Genetic predisposition to childhood cancer.

The etiology of childhood cancer remains largely unknown. Recent evidence suggests that genetic factors play a substantial role in pediatric tumorigenesis. Unlike adult cancers, pediatric cancers typically have a higher prevalence of germline pathogenic variants in cancer predisposition genes. Inherited cancer predisposition syndromes account for approximately 10% of all childhood cancers. Over the years, the diagnosis of cancer predisposition syndromes was based on clinical suspicion prompting referral to a specialized geneticist. However, advances in molecular technologies have led to a shift toward a "genotype-first" approach. Identification of genetic variants related to cancer predisposition enables tailored treatment, improves clinical outcome, optimizes surveillance, and facilitates genetic counseling of the affected child and the family.

Infections in Children with Acute Lymphoblastic Leukemia.

Background and Objectives: Infections are the most common and potentially life-threatening complications of the treatment of children with acute lymphoblastic leukemia (ALL). The aim of this study was to determine epidemiological, clinical, and microbiological characteristics of infections in pediatric patients with ALL. Materials and Methods: Twenty-three children (16 males and 7 females, with a mean age of 5.9 years (range of 1.3 to 12.2 years)) with ALL, treated at the Division of Hematology, Oncology, and Clinical Genetics, Department of Pediatrics, Clinical Hospital Center Rijeka, Croatia, from 1 January 2015 to 31 December 2020, were included in the study. Results: One hundred and four infectious episodes (IEs) were reported (an average of 4.5 IE per patient). IEs were more frequent in the intensive phases of antileukemic treatment. Neutropenia was present in 48 IEs (46.2%) with a duration greater than 7 days in 28 IEs (58.3%). The respiratory tract was the most common infection site (48.1%). We documented 49 bacterial (47.1%), 4 viral (3.9%), 4 fungal (3.9%), and 10 mixed isolates (9.6%), while in 37 IEs (35.6%), a pathogen was not isolated. The most common causes of bacteremia were coagulase-positive staphylococci. The most frequent empirical therapy was third- and fourth-generation cephalosporins, followed by piperacillin/tazobactam. The modification of first-line antimicrobial therapy was performed in 56.9% of IEs. Granulocyte-colony stimulating factor was administered in 53.8% of IEs, and intravenous immunoglobulins were administered in 62.5% of IEs. One patient required admission to the intensive care unit. No infection-related mortality was reported. Conclusions: ALL patients have frequent IEs. Close monitoring, the identification of risk factors, the rapid empirical use of antibiotics in febrile neutropenia, and the timely modification of antimicrobial therapy play key roles in reducing infection-related morbidity and mortality in children with ALL.

Paediatric very rare tumours registration and management in European countries with low health expenditure average rates.

PURPOSE: Within the Paediatric Rare Tumours Network-European Registry (PARTNER) project, we aimed to evaluate the situation on the registration and management of paediatric patients affected by very rare tumours (VRT) in the European low health expenditure average rates (LHEAR) countries. METHODS: A survey regarding infrastructure, organisation, and clinical decision-making information on VRT was designed. This survey was distributed to the representatives of LHEAR countries involved in the activities of the PARTNER Work Package 7. RESULTS: Eighteen answers from 17 countries were collected regarding the national organisation, methods of registration of VRT cases, the availability of medical experts in VRT, the access to updated diagnostic and therapeutic procedures (such as proton therapy, immunotherapy and, targeted therapies), and research on paediatric VRT. A high variability in the registration and management of patients with VRT has been observed with additional wide inequalities in pathology review, uniformity of clinical decisions, availability of selected procedures, and diagnostic and research tools. CONCLUSION: In the majority of LHEAR countries, no clinical or research structures have been implemented for children and adolescents with VRT. Therefore, VRT still have an orphan status in these countries. These significant differences on the technology access and use between European regions need to be addressed.

Late Adverse Effects after Treatment for Childhood Acute Leukemia.

The aim of this review is to raise awareness and knowledge among healthcare professionals and policymakers about late adverse effects in survivors of childhood leukemia. With contemporary treatment, over 90% of children with acute lymphoblastic leukemia (ALL) and over 60% with acute myeloid leukemia (AML) are cured. Large cohort studies demonstrate that 20% of ALL and most AML survivors have at least one chronic health condition by 20-25 years after diagnosis. These are life-changing or threatening in some survivors and contribute to increased premature mortality. We describe the frequency, causes, clinical features, and natural history of the most frequent and severe late adverse effects in childhood leukemia survivors, including subsequent malignant neoplasms, metabolic toxicity, gonadotoxicity and impaired fertility, endocrinopathy and growth disturbances, bone toxicity, central and peripheral neurotoxicity, cardiotoxicity, psychosocial late effects, accelerated ageing and late mortality. The wide range of late effects in survivors of haemopoietic stem cell transplant is highlighted. Recent developments informing the approach to long-term survivorship care are discussed, including electronic personalized patient-specific treatment summaries and care plans such as the Survivor Passport (SurPass), surveillance guidelines and models of care. The importance of ongoing vigilance is stressed given the increasing use of novel targeted drugs with limited experience of long-term outcomes. CONCLUSION: It is vital to raise awareness of the existence and severity of late effects of childhood leukemia therapy among parents, patients, health professionals, and policymakers. Structured long-term surveillance recommendations are necessary to standardize follow-up care.

The Relevance of ß-Thalassemia Heterozygosity in Pediatric Clinical Practice: Croatian Experience.

(1) Background: Thalassemia syndromes are common monogenic disorders that represent a significant global health issue. No systematic epidemiological or molecular investigations on thalassemias in the Croatian population have been reported to date. (2) Methods: This prospective study included 70 children with a presumptive diagnosis of thalassemia and their 42 first-degree relatives. Molecular characterization was performed using direct sequencing and gap-PCR methods. (3) Results: We identified 46 (30 children and 16 first-degree relatives) ß-thalassemia heterozygous carriers from 24 unrelated families, carrying eight different mutations and one hemoglobin variant. Five variants account for approximately 85% of all affected ß-globin alleles: Hb Lepore-Boston-Washington (32.6%), HBB:c.93-21G>A (19.6%), HBB:c.315+1G>A (13.1%), HBB:c.92+1G>A (10.9%), and HBB:c.92+6T>C (8.7%) variants. (4) Conclusions: ß-thalassemia carriers need more detailed genetic profiling since genetic modifiers can significantly impact their phenotype. Our study provides important new insights into the relevance of ß-thalassemia heterozygosity in pediatric clinical practice.

Diagnostic Performance of F-18 FDG PET/CT in the Detection of Recurrent Colorectal Cancer: Correlation with Biochemical Markers and Conventional Imaging Modalities.

Background/Objectives: Although the role of PET/CT imaging is well established in oncology, its diagnostic value in routine monitoring for recurrent colorectal cancer (CRC) is still controversial. The aim was to evaluate the diagnostic value of F-18 FDG PET/CT in detecting recurrent CRC in correlation with CEA, CA 19-9 levels, and conventional imaging modalities (CIM). Methods: Between 2009 and 2023, a retrospective study was performed including 134 CRC patients referred for PET/CT imaging on the suspicion of recurrence, based on elevated CEA and/or CA 19-9 and/or equivocal CIM findings. According to our institution's Tumor Board CRC protocol, after the initial treatment, which was dependent on the TNM stage (neoadjuvant therapy, primary resection, or adjuvant treatment), patients underwent a standard 5-year surveillance including CEA and CA 19-9 measurements, CIM, and colonoscopy, every six months. The statistics, including univariate and multivariate analyses were conducted using the IBM SPSS 20.0 statistical software. p-values < 0.05 were considered statistically significant. Results: Recurrent CRC was confirmed in 54/134 (40.3%) patients with elevated tumor markers. PET/CT showed high diagnostic performance in detecting recurrent CRC with sensitivity, specificity, PPV, NPV, and accuracy of 94.4%, 82.5%, 78.5%, 95.7%, and 87.3%, respectively. The CEA showed a high sensitivity of 98.1% but both low specificity and accuracy of 15% and 48.5%, respectively. The sensitivity, specificity, and accuracy for CA 19-9 and CIM for diagnosis of CRC recurrence were 44.4%, 67.5%, 58.2%, and 51.9%, 98.8%, 79.9%, respectively. The AUC for PET/CT, elevated CEA levels, CIM, and elevated CA 19-9 levels was 0.885 (95% CI: 0.824-0.946; p < 0.001), 0.844 (95% CI: 0.772-0.916; p < 0.001), 0.753 (95% CI: 0.612-0.844; p < 0.001), and 0.547 (95% CI: 0.442-0.652; p = 0.358), respectively. Univariate analysis showed that both PET/CT and CIM positive results were highly associated with CRC recurrence (p < 0.001 and p < 0.001, respectively). At the same time, gender, mucinous tumor type, presence of initial lymph node metastasis (N+), and presence of initial distant metastasis (M+) had no significance (p = 0.211, p = 0.158, p = 0.583, and p = 0.201, respectively). Our multivariate analysis showed that independent predictors for CRC recurrence are positive PET/CT scans (p < 0.001), positive CIM results (p = 0.001), and elevated CA 19-9 levels (p = 0.023). Although CA 19-9 was not detected as a statistically significant predictor in the univariate analysis (p = 0.358), in a multivariate analysis it was recognized as a significant predicting factor in detecting the CRC recurrence (p = 0.023). Conclusions: F-18 FDG PET/CT showed high diagnostic efficacy in CRC recurrence detection, in correlation with CEA levels, CA 19-9 levels, and CIM. This imaging modality should be routinely integrated into the post-operative follow-op in patients with elevated tumor markers.

Rational Antibiotic Prescribing Is Underpinned by Dental Ethics Principles: Survey on Postgraduate and Undergraduate Dental Students' Perceptions.

BACKGROUND: Dentists bear the burden of responsibility for antimicrobial resistance since antibiotics are the drugs most prescribed by dentists. Often, "inappropriate" antibiotic use is considered as a "gray area" by dentists mainly due to ethical challenges associated with the clinical judgement depending on patients and/or prescribers. AIM: The study aimed to assess whether and in what way dental ethical principles underpin rational antibiotic use by investigating perceptions of postgraduate and undergraduate dental students without formal knowledge of dental ethics. METHOD: A cross-sectional anonymous survey comprised nine close-ended questions and was conducted among dental students (n = 125). The investigated practice of appropriate antibiotic prescribing in the survey relied on the respect of three basic principles of ethics: autonomy, non-maleficence, and beneficence. RESULTS: Results show that dental students exhibit a lack of dental ethics knowledge that results in an inappropriate antibiotic-prescribing practice: prescribing an antibiotic when it is not necessary, without examination, or for indications that are not within the competence of the dentist. Multivariate regression analysis revealed that there was a significant difference between under- and postgraduates. CONCLUSIONS: Within the pharmacology course, a review of the clinical scenarios which cover both ethical and clinical complexities regarding the appropriate use of antibiotics should be introduced as an educational approach.

Parenteral iron therapy in children with iron deficiency anemia.

Iron deficiency anemia (IDA) continues to be a global public health problem. Oral iron is the universally accepted first-line therapy, and most children have a prompt and favorable response to oral formulations. In subsets of children who fail to respond due to intolerance, poor adherence, or inadequate intestinal absorption, parenteral iron is indicated. Despite numerous studies in adults with IDA of diverse etiologies, pediatric studies on parenteral iron use are very limited. Although mostly retrospective and small, these studies have documented the efficacy and safety profile of intravenous iron formulations. In this editorial the author comments on the most important published data and underscores the need to seriously consider parenteral iron use in children unresponsive to oral therapy.

Panhypopituitarism caused by a suprasellar germinoma: A case report.

BACKGROUND: Suprasellar germinomas are rare intracranial tumors frequently associated with permanent endocrine disorders. We present the clinical picture, treatment, and complications of suprasellar germinoma at pediatric age which, besides being life-threatening, has lifelong endocrinological consequences. CASE SUMMARY: A 12-year-old female patient was presented having had intensive headaches for three weeks and visual disturbances for six months. An ophthalmological examination revealed bilateral papilledema and a marked loss of vision. Emergency brain magnetic resonance imaging (MRI) showed a suprasellar tumor, involving the infundibulum and the optic chiasm, extending to the third ventricle. Laboratory tests confirmed decreased levels of thyroxine, cortisol, gonadotropins, and insulin-like growth factor 1. Maximal tumor reduction was performed, and immunohistopathology established the diagnosis of suprasellar germinoma. MRI of the spine and cerebrospinal fluid cytology confirmed the localized disease. Adjuvant chemotherapy and radiotherapy were performed according to the SIOP CNS GCT II protocol. A post-treatment MRI showed no residual tumor, but pituitary function had not recovered. Three and a half years after the end of the treatment, the patient is in a complete remission, requiring hormonal replacement therapy, continuous education, and psychological support. CONCLUSION: This complex case highlights the importance of timely diagnosis, a multidisciplinary approach, and close follow-up in children with suprasellar germinomas.

Familiarity with ChatGPT Features Modifies Expectations and Learning Outcomes of Dental Students.

OBJECTIVES: The number of approvals for AI-based systems is increasing rapidly, although AI clinical trial designs lack consideration of the impact of human-AI interaction. Aim of this work was to investigate how reading of an AI system (ChatGPT) features/descriptions could influence the willingness and expectations for use of this technology as well as dental students' learning performance. METHODS: Dental students (N = 104) were asked to learn about side effects of drugs used in dental practice via reading recommended literature or ChatGPT. Expectations towards ChatGPT were measured by survey, before and after reading of a system features description, whilst learning outcomes were evaluated via pharmacology quiz. RESULTS: Students who used ChatGPT (YG group) showed better results on the pharmacology quiz than students who neither read the description nor employed ChatGPT for learning (NN condition). Moreover, students who read the description of ChatGPT features yet did not use it (NG) showed better results on the pharmacology quiz compared with the NN condition, although none of them employed ChatGPT for learning. The NG students compared to the YG students had less trust in AI system assistance in learning, and after the AI system description reading, their expectations changed significantly, showing an association with quiz scores. CONCLUSIONS: A majority of students in our cohort was reluctant to use ChatGPT. Furthermore, familarity (reading) with ChatGPT features appear to alter the expectations and enhance learning performance of students.suggesting an AI description-related cognitive bias. Hence the content description of ChatGPTshould be reviewed and verified prior to AI system use for educational purposes.

Alterations of Nutritional Status in Children and Adolescents with Acute Lymphoblastic Leukemia.

Malnutrition is often observed in pediatric cancer patients and has been recognized as a risk factor for relapse and survival. Maintaining an appropriate nutritional status during anticancer treatment has, therefore, been more and more frequently perceived as an additional requirement for optimal therapy outcomes. The aim of our study was to establish alterations of nutritional status in 26 children and adolescents treated for acute lymphoblastic leukemia (ALL) at the Children's Hospital in Zagreb, Croatia, between 2016 and 2021, by using anthropometric measures and serum albumin levels. The majority of patients (53.8% female, median 4 years, 52.2% intermediate-risk leukemia group) had normal weight at the beginning of chemotherapy. The percentage of overweight/obese patients increased from 4.2% at diagnosis to 37.5% at the end of intensive therapy. Apart from a significant increase in body weight (BW) and body mass index (BMI) for age, a notable decline in body height/body length (BH/BL) for age in the observed period was recorded, especially in high-risk leukemia patients. The alterations in serum albumin values were not significant, nor was their correlation with BMI. Dietary consultation was offered to all patients, while children with a decline in BMI and BH/BL received additional nutritional support.

Management of Childhood Iron Deficiency Anemia in a Developed Country-A Multi-Center Experience from Croatia.

Iron deficiency anemia (IDA) continues to be a global public health concern, mostly in the developing countries. However, precise epidemiological data on childhood IDA in Croatia are lacking. In order to establish its frequency, underlying etiologies, the rationale for tertiary care visits, diagnostic practices, and current treatment regimens of IDA, medical records of children referred to pediatric hematologists for iron deficiency in a five-year period at tertiary institutions (Zagreb, Rijeka, Split, Osijek) throughout Croatia were retrospectively analyzed. Eight hundred and sixty-four children, predominately of preschool age, were referred mainly by the primary care pediatricians, who, in general, performed basic diagnostics but failed to initiate oral iron therapy in half of the patients. Approximately one-third of patients were symptomatic, with inadequate nutrition prevailing as underlying etiology. Dextriferron was the preferred iron formulation among hematologists, with a median dose of 5 mg/kg, with acceptable compliance rates (63.5-93.2%). Hospital admission rates varied among the centers (9.4-35%), and so did transfusion policies (6.4-22.9%). The greatest difference was observed in the frequency of parenteral iron administration (0.3-21.5%). In conclusion, the burden of childhood IDA, even in a high-income country, remains substantial, necessitating consistent implementation of national guidelines and additional education of primary health care providers.

Melatonin Action in Type 2 Diabetic Parotid Gland and Dental Pulp: In Vitro and Bioinformatic Findings.

Type 2 diabetes mellitus (T2DM) is associated with functional deterioration of the salivary gland and dental pulp, related to oxidative stress. The aim was to integrate experimental and bioinformatic findings to analyze the cellular mechanism of melatonin (MEL) action in the human parotid gland and dental pulp in diabetes. Human parotid gland tissue was obtained from 16 non-diabetic and 16 diabetic participants, as well as human dental pulp from 15 non-diabetic and 15 diabetic participants. In human non-diabetic and diabetic parotid gland cells (hPGCs) as well as in dental pulp cells (hDPCs), cultured in hyper- and normoglycemic conditions, glial cell line-derived neurotrophic factor (GDNF), MEL, inducible nitric oxide synthase (iNOS) protein expression, and superoxide dismutase (SOD) activity were measured by enzyme-linked immunosorbent assay (ELISA) and spectrophotometrically. Bioinformatic analysis was performed using ShinyGO (v.0.75) application. Diabetic participants had increased GDNF and decreased MEL in parotid (p < 0.01) and dental pulp (p < 0.05) tissues, associated with increased iNOS and SOD activity. Normoglycemic hDPCs and non-diabetic hPGCs treated with 0.1 mM MEL had increased GDNF (p < 0.05), while hyperglycemic hDPCs treated with 1 mM MEL showed a decrease in up-regulated GDNF (p < 0.05). Enrichment analyses showed interference with stress and ATF/CREB signaling. MEL induced the stress-protective mechanism in hyperglycemic hDPCs and diabetic hPGCs, suggesting MEL could be beneficial for diabetes-associated disturbances in oral tissues.

Ethical considerations on artificial intelligence in dentistry: A framework and checklist.

OBJECTIVE: Artificial Intelligence (AI) refers to the ability of machines to perform cognitive and intellectual human tasks. In dentistry, AI offers the potential to enhance diagnostic accuracy, improve patient outcomes and streamline workflows. The present study provides a framework and a checklist to evaluate AI applications in dentistry from this perspective. METHODS: Lending from existing guidance documents, an initial draft of the checklist and an explanatory paper were derived and discussed among the groups members. RESULTS: The checklist was consented to in an anonymous voting process by 29 Topic Group Dental Diagnostics and Digital Dentistry, ITU/WHO Focus Group AI on Health's members. Overall, 11 principles were identified (diversity, transparency, wellness, privacy protection, solidarity, equity, prudence, law and governance, sustainable development, accountability, and responsibility, respect of autonomy, decision-making). CONCLUSIONS: Providers, patients, researchers, industry, and other stakeholders should consider these principles when developing, implementing, or receiving AI applications in dentistry. CLINICAL SIGNIFICANCE: While AI has become increasingly commonplace in dentistry, there are ethical concerns around its usage, and users (providers, patients, and other stakeholders), as well as the industry should consider these when developing, implementing, or receiving AI applications based on comprehensive framework to address the associated ethical challenges.

Responsible Use of Artificial Intelligence in Dentistry: Survey on Dentists' and Final-Year Undergraduates' Perspectives.

The introduction of artificial intelligence (AI)-based dental applications into clinical practice could play a significant role in improving diagnostic accuracy and reforming dental care, but its implementation relies on the readiness of dentists, as well as the health system, to adopt it in everyday practice. A cross-sectional anonymous online survey was conducted among experienced dentists and final-year undergraduate students from the School of Dental Medicine at the University of Belgrade (n = 281) in order to investigate their current perspectives and readiness to accept AI into practice. Responders (n = 193) in the present survey, especially final-year undergraduates (n = 76), showed a lack of knowledge about AI (only 7.9% of them were familiar with AI use) and were skeptical (only 34% of them believed that AI should be used), and the underlying reasons, as shown by logistic regression analyses, were a lack of knowledge about the AI technology associated with a fear of being replaced by AI, as well as a lack of regulatory policy. Female dentists perceived ethical issues more significantly than men regarding AI implementation in the practice. The present results encourage an ethical debate on education/training and regulatory policies for AI as a prerequisite for regular AI use in dental practice.

Deep convolutional neural network algorithm for the automatic segmentation of oral potentially malignant disorders and oral cancers.

This study aimed to develop an algorithm to automatically segment the oral potentially malignant diseases (OPMDs) and oral cancers (OCs) of all oral subsites with various deep convolutional neural network applications. A total of 510 intraoral images of OPMDs and OCs were collected over 3 years (2006-2009). All images were confirmed both with patient records and histopathological reports. Following the labeling of the lesions the dataset was arbitrarily split, using random sampling in Python as the study dataset, validation dataset, and test dataset. Pixels were classified as the OPMDs and OCs with the OPMD/OC label and the rest as the background. U-Net architecture was used and the model with the best validation loss was chosen for the testing among the trained 500 epochs. Dice similarity coefficient (DSC) score was noted. The intra-observer ICC was found to be 0.994 while the inter-observer reliability was 0.989. The calculated DSC and validation accuracy across all clinical images were 0.697 and 0.805, respectively. Our algorithm did not maintain an excellent DSC due to multiple reasons for the detection of both OC and OPMDs in oral cavity sites. A better standardization for both 2D and 3D imaging (such as patient positioning) and a bigger dataset are required to improve the quality of such studies. This is the first study which aimed to segment OPMDs and OCs in all subsites of oral cavity which is crucial not only for the early diagnosis but also for higher survival rates.

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.

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.