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Germ cell tumors (GCTs) are a rare group of neoplasms that arise from pluripotent stem cells. They display variable behavior depending on age, histology, primary tumor site, and stage of disease. In pediatric GCTs serum alfa fetoprotein (AFP) is the most frequently used marker for diagnosis and monitoring, although it is not specific only for these diseases. In this review, we discuss extracranial GCTs and the usefulness of AFP in their management. [ABSTRACT FROM AUTHOR]

Key Clinical Message We report a rare clinical presentation of childhood Hodgkin lymphoma with immune thrombocytopenia. Diagnostic biopsy of the abdominal mass was performed after administration of intravenous immunoglobulins, steroids, and platelet transfusion. Concomitant thrombocytopenia complicated the whole diagnosis work up and the initial management of neoplasia. [ABSTRACT FROM AUTHOR]

Abstract: Aim: Presenting features, treatment and outcome of 134 newborns with neuroblastoma diagnosed over a 27-year period are described. Methods: Analyses were performed on the entire cohort and on patients distributed over three periods of diagnosis. Results: Twenty-seven tumours (20.1%) were detected prenatally. Localised disease prevailed (65.7%) with an increase of stage 1 patients over time from 18.8% to 46.5%. Disseminated disease accounted for 34.3% of tumours with only one stage 4 and 45 stage 4S. Five-year overall survival (OS) of the entire cohort was 88.3%. Five/88 patients with localised disease died, including three who died of complications (OS, 95.3%). The only stage 4 patient survived. Eleven/45 stage 4S patients died, including 7/18 symptomatic and 4/27 asymptomatic (OS, 74.1%). Conclusion: The outcome of neuroblastoma in newborns is excellent. In localised tumours, surgery-related deaths outnumbered deaths due to disease. Symptomatic stage 4S patients were at greater risk of dying. [Copyright &y& Elsevier]

The authors report two pediatric cases of transient mutism that occurred after surgical removal of a medulloblastoma and a pilocytic astrocytoma of the vermis and discuss the pathophysiology of this syndrome. Transient mutism has been described for the first time quite recently, even in cases where these tumors were also surgically removed before. Perhaps improvement in imaging and in surgical techniques made neurosurgeons more daring and some interventions that were judged impossible are routinely performed today. If this is the case, postoperative transient cerebellar mutism might be considered the price that must be paid in order to cure more patients with cerebellar tumors. [ABSTRACT FROM AUTHOR]

Noonan syndrome (NS) is an autosomal dominant disorder that varies in severity and can involve multiple organ systems. In approximately 50% of cases, it is caused by missense mutations in the PTPN11 gene (12q24.13). NS is associated with a higher risk of cancer occurrence, specifically hematological disorders. Here, we report a case of a child who was diagnosed at birth with a transient myeloproliferative disorder (TMD). After two years, the child developed hyperdiploid B-cell precursor acute lymphoblastic leukemia (BCP-ALL), receiving a two-year course of treatment. During her continuous complete remission (CCR), a heterozygous germline mutation in the PTPN11 gene [c.218 C>T (p.Thr73lle)] was identified. At the age of ten, the child presented with massive splenomegaly, hyperleukocytosis, and thrombocytopenia, resulting in the diagnosis of juvenile myelomonocytic leukemia (JMML). After an initial response to antimetabolite therapy (6-mercaptopurine), she underwent haploidentical hematopoietic stem cell transplantation (HSCT) and is currently in complete remission. The goal of this review is to gain insight into the various hematological diseases associated with NS, starting from our unique case. [ABSTRACT FROM AUTHOR]

Background: A multi-disciplinary approach has led to an improvement in prognosis of childhood cancers. However, in parallel with the increase in survival rate, there is a greater occurrence of long-term toxicity related to antineoplastic treatment. Hypogonadism and infertility are among the most frequent endocrinological sequelae in young adult childhood cancer survivors. The aim of this study was to identify which category of patients, grouped according to diagnosis, therapy, and age at treatment, shows the worst reproductive function in adulthood. Methods: We evaluated morpho-volumetric development of the testis, endocrine function of the hypothalamic–pituitary–gonadal axis, and sperm parameters in 102 young adult childhood cancer survivors. Results: Overall, about one-third of patients showed low total testicular volume, total testosterone (TT) <3.5 ng/mL, and altered sperm count. Hodgkin's disease, hematopoietic stem cell transplantation, and non-cranial irradiation associated to chemotherapy were risk factors for poor gonadal function. Patients treated in pubertal age showed lower total testicular volume; however, the difference was due to more gonadotoxic treatment performed in older age. Testicular volume was more predictive of spermatogenesis than follicle-stimulating hormone (FSH), while anti-Müllerian hormone (AMH) was not useful in the evaluation of testicular function of male childhood cancer survivors. Conclusions: Pre-pubertal subjects at high risk of future infertility should be candidates for testicular tissue cryopreservation. [ABSTRACT FROM AUTHOR]

Natural killer (NK) cell lymphomas are rare in the USA and Europe but more common in Asia and Central America although very rare among children. We report a case of Epstein - Barr virus-positive NK lymphoma/leukemia, that showed peculiar features represented by a very long clinical course with a significant interval between the first clinical signs and the diagnosis, detection of neoplastic cells in the peripheral blood but not in the bone marrow, and good response to treatment and clinical outcome. [ABSTRACT FROM AUTHOR]

Background: Infants diagnosed with stage 4 s neuroblastoma commonly experience spontaneous disease regression, with few succumbing without response to therapy. We analyzed a large cohort of such infants enrolled in the Italian Neuroblastoma Registry to detect changes over time in presenting features, treatment and outcome. Methods: Of 3355 subjects aged 0–18 years with previously untreated neuroblastoma diagnosed between 1979 and 2013, a total of 280 infants (8.3%) had stage 4 s characteristics, 268 of whom were eligible for analyses. Three treatment eras were identified on the basis of based diagnostic and chemotherapy adopted. Group 1 patients received upfront chemotherapy; Group 2 and 3 patients underwent observation in the absence of life-threatening symptoms (LTS), except for Group 3 patients with amplified MYCN gene, who received more aggressive therapy. Results: The three groups were comparable, with few exceptions. Ten-year overall survival significantly increased from 76.9 to 89.7% and was worse for male gender, age 0–29 days and presence of selected LTS on diagnosis, elevated LDH, and abnormal biologic features. Infants who underwent primary resection ± chemotherapy did significantly better. On multivariate analysis, treatment eras and the association of hepatomegaly to dyspnea were independently associated with worse outcome. Conclusions: Our data confirm that stage 4 s neuroblastoma is curable in nearly 90% of cases. Hepatomegaly associated to dyspnea was the most important independent risk factor. The cure rate could be further increased through timely identification of patients at risk who might benefit from surgical techniques, such as intra-arterial chemoembolization and/or liver transplantation, which must be carried out in institutions with specific expertise. [ABSTRACT FROM AUTHOR]

The article introduces various topics discussed in the present issue, including pediatric tumors, the need for a multidisciplinary approach, and an overview on adrenocortical tumors in childhood.

Simple Summary: Diencephalic Syndrome (DS) is a rare disorder secondary to an intracranial neoplasm typically located in the hypothalamic region or its vicinity. Lack of specific symptoms and latency of overt neurologic impairment are misleading and delay diagnosis. A multidisciplinary evaluation is essential to exclude the most frequent causes of failure to thrive, and it is essential to underline the need for pediatricians to focus their attention on this dangerous cause of poor weight gain or stunting in childhood in order to make an early diagnosis and improve prognosis and quality of life. Background: Diencephalic Syndrome is an atypical early manifestation of low-grade gliomas; so, it is important to detect it in patients that experience a failure to thrive despite adequate length growth and food intake. The purpose of this article is to focus attention on this rare but potentially dangerous cause of poor weight gain or stunting in childhood. Materials and Methods: We describe four patients with Diencephalic Syndrome and low-grade gliomas who were evaluated in our institution from January 2017 to December 2021. Case Description and Results: two patients presented with suspected malabsorption, and two presented with a suspected eating disorder. In all cases, neurological symptoms appeared late, explaining the reason for the diagnostic delay, which impacts negatively on prognosis and on quality of life. Currently, patients 1 and 2 have stable disease in second-line therapy, patient 3 has stable disease post end of second-line therapy, and patient 4 has stable disease in first-line therapy. Everyone is in psychophysical rehabilitation. Conclusions: A multidisciplinary evaluation is essential in order to make an early diagnosis and improve prognosis and quality of life. [ABSTRACT FROM AUTHOR]

Background: Lung ultrasound (LUS) is a widely available technique allowing rapid bedside detection of different respiratory disorders. Its reliability in the diagnosis of community-acquired lung infection has been confirmed. However, its usefulness in identifying infections caused by specific and less common pathogens (e.g., in immunocompromised patients) is still uncertain. Methods: This systematic review aimed to explore the most common LUS patterns in infections caused by intracellular, fungal pathogens or mycobacteria. Results: We included 17 studies, reporting a total of 274 patients with M. pneumoniae, 30 with fungal infection and 213 with pulmonary tuberculosis (TB). Most of the studies on M. pneumoniae in children found a specific LUS pattern, mainly consolidated areas associated with diffuse B lines. The typical LUS pattern in TB consisted of consolidation and small subpleural nodes. Only one study on fungal disease reported LUS specific patterns (e.g., indicating "halo sign" or "reverse halo sign"). Conclusions: Considering the preliminary data, LUS appears to be a promising point-of-care tool, showing patterns of atypical pneumonia and TB which seem different from patterns characterizing common bacterial infection. The role of LUS in the diagnosis of fungal disease is still at an early stage of exploration. Large trials to investigate sonography in these lung infections are granted. [ABSTRACT FROM AUTHOR]

Clear cell sarcoma of the kidney (CCSK) is a rare pediatric renal tumor with a worse prognosis than Wilms' tumor. Although recently, BCOR internal tandem duplication (ITD) has been found as a driver mutation in more than 80% of cases, a deep molecular characterization of this tumor is still lacking, as well as its correlation with the clinical course. The aim of this study was to investigate the differential molecular signature between metastatic and localized BCOR-ITD-positive CCSK at diagnosis. Whole-exome sequencing (WES) and whole-transcriptome sequencing (WTS) were performed on six localized and three metastatic BCOR-ITD-positive CCSKs, confirming that this tumor carries a low mutational burden. No significant recurrences of somatic or germline mutations other than BCOR-ITD were identified among the evaluated samples. Supervised analysis of gene expression data showed enrichment of hundreds of genes, with a significant overrepresentation of the MAPK signaling pathway in metastatic cases (p < 0.0001). Within the molecular signature of metastatic CCSK, five genes were highly and significantly over-expressed: FGF3, VEGFA, SPP1, ADM, and JUND. The role of FGF3 in the acquisition of a more aggressive phenotype was investigated in a cell model system obtained by introducing the ITD into the last exon of BCOR by Crispr/Cas9 gene editing of the HEK-293 cell line. Treatment with FGF3 of BCOR-ITD HEK-293 cell line induced a significant increase in cell migration versus both untreated and scramble cell clone. The identification of over-expressed genes in metastatic CCSKs, with a particular focus on FGF3, could offer new prognostic and therapeutic targets in more aggressive cases. [ABSTRACT FROM AUTHOR]

Purpose: We aimed to evaluate long-term lung function and respiratory outcomes in young adults who survived common pediatric malignancies, treated in a single center. Methods: We enrolled young adults who had been treated during their childhood or adolescence for hematological or solid cancer at our Pediatric Oncology Unit, and performed pulmonary function tests (PFT) and clinical evaluation. PFT included spirometry and Diffusing Capacity of Lung for Carbon Monoxide (DLCO). Results: We included 121 survivors, mean age 23 years at follow-up, median 15 years from diagnosis. The most common diagnoses were hematological malignancies, mainly acute lymphoblastic leukemia, whereas 31% of the patients were treated for nonhematological cancer, mainly neuroblastoma. Treatments consisted of chemotherapy alone or in combination with radiotherapy and/or hematopoietic stem cell transplantation. Most of the patients denied respiratory symptoms throughout the years. In the whole group only eight patients (6%) had abnormal PFT, consisting mainly in a restrictive pattern and reduced DLCO. PFT abnormalities were of mild degree in most of the cases. Overall, the mean values of forced vital capacity, forced expiratory volume in 1 second, and DLCO were normal, but lower in females, in those who received radiotherapy and in those treated for lymphoma. Conclusion: In a group of young adults, surviving the most common childhood malignancies, we found a preserved lung function after a median follow-up of 15 years. The constantly increasing survival in childhood cancer is now associated with a trend toward an improvement in long-term respiratory outcomes. [ABSTRACT FROM AUTHOR]

Neuroblastoma is themost common extracranial solid tumor in childhood, arising in the sympathetic nervous system, metastatic in half of the patients at diagnosis, with bone and bonemarrow as themost frequent sites involved. Most neuroblastomas express the noradrenalin transporter molecule and take up metaiodobenzylguanidine (mIBG), providing a sensitive and specific method of assessing primary tumor and metastatic sites (soft tissue, bone marrow, and bone) when labeled with iodine-123, both at diagnosis, for staging, and as a prognostic factor for evaluation of response to therapy, especially when a semiquantitative scoring method is used. mIBG labeled with iodine-131 has demonstrated activity for targeted therapy of neuroblastoma in both relapsed and newly diagnosed patients, and is being used in clinical trials to optimize treatment of high-risk patients. [ABSTRACT FROM AUTHOR]

The protein cyclin D1 (CD1), which belongs to a family of proteins functioning as regulators of CDKs (cyclin-dependent kinases) throughout the cell cycle, has been immunohistochemically detected in a wide variety of human malignant tumors. The aim of the present study was to investigate immunohistochemically the expression and distribution of CD1 in the developing human peripheral sympathetic nervous system (PSNS) and in childhood peripheral neuroblastic tumors (neuroblastomas, ganglioneuroblastomas, and ganglioneuromas). The above mentioned fetal and neoplastic tissues represent an in vivo model in which undifferentiated neuroblastic cells undergo ganglion cell differentiation. During development, a strong nuclear expression of CD1 was restricted to neuroblasts, disappearing progressively from the maturing ganglion cells with increasing gestational age. In neoplastic tissues, CD1 immunoreactivity was restricted to neuroblastic cell component of all neuroblastomas and ganglioneuroblastomas, whereas it was absent or only focally detectable in maturing/mature ganglion cell component of differentiating neuroblastomas, ganglioneuroblastomas, and ganglioneuromas. We conclude that CD1 is a reliable marker, which can be used routinely to stain neuroblastic cells in both developing and neoplastic tissues. Furthermore, our results indicate that CD1 expression in childhood peripheral neuroblastic tumors recapitulates the changes during normal development of PSNS, as previously reported for Bcl-2 oncoprotein, c-ErbB2, insulin-like growth factor 2, β-2-microglobulin, and cathepsin D. This is consistent with the current view that childhood peripheral neuroblastic tumors exhibit gene expression profiles mirroring those occurring during PSNS development. [ABSTRACT FROM AUTHOR]

Simple Summary: Optimal management of small suprarenal masses (sSRMs) is not clearly defined in the literature. Among the differential diagnosis of these sSRMs without a clearly defined clinical management, neuroblastoma is the malignant neuroblastic tumor, with very good prognosis in most cases at this age and a very intriguing biology. The concept of the sSRM study is to attempt to safely minimize invasive procedures (including surgery) without jeopardizing the final outcome. We report the first International Society of Paediatric Oncology European Neuroblastoma (SIOPEN) cooperative prospective study of expectant observation as primary approach for neonates and infants less than or equal to 90 days of age with small localized suprarenal masses. In most cases, patients avoided surgery and, consequently, morbidity and mortality related to surgery. The study contributes to improving knowledge about the natural history and biology of neuroblastoma during early infancy. Background: To assess whether expectant observation of infants ≤ 90 days old with small suprarenal masses (sSRMs) could avoid unnecessary surgery without impacting outcome. Methods: Infants ≤ 90 days with a ≤ 5 cm mass, without midline extension or lymph node or distant spread were registered (ClinicalTrials.org:NCT01728155). Once staging was completed, they were followed with ultrasound, MRI and urinary catecholamines. Surgical resection was only planned if there was a ≥40% mass volume increase or for a mass persisting after 48 weeks of the planned observation. Results: Over a 5-year period, 128 infants were registered. No infant had detectable MYCN amplification in the peripheral blood. Surgery was performed in 39 (30.5%) patients, in 18 during and in 21 after the planned 48-week observation, and 74% were confirmed to be neuroblastomas. Non-life-threatening surgical complications occurred in two cases. The 3-year overall survival and event-free survival were 100% and 87.1%, respectively. The 16 events observed were volume increase (N = 11) and progression to neuroblastoma stage MS (N = 5). Patients with solid masses or MIBG-positive masses had lower EFS. Conclusions: Expectant observation for infants with sSRMs with clinical follow-up and timely imaging (including MRI scan) is safe and effective, allowing surgery to be avoided in the majority of them. [ABSTRACT FROM AUTHOR]

Bilateral adrenal neuroblastoma (NB) is rare and is mainly stage 4S. Its incidence, presenting features, management, and outcome have not been fully defined yet. We searched the Italian NB Registry (RINB) for stage 4S NB infants with bilateral adrenal primary tumor to compare them with stage 4S NB with unilateral tumor. Between 1979 and 2016, the RINB enrolled 3731 NB patients aged 0-18 years including 317 infants (8.5%) diagnosed with stage 4S NB. Eleven/317 (3.5%) had a bilateral adrenal primary tumor (Group 1) and 190/317 (59.9%) had a unilateral tumor (Group 2). Group 1 infants were significantly younger (51 vs. 89 days) but were comparable with Group 2 for any other presenting features. In the absence of specific protocols, upfront treatment was based on symptoms, size of adrenal tumors, and biology, and consisted of observation in 5 cases, radiotherapy in one, chemotherapy in 2, and surgery in 3. Five/11 developed progression and 2 of them, both with MYCN amplification, died. The 5-year EFS rates of Group 1 and 2 were 54.5% vs. 73.3% (P=.14) and 5-year OSs were 81.8% and 89.4%, respectively (P=.44). Our data support the hypothesis that 4S NB infants with bilateral adrenal tumors can have favorable outcome with personalized therapeutic approach. The three patients with MYCN amplified tumor benefited from upfront aggressive chemotherapy, in accordance with current protocols. Because of the rarity of this intriguing form of neuroblastoma, collaborative prospective studies are warranted, especially in view of gaining a better insight on its biological and genetic features. [ABSTRACT FROM AUTHOR]

Neuroblastoma (NB) is a tumor of the developing sympathetic nervous system. Despite recent advances in understanding the complexity of NB, the mechanisms that determine its regression or progression are still largely unknown. Stage 4S NB is characterized by a favorable course of disease and often by spontaneous regression, while progression to true stage 4 is a very rare event. Here, we focused on genomic analysis of an NB case that progressed from stage 4S to stage 4 with a very poor outcome. Array-comparative genomic hybridization (a-CGH) on tumor-tissue DNA, and whole-exome sequencing (WES) on exosomes DNA derived from plasma collected at the onset and at the tumor progression, pointed out relevant genetic changes that can explain this clinical worsening. The combination of a-CGH and WES data allowed for the identification iof somatic copy number aberrations and single-nucleotide variants in genes known to be responsible for aggressive NB. KLRB1, MAPK3 and FANCA genes, which were lost at the time of progression, were studied for their possible role in this event by analyzing in silico the impact of their expression on the outcome of 786 NB patients. [ABSTRACT FROM AUTHOR]

We undertook a pilot study to evaluate and potentially reduce the level of burnout in the operators of two oncology centers. The study included 65 doctors and nurses of an adult (Group A) and a pediatric oncology unit (Group B). We used the Maslach Burnout Inventory to estimate the level of burnout obtained in three dimensions: emotional exhaustion, distancing (cognitive and emotional) and reduced personal achievement. Data showed a medium–high level of burnout in Group A and a medium–low level in Group B. In the second part of the study, Group B underwent a program of art therapy interventions with the aim of reducing the level of burnout. Comparing the responses from Group B participants before and after the intervention indicated a statistically significant decreased level of burnout. In conclusion, burnout syndrome exists among oncology unit personnel and can be effectively treated with art therapies. Attention devoted to this aspect is required in order to improve the workers' well-being, thus enhancing attention and dedication to patients. Copyright © 2007 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Background The incidence of paediatric cancers has increased in recent years; however, with advances in the treatment of paediatric cancer, almost 80% of children and adolescents who receive a diagnosis of cancer become long-term survivors. Given the high stress levels associated with cancer, it becomes important to ascertain the risk and likelihood of psychiatric disorders in adult paediatric cancer survivors. Aims This study aims to investigate the relationship between defence styles and predisposition to psychiatric diseases in adults with a history of paediatric cancer. Methods We performed an explorative study on a sample of 66 clinically healed adults with a history of paediatric cancer (survivors) during follow-up visits at the University Hospital ‘Policlinico G Rodolico’ of Catania (Italy) and 98 healthy controls among medicine students. We administered the Defence Mechanism Inventory (DMI) to assess defence styles. The Symptom Checklist90-Revised (SCL-90-R) and the Davidson Trauma Scale (DTS) were administered to assess psychopathological indices. We conducted comprehensive statistical analysis based on correlation analysis and mediation analysis to investigate the relationship between defence styles and psychopathological outcomes in survivors compared with controls. Results The survivors obtained statistically significant lower values in TAO, PRO and TAS defence styles and a higher value in REV. Both groups showed non-pathlogical mean scores in DTS and SCL-90-R (with an exception of the obsessive-compulsive subscale), with lower mean values among survivors. The results of mediation analysis showed that TAS had mediation effects on interpersonal sensitivity, anxiety, PSDI, GSI and avoidance, while TAO had mediation effects on DTS total score and intrusivity. Thus, for these psychopathological indices, the effect of the oncological pathology was indirect and mediated by TAO or TAS. Our analysis exlcluded mediation effects between the remaining variables and defence styles. Conclusion Integrating data from mediation and correlation analysis, we found how the decreasing of TAS utilization in survivors as the consequence of cancer history, has decreased interpersonal sensitivity, anxiety and GSI score in these subjects compared with controls. Similary, the decrease of TAO utilization played a role in lower values of DTS total score and intrusivity subscale. Unexpectedly, our analysis excluded relationships between cancer history, other defence styles and psycopathological scores as we initially assumed. [ABSTRACT FROM AUTHOR]

• QUARTET provides a valuable resource of paediatric radiation oncology data. • Advanced radiotherapy techniques and modern infrastructure are widely available. • With plan rejection rates of 40%, prospective case review is recommended. • Prospective review enabled correction of 92% of unacceptable variations. • Consistency in target delineation remains the biggest challenge in planning. SIOP Europe's QUARTET project launched in 2016; aiming to improve access to high-quality radiotherapy for children and adolescents treated within clinical trials across Europe. The aim of this report is to present the profile of institutions participating in six QUARTET-affiliated trials and a description of the initial individual case review (ICR) outcomes. This is a two-part analysis. Firstly, using facility questionnaires, beam output audit certificates, and advanced technique credentialing records to create a profile of approved institutions, and secondly, collating trial records for ICRs submitted prior to 31/10/2022. Trials included are: SIOPEN HR-NBL1, SIOPEN-LINES, SIOPEN- VERITAS, SIOP-BTG HRMB, EpSSG-FaR-RMS, and SIOPEN HR-NBL2. By 31/10/2022, a total of 103 institutions had commenced QUARTET site approval procedures to participate in QUARTET-affiliated trials; 66 sites across 20 countries were approved. These participating institutions were often paediatric referral sites with intensity modulated radiotherapy or proton beam therapy, designated paediatric radiation oncologists, and paediatric adapted facilities and imaging protocols available. In total, 263 patient plans were submitted for ICR, 254 ICRs from 15 countries were completed. ICRs had a rejection rate of 39.8%, taking an average of 1.4 submissions until approval was achieved. Target delineation was the most frequent reason for rejection. The QUARTET facility questionnaire is a valuable tool for mapping resources, personnel, and technology available to children and adolescents receiving radiotherapy. Prospective ICR is essential for paediatric oncology clinical trials and should be prioritised to reduce protocol violations. [ABSTRACT FROM AUTHOR]

The authors describe the sixth pediatric case to date of primary vulvar melanoma associated with lichen sclerosus and propose a practical management for such a rare cancer. [ABSTRACT FROM AUTHOR]

The treatment of neuroblastoma is based on the International Neuroblastoma Risk Group stratification considering life-threatening symptoms, image-defined risk factors (IDRFs), presence and site of metastases, biology, and histopathology. The authors present an infant with bilateral nonmetastatic adrenal neuroblastoma with favorable biology. Both tumors were resectable and without IDRFs, but bilateral resection was considered mutilating, so it was decided to operate one side only. The authors suggest considering bilaterality among IDRFs. [ABSTRACT FROM PUBLISHER]

The tumor lysis syndrome (TLS) is an oncology emergency triggered by a massive and abrupt release of intracellular substances (potassium, phosphate, and purine metabolites) into the bloodstream. It may occur spontaneously or, more frequently, as a consequence of chemotherapy or radiation therapy. When the accumulation of these metabolites overwhelms the normal homeostatic mechanism, the TLS develops and leads to hyperkalemia, hyperphosphatemia, hyperuricemia, and hypocalcaemia. These metabolic derangements can progress to clinical manifestations including acute renal failure, cardiac arrhythmias, central nervous system toxicity, and even death. The key to prevent and manage TLS is the identification of high-risk patients to give them appropriate treatment measures when necessary. [ABSTRACT FROM AUTHOR]

Acute lymphoblastic leukemia (ALL) is the most common cancer in childhood, originating froma neoplastic deviation of B or T lymphocyte. Cytogenetic, cytofluorimetric, and genomic analyses clearly defined several subtypes of ALL. However, the leukemogenic process is characterized by different pathways' alteration which are still to be determined, in the attempt to identify specific targets to be druggable. In this review, we explore the main molecular pathways, which are commonly shared between different subtypes of pediatric ALL. These cell-signaling pathways affect many functions, including cell proliferation, apoptosis, migration, and differentiation. The PI3K/AKT/mTOR pathway is one of the most studied, with higher expected promises of being targetable. RAS pathway is also widely studied in all types of cancer. TheWnt/Beta catenin has been recently studied in ALL. Finally, CXCL12/CXCL4 axis has a crucial role in regulating hematopoietic stem cell and bone marrow niche. The complete characterization of these pathways will allow us to design a specific patient-disease profile associated with a tailored treatment, with the highest grade of efficacy and the lowest grade of toxicity. [ABSTRACT FROM AUTHOR]

Due to its many clinical and biologic characteristics, neuroblastoma (NB) is a polyhedric neoplasm. It is a very complex, extremely heterogeneous disease that can regress spontaneously even without therapy. However, it frequently shows a very aggressive behavior, refractory to current intensive multimodal therapy. The tumor, originating from primordial neural crest cells, is biochemically unique for its metabolic pathways of catecholamine synthesis and metabolism. Homovanillic acid (HVA), the main metabolite of dopamine, and vanillylmandelic acid (VMA), the main metabolite of adrenalin and noradrenalin, are sensitive and convenient markers of NB since they are found in large amounts in patient's urine. The rate of NB patients with positive VMA and/or HVA at the diagnosis varies with the stage of the disease, with high-stage tumors being more likely to have abnormal levels. Other less specific NB tumor serummarkers are neuron-specific enolase, ferritin, and lactate dehydrogenase. NB is one of the few pediatric tumors in which tumor markers have been shown to have a role in the diagnosis, prognosis, and disease monitoring. [ABSTRACT FROM AUTHOR]

Pediatric adrenocortical tumors (ACTs) are rare in children. Most tumors are hormonally active with overproduction of androgens and glucocorticoids, and less frequently mineralocorticoids and estrogens. Patients usually present with clinical signs of virilization or Cushing syndrome, while only a minority of ACTs are incidentally discovered. Unfortunately, the clinical behavior of pediatric ACTs is often unpredictable, and the distinction between benign and malignant tumors is still challenging. The present review deals with the main clinical and laboratory features which can help to diagnose pediatric ACTs, with special emphasis on the pathological criteria useful to stratify patients into three different prognostic categories: (1) patients with benign tumors; (2) patients with malignant tumors; and (3) patients with borderline tumors (tumors with indeterminate malignancy). In this regard, general guidelines and histological illustrations are provided to offer a practical approach for a correct identification of morphological predictors of clinical outcome. [ABSTRACT FROM AUTHOR]

Introduction Pleuropulmonary blastoma is a very rare, aggressive, embryonal pulmonary neoplasm which mostly affects children under the age of 5. According to the histopathological features, three subtypes of pleuropulmonary blastoma have been recognized: type I (purely cystic), type II (grossly visible cystic and solid elements) and type III (purely solid). Characteristics of type I and type II blastoma allow an earlier diagnosis compared with type III. Here we present a case report of an unusual presentation of type III pleuropulmonary blastoma. Case presentation We describe the case of a 7-month-old female baby of Italian mother and Kurdish father who was diagnosed with type III pleuropulmonary blastoma, which entirely occupied her right hemithorax. Conclusions The reported case is an unusual presentation because type III pleuropulmonary blastoma typically occurs in older children. The complete re-expansion of her residual, previously totally compressed, right lung observed immediately after the resection of the lesion suggests an atypical rapid growth of this embryonal tumor in the late phase of gestation or after delivery. This case report suggests that, in addition to other childhood tumors, type III pleuropulmonary blastoma should be included in the differential diagnosis of solid nonhomogeneous thoracic large masses, compressing the mediastinal and chest wall structures in infants. This is an original case report of interest for several specialities such us pediatrics, radiology, surgery and oncology. [ABSTRACT FROM AUTHOR]

BACKGROUND: Nasopharyngeal carcinoma (NPC) is very rare in childhood. It differs from its adult counterpart in the prevalence of the nonkeratinizing, undifferentiated subtype and by an advanced clinical stage at onset and better chances of survival. The risk of long-term treatment-related toxicity also may be a more important issue in younger individuals. METHODS: A prospective chemoradiotherapy protocol for pediatric NPC was started in Italy in 2000 within the framework of the Rare Tumors in Pediatric Age (TREP) project. Three courses of cisplatin/5-fluorouracil induction chemotherapy were followed by radiotherapy (doses up to 65 grays) with concomitant cisplatin. RESULTS: Forty-six patients (ages 9-17 years) were considered eligible for the study over a 10-year period. The ratio of observed to expected cases based on epidemiological data was approximately 1 for both children and adolescents. All but 1 patient had lymph node involvement, and 5 patients had distant metastases. The rate of response to primary chemotherapy was 90%. The 5-year overall and progression-free survival rates were 80.9% and 79.3%, respectively (median follow-up, 62 months). The only statistically significant prognostic variable was the presence or absence of distant metastases. A 65% incidence of late sequelae was reported. CONCLUSIONS: This study demonstrates the feasibility and efficacy of a prospective protocol even for such rare tumors as pediatric NPC. The use of lower radiotherapy doses than those used in adults did not affect locoregional failure rates. Long-term follow-up will be needed to obtain more information on both survival and treatment sequelae. The next objective will be to establish broader, international prospective cooperation schemes. Cancer 2011. © 2011 American Cancer Society. [ABSTRACT FROM AUTHOR]

Purpose: We analyzed whether the prognosis can differ among Wilms tumors (WT) labeled as Stage III according to currently adopted classification systems. Methods and Materials: Patients with nonanaplastic Stage III WT consecutively registered in two Associazione Italiana Ematologia Oncologia Pediatrica (AIEOP) trials (CNR-92, TW-2003) were the subjects in the present analysis. The steady mainstay of therapy was primary nephrectomy, followed by three-drug chemotherapy with vincristine, dactinomycin, doxorubicin, and abdominal radiotherapy (RT). Results: Ninety-nine WT patients met the criteria for classification as Stage III according to a revised version of the National Wilms Tumor Study–3 staging system (51 patients in CNR-92, 48 patients in TW-2003). Regional lymph nodes (LN) were not biopsied in 16 patients. After a median follow-up of 66 months, the 4-year disease-free survival (DFS) and overall survival (OS) rates were 85% ± 4% and 92% ± 3%, respectively, for the whole group. For 38 children with positive LN, the 4-year DFS rate was 73% ± 7%, as opposed to 98% ± 2% for the 45 children with Stage III WT according to the other criteria but with negative biopsied LN (p = 0.001). The subgroup with the worst prognosis consisted of children more than 2 years old with positive LN (DFS 67% ± 8%). A delay between surgery and RT > 30 days had an adverse impact on the abdominal tumor relapse rate. Conclusions: This study provides further evidence that Stage III tumors with LN metastases might be distinguished from WTs meeting the other criteria for classification as Stage III. The worse outcome of the former may warrant a prospective study on the effects of intensified therapy. A subclassification of Stage III tumors is discussed. [ABSTRACT FROM AUTHOR]

Abstract: Metanephric stromal tumor (MST) is a rare pediatric neoplasm unique to the kidneys that is currently included in the spectrum of metanephric tumors, along with metanephric adenoma and adenofibroma. We herein report an unusual case of pediatric renal stromal tumor overlapping with MST and solitary fibrous tumor (SFT). Histologically, the tumor was composed of bland-looking spindle to stellate cells embedded in a fibro-sclerotic stroma that focally surrounded native entrapped renal tubules or blood vessels with abortive rings or collarettes. Alternating hypercellular and hypocellular areas and a focal hemangiopericytomatous-like vascular pattern imparted to the tumor a resemblance to SFT. Angiodysplasia of intratumoral arterioles was also observed, but juxtaglomerular cell hyperplasia was not a feature. Immunohistochemically, the neoplastic cells showed a polyphenotypic profile, including diffuse expression of vimentin and CD34, and focal immunoreactivity for alpha-smooth muscle actin, EMA, and CD99. However, the most striking finding was diffuse nuclear and cytoplasmic expression of S-100 protein. Although this protein has been reported to stain the heterologous glial and/or cartilaginous components that can be occasionally encountered in MST, this marker has not been previously reported in the fibroblastic component of MST. Pathologist should be aware of similar unusual unclassified tumors to avoid potential confusion with other benign or malignant S-100 protein-positive tumors. [Copyright &y& Elsevier]

Background: Thymic epithelial tumours (thymoma and carcinoma) are exceptionally rare in children. We describe a national multicentre series with a view to illustrating their clinical behaviour and the results of treatment. Methods: From January 2000 all patients under 18 years of age diagnosed with "rare paediatric tumours" were centrally registered by the Italian centres participating in the TREP project (Tumori Rari in Età Pediatrica [Rare Tumours in Paediatric Age]). The clinical data of children with a thymic epithelial tumour registered as at December 2009 were analyzed for the purposes of the present study. Results: Our series comprised 4 patients with thymoma and 5 with carcinoma (4 males, 5 females; median age 12.4 years). The tumour masses were mainly large, exceeding 5 cm in largest diameter. Based on the Masaoka staging system, 3 patients were stage I, 1 was stage III, 1 was stage IVa and 4 were stage IVb. All 3 patients with stage I thymoma underwent complete tumour resection at diagnosis and were alive 22, 35 and 93 months after surgery. One patient with a thymoma metastasizing to the kidneys died rapidly due to respiratory failure. Thymic carcinomas were much more aggressive, infiltrating nearby organs (in 4 cases) and regional nodes (in 5), and spreading to the bone (in 3) and liver (in 1). All patients received multidrug chemotherapy (platinum derivatives + etoposide or other drugs) with evidence of tumour reduction in 3 cases. Two patients underwent partial tumour resection (after chemo-radiotherapy in one case) and 4 patients were given radiotherapy (45-54 Gy). All patients died of their disease. Conclusions: Children with thymomas completely resected at diagnosis have an excellent prognosis while thymic carcinomas behave aggressively and carry a poor prognosis despite multimodal treatment. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented on neurological complications during the treatment of childhood cancer.

In the last decade, the survival of subjects affected by cancer in childhood has significantly improved. The increased lifespan of childhood cancer survivors (CCS) led to a greater risk for long-term, therapy-related morbidity. To identify the clinical predictors of metabolic adverse outcomes in CCS (average off-therapy period: 12 years), we recruited 126 survivors of different childhood cancers (86.5% hematological cancers) who received at least anticancer chemotherapy, consecutively approached during their annual oncohematological outpatient visit. At examination, anthropometric measures and cancer-related history were collected. Moreover, a fasting venous sample was carried out for measuring fasting plasma glucose and insulin, glycated hemoglobin, lipid panel, and transaminases. We calculated the indexes of insulin resistance (HOMA-IR, McAuley, and QUICKI) and secretion (HOMA-β), liver steatosis (Hepatic Steatosis Index) and fibrosis (FIB-4 and NAFLD fibrosis score), and visceral fat dysfunction (Visceral Adiposity Index). More than one-third of the subjects (37.3%) did not have normal weight, with 11.1% of them affected by obesity. At recruitment, obese subjects were at significantly higher risk for impaired fasting glucose, metabolic syndrome, visceral adipose dysfunction, and liver steatosis/fibrosis. Subjects who received bone marrow transplantation were prone to insulin resistance, while survivors of lymphoma presented a visceral adipose dysfunction These results suggest a carefully metabolic monitoring of CCS, particularly in subgroups at higher risk, to early detect these conditions, promptly begin therapeutic interventions, and mitigate the dysmetabolic-related health burden. [ABSTRACT FROM AUTHOR]

Pediatric small round blue cell tumors (SRBCTs) are a heterogeneous group of neoplasms with overlapping morphological appearance. Accordingly, their diagnosis is one of the most difficult in the field of surgical pathology. The most common tumors include rhabdomyosarcoma, Ewing's sarcoma, neuroblastoma, lymphoblastic lymphoma and Wilms' tumor (the blastemal component). Over time their diagnosis has become more difficult due to the increasing use of small biopsies. However, the advent of immunohistochemistry has improved the quality of diagnosis in most cases by the application of an adequate panel of immunomarkers. Recently, WT1 and Cyclin D1 have been shown to be useful in the differential diagnosis of SRBCTs on surgically-resected specimens, showing a diffuse cytoplasmic positivity of the former in all RMSs and a diffuse nuclear staining of the latter in both EWS and NB. The aim of the present study was to investigate the expression of WT1 and Cyclin D1 on small biopsies from a series of 105 pediatric SRBCTs to evaluate their diagnostic utility. Both immunomarkers were differentially expressed, with a diffuse and strong cytoplasmic staining for WT1 limited to all cases of RMS, and a diffuse nuclear staining for cyclin D1 restricted to all cases of EWS and NB. Notably, the expression of WT1 and cyclin D1 was also retained in those cases in which the conventional tumor markers (myogenin, desmin and MyoD1 for RMS; CD99 for EWS; NB84 for NB) were focally expressed or more rarely absent. The present study shows that WT1 and Cyclin D1 are helpful immunomarkers exploitable in the differential diagnosis of pediatric SRBCTs on small biopsies, suggesting their applicability in routine practice. [ABSTRACT FROM AUTHOR]

Teratoma is the most common germ cell tumour in childhood; mature (MT) and immature teratomas (IT) are benign tumours, but if they recur, they can be in some cases malignant. The aim of this paper is to evaluate Italian patients with MT and IT enrolled from 1991 to 2001, in a prospective multicentric study. One hundred and eighty-three patients, observed in 15 Italian Centers of Paediatric Oncology and three Paediatric Surgical Units were enrolled. Clinical data, treatment and results were all analysed. Initial evaluation and subsequent follow up included clinical examination, tumour markers and imaging procedures. Surgical resection was recommended for all the tumours. Histology was centrally reviewed and IT was classified as grading 1–3. Chemotherapy (CT) with Vinblastine, D-actinomycin and cyclophosphamide was indicated for extra-testicular IT grade 2 or 3. MT was diagnosed in 127 patients (93 F and 34 M, age 1–192 months, median 24): 58 patients had gonadic tumour (23 testicular, 35 ovaric), 69 extragonadic (45 sacrococcygeal, 11 mediastinic, 7 retroperitoneal, 6 in other sites). A complete resection was performed in 117 patients, a partial resection in eight patients and biopsy in one. IT was diagnosed in 56 patients (34 F, 22 M, age 1–168 months, median 7). The T grading was 1 in 14 cases, 2 in 26, 3 in 16; 28 had gonadic T (17 ovary, 11 testis), 28 extragonadic (sacrococcygeal 19, mediastinic 3, retroperitoneal 2, other sites 4). CT was administered in eight patients; 15/182 patients relapsed (1 in a metastatic site) and in 5/15 the relapse showed malignant histology. Seven MT (5.5%) relapsed (five sacrococcygeal, one retroperitoneal, one mediastinic): surgery at diagnosis had been complete in five and with residual in two; the relapse was malignant in two patients with sacrococcygeal (sc) tumours, who had a complete resection and a partial resection respectively. Eight IT (14.2%) relapsed (four ovary, three sc, one retroperitoneal). The initial surgical resection had been complete in one, with residual in six, and a biopsy had been performed in one. A malignant recurrence occurred in two patients with sc tumours (after partial resection in one and after biopsy + CT in one) and in one patient with ovarian IT after a partial resection. All the patients underwent surgical excision of the recurred mass; CT according to Protocol for Malignant GCT was administered to those who had malignant recurrence; 122/126 patients with MT and 53/56 with IT are alive without disease with a follow up of 8–144 months (median 56). Two patients with malignant relapse (one with sc MT, one with sc IT) died because of the progression of the disease. Another two died due to severe malformations (one MT, one IT) and three were lost to follow up (two MT, one IT). The overall survival (OS) at 10 years is 98% (95% CI 93.9–99.4); the event free survival (EFS) is 90.4% (95 CI 84.8–94.0). At Cox analysis no significant difference in EFS was found regarding age and site of the primary tumour, while females ( P = 0.011), patients with grade 1–3 histology ( P = 0.025) and patients with incomplete resection appeared at higher risk of death or relapse ( P < 0.001), with a seven, three and eightfold increase in risk, respectively. Our data showed that incomplete resection and female gender are important risk factors for relapse or death, more so than IT histology. The number of patients treated with CT is not sufficient to evaluate the efficacy of CT in avoiding malignant relapse. [ABSTRACT FROM AUTHOR]

Cytogenetic studies of acute monoblastic leukemia cases presenting MLL-MLLT10 (alias MLL-AF10) fusion show a broad heterogeneity of chromosomal breakpoints. We present two new pediatric cases (French–American–British type M5) with MLL-MLLT10 fusion, which we studied with fluorescence in situ hybridization. In both we detected a paracentric inversion of the 11q region that translocated onto chromosome 10p12; one case displayed a variant complex pattern. We review the cytogenetic molecular data concerning the proximal inversion breakpoint of 11q and confirm its heterogeneity. [Copyright &y& Elsevier]

Background: Desmoplastic small round cell tumor (DSRCT) is a rare pediatric soft tissue neoplasm composed of small round tumor cells with prominent stromal desmoplasia, polyphenotypic differentiation and EWSR1-WT1 gene fusion. We, herein, present a unique case of DSRCT, exhibiting a pure spindle cell morphology, absence of desmoplastic stroma and showing a novel EWS-WT1 fusion transcript. Methods: A 12-year-old boy presented multiple intra-abdominal, confluent and mass-forming nodules that affected the entire abdominal and pelvic cavities. Results: Histologically, the nodules were composed of spindle cells with scant cytoplasm and oval nuclei arranged into short, intersecting fascicles and set in a scant, non-desmoplastic, stroma. Immunohistochemically, neoplastic cells were stained with vimentin, desmin, WT-1 (C-terminus antibodies) and EMA. Reverse-transcriptase polymerase chain reaction (RT-PCR) analysis showed the presence of an unusual chimeric transcript, composed of an in-frame junction of exon 9 of EWS to exon 7 of WT1, confirming the histological diagnosis of DSRCT. Conclusions: The present case contributes to widen the morphological spectrum of this entity; notably, the additional presence of a novel chimeric fusion transcript contributes to making the present case even more unique. Whether the detection of the above-mentioned fusion transcripts could explain the unusual morphology of the tumor remains to be established. [ABSTRACT FROM AUTHOR]

Pediatric cancer survivors are at increased risk for psychological distress. We sought to understand the severity and symptoms' co-occurrence among pediatric survivors compared to controls by rating both self- and parent-reported symptomatology. Forty survivors (22 males; mean age at study time: 12.9 years) participated in the study. Most survivors (85%) had a diagnosis of acute lymphoblastic leukemia. Seventy-nine healthy controls with the same age and gender distribution as the patients were included. A standardized assessment of psychological functioning was conducted by self- and parent-reported symptoms evaluations. The self-reported anxious symptom severity was significantly higher in survivors. A significantly higher proportion of survivors compared to controls had clinically significant anxiety, depression, and combined anxiety symptoms (i.e., social anxiety, separation anxiety, or physical symptoms). In both study groups, the self-reported emotional and somatic symptoms were significantly associated. The multi-informant assessments of the psychological symptoms revealed distinct associations between the child- and parent-reported symptoms in the survivors' group: the survivors' self-reports of depressive symptoms, somatic symptoms, and functional impairment were significantly correlated with the parent reports of child behavioral concerns, somatic complaints, and functional impairment, respectively. Conclusion: Self-reported symptoms showed similar comorbidity profiles in survivors and control peers. The multi-informant assessments detected differences in the association of self- and parent-reported symptoms between the survivor and control groups. The present study showed that multi-informant assessment is critical to understanding symptom profiles and to informing intervention with particular regard to parental participation and support. [ABSTRACT FROM AUTHOR]

Introduction: Pleuropulmonary blastoma is a very rare, aggressive, embryonal pulmonary neoplasm which mostly affects children under the age of 5. According to the histopathological features, three subtypes of pleuropulmonary blastoma have been recognized: type I (purely cystic), type II (grossly visible cystic and solid elements) and type III (purely solid). Characteristics of type I and type II blastoma allow an earlier diagnosis compared with type III. Here we present a case report of an unusual presentation of type III pleuropulmonary blastoma.Case Presentation: We describe the case of a 7-month-old female baby of Italian mother and Kurdish father who was diagnosed with type III pleuropulmonary blastoma, which entirely occupied her right hemithorax.Conclusions: The reported case is an unusual presentation because type III pleuropulmonary blastoma typically occurs in older children. The complete re-expansion of her residual, previously totally compressed, right lung observed immediately after the resection of the lesion suggests an atypical rapid growth of this embryonal tumor in the late phase of gestation or after delivery. This case report suggests that, in addition to other childhood tumors, type III pleuropulmonary blastoma should be included in the differential diagnosis of solid nonhomogeneous thoracic large masses, compressing the mediastinal and chest wall structures in infants. This is an original case report of interest for several specialities such us pediatrics, radiology, surgery and oncology. [ABSTRACT FROM AUTHOR]

An abstract of the conference paper "Predictive clinical and hematological factors in the differential diagnosis between malignancy and arthritis in children: a case-control study," by Silvia Marino, and colleagues, is presented.

Background: Thymic epithelial tumours (thymoma and carcinoma) are exceptionally rare in children. We describe a national multicentre series with a view to illustrating their clinical behaviour and the results of treatment.Methods: From January 2000 all patients under 18 years of age diagnosed with "rare paediatric tumours" were centrally registered by the Italian centres participating in the TREP project (Tumori Rari in Età Pediatrica [Rare Tumours in Paediatric Age]). The clinical data of children with a thymic epithelial tumour registered as at December 2009 were analyzed for the purposes of the present study.Results: Our series comprised 4 patients with thymoma and 5 with carcinoma (4 males, 5 females; median age 12.4 years). The tumour masses were mainly large, exceeding 5 cm in largest diameter. Based on the Masaoka staging system, 3 patients were stage I, 1 was stage III, 1 was stage IVa and 4 were stage IVb.All 3 patients with stage I thymoma underwent complete tumour resection at diagnosis and were alive 22, 35 and 93 months after surgery. One patient with a thymoma metastasizing to the kidneys died rapidly due to respiratory failure.Thymic carcinomas were much more aggressive, infiltrating nearby organs (in 4 cases) and regional nodes (in 5), and spreading to the bone (in 3) and liver (in 1). All patients received multidrug chemotherapy (platinum derivatives + etoposide or other drugs) with evidence of tumour reduction in 3 cases. Two patients underwent partial tumour resection (after chemo-radiotherapy in one case) and 4 patients were given radiotherapy (45-54 Gy). All patients died of their disease.Conclusions: Children with thymomas completely resected at diagnosis have an excellent prognosis while thymic carcinomas behave aggressively and carry a poor prognosis despite multimodal treatment. [ABSTRACT FROM AUTHOR]