is a very rare tumor in pediatrics since only around 100 cases have been reported so far. Within ENBs, we can distinguish tumors with different biological behavior ranging from localized forms with slow evolution to aggressive and metastatic forms at onset. In addition, precisely diagnosing undifferentiated tumors and distinguishing them from other etiologies of sinonasal tumors are sometime difficult. Added to its very low incidence, these characteristics make the study of ENB complicated. The standard treatment currently includes broad surgery followed by radiation therapy in localized resectable tumors. Neoadjuvant chemotherapy is indicated in large unresectable tumors and in metastatic forms. However, in certain indications, such as high-grade operable tumors, the role of perioperative chemotherapy remains to be defined. The objective of this analysis is to detail current knowledge regarding ENBs' epidemiological, biological, clinical and radiological characteristics as well as how to manage ENB in young patients.

[Cross-cultural experience of knowledge sharing in relation to pain]. / Expérience interculturelle de partage de savoirs autour de la douleur.

Health professionals working in paediatric oncology met in Bamako, Mali, as part of a healthcare partnership between the Gabriel-Touré Hospital in Bamako and the Curie Institute in Paris. Open to dialogue and intercultural encounters, the hospital medical and paramedical teams exchanged views on their practices with a particular focus on pain management.

NUT carcinoma in children and adults: A multicenter retrospective study.

BACKGROUND: Nuclear protein of the testis (NUT) carcinoma (formerly NUT midline carcinoma) is an aggressive tumor defined by the presence of NUT rearrangement with a poor prognosis. This rare cancer is underdiagnosed and poorly treated. OBJECTIVE: The primary objective of this study was to describe the clinical, radiologic, and biological features of NUT carcinoma. The secondary objective was to describe the various treatments and assess their efficacy. METHODS: This retrospective multicenter study was based on review of the medical records of children and adults with NUT carcinoma with specific rearrangement or positive anti-NUT nuclear staining (>50%). RESULTS: This series of 12 patients had a median age of 18.1 years (ranges: 12.3-49.7 years). The primary tumor was located in the chest in eight patients, the head and neck in three patients, and one patient had a multifocal tumor. Nine patients presented regional lymph node involvement and eight distant metastases. One-half of patients were initially misdiagnosed. Specific NUT antibody was positive in all cases tested. A transient response to chemotherapy was observed in four of 11 patients. Only two patients were treated by surgery and five received radiotherapy with curative intent. At the end of follow-up, only one patient was still in remission more than 12 years after the diagnosis. Median overall survival was 4.7 months (95% confidence interval [CI]: 2.1-17.7). CONCLUSION: NUT carcinoma is an aggressive disease refractory to conventional therapy. Early diagnosis by NUT-specific antibody immunostaining in cases of undifferentiated or poorly differentiated carcinoma to identify the specific rearrangement of NUT gene is useful to propose the optimal therapeutic strategy.