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.

Melatonin Mitigates iNOS-Related Effects of HEMA and Camphorquinone in Human Dental Pulp Cells: Relevance for Postoperative Sensitivity Mechanism in Type 2 Diabetes.

High elution and diffusion of 2-hydroxylethyl methacrylate (HEMA) and camphorquinone (CQ) through dentinal tubules may induce pulp injury and postoperative sensitivity. We aimed to investigate the melatonin protective effect in HEMA- and CQ-treated human dental pulp cells (hDPCs) as well as its relevance in a mechanism for postoperative sensitivity in diabetic patients. hDPCs were exposed to HEMA (5 mM) and/or CQ (1 mM) in the absence and presence of melatonin (MEL) (0.1 mM and 1 mM). Heme oxygenase-1 (HMOX1), NADPH oxidase-4 (NOX4), BCL-2-associated X-protein (BAX), B-cell lymphoma-2 (BCL-2) and caspase-3 (CASP3) gene expression levels, and superoxide dismutase (SOD) activity were measured in hDPCs while inducible nitric oxide synthase (iNOS) and melatonin protein expression were measured in human dental pulp as well, by RT-PCR, by ELISA, and spectrophotometrically. Bioinformatic analyses were performed by using the ShinyGO (v.0.75) application. Type 2 diabetic patients showed a higher incidence of postoperative sensitivity and lower melatonin and higher iNOS content in dental pulp tissue compared with non-diabetic patients. Melatonin, when co-added in hDPC culture, reverses HEMA and CQ cytotoxic effects via anti-apoptotic and anti-inflammatory/antioxidant iNOS-related effects. Enrichment analyses showed that genes/proteins, altered by HEMA and CQ and normalized by melatonin, are the most prominently overrepresented in type 2 diabetes mellitus pathways and that they share subcellular localization in different oligomeric protein complexes consisting of anti- and pro-apoptotic regulators. This is the first evidence of the ability of melatonin to counteract iNOS-mediated inflammatory and stress effects in HEMA- and CQ-treated hDPCs, which could be of significance for the modulation of presently observed immediate postoperative sensitivity after composite restoration in type 2 diabetic patients.

Childhood leukemia and non-Hodgkin's lymphoma survivors lack knowledge about their past disease and possible late effects. I-BFM ELTEC study with Chilean and Croatian participation.

PURPOSE: Late effects in childhood cancer survivors are a major cause of morbidity and mortality. The objective was to establish knowledge about the disease, late effects, self-care practices, application of health knowledge/education, sources of information, and biopsychosocial impact of cancer, and compare the results of Chile and Croatia. METHODS: One-hundred-and-seventy-one, 5-year survivors who were treated for leukemia or non-Hodgkin's lymphoma responded to a questionnaire (119 in Chile and 52 in Croatia). The questionnaire was reviewed by BFM-ELTEC. RESULTS: Health knowledge about past diagnosis and general treatment had 96% Chilean and 85% Croatian survivors. Ninety percent of Chilean and 73% of Croatian survivors were unaware of possible late effects, and half did not know which specialist to visit for follow-up. Forty-six percent of Chilean and 35% of Croatian survivors knew about healthy lifestyles, but most did not practice them. The 74% of Chileans and 87% of Croatian survivors recalled having received health education during treatment. About 50% of survivors in both groups were afraid or anguish, but it was also a growth experience for 60% of Chilean and 42% of Croatian survivors. Eighty-seven percent Chilean and 77% Croatian survivors considered themselves physically independent, while 76% and 75% felt psychologically independent, respectively. CONCLUSION: A significant lack of knowledge about the specific treatment, late effects, and future health in both countries was detected. They did not achieve significant learning with the education received. Psychological sequelae were found that are important to prevent.

Salivary VEGF and post-extraction wound healing in type 2 diabetic immediate denture wearers.

OBJECTIVE: Oral wound healing in healthy could be promoted by VEGF in saliva, and immediate denture wearing, but data in type 2 diabetes are lacking. Aims were to investigate the timeline of extraction wound healing in diabetic participants wearing immediate dentures and its correlation to salivary VEGF, as well as to examine the impact of the palatal plate on tissue VEGF during palatal wound healing in rat diabetic model. MATERIAL AND METHODS: Healthy (42) and type 2 diabetic (36) denture wearers, candidates for teeth extractions were included. Extraction wound healing was followed via measurements of socket closure, gingival hyperaemia, pain and presence of necrosis on 3rd, 7th, 14th and on 21st-day post-extraction. Salivary VEGF was measured before and on the 3rd and 21st day after the extraction. In streptozotocin-induced diabetic (30) as well as non-diabetic rats (30), tissue VEGF was measured in palatal wounds healing under or without a palatal plate. RESULTS: Type 2 diabetic prosthetic patients exhibit delayed socket closure, with pronounced hyperaemia, pain and necrosis. Salivary VEGF is increased in diabetes and positively correlates to socket closure while negatively with pain on 21st day after the extraction. Palatal incision induced VEGF increase in non-diabetic and diabetic, but less pronounced in diabetic rats. Wound healing under the palatal plate exhibit higher tissue VEGF. CONCLUSION: Type 2 diabetes-induced increase in salivary VEGF may mitigate diabetes-induced detrimental effects on extraction wound healing. Lack of adequate tissue VEGF response to injury may underly dysregulation of diabetic oral wound healing.

Clinical Perspectives of Non-Coding RNA in Oral Inflammatory Diseases and Neuropathic Pain: A Narrative Review.

Non-coding RNAs (ncRNAs) represent a research hotspot by playing a key role in epigenetic and transcriptional regulation of diverse biological functions and due to their involvement in different diseases, including oral inflammatory diseases. Based on ncRNAs' suitability for salivary biomarkers and their involvement in neuropathic pain and tissue regeneration signaling pathways, the present narrative review aims to highlight the potential clinical applications of ncRNAs in oral inflammatory diseases, with an emphasis on salivary diagnostics, regenerative dentistry, and precision medicine for neuropathic orofacial pain.

Pancreatoblastoma in children: EXPeRT/PARTNER diagnostic and therapeutic recommendations.

Pancreatoblastoma (PBL) is a rare malignant epithelial neoplasm that affects typically young children. Signs related to advanced upper-abdominal tumor accompanied by elevated serum α-fetoprotein levels in a young child suggest PBL, however histopathological confirmation is mandatory. The mainstay of the treatment is a complete surgical resection. Unresectable and/or metastatic PBL may become amenable to complete delayed surgery after neoadjuvant chemotherapy. This manuscript presents the international consensus recommendations for the diagnosis and treatment of children with PBL, established by the European Cooperative Study Group for Pediatric Rare Tumors (EXPeRT) within the EU-funded PARTNER (Paediatric Rare Tumors Network - European Registry) project.

Facing the challenges of very rare tumors of pediatric age: The European Cooperative Study Group for Pediatric Rare Tumors (EXPeRT) background, goals, and achievements.

It has become increasingly clear in recent years that we need to develop ad hoc strategies to combat very rare tumors (VRT) of pediatric age. In 2008, several schemes being run in different countries were pooled together to create the European Cooperative Study Group for Pediatric Rare Tumors (EXPeRT) project: a cooperative study group that aimed to promote research in the relatively uncharted territory of rare tumors of pediatric age. EXPeRT members were able to activate different levels of cooperation to achieve their goals, and to obtain dedicated funding by participating in EU-financed projects. Their experiences emphasize the merits of networking, seeking new partnerships, joining forces, and pooling resources to extend the reach of research efforts, and ultimately improve the quality of patient care. Between 2018 and 2021, the EXPeRT has been active in establishing the Pediatric Rare Tumors Network - European Registry (PARTNER). This project had the main purposes of building a European common registry of pediatric VRT, but also the major task of developing diagnostic and treatment guidelines for VRT (or at least part of them). These clinical recommendations are the subject of a series of papers on Pediatric Blood and Cancer.

Salivary gland carcinoma in children and adolescents: The EXPeRT/PARTNER diagnosis and treatment recommendations.

Salivary gland carcinomas (SGCs) are rare during childhood and adolescence. Consequently, no standardized recommendations for the diagnosis and therapeutic management of pediatric SGC are available, and pediatric oncologists and surgeons generally follow adult guidelines. Complete surgical resection with adequate margins constitutes the cornerstone of treatment. However, the indications and modalities of adjuvant therapy remain controversial and may be challenging in view of the potential long-term toxicities in the pediatric population. This paper presents the consensus recommendations for the diagnosis and treatment of children and adolescents with SGCs, established by the European Cooperative Study Group for Pediatric Rare Tumors (EXPeRT) within the EU-funded PARTNER project (Paediatric Rare Tumours Network - European Registry).

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).

Consensus recommendations from the EXPeRT/PARTNER groups for the diagnosis and therapy of sex cord stromal tumors in children and adolescents.

As part of the European Union-funded project designated Paediatric Rare Tumours Network - European Registry (PARTNER), the European Cooperative Study Group for Pediatric Rare Tumors (EXPeRT) is continuously developing consensus recommendations in order to harmonize standard care for very rare solid tumors of children and adolescents. This paper presents the internationally recognized recommendations for the diagnosis and treatment of sex cord stromal tumors (SCST). The clinical approach to sex cord stromal tumors of the testis (TSCST) and ovary (OSCST) depends on histological differentiation and tumor stage. Virtually all TSCSTs present as localized nonmetastatic tumors, with excellent prognosis after complete resection. In contrast, the prognosis of OSCSTs may be adversely affected by tumor spillage during surgery or presence of metastases. In these cases, cisplatin-based chemotherapy is recommended. Of note, some SCSTs may develop in the context of tumor predisposition syndromes, for example, DICER-1, so that specific follow-up is indicated. SCSTs should be diagnosed and treated according to standardized recommendations that include reference pathology, genetic testing for tumor predisposition syndromes in selected cases, and stratified adjuvant chemotherapy in patients with unfavorable risk profile. To ensure high quality of diagnosis and therapy, patients should be enrolled into prospective registries.

The European Paediatric Rare Tumours Network - European Registry (PARTNER) project for very rare tumors in children.

The PARTNER project (Paediatric Rare Tumours Network - European Registry) was launched in 2016. PARTNER aims to create a European Registry dedicated to children and adolescents with very rare tumors (VRT). It links existing national registries and provides a registry for those countries in which a VRT registry has not yet been created. This consortium is composed of the various national cooperative groups and their respective member institutions. The strategic value of this project is based on the Europe-wide data collection concerning the treatment of VRTs. These data are provided to experts and constitute the basis for new clinical practice guidelines for use by ERN (European Reference Network) and non-ERN institutions. The proposed tasks and milestones will increase collaboration in the field of pediatric oncology among member states and will also facilitate the inclusion of low health expenditure average rate (LHEAR) countries in this process. In addition, this project creates a platform for VRTs that may represent a model on how to elaborate a comprehensive approach (case registration, international case consultation and treatment recommendations, and website to provide information for parents/patients) for rare diseases.

Pleuropulmonary blastoma in children and adolescents: The EXPeRT/PARTNER diagnostic and therapeutic recommendations.

Pleuropulmonary blastoma (PPB) is a rare cancer occurring mainly during early childhood and often associated with germline DICER1 mutations. It is classified by the macroscopic appearance into three interrelated clinico-pathologic entities on a developmental continuum. Complete tumor resection is a main prognostic factor and can be performed at diagnosis or after neoadjuvant treatment that includes chemotherapy and in some cases radiotherapy. Optimal modalities of neo- or adjuvant treatments can be challenging taking into account potential long-term toxicities in this young population. This paper presents the recommendations for diagnosis and treatment of children and adolescents with PPB elaborated by the European Cooperative Study Group for Pediatric Rare Tumors (EXPeRT) within the European Union-funded project PARTNER (Paediatric Rare Tumours Network - European Registry).

Bone microRNA-21 as surgical stress parameter is associated with third molar postoperative discomfort.

OBJECTIVE: To evaluate an association between bone levels of inflammation/oxidative stress mediators and postoperative discomfort after third molar conventional or piezosurgery. MATERIAL AND METHODS: Twenty-six subjects with bilaterally impacted mandibular third molars, who underwent either piezo or conventional surgery, were included in a split-mouth design study. MicroRNA-21 (miR-21) expression, interleukin-1 beta (IL-1ß), and vascular endothelial growth factor (VEGF) proteins, as well as superoxide dismutase (SOD) activity in alveolar bone, were evaluated. Pain intensity, the first pain appearance, analgesic first use and total dose taken, trismus, and swelling were clinically recorded. RESULTS: MiR-21 expression was higher while VEGF protein was lower in piezosurgery vs. conventional groups. The differences in IL-1ß protein and SOD activity were not significant between groups. The pain intensity on the first day was significantly decreased in piezosurgery group. The first pain appearance and the first analgesic taken were reported sooner in conventional vs. piezosurgical group. Significantly pronounced trismus on the third day following conventional surgery was found. In conventional group, significantly increased trismus was observed on the third compared to the first postoperative day. MiR-21 showed significant correlation with the first pain appearance. CONCLUSION: Delayed onset of less pronounced postoperative pain after piezosurgical vs. conventional extraction of impacted lower third molar was significantly associated with expression of bone miR-21. CLINICAL RELEVANCE: Alveolar bone miR-21 may reflect surgical stress and is associated with third molar postoperative pain onset.

Pediatric tertiary emergency care departments in Zagreb, Rijeka, and Split before and during the coronavirus disease 2019 pandemic: a Croatian national multicenter study.

AIM: To assess the number of visits to pediatric emergency departments in Croatia and reasons for visiting before and during the coronavirus disease 2019 (COVID-19) pandemic. METHODS: We reviewed the medical records of pediatric patients visiting emergency departments of four tertiary medical centers between February 25 and April 25, 2018 and 2019, and between February 25 and April 24, 2020. Antimicrobial prescription was analyzed as well. RESULTS: There were altogether 46 544 visits - 18218 in 2018, 19699 in 2019, and 8634 in 2020. The overall number of visits in 2020 significantly decreased compared with 2018 and 2019 (52% and 56% reduction, respectively), mostly due to a decreased number of visits due to certain infectious diseases: acute gastroenteritis (89.2%), sepsis/bacteremia (81.2%), urinary tract infections (55.3%), and lower respiratory tract infections (58%). Most visits were self-referrals regardless of the analyzed period, and the majority of patients did not require hospitalization. There were no significant differences in the number of visits requiring urgent medical care, such as those due to seizures and urgent surgery. The most frequently prescribed antibiotic in all periods was amoxicillin, followed by amoxicillin/clavulanate and oral cephalosporins. CONCLUSION: A significant reduction in the number of pediatric emergency department visits and hospital admissions is indirectly related to the COVID-19 pandemic. Most of the reduction was due to a decreased number of infectious disease cases. However, the number of visits requiring urgent medical intervention did not change.

A Phase 2, International, Multicenter, Open-label Clinical Trial of Subcutaneous Tbo-Filgrastim in Pediatric Patients With Solid Tumors Undergoing Myelosuppressive Chemotherapy.

This phase 2, multicenter, open-label trial investigated the safety and tolerability of tbo-filgrastim in pediatric patients receiving myelosuppressive chemotherapy. In total, 50 patients 1 month to below 16 years of age with solid tumors without bone marrow involvement were stratified into 3 age groups (2 infants, 30 children, 18 adolescents) and prophylactically administered tbo-filgrastim 5 µg/kg body weight once daily subcutaneously. The administration started after the last chemotherapy treatment in week 1 of the first cycle and continued until the expected neutrophil nadir had passed, and the neutrophil count had recovered to 2.0×10/L. The primary endpoint was safety and tolerability of tbo-filgrastim; secondary endpoints included efficacy. The mean (SD) number of doses administered was 9.2 (2.83) in children and 7.3 (1.88) in adolescents. Serious treatment-emergent adverse events were reported in 24% of patients; the most common were febrile neutropenia (FN) (12%), anemia (8%), and thrombocytopenia (8%). Nine patients (18%) experienced mild treatment-related treatment-emergent adverse events; the most common were musculoskeletal and connective tissue disorders (8%). No deaths or withdrawals occurred. The incidence of severe neutropenia (SN) was 52% and the mean (SD) duration of SN was 1.8 (2.21) days; FN incidence was 26%. A daily dose of tbo-filgrastim 5 µg/kg body weight administered to pediatric patients demonstrated a safety profile consistent with the safety profile in adult patients. The incidence of FN was on the lower end of the range reported in the literature and the SN results provide supportive data on the efficacy of tbo-filgrastim in pediatric patients.

Clinical antibacterial effectiveness and biocompatibility of gaseous ozone after incomplete caries removal.

OBJECTIVES: To evaluate local effect of gaseous ozone on bacteria in deep carious lesions after incomplete caries removal, using chlorhexidine as control, and to investigate its effect on pulp vascular endothelial growth factor (VEGF), neuronal nitric oxide synthase (nNOS), and superoxide dismutase (SOD). MATERIALS AND METHODS: Antibacterial effect was evaluated in 48 teeth with diagnosed deep carious lesion. After incomplete caries removal, teeth were randomly allocated into two groups regarding the cavity disinfectant used: ozone (open system) or 2% chlorhexidine. Dentin samples were analyzed for the presence of total bacteria and Lactobacillus spp. by real-time quantitative polymerase chain reaction. For evaluation of ozone effect on dental pulp, 38 intact permanent teeth indicated for pulp removal/tooth extraction were included. After cavity preparation, teeth were randomly allocated into two groups: ozone group and control group. VEGF/nNOS level and SOD activity in dental pulp were determined by enzyme-linked immunosorbent assay and spectrophotometric method, respectively. RESULTS: Ozone application decreased number of total bacteria (p = 0.001) and Lactobacillus spp. (p < 0.001), similarly to chlorhexidine. The VEGF (p < 0.001) and nNOS (p = 0.012) levels in dental pulp after ozone application were higher, while SOD activity was lower (p = 0.001) comparing to those in control pulp. CONCLUSIONS: Antibacterial effect of ozone on residual bacteria after incomplete caries removal was similar to that of 2% chlorhexidine. Effect of ozone on pulp VEGF, nNOS, and SOD indicated its biocompatibility. CLINICAL RELEVANCE: Ozone appears as effective and biocompatible cavity disinfectant in treatment of deep carious lesions by incomplete caries removal technique.

Simple predictors of the re- occurrence of severe febrile neutropenia episode: a single-center retrospective cohort study in pediatric patients with malignant diseases.

AIM: To identify the risk factors of a repeated episode of severe febrile neutropenia (FN) and to build an accurate and easy-to-use predictive model. METHODS: This single-center retrospective cohort study conducted at the Clinical Hospital Center Children's Hospital Rijeka from January 1, 2008 to December 31, 2016 included pediatric patients with malignant diseases who experienced at least one FN episode. The association of the second severe FN episode appearance with relevant clinical and laboratory data was analyzed by logistic regression. RESULTS: Out of 45 patients with one FN episode, 25 (56%) had severe FN and 11 (24%) had repeated severe FNs. Significant predictors of a repeated severe FN episode were the first FN episode duration of 9 or more days and red blood cells ≤3.0×1012/L. The predictive model constructed by crossing these two indicators had the accuracy of 87% (95% confidence interval [CI] 73%-94%), sensitivity of 82% (95% CI 53%-97%), and specificity of 88% (95% CI 79%-93%). CONCLUSION: The first FN episode duration and anemia are significantly associated with the risk for severe FN re-occurrence. These factors may be useful in the identification of children with cancer who are at high risk for adverse outcome at any future fever onset and may benefit from early intensive treatment.

Malignant Perivascular Epitheloid Cell Tumor with an Unusual Immunophenotype in a Ten-Year-Old Child.

Introduction: Perivascular epitheloid cell tumors (PEComa) represent a group of usually benign mesenchymal neoplasms. Malignant variants are usually found only in adults.Case: We present a 10-year-old girl with infraclavicular malignant PEComa, negative for HMB-45 and Melan A but focally positive for MITF.Conclusion: To the best of our knowledge, no malignant variant of PEComa has been described in soft tissue in a child. Generally, PEComas are immunoreactive for HMB-45 and/or Melan A while our case was negative for both. Further studies are necessary to elucidate the significance of this immunohistochemical finding.