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)

Excess healthcare expenditure in adults treated for solid cancer in childhood: a cohort study in France

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Care management for foreign children, adolescents, young adults with cancer, and their families

International audienceBACKGROUND: Little is known about care management for foreign patients in pediatric oncology in European centers. We aimed to describe care given to children, adolescents, and young adults who came to France for cancer treatment, and to determine whether their geographical origin had an influence on decision making. PROCEDURE: We conducted a monocentric retrospective study on all foreign patients aged 0-25 years and hospitalized for at least one night in Institut Curie (Paris, France) from 2009 to 2013. We analyzed the potential advantages of receiving treatment in France as well as their social and familial consequences. RESULTS: A total of 93 foreign patients' files were retrieved. Most of these patients came from Africa (70%). In accord with the specific expertise of the institution, retinoblastoma was the most frequent tumor type (39%). An antitumor treatment had already been administrated in the native country in 44% of patients. We considered that 66% of patients received a significant medical advantage from care in our institution. The treatment provided in France was considered impossible in the native country in 44% of cases. The social and familial impact on the patients' families was high (59%). Almost all patients (96%) received the treatment that would have been proposed to their French counterparts. CONCLUSIONS: There were notable medical advantages for foreign patients who come to France for their oncologic treatment despite important familial consequences. Patients' geographical origin did not have an influence on medical decisions

Increased Cardiac Risk After a Second Malignant Neoplasm Among Childhood Cancer Survivors, a FCCSS Study

International audienceBACKGROUND Advances in cancer treatment have significantly improved childhood cancer survival, with five-year survival exceeding 80% in most European and North American countries today. The adult population of childhood cancer survivors (CCS) exceeds 300,000 people in the USA alone, and is growing. Many late-effects have been observed at a higher rate than the general population. Cardiac disease (CD) and second malignant neoplasms (SMN) are among the most serious and life-threatening late adverse effects experienced by CCS. Previous work has identified important risk factors of CD, but the impact of other late-effects as SMN have been ignored. We have studied the effect of a SMN on both the cumulative incidence and the instantaneous risk of CD accounting for the competing risk of death

Risk of Renal or Urinary Related Hospitalization in Survivors of Childhood Cancer: Results from the French Childhood Cancer Survivor Study

International audienceBACKGROUND: Hospitalization rates can be used as an indirect indicator of the burden and severity of adverse health outcomes in childhood cancer survivors (CCS). We aimed to determine the long-term risks of hospitalization related to renal and urinary diseases among 5-year CCS. METHODS: The French Childhood Cancer Survivor Study cohort was linked with data from the French National Healthcare System database, which enabled the identification of hospitalizations related to renal or urinary diseases. Clinical and detailed treatment data were collected from medical records. Dose-volume histograms were estimated for all patients treated with radiotherapy. Standardized Hospitalization Ratios and absolute excess risks (AER) were calculated. Relative risks were estimated using Poisson regression. RESULTS: A total of 5,498 survivors were followed for 42,118 person-years (PY). Survivors experience 2.9 times more renal hospitalizations than expected in the general population, with an AER of 21.2/10,000 PY. Exposing more than 10% of the kidneys' volume to at least 20 Gray increases the risk of being hospitalized for renal causes by 2.2 (95% confidence interval, 1.3-3.6). Nephrectomized survivors treated with high doses of ifosfamide (>60 g/m²) have an extremely high risk of hospitalization for renal causes. Patients with comorbidities have about a 3-fold higher risk, and nephrectomized patients a 2-fold higher risk of being hospitalized for renal causes compared with other subjects. In the case of hospitalization for urinary causes, treatment by anthracycline administration was found to be associated with an almost 2-fold higher risk of hospitalization compared with the general population. CONCLUSIONS: These results support the need for careful monitoring of long-term renal diseases in survivors who have undergone nephrectomy, those treated with high doses of radiation (≥20 Gy) even to small volumes of the kidneys, and those with predisposing risk factors. IMPACT: This study provides new evidence with potential impact on surveillance guidelines related to dose-volume indicators associated with renal toxicity

MMP2 as an independent prognostic stratifier in oral cavity cancers

Background Around 25% of oral cavity squamous cell carcinoma (OCSCC) are not controlled by the standard of care, but there is currently no validated biomarker to identify those patients. Our objective was to determine a robust biomarker for severe OCSCC, using a biology-driven strategy. Patients and methods Tumor and juxtatumor secretome were analyzed in a prospective discovery cohort of 37 OCSCC treated by primary surgery. Independent biomarker validation was performed by RTqPCR in a retrospective cohort of 145 patients with similar clinical features. An 18-gene signature (18 G) predictive of the response to PD-1 blockade was evaluated in the same cohort. Results Among 29 deregulated molecules identified in a secretome analysis, including chemokines, cytokines, growth factors, and molecules related to tumor growth and tissue remodeling, only soluble MMP2 was a prognostic biomarker. In our validation cohort, high levels of MMP2 and CD276, and low levels of CXCL10 and STAT1 mRNA were associated with poor prognosis in univariate analysis (Kaplan-Meier). MMP2 (p = .001) and extra-nodal extension (ENE) (p = .006) were independent biomarkers of disease-specific survival (DSS) in multivariate analysis and defined prognostic groups with 5-year DSS ranging from 36% (MMP2highENE+) to 88% (MMP2lowENE-). The expression of 18 G was similar in the different prognostic groups, suggesting comparable responsiveness to anti-PD-1. Conclusion High levels of MMP2 were an independent and validated prognostic biomarker, surpassing other molecules of a large panel of the tumor and immune-related processes, which may be used to select poor prognosis patients for intensified neoadjuvant or adjuvant regimens

PD-L1 and ICOSL discriminate human Secretory and Helper dendritic cells in cancer, allergy and autoimmunity

International audienceAbstract Dendritic cells (DC) are traditionally classified according to their ontogeny and their ability to induce T cell response to antigens, however, the phenotypic and functional state of these cells in cancer does not necessarily align to the conventional categories. Here we show, by using 16 different stimuli in vitro that activated DCs in human blood are phenotypically and functionally dichotomous, and pure cultures of type 2 conventional dendritic cells acquire these states (termed Secretory and Helper) upon appropriate stimuli. PD-L1highICOSLlow Secretory DCs produce large amounts of inflammatory cytokines and chemokines but induce very low levels of T helper (Th) cytokines following co-culturing with T cells. Conversely, PD-L1lowICOSLhigh Helper DCs produce low levels of secreted factors but induce high levels and a broad range of Th cytokines. Secretory DCs bear a single-cell transcriptomic signature indicative of mature migratory LAMP3+ DCs associated with cancer and inflammation. Secretory DCs are linked to good prognosis in head and neck squamous cell carcinoma, and to response to checkpoint blockade in Melanoma. Hence, the functional dichotomy of DCs we describe has both fundamental and translational implications in inflammation and immunotherapy

Increased Cardiac Risk After a Second Malignant Neoplasm Among Childhood Cancer Survivors

International audienceBACKGROUND Childhood cancer survivors (CCS) are at an elevated risk of developing both a second malignant neoplasm (SMN) and cardiac disease. OBJECTIVES This study sought to assess the excess of occurrence of cardiac disease after a SMN among CCS. METHODS Analyses included 7,670 CCS from the French Childhood Cancer Survivors Study cohort diagnosed between 1945 and 2000. To account for the time dependence of the occurrence of a SMN, we employed a landmark approach, considering an additive regression model for the cumulative incidence of cardiac disease. We estimated the effect of a SMN on the instantaneous risk of cardiac disease using a proportional cause-specific hazard model, considering a SMN as a time-dependent exposure. In both models, we adjusted for demographic and treatment information and considered death as a competing event. RESULTS In 7,670 CCS over a median follow-up of 30 years (IQR: 22-38 years), there were 378 cases of cardiac disease identified, of which 49 patients experienced a SMN. Patients who survived 25 years after their childhood cancer diagnosis and had a SMN in that time frame had a significantly increased cumulative incidence of cardiac disease, which was 3.8% (95% CI: 0.5% to 7.1%) higher compared with those without a SMN during this period. No SMN-induced excess of cardiac disease was observed at subsequent landmark times. SMNs were associated with a 2-fold increase (cause-specific HR: 2.0; 95% CI: 1.4-2.8) of cardiac disease. CONCLUSIONS The occurrence of a SMN among CCS is associated with an increased risk of cardiac disease occurrence and risk at younger ages.

The risk of valvular heart disease in the French Childhood Cancer Survivors’ Study: Contribution of dose-volume histogram parameters

International audienceBackground and purpose: Valvular Heart Disease (VHD) is a known complication of childhood cancer after radiotherapy treatment. However, the dose-volume-effect relationships have not been fully explored. Materials and methods: We obtained individual heart Dose Volume Histograms (DVH) for survivors of the French Childhood Cancer Survivors Study (FCCSS) who had received radiotherapy. We calculated the Mean Dose to the Heart (MHD) in Gy, as well as the heart DVH parameters (Vd Gy, which represents the percentage of heart volume receiving at least d Gy), fixing the thresholds to 0.1 Gy, 5 Gy, 20 Gy, and 40 Gy. We analyzed them furtherly in the subpopulation of the cohort that was treated with a dose lower than 5 Gy (V0.1Gy|V5Gy=0%), 20 Gy (V5Gy|V20Gy=0%), and 40 Gy (V20Gy|V40Gy=0%), respectively. We investigated their role in the occurrence of a VHD in this population-based observational cohort study using the Cox proportional hazard model, adjusting for age at cancer diagnosis and chemotherapy exposure. Results: Median follow-up was 30.6 years. Eighty-one patients out of the 7462 (1 %) with complete data experienced a severe VHD (grade ≥ 3). The risk of VHD increased along with the MHD, and it was associated with high doses to the heart (V40Gy 50 %, HR = 5.03, 95 % CI: [2.35–10.76]). Doses 5–20 Gy to more than 50 % (V5Gy|V20Gy=0% >50 %) of the heart induced a marginally non-significant estimated risk. We also observed a remarkable risk increase with attained age. Conclusions: Our results provide new insight into the VHD risk that may impact current treatments and long-term follow-up of childhood cancer survivors

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)