Search

Nijmegen Breakage Syndrome (NBS) is a rare autosomal recessive disease, affecting mainly patients of Slavic origin. It is caused by a defect in NBN gene, resulting in defective nibrin protein formation. This leads to chromosomal instability, which predisposes to cancer, with lymphoid malignancies predominating. Nibrin is also involved in gonadal development and its disfunction in females with NBS frequently results in a pure gonadal dysgenesis (PGD) causing hypergonadotropic hypogonadism. However, only a few ovarian tumors in NBS patients have been reported to date. We describe the first case of a girl with NBS with PGD, who developed metachronous bilateral ovarian germ cell tumors (dysgerminoma and gonadoblastoma). Pathogenesis of PGD, neoplastic transformation and therapeutic approach in females with NBS are discussed.

Inflammatory myofibroblastic tumor (IMT) is a rare borderline malignancy, usually treated with surgery only. Exceedingly rare cases of inoperable, recurrent, or metastatic IMTs pose a therapeutic challenge. We report successful treatment of a 7-year-old girl with an inoperable anaplastic lymphoma kinase (ALK)-negative IMT of the tongue. The patient underwent various anti-inflammatory (steroids, nonsteroidal anti-inflammatory drugs, clarithromycin) and antiproliferative (chemotherapy) therapies to enable tumor regression and complete resection. Ultimately, next-generation sequencing of the tumor revealed a TFG-ROS-1 translocation, allowing for an off-label targeted therapy with crizotinib. Crizotinib treatment caused slight tumor regression but evident change of its structure, allowing for complete non-mutilating resection. Two histopathology examinations revealed complete disappearance of neoplastic cells following therapy. The patient remains disease-free 22 months after the delayed surgery. In children with inoperable ALK-negative IMTs, molecular testing must be performed to identify other targetable oncogenic fusions, including TFG-ROS1.

Background: Infectious complications (IC) caused by bacterial strains often impede anticancer therapy. The study aimed to retrospectively analyze bacterial IC that could help predict the risk and o...

The aim was to evaluate the incidence, clinical course, and outcome of adenoviral infection (AdVI) in pediatric patients diagnosed and treated due to cancer and in pediatric recipients of hematopoietic stem cell. Over a 72-month period, all-in 5599 children with cancer: 2441 patients with hematological malignancy (HM) and 3158 with solid tumors (ST), and 971 patients after transplantation: 741 after allogeneic (allo-HSCT) and 230 after autologous (auto-HSCT) were enrolled into the study. Among cancer patients, 67 episodes of AdVI appeared in 63 (1.1%) children, including 45 (1.8%) with HM and 18 (0.6%; P < .001) with ST. Within transplanted patients, AdVIs were responsible for 88 episodes in 81 (8.3%) children (P < .001), including 78 (10.5%) patients after allo-HSCT and 3 (1.3%) after auto-HSCT. Time to develop AdVI was short, especially after allo-HSCT. The most common clinical manifestation in cancer patients was enteritis diagnosed in 63 (94.0%) cases, while among HSCT recipient asymptomatic adenoviremia was found in 36 (40.9%) cases and the most common clinical manifestation was urinary tract infection. Cancer patients with disseminated disease, as well as HSCT recipients with either asymptomatic viremia or disseminated disease, received antiviral treatment. The most commonly used first-line therapy was cidofovir. None of the cancer patients died due to AdVI, while within HSCT recipients three patients developed disseminated adenoviral disease and died despite antiviral treatment. In cancer patients, AdVIs are rare and associated with very good prognosis even without specific treatment. However, in allo-HSCT recipients, disseminated disease with fatal outcome is more likely to occur.

The objective of the study was the analysis of incidence and outcome of invasive fungal disease (IFD) in children treated for malignancy (PHO, paediatric hematology-oncology) or undergoing hematopoietic cell transplantation (HCT) over a period of six consecutive years in nationwide study. A total number of 5628 patients with newly diagnosed malignancies and 971 patients after HCT (741 allo-HCT and 230 auto-HCT) were screened for infectious complications in biennial reports. IFD incidence was lower among PHO patients: 8.8% vs 21.2% (P .0001) and survival from IFD was better: 94.2% vs 84.1% (P .0001). Auto-HCT patients had lower incidence (10.9% vs 24.4%) and lower mortality than allo-HCT patients. Introduction of national antifungal prophylaxis programme in HCT and acute leukaemia patients decreased incidence of IFD in HCT (from 23.1% to 13.4%) and AML on conventional chemotherapy (from 36% to 23%) but not in ALL patients during chemotherapy. In multivariate analysis, the incidence of IFD was higher in patients after HCT, diagnosed for ALL, AML or NHL, and in patients 10 years old. Factors contributing to death with infection were as follows: undergoing HCT, diagnosis of acute leukaemia (ALL or AML) and duration of treatment of infection 21 days. In conclusion, the incidence of IFD in allo-HCT and in AML patients on chemotherapy has decreased after introduction of national programme of antifungal prophylaxis, while the incidence of IFD in ALL patients on chemotherapy did not change significantly. The outcome of IFD both in PHO and HCT patients has largely improved in comparison with historical international data.

Objective: The study was to assess whether tumour expressions of hypoxia-inducible factor (HIF)-1α, glucose transporter (GLUT)-1, carbonic anhydrase (CA) IX and vascular endothelial growth ...

Objectives: The analysis of epidemiology, risk factors and outcome of infections in children with malignant bone tumors (MBT) undergoing chemotherapy. Methods: In this retrospective nationwide multicenter cross-sectional study, a total number of 126 children with MBT including 70 with Ewing sarcoma (ES) and 56 with osteosarcoma (OSA) were screened for infections over a period of 72 consecutive months. Results: The risk of infection was 7.15-fold higher in patients with ES as compared to the OSA group, especially concerning bacterial infections (4.1-fold increase risk). Bacterial infections occurred in 74.3% patients with ES and in 41.1% with OSA. The median time from diagnosis to first infection was 4.9 months. 33.0% of bacterial episodes were diagnosed as bloodstream (BSI), 31.1% as gastrointestinal tract, 30.1% as urinary tract infection. Infection-related mortality (IRM) from bacterial infection was 6% and 15% in ES and OSA patients, respectively. Cumulative incidence was 7.1% for invasive fungal disease and 6.3% for viral infections. The only significant risk factor for IRM was time to infection ≥5 months since the beginning of chemotherapy. All patients who have died from infection had BSI and were in neutropenia. Conclusions: Infections in the children with MBT in our study occurred with high frequency, especially in patients with ES. The most frequent were bacterial infections, while fungal and viral infections were episodic. Among the bacterial infections, bloodstream, urinary tract and gastrointestinal tract infections occurred with similar frequency. All deceased patients died due to BSI. Bacterial infection occurring ≥5 months since the beginning of chemotherapy was a risk factor for death.

Background Malignant peripheral nerve sheath tumor (MPNST) is rare, aggressive soft tissue sarcoma which may affect children. Objective We aimed to assess prognostic significance of immunohistochemical (IHC) markers, osteopontin, fibronectin, survivin, cyclin D1 and p53, in pediatric MPNST. Methods A total of 26 pediatric MPNST patients were enrolled in the current study with a median follow-up of 51 months. IHC staining using commercially available monoclonal antibodies were employed to detect analyzed antigens on tissue microarrays. Eventually, all markers were subclassified to high (H) and low (L) expression categories in all analyzed tumors. Results High IHC expressions of survivin, cyclin D1, osteopontin, fibronectin, and p53 were detected in 18 (69.2%), 13 (50%), 16 (61.5%), 16 (61.5%), and 13 (50%) tumors, respectively. A significant correlation was demonstrated between cyclin D1 and osteopontin (p= 0.004). Both markers were associated with neurofibromatosis type 1 (NF1) status (p= 0.041 and p= 0.037, respectively). H-fibronectin was more prevalent in deeply located tumors (p= 0.046). None of the markers was associated with IRS stage, age at diagnosis, and tumor size. Univariate analysis identified IRS stage, regional lymph node metastases, NF1, and cyclin D1 as variables associated with overall survival (OS), whereas tumor depth, osteopontin, and cyclin D1 - for relapse-free survival (RFS). Subsequent multivariate analysis identified cyclin D1 and p53 as independent variables predicting RFS, whereas cyclin D1 and regional lymph nodes status were independent predictors for OS.

Although all tumours are rare in childhood, there are some particularly rare paediatric cancers which have not benefited from advances made by the international paediatric oncology network. To establish a shared definition and produce a list of these entities, the European Union Joint Action on Rare Cancers (JARC) promoted a consensus effort. The definition was based on the incidence rates estimated using the information network on rare cancers (RARECAREnet) database, pooling data from 94 population-based cancer registries and 27 countries. The RARECAREnet list of cancers was used to estimate the incidence rates. This list groups cancers by combining the International Classification of Diseases for Oncology, third edition, morphology and topography codes. According to the consensus, very rare paediatric cancers were identified as those with an annual incidence 2/1000000 (i.e. thyroid and testicular cancers and skin melanoma), but the consensus experts considered them as ‘very rare’ according to their clinical needs (e.g. shortage of knowledge and clinical expertise as the other rare paediatric cancers). The JARC consensus produced a definition and a list of very rare paediatric cancers which may represent a starting point for prioritising research on these tumours, based on data and patients’ clinical needs.

Background Children with progressive (PD) or relapsed disease (RD) of pleuropulmonary blastoma (PPB) type II/III are known to have a very poor outcome. Methods A retrospective review of children registered in national and European databases and trials (2000-2018) with diagnosis of PPB type II/III and PD or RD was performed. Results A total of 35 patients with PPB were analysed: patients with PD (n = 9) and RD (n = 26). Patients experienced PD at the median age of 3.9 years [range, 0.5-17.8] despite surgery, chemotherapy (CHT, n = 9) and radiotherapy (RT, n = 1) with a median time to progression of 0.58 years [range, 0.02-1.27] from diagnosis. All of them died. Patients suffered from RD at the median age of 4.3 years [1.7-15.1], median delay to relapse 1.03 years [range, 0.03-2.95]. RD occurred locally (n = 12), combined (n = 1) and in metastatic sites (n = 13): central nervous system (n = 11) and unspecified site (n = 2). Patients were treated with salvage CHT (n = 20), surgery (n = 10) ± RT (n = 10). After a median follow-up of 4.2 years [range, 2.1-14.6], a second complete remission (CR) was achieved in nine out of 26 patients. Patients were alive in the second CR (n = 6), in the third CR (n = 1), in partial remission (n = 2) and lost of follow-up (n = 1). Five-year event-free survival (EFS) and overall survival (OS) for patients with RD were both 37% (±19, CI 95%). Local therapy (surgery, RT) had a favourable impact on OS (p = 0.03 and 0.02, respectively). Conclusions Cure of patients with RD of PPB type II/III with multimodal treatment is possible but rare. Progressive PPB is fatal and patients need new treatment options.

Simple Summary Melanotic Neuroectodermal Tumor of Infancy (MNTI) is a very rare neoplasm that most commonly develops within maxilla in infants. It usually has a benign clinical course and is treated with only surgery. However, patients with large, inoperable, metastatic or multiply recurring MNTI may require systemic treatment. The role of pre- and post-surgery chemotherapy (CHT) in the management of MNTI is unclear. Here, we have presented the disease courses and outcomes of four infants treated with multidrug CHT due to inoperable/recurrent MNTI. Additionally, a systematic literature review was performed which revealed 38 similar cases in the last 42 years. Most children with primarily inoperable MNTI responded to CHT, which allowed physicians to perform complete, non-mutilating delayed surgery. However, it is still uncertain whether CHT administered after incomplete resection of MNTI prevents recurrence. This study aimed to contribute to the establishment of standards of management in patients with inoperable, metastatic or persistently recurring MNTIs, which are currently lacking. Abstract Melanotic Neuroectodermal Tumor of Infancy (MNTI) is a very rare pediatric neoplasm of neural crest origin. In most cases, it develops in infants as a localized tumor of the maxilla, and surgery is usually curative. In less than 10% of patients with inoperable, metastatic or persistently recurring MNTI, chemotherapy (CHT) may be considered; however, its role is still unclear. The aim of our study was to assess the efficacy of CHT in children with large, inoperable, metastatic and/or recurrent MNTI. Four such infants, treated with CHT in Polish and German centers of pediatric oncology, were presented. Additionally, a systematic literature search of the PubMed/MEDLINE, Scopus and Web of Science databases was performed, yielding 38 similar cases within the last 42 years. Neoadjuvant CHT, based mainly on the protocols for neuroblastoma, was often effective, allowing for complete delayed surgery in most cases. However, the role of adjuvant CHT in preventing recurrences after incomplete resection of MNTI remains unclear. Disseminated inoperable MNTI was almost universally associated with poor response to CHT and unfavorable outcome. Further investigations to elaborate standards of management in patients with inoperable, metastatic or persistently recurring MNTIs are necessary to improve outcomes.

Thymic tumors are epithelial tumors arising from the anterior mediastinum and constitute 0.2-1.5% of all adult malignancies but are exceptional in pediatric population. Thymic epithelial tumors (TETs) encompass a variety of histologic subtypes associated with different clinical outcomes. Due to its rarity in children, TETs' management requires a multidisciplinary approach. However, prognosis remains still poor, especially among patients with thymic carcinoma. This study presents the internationally recognized recommendations for the diagnosis and treatment of thymic tumors in children and adolescents, established by the European Cooperative Study Group for Pediatric Rare Tumors (EXPeRT) group within the EU-funded project Paediatric Rare Tumours Network - European Registry (PARTNER).

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).

Pancreatoblastoma (PBL) is a rare malignant epithelial neoplasm affecting 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 examination is required for diagnosis. The mainstay of treatment is a complete surgical resection. Inoperable and/or metastatic PBL may become amenable to complete, delayed surgery after neo-adjuvant chemotherapy. This manuscript presents the internationally 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.

As part of the European Union-funded project designated PARTN-ER, 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 non-metastatic 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 e.g. 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.

Introduction: Pediatric rhabdomyosarcoma (RMS) is a rare disease, affecting 4.5-6.0 per 1 000 000 children a year. Bladder and/or prostate (B&P) is the primary tumor site in approximately 10% of patients. Initial symptoms of B&P RMS in children may mimic more common, benign conditions such as urinary tract infections (UTIs), functional disorders, and congenital anomalies of the urinary tract. Aim: The study aims to emphasize the role of careful clinical examination and strict following the diagnostic guidelines in early detection of pediatric B&P RMS in primary care and emergency department settings. Case study: We present two male patients aged 2.5 and 3 years with embryonal B&P RMS initially manifesting as atypical and/or recurrent UTI. In both children, proper diagnoses were delayed due to careless physical examination and failure to adhere to the current guidelines for UTI management. Despite symptoms of an atypical and severe course of UTI, no imaging examinations had been performed for several weeks until dramatic deteriorations of patients’ general conditions occurred. Results and discussion: The prolonged diagnostic processes caused unnecessary suffering of both children and significant delay of oncological treatment in one. In the latter patient, bladder preservation was not possible, resulting in decreased quality of life. Conclusions: Due to its rarity, B&P RMS is infrequently included in the differential diagnosis in children with recurrent or atypical UTI. However, thorough physical examination and adherence to the guidelines of UTI management enable timely diagnosis of underlying malignancy. Early diagnosis of B&P RMS leads to a better prognosis, less intensive treatment, and improved quality of life of B&P RMS survivors.

Introduction Very little is known about the characteristics of mesothelial tumours in the paediatric population. In adults with malignant mesothelioma, the pemetrexed-based regimen with cytoreductive surgery (CRS) is a standard of care in limited tumours, but long-term survival is uncommon. Material and methods The European Cooperative Study Group on Pediatric Rare Tumors (EXPeRT) retrospectively reviewed children, adolescents and young adults (≤21 year) diagnosed with mesothelial tumours treated between 1987 and 2018. Results Thirty-three patients were identified, 15 male and 18 female patients. One patient's exposure to asbestos was documented. Primary tumour was mainly in the peritoneum (23 patients). Histology was multicystic mesothelioma of the peritoneum (MCM) (six patients) or malignant mesothelioma (MM) (27 patients). Among MM, the first-line treatment comprised preoperative chemotherapy (14 cases), surgery only (three cases), chemotherapy only (five cases), adjuvant chemotherapy (three cases) or palliative treatment (two cases). The response rate to cisplatin–pemetrexed was 50% (6/12 cases). CRS with hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) was performed in 19 patients (upfront in three, after neoadjuvant therapy in 12, or after tumour progression in six patients, including three twice). After a median follow-up of 6.7 years (range, 0–20), five-year overall and event-free survivals were 82.3% (95% CI, confidential interval ((CI), 67.8–99.9) and 45.1% (95% CI, 28.4–71.7), respectively. All patients with MCM are alive after surgery (five patients) and CRS-HIPEC (one patient). Conclusions Paediatric mesothelioma is exceptional and seems to be different from its adult counterpart with few asbestos exposures, more peritoneal primary, and a better outcome. The cisplatin–pemetrexed regimen showed promising efficacy. Relapses could be salvaged with active therapy including CRS-HIPEC.

IntroductionMarkers of inflammation such as neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and lymphocyte-to-monocyte ratio (LMR) have been found to be associated with survival in cancer patients. The aim of the current study was to establish the prognostic significance of simple laboratory markers of systemic inflammation in paediatric patients diagnosed with Wilms tumour (WT). Additionally, we aimed to compare the complete blood count (CBC) parameters of WT patients and the non-oncological control group.Material and methodsThe study group included 88 children diagnosed with WT. Clinicopathological data, as well as CBC, C-reactive protein (CRP) and lactate dehydrogenase (LDH) levels at diagnosis, were obtained. Additionally, the laboratory results of 62 healthy control paediatric patients were collected. Uni- and multivariate proportional Cox’s hazard analyses were computed to create a model predicting relapse-free survival (RFS) and overall survival (OS) in the study group.ResultsHigh CRP, LDH, and NLR were associated with a higher stage of WT and shorter RFS, whereas all parameters correlated with OS. In multivariate analysis, only LDH levels had adverse significance in predicting RFS. C-reactive protein and LMR retained their prognostic value in the multivariate model predicting OS. Comparing the WT group with controls, high LDH, high CRP, high NLR, and high PLR were associated with WT presence.ConclusionsPreoperative LDH, CRP, NLR, PLR, and LMR have significant prognostic value in patients with WT independently of age and stage. Combined low CRP and high LMR identified the group of patients with excellent OS. Patients with high LDH were characterized by the highest risk of relapse.

A simple, rapid, reliable and sensitive method based on liquid chromatography with fluorescence detection (LC-FL) for the quantification of doxorubicin (DOX) in human plasma and urine samples was developed. The assay was carried out after the solid-phase extraction procedure (SPE) with hydrophilic-lipophilic balance (HLB) cartridges, and with daunorubicin hydrochloride (DAU) used as the internal standard. Chromatographic separation was performed on a Discovery HS C18 column in isocratic elution mode, and the detection of the analytes set at excitation and emission wavelengths of 487 and 555 nm, respectively. The developed LC-FL method has been validated for accuracy, precision, selectivity, linearity, recovery and stability. The limits of detection and quantification for DOX were 0.5 and 1 ng/mL in both biological fluids, respectively. Linearity was confirmed in the range of 1–1000 ng/mL and 0.001–25 μg/mL in plasma and urine samples, respectively, with a correlation coefficient greater than 0.9994. The proposed LC-FL method is selective, precise and accurate, and has been successfully applied for drug monitoring in pediatric cancer patients treated with DOX as a component of OEPA (Oncovin (Vincristine)-Etoposide-Prednisone-Adriamycin) and IOA (Ifosfamide-Oncovin-Adriamycin) chemotherapeutic schemes. Moreover, real exposure of hospital personnel to the anthracycline drugs in plasma and urine was evaluated in clinical practice.

Purpose Selected cell-cycle regulators and extracellular matrix proteins were found to play roles in malignant peripheral nerve sheath tumor (MPNST) biology. We aimed to analyze whether initial tumor tissue expressions of survivin, p53, cyclin D1, osteopontin (OPN) and fibronectin (FN) correlate with the response to neo-adjuvant CHT (naCHT) in children with advanced inoperable MPNST. Methods The study included 26 children with MPNST (M/F 14/12, median age 130 months) treated in Polish centers of pediatric oncology between 1992 and 2013. Tissue expression of markers was studied immunohistochemically in the manually performed tissue microarrays and assessed semi-quantitatively as low and high, based on the rate of positive cells and staining intensity. Results Good response to naCHT was noted in 47.6%, while poor-in 52.4% of patients. The response to naCHT was influenced negatively by the presence of neurofibromatosis NF1 and high initial tumor tissue expression of OPN, survivin, p53 and cyclin D1. Patients with high tumor expression of either OPN, survivin or p53 and those with simultaneous high expression of ≥ 3 of the markers, responded significantly worse to naCHT, than patients, in whom expression of ≤ 2 markers were detected at diagnosis. Nearly, 85% of patients expressing ≥ 3 markers, responded poor to CHT; while 87.5% of children, expressing ≤ 2 markers, were good responders. Conclusion The initial tumor tissue expression of OPN, survivin, p53 and cyclin D1 may serve as markers to predict response to naCHT in pediatric advanced MPNST. Future studies in more numerous group of patients are needed to confirm these preliminary results.

Introduction: The improvements made in the field of pediatric oncology in the last decades due to the propensity to develop national and international cooperative protocols have not been historically seen for a number of very rare pediatric neoplasms whose common denominator lies in their having been treated as orphan diseases. For several years now, this situation has fortunately been gradually changing, and various projects dedicated to these rare diseases have been developed in several countries.Areas covered: This paper describes the schemes dedicated to rare pediatric tumors in countries with different development levels, with a particular reference to the EXPeRT (European Cooperative Study Group for Pediatric Rare Tumors) project.Expert opinion: Experience gained in recent years on rare tumors in childhood underscores the importance of cooperation and networking. Further efforts are now needed to extend research and improve the quality of patients care. The pediatric study groups that have i...

BACKGROUND Endothelial cell malignancies are extremely rare in childhood. New identification of genetic abnormalities (WWTR1:CAMTA1 translocation) helps to recognize potential therapeutic targets. Little is known about treatment and outcome of these patients. METHODS Clinical course, treatment, and outcome in patients with endothelial cell malignancies treated within the Cooperative Weichteilsarkom Studiengruppe (CWS) trials CWS-91, -96, -2002P, and the Soft-Tissue Sarcoma Registry (SoTiSaR) were analyzed (1991-2019). RESULTS Patients had angiosarcoma (AS) (n = 12), malignant epithelioid hemangioendothelioma (EHE) (n = 16), and kaposiform hemangioendothelioma (KHE) (n = 13). The median age was 5.39 years (range, 0.8-17.34); 33 patients had localized disease (LD), and 8 patients had metastatic disease. Therapy consisted of chemotherapy (CHT) (AS n = 8, EHE n = 9, KHE n = 5), interferon or new agent therapy (EHE n = 5, 2 KHE n = 2), microscopically or macroscopically complete resection (AS n = 3, EHE n = 6, KHE n = 3), and radiotherapy (AS n = 6, EHE n = 2, KHE n = 1). Two patients (KHE) had watch-and-wait strategy resulting in stable disease. Complete remission (CR) was achieved in AS (10/12; 83%), EHE (10/16; 63%), and KHE (5/13; 38%). The five-year EFS and OS for patients with AS was 64% (± 29 CI 95%) and 80% (± 25, CI 95%), with EHE 62% (± 24, CI 95%) and 78% (± 23, CI 95%), with KHE 33% (± 34, CI 95%) and 92% (± 15, CI 95%), respectively. Complete resection was a significant prognostic factor for AS, LD for EHE. CONCLUSIONS Endothelial cell malignancies in childhood have a fair outcome with multimodal treatment. New treatment options are needed for metastic disease.

Background Hodgkin (HL) and non-Hodgkin lymphoma (NHL) represent a spectrum of lymphoid malignancies that are often curable with currently applied treatment regimens; however, 15%-30% of lymphoma patients still suffer from relapsed or refractory (rel/ref) disease. Although hematopoietic stem cell transplantation (HSCT) improves outcomes of second-line therapy for lymphoma in childhood, the complication rates in this group of patients, especially infectious complications (IC), remain unclear. Objective The aim of this population-based cohort study was a retrospective analysis of incidence, epidemiology and profile of bacterial infections (BI), invasive fungal disease (IFD), and viral infections (VI) in primary or rel/ref lymphoma patients, both HL and NHL. Patients and methods We subdivided lymphoma patients into three groups: patients with primary conventional chemotherapy/radiotherapy regimens (group A), patients with rel/ref lymphoma treated with second-line chemotherapy (group B), and rel/ref lymphoma patients who underwent HSCT (group C). The medical records of the patients were biannually reported by each pediatric oncology center, and the data were analyzed centrally. Results Within 637 patients with primary lymphoma, at least one IC was diagnosed in 255 (40.0%), among 52 patients with rel/ref lymphoma 24 (46.2%) ICs were observed, and in transplanted group, 28 (57.1%) out of 49 children were diagnosed with IC (P = .151). The distribution of etiology of IC differed between the patient groups (A, B, C), with a predominance of BI in group A (85.6% vs 72.0% and 47.9%, respectively), VI in group C (9% and 16.0% vs 46.6%, respectively), and IFD in group B (5.4% vs 12.0% vs 5.5%, respectively). Overall, 500 (68.0%) episodes of bacterial IC were diagnosed in the entire group. Apart from HL patients treated with chemotherapy, in all the other subgroups of patients Gram-positives were predominant. The rate of multidrug-resistant bacteria was high, especially for Gram-negatives (41.1% in group A, 62.5% in group B, and 84.6% in group C). The infection-related mortality was comparable for each group. Conclusions The incidence of IC was comparable during first- and second-line chemotherapy and after HSCT, but their profile was different for primary or re/ref lymphoma and depended on the type of therapy.

Introduction The treatment-related mortality in currently published studies of acute lymphoblastic leukemia (ALL) in children is 2–4%, mainly due to infections. The aim of the study was to analyse the incidence, epidemiology, profile of infection and the death rate in children with ALL. Patients and methods The retrospective analysis included 1363 patients, aged 1–18 years, with newly diagnosed ALL, who were treated in 17 pediatric hematology centers between 2012 and 2017 in Poland. The patients received therapy according to the ALL IC-BFM 2002 and 2009 (International Berlin-Frankfurt-Munster Study Group) protocols. Results In our study, 726 out of 1363 (53.2%) children were reported to have a microbiologically documented bacterial infection during chemotherapy. 1511 episodes of these infection were diagnosed. A total number of 251/1363 (18.4%) children experienced a viral infection. 304 episodes were documented by PCR test (polymerase chain reaction). A fungal infection was reported in 278 (20.4%) children, including 10.1% of probable, 6.0% of proven, 83% of possible diagnosis. A higher frequency of fungal infection was noted in the recent years. In our material, the rate of death was 2.4%, mainly due to fungal infection. Conclusions Our results present the epidemiology of infectious disease in the Polish ALL patient population. The most frequent were bacterial infections, followed by fungal and viral ones. Similar to the previously published data, the mortality rate in our material was 2.4%.

The analysis of biogenic amines (BAs) and their metabolites is helpful for the diagnosis of central nervous system disorders and other neuroendocrine and cancer disturbances. In the study, a developed micellar electrokinetic chromatography method, coupled with diode array detection (MEKC-DAD), was validated to monitor levels of adrenaline (A), noradrenaline (NA), dopamine (DA), L-Tryptophan (L-Tryp) and L-Tyrosine (L-Tyr) in real human urine samples. These neurotransmitters were isolated from urine samples using solid-phase microextraction (SPME) and methanol containing 1-ethyl-3-methylimidazolium tetrafluoroborate ionic liquid as the desorption phase. The method was linear for DA, A and L-Tyr in the range of 0.5–20 μg/mL and for NA and L-Tryp in the range of 0.25–20 μg/mL. The good linearity for BAs was confirmed by the correlation coefficient (R2) from 0.9989 for A to 0.9997 for NA and L-Tryp, respectively. The validation assays for accuracy, precision, limit of detection, limit of quantification, absolute recovery, and stability of the analytes were consistent with the requirements recommended by the FDA and ICH guidelines. Next, the validated SPME-MEKC method was successfully used for the quantification of A, NA, DA, L-Tryp and L-Tyr in real human urine samples collected from pediatric patients suffering from neuroblastoma, ganglioneuroblastoma, Wilms’ tumor, rhabdoid tumor and lipoblastomatosis, as well as from healthy volunteers. Finally, the levels of BAs in cancer patients were evaluated as to whether they can be used as biomarkers of various health disturbances.

Malignant peripheral nerve sheath tumor (MPNST) in children is a rare mesenchymal malignancy developing predominantly in the setting of neurofibromatosis type 1. The prognosis in advanced MPNST is poor therefore new prognostic markers are highly needed for optimal therapeutic decisions. In many solid tumors, the bidirectional interactions between hypoxia and inflammation in the tumor microenvironment via functions of tumor-associated cells, like neutrophils, lymphocytes and macrophages, have been investigated recently. There is no data whether in MPNST hypoxic microenvironment may translate into systemic inflammation, which is a well-established factor for worse prognosis in cancer patients. Therefore, we investigated the prognostic significance of markers of tumor hypoxia and systemic inflammation in 26 pediatric malignant peripheral nerve sheath tumors (MPNST). Tumor tissue microarrays were stained for hypoxia-inducible factor-1α (HIF1A), solute carrier family 2 member 1 (SLC2A1, also known as glucose transporter 1 (GLUT1)), carbonic anhydrase 9 (CA9), and vascular endothelial growth factor A (VEGFA) and classified into low- or high-expression⁠ groups. Baseline complete blood counts and C-reactive protein (CRP) levels were collected for all cases. Neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and lymphocyte-to-monocyte ratio (LMR) were calculated from age-adjusted complete blood count parameters. Both 10-year RFS and OS were significantly lower in patients with high NLR values (17% vs. 75%, p = 0.009, q = 0.018, and 31% vs. 100%, p = 0.0077, q = 0.014, respectively). Ten-year-OS was significantly lower in patients with high expression of SLC2A1 (20.00% vs. 94%, p &lt, 0.001, log-rank), high expression of HIF1A (23% vs. 79%, p = 0.016, log-rank), and CRP higher than 31 mg/L (11% vs. 82%, p = 0.003, q = 0.009). Cox’s proportional hazard regression analysis revealed that high expression of SLC2A1 (HR = 3.31, 95% CI = 1.08–10.09, p = 0.036) and VEGFA (HR = 4.40, 95% CI = 0.95–20.34, p = 0.058) were the independent factors predicting relapse, whereas high SLC2A1 was identified as the independent risk factor for death (HR = 12.20, 95% CI = 2.55–58.33, p = 0.002). Patients with high expression of hypoxic markers and low or high NLR/CRP values had the highest events rate, patients with low hypoxic markers and high NLR/CRP had intermediate events rate, while patients with low hypoxic markers and low NLR/CRP had the lowest events rate. SLC2A1 and VEGFA are promising novel prognostic factors in pediatric MPNST. Correlations between hypoxic and systemic inflammatory markers suggest the interplay between local tumor hypoxia and systemic inflammation.

The unbalanced secretion of biogenic amines (BAs) is considered to be a relevant biochemical biomarker in the screening for neuroendocrine tumors, such as: neuroblastoma and pheochromocytoma. However, there is still a need to improve the bioanalytical procedures for BA determination in biological samples due to their instability (photo- and thermosensitivity, easy oxidation) and low concentration in the body fluids. In this study, the primary analytical challenge was to optimize the method of extraction of seven compounds from among BAs and their precursors from urine samples. Several methods based on liquid-liquid extraction (LLE) or solid phase extraction (SPE) techniques were tested. By optimization of the extraction and data analysis using chemometric tool, the dispersive liquid-liquid microextraction (DLLME) has been chosen due to its low solvents consumption, high efficiency of isolation, preconcentration and suitable clean-up of biological matrix. Further, α-cyclodextrin-modified micellar electrokinetic chromatography (MEKC) with ultraviolet detection (UV) has been applied for quantification of the analyzed biologically active compounds with limits of detection (LOD) and limits of quantification (LOQ) at 0.15 and 0.5μgmL-1, respectively. Finally, the optimized and validated DLLME-MEKC-UV method has been employed for the analysis of real urine samples, obtained from 6 children with neuroendocrine tumors and 6 healthy children. It was stated that concentrations of BA could serve to differentiate between the patients and healthy children. This pilot study indicates that the elaborated fast and sensitive DLLME-MEKC-UV method for determination of panel of biomarkers could be successfully applied in everyday clinical practice to help to confirm the clinical diagnosis of neuroendocrine tumors in children.

The coexistence of two rare conditions in the same patient is a challenge. This paper reports on a case of a 14.5-year-old boy diagnosed concurrently with latent tuberculosis infection (LTBI) and a nasopharyngeal carcinoma (NPC). The initial symptom was the enlargement of the right cervical lymph nodes. Ultrasound imaging was initially suggestive of LTBI. A positive skin tuberculin test and positive serological examination with interferon gamma release assays were conducted. However, the histopathological examination of the lymph nodes biopsy did not reveal acid-fast bacilli. Therefore, the diagnosis of LTBI was set. Histopathological examination of lymph nodes biopsy showed metastases of NPC. The primary tumour was revealed by magnetic resonance imaging in the nasopharynx. Based on the results of the positron emission tomography combined with computer tomography, the patient was classified to the stage IVB according to clinical classification of head and neck carcinomas (UICC/AJCC TNM 7 from 2009). Due to an advanced stage of NPC, intensive chemotherapy followed by a combined chemo-radiotherapy was initiated according to NPC-2003-GPOH protocol. Concurrently a chemoprophylactic treatment of tuberculosis infection, using isonicotinylhydrazide (INH) and rifampicin (RMP) was conducted. During treatment hepatotoxicity stage IV WHO was noted, which did not allow for the continuation of chemotherapy. Anti-tuberculosis medications were identified as the cause of this complication. Withdrawing INH and RMP led to normalisation of aminotransferase levels and enabled further oncological treatment. Treatment was finished and the patient currently remains cancer-free. A three-month period of anti-tuberculosis chemoprophylaxis was sufficient. In imaging investigations, there are no signs of tuberculosis.

Exosomal heat shock proteins (Hsps) are involved in intercellular communication both in physiological and pathological conditions. They play a role in key processes of carcinogenesis including immune system regulation, cell differentiation, vascular homeostasis and metastasis formation. Thus, exosomal Hsps are emerging biomarkers of malignancies and possible therapeutic targets. Adolescents and young adults (AYAs) are patients aged 15–39 years. This age group, placed between pediatric and adult oncology, pose a particular challenge for cancer management. New biomarkers of cancer growth and progression as well as prognostic factors are desperately needed in AYAs. In this review, we attempted to summarize the current knowledge on the role of exosomal Hsps in selected solid tumors characteristic for the AYA population and/or associated with poor prognosis in this age group. These included malignant melanoma, brain tumors, and breast, colorectal, thyroid, hepatocellular, lung and gynecological tract carcinomas. The studies on exosomal Hsps in these tumors are limited; however; some have provided promising results. Although further research is needed, there is potential for future clinical applications of exosomal Hsps in AYA cancers, both as novel biomarkers of disease presence, progression or relapse, or as therapeutic targets or tools for drug delivery.

The aim of the work was to develop a simple, sensitive and accurate liquid chromatography with fluorescence detection (LC-FL) method for the determination of epirubicin in human urine and plasma. Solid phase extraction with HLB cartridges and mixture of dichloromethane:2-propanol:methanol (2:1:1, v/v/v) as the eluent, was used to prepare the samples. The chromatographic analysis was carried out on a Synergi Hydro-RP column with a mobile phase consisting of 40 mM phosphate buffer (pH 4.1) and acetonitrile (69:31, v/v). Epirubicin was monitored at 497 nm and 557 nm for excitation and emission wavelengths, respectively. Validation data confirmed that the limit of detection and limit of quantification was 0.25 ng/mL and 0.5 ng/mL in both matrices. Next, the optimized LC-FL method was applied to determine the level of epirubicin in real samples taken from a 19-year-old patient with metastatic alveolar rhabdomyosarcoma (RMA) to create a drug profile. Plasma and urine samples were collected for 24 h after the end of a 6-hour infusion of epirubicin. The obtained results confirmed that the optimized and validated LC-FL method can be successfully used in drug monitoring therapy, pharmacokinetic and clinical studies. Moreover, the current work is also drawing attention to the relatively high level of epirubicin in the patient urine, which requires compliance with the safety rules in contact with this biological fluid by both medical staff and others, e.g. family members.

Objectives: The analysis of epidemiology, risk factors and outcome of infections in children with malignant bone tumors (MBT) undergoing chemotherapy. Methods: In this retrospective nationwide multicenter cross-sectional study, a total number of 126 children with MBT including 70 with Ewing sarcoma (ES) and 56 with osteosarcoma (OSA) were screened for infections over a period of 72 consecutive months. Results: The risk of infection was 7.15-fold higher in patients with ES as compared to the OSA group, especially concerning bacterial infections (4.1-fold increase risk). Bacterial infections occurred in 74.3% patients with ES and in 41.1% with OSA. The median time from diagnosis to first infection was 4.9 months. 33.0% of bacterial episodes were diagnosed as bloodstream (BSI), 31.1% as gastrointestinal tract, 30.1% as urinary tract infection. Infection-related mortality (IRM) from bacterial infection was 6% and 15% in ES and OSA patients, respectively. Cumulative incidence was 7.1% for invasive fungal disease and 6.3% for viral infections. The only significant risk factor for IRM was time to infection ≥5 months since the beginning of chemotherapy. All patients who have died from infection had BSI and were in neutropenia. Conclusions: Infections in the children with MBT in our study occurred with high frequency, especially in patients with ES. The most frequent were bacterial infections, while fungal and viral infections were episodic. Among the bacterial infections, bloodstream, urinary tract and gastrointestinal tract infections occurred with similar frequency. All deceased patients died due to BSI. Bacterial infection occurring ≥5 months since the beginning of chemotherapy was a risk factor for death.

The main aim of the presented study was to develop a reliable and non-time-consuming method for the simultaneous separation of biogenic amines (BAs) like noradrenalin, adrenalin, dopamine and their main metabolites - homovanillic acid (HVA), vanillylmandelic acid (VMA), 3,4-dihydroxyphenylacetic acid (DOPAC) - in urine samples. To achieve this, the validated α-cyclodextrin (α-CD)-modified micellar electrokinetic chromatography method with DAD was proposed. The optimized separation parameters were as follows: background electrolyte was composed of 10mM sodium tetraborate decahydrate, 30mM SDS, 15% (v/v) methanol and 25mM α-CD, adjusted to pH 9.36 with 1N NaOH; uncoated fused silica capillary (75μm i.d.×60.2cm length); λ=200nm; injection time 5s, applied voltage 25kV; temperature 25 (±0.1)°C. Next, the developed MEKC method was practically applied to evaluate the levels of selected acidic metabolites of catecholamines like HVA, VMA and DOPAC in urine samples collected from patients diagnosed with neuroblastoma (NB), melanotic neuroectodermal tumor of infancy (MNTI).

Infections in children treated for hematological malignancies pose a direct threat to life and are one of the most common causes of treatment failure in this group of patients. Unequivocal diagnosis at the early stages of infection together with an appropriate and timely treatment may be often difficult due to poor manifestation and nonspecific clinical symptoms of the infection progress. Inflammatory markers make a useful diagnostic tool for this purpose. They significantly help to diagnose, monitor, stratify and predict the outcome in severe infections. This article describes selected biomarkers, both those commonly used in clinical practice, such as erythrocyte sedimentation rate, C-reactive protein, procalcitonin as well as less common like IL-6, IL-8 and moreover one promising novel marker – pentraxin 3. The authors emphasize their diagnostic value, clinical usefulness and significance in the treatment efficacy monitoring.

Langerhans cell histiocytosis (LCH) is a rare disease of unknown etiology and varied picture and clinical course. The intensity and the outcome of LCH treatment depend on the amount and type of the affected organs, their dysfunction and age of the patient. In this paper we present the diagnostic difficulties in a 19-month-old girl with multisystem LCH, manifesting mainly by persistent fever, deep anemia, hepatosplenomegaly and lymphadenopathy, coexisting with EBV infection and urinary tract infection. On diagnosis, LCH was suspected once the bone lesions were detected on CT scans, which, however, were not confirmed in the bone scintigraphy. Histopathological diagnosis of LCH was based on the histopathological examination of the cervical lymph node, in which CD1a expression was detected. Myelogram morphologically was assessed as normal; however, bone marrow smears were respectively found to express CD1a. The patient received aggressive and long-lasting treatment according to the protocol LCH in 2009, yielding a complete clinical remission of LCH.

Although childhood rhabdomyosarcoma typically metastasizes to lungs, various processes may mimic metastatic etiology. Described herein is the case of an 8½-year-old boy with orbital embryonal rhabdomyosarcoma (RME) in whom three small foci were detected within both lungs on computed tomography. The lesion number and size, however, did not fulfil the Cooperative Weichteilsarkom Study Group 2006 protocol criteria for lung metastasis. Chemotherapy for localized RME produced primary tumor regression and vanishing of the left lung lesion. Two lesions in the right lung remained unchanged. On thoracoscopy multiple minute nodules disseminated in both lungs were detected. Histopathology excluded RME spread but indicated anthracosis in the lung parenchyma and intrapulmonary lymph nodes. Heavy smoking by parents and previous home furnace combustion appeared to be predisposing factors. Uncommon non-malignant intrapulmonary diseases, including anthracosis, should be considered when staging pediatric cancer.

Introduction Cutaneous melanoma is rare in childhood and published studies have mainly been retrospective single-institution series or small case series. Given the absence of clinical protocols dedicated to pediatric melanoma, the treatment approach is generally extrapolated from the ones applied to adults. Methods Coordinated by the European Cooperative Study Group for Pediatric Rare Tumors (EXPeRT), this study collected patients prospectively registered between 2002 and 2012 under national cooperative projects dedicated to rare pediatric tumors in Italy, Poland, Germany, and France. Additional cases were collected from dermatology registries in Germany and Israel. Results A total of 219 patients aged 0-18 years (median 14.4) were included in the analysis. Sentinel lymph node biopsy was performed in 112 patients (76% of those with Breslow thickness > 0.75 mm) and was positive in 37.5%. Systemic therapy was used in 33 cases. In stage III cases, survival rates were similar for patients who received (23 cases) or not (21 cases) adjuvant therapy. For the whole series, 3-year overall and disease-free survival rates were 91.4% and 84.0%, respectively (median follow-up 41.8 months). Tumor site, tumor stage, and ulceration influenced survival rates. Patients treated by pediatric oncologists (n = 140) were more likely to have advanced disease than those treated by dermatologists (n = 79). Discussion This study would suggest that the clinical history of melanoma in children and adolescents might resemble that of adult counterpart. Cooperative efforts are needed to make new drugs more readily available to pediatric patients to increase the outcome of patient with advanced disease.

Objective: Osteopontin (OPN) is aglyco-phosphoprotein, involved in tissue remodeling, inflammation and boneresorption. In various adult neoplasms OPN was shown to correlate with cancer progression, invasiveness and metastasis. Aim: to define the role of OPN in malignancies of children and young adults. Material and methods: a structured PubMed and Google Scholar literature analysis based on reports published in English between I'1995 and XII'2015. Results: 14 studies (four on hematological malignancies, four on bone tumors, three on CNS tumors, two on dendritic proliferative diseases and one on renal tumors) were identified. Higher levels of serum and cerebro-spinal fluid OPN protein, and high expressions of OPN mRNA and SPP1 gene were present in more aggressive and advanced childhood malignancies. In children with acute lymphoblastic leukemia with CNS involvement and with atypical teratoid/rhabdoid tumor (AT/RT) and medulloblastoma, the serum and CSF OPN levels reflected tumor bulk and response to therapy, while in children with AT/RT and multisystem Langerhans cell histiocytosis with high-risk organs involvement, high OPN serum levels correlated with poorer survival. To the contrary, in osteosarcoma, high OPN mRNA and SPP1 gene expressions correlated with better survival and good response to chemotherapy. Conclusions: The literature review suggests that OPN may play important roles in the development and progression of selected cancers of children and young adults, including acute lymphoblastic leukemia, malignant gliomas, AT/RT and Langerhans cell histiocytosis. However, limited number of published studies prevents from definite concluding on the clinical utility of OPN as a marker of diagnosis, prognosis and treatment monitoring in these pediatric cancers. Further studies performed in more numerous groups of patients with particular types of cancers of children and young adults are warranted.

Hepatic angiosarcoma is a rare, aggressive, malignant neoplasm with fewer than 50 cases reported in children. Prognosis is poor, with a minority surviving beyond 2 years after diagnosis. We report eight cases of pediatric hepatic angiosarcoma, diagnosed at a mean age of 3 years. Seven were initially diagnosed with an infantile hepatic hemangioendothelioma (IHHE) or hemangioma and the eighth with a "vascular tumor." Two patients, who received liver transplant, survived. We suggest hepatic hemangiomas can rarely transform into angiosarcomas and a subset of IHHEs (Type II) are actually a low-grade form of angiosarcoma rather than a benign lesion.

Neuroblastic tumors (NB) are the most common extracranial pediatric neural crest-derived tumors, with a dismal outcome in a substantial group of patients. The study objective was to evaluate the patho-clinical correlations and prognostic impact of the proliferation index (PI) measured with two markers, Ki67 and topoisomerase II alpha (Topo2A), in a NB series. A retrospective analysis of 118 NB from 103 consecutive patients was performed. Analyzed data included tumor stage, histology, mitosis/karyorrhexis index (MKI), MYCN status, and overall survival. Patients' median follow-up period was 50 months. Ki67 and Topo2A PI were assessed immunohistochemically on representative tissue slides in hot spots. PI for Ki67 was in the range 0-72% (median 18%) and for Topo2A was in the range 0-58% (median 20%), being strongly interrelated (r = 0.83). Median PIs with both markers were lower in children older than 18 months (> 18 m) than in the younger patients, with p = 0.0002 and p = 0.005 respectively. Higher Ki67 and Topo2A correlated with metastatic stage, higher MKI, and inversely with increasing tumor differentiation. The cut-off values of PI Ki67 > 30% and Topo2A > 20% were associated with fatal outcome of the disease. In the subgroup of patients > 18 m already at cut-offs Ki67 > 10% and Topo2A > 15% a fatal outcome was predicted by Kaplan-Meyer analysis. Cox regression analysis identified cumulative PI (joint Ki67 and Topo2A index) as an independent prognostic factor. The conclusion is that the proliferation index measured with the examined markers provides substantial prognostic information in NB, especially in infants. PI assessment should become an element of the standard pathological checkup list of NB tumors.

Objectives The aim of this retrospective international analysis was to evaluate the role of risk factors in pediatric patients with adrenocortical carcinoma (ACC) observed in European countries (2000–2013) in an attempt to identify factors associated with poor prognosis. Procedures Data were retrieved from databases of Germany, France, Poland, and Italy, which form the European Cooperative Study Group on Pediatric Rare Tumors (EXPeRT). Patients were less than 18 years old, with at least one of the following tumor-related risk factors: metastases, volume more than 200 cm3, Cushing syndrome, vascular or regional lymph node invasion, initial biopsy, or incomplete excision. Role of patients’ age was also evaluated. Results Eighty-two patients were evaluated: 62 with localized disease and 20 with metastases. The 3-year progression-free survival (PFS) and overall survival (OS) were 39% and 55% for the whole population, respectively, and 51% and 73% for localized diseases, respectively. Concerning the whole population, PFS and OS were influenced by distant metastases, tumor volume, lymph node involvement, age, and presence of two or more risk factors. Factors significant only at OS were vascular involvement and incomplete surgery. At multivariable analysis, the main factors at PFS were volume more than 200 cm3 (hazard ratio [HR]: 2.6, 95% confidence interval [CI]: 1.18–5.70) and presence of distant metastases (HR: 8.26, 95% CI: 3.49–19.51). The OS was significantly influenced by the presence of metastases (P < 0.0001). Concerning patients with localized tumors, the only significant prognostic factor was volume more than 200 cm3 with a HR of 4.38 (95% CI: 1.60–12.00) for PFS and of 3.68 (95% CI: 1.02–13.30) for OS. Conclusions Distant metastases and large tumor volume were the main unfavorable prognostic factors. Presence of two or more factors related to ACC was associated with an aggressive behavior of disease.

Purpose. Langerhans cell histiocytosis (LCH) is an infrequent disorder of unknown origin associated with histiocytic proliferation. The bones' involvement (including cranial bones) is the most frequent manifestation of pediatric LCH. Imaging of skull LCH is based predominantly on conventional radiography, CT, scintigraphy, and sometimes MRI. The aim of the study was to investigate the role of sonography (US) in the diagnosis and monitoring of bone lesions in children with localized LCH of the skull. Methods. Twenty-seven children (15 boys/12 girls, mean age 6.1 years) were diagnosed between 1991 and 2005 in the Department of Pediatrics at the Medical University of Gdansk, Poland. Fourteen children (52%) had localized LCH of the skull. Results. All lesions of the skull visible on CT were visualized on US examination. Overall, 30 focal lesions were revealed by US. The largest bone lesions were accompanied by changes within the adjacent soft tissues. CT revealed 26 lesions, the location and size of which corresponded to the lesions seen on US, but soft-tissue changes adjacent to the bony lesions were difficult to visualize. Conclusions. The US appearance of focal LCH lesions in cranial bones in children is not pathognomonic, but is characteristic enough to suggest an initial diagnosis and to monitor the evolution of lesions during treatment. US should be considered an additional diagnostic tool for LCH of the skull. Although US of localized LCH cannot replace CT, it could reduce the number of follow-up CT examinations. © 2012 Wiley Periodicals, Inc. J Clin Ultrasound, 2013

Many components of oncologic treatment increase serum sIL-2Rα level, which may falsely suggest a relapse. We tried to establish whether granulocyte colony stimulating factor (G-CSF) and central vein catheter (CVC)-related sepsis increase serum sIL-2Rα level to values on relapse of childhood soft tissue sarcomas (STS) and how to distinguish real relapse from a "false" one. Serum sIL-2Rα, B2-M, LDH, CRP and ESR levels and rates of markers' elevated values were determined prospectively in 18 STS children: pre-treatmently (ST1), in complete remission (CR; ST2), in CR during G-CSF therapy (ST3), in CR during CVC-related sepsis (ST4), on relapse (ST5) and after treatment (ST6) and once in 50 healthy pediatric controls. It appeared that pre-treatment serum sIL-2Rα, LDH, CRP and ESR but not B2-M declined significantly with remission (ST2) achievement. At ST5 sIL-2Rα, B2-M, LDH and CRP increased from ST2 to ST1 values. SIL-2Rα levels at ST3 and ST4 rose significantly in all patients from ST2 to ST1 and ST5 values. At ST3 also serum LDH and B2-M increased to values at ST1 and ST5 and exceeded significantly those at ST2 and ST4. At ST4 CRP but not B2-M and LDH, rose significantly in most patients to values at ST1 and ST5. Thus, serum sIL-2Rα monitoring in pediatric STS reflects well response to chemotherapy unless samples are collected during G-CSF therapy or CVC-related sepsis. Determination of serum B2-M, LDH and CRP together with sIL-2Rα may help to distinguish between "real" relapse and "false" sIL-2Rα increase due to G-CSF administration or CVC-related sepsis.

HER receptor family plays an important role in normal embryonic development and is involved in pathogenesis and progression of some types of cancer. Neuroblastic tumors (NT) are common pediatric neoplasms with a poor outcome in a significant number of patients. The biological and prognostic role of HER family in NT is not well established. In the current study we evaluated HER1-4 receptors expression, their prognostic significance and clinicopathological correlations in a series of 103 NTs by immunohistochemical assessment of HER1-4 expression and FISH analysis of EGFR and HER2 copy number status. HER receptors are commonly expressed in NT but it was not due to EGFR or HER2 amplification. EGFR, HER2 and HER4 show correlation with tumor histology. It seems that these receptors take part in neuroblastic cell differentiation and Schwannian stroma development. EGFR and HER2 positivity are more frequently found in favorable histological risk group of tumours (P = 0.004 and P = 0.01 respectively) while high expression of HER4 is significantly more often found in patients with metastatic disease (P = 0.03). Moreover tumors with HER2 polysomy were more often found in children ≤ 18 months, with localized disease, and favorable histological group. Our study showed that the role of HER family members in NT biology is interrelated and complex but their expression level may present a novel prognostic factor for NT patients outcome.

The rarity of malignant and intermediate vascular tumors in children means that little is known about their clinical course, optimal treatment, and variables predicting survival. A total of 32 children with malignant vascular tumors (14 angiosarcomas [AS], 5 epithelioid hemangioendotheliomas, and 13 intermediate vascular tumors, including other hemangioendotheliomas plus adult-type hemangiopericytomas), registered in the German and Polish Paediatric Soft Tissue Sarcomas Study Groups, were treated following the Cooperative Weichteilsarkom Studiengruppe (CWS)-81, -86, -91, and -96 protocols. Male sex, AS histology, tumor size >5 cm, and T2 invasiveness were independent predictors of inferior 5-year overall survival, while AS histology and T2 invasiveness were predictors of inferior 5-year event-free survival. AS histology was the most important negative prognostic factor for overall survival and event-free survival. Completeness of primary tumor excision was a good prognostic factor for survival in univariate, but not multivariate, analysis. Local therapy (radiotherapy and delayed surgery) were provided to the minority of patients (28% and 38%, respectively) late in the course of disease (after a mean of 9 and 6 months, respectively) and did not prevent local relapses. Response to systemic treatment was poor (44%) and did not prevent local and distant relapses. The clinical course and outcome in childhood epithelioid HE seems to be similar to intravascular tumors and less aggressive than AS. RTX and delayed surgery should be performed more frequently and earlier in the disease course. An urgent need for modification of systemic therapy is needed because of the development of many metastatic and/or combined relapses and poor response to classic chemotherapy. The problem of effective therapy for childhood AS is the most appaling: 13 of 14 patients died of progression despite multimodal treatment.

The study was to determine clinical utility of serum soluble interleukin (IL)-2 receptor (sIL-2Ralpha), beta(2)-microglobulin (beta(2)-M), lactate dehydrogenase (LDH) and erythrocyte sedimentation rate (ESR) as markers of diagnosis, prognosis and monitoring of response to therapy in childhood Hodgkin's lymphoma (HL). The markers were measured prospectively before treatment and in complete remission (CR) during and after therapy in 30 children with HL (F/M:19/11; median age: 11.3 years) and once in 50 healthy children (F/M: 24/26; median age: 8.7 years). Median pretreatment levels of all analysed markers were significantly higher than in healthy controls. Increased pretreatment sIL-2Ralpha, LDH and ESR correlated with bulky disease; sIL-2Ralpha, beta(2)-M and ESR with presence of B symptoms and sIL-2Ralpha and LDH with advanced HL stages. There was a correlation between sIL-2Ralpha and LDH and between beta(2)-M and ESR. The levels and rates of elevated markers reflected well the response to chemotherapy, decreasing significantly when patients achieved CR and further on with therapy continuation. Since all patients survived thus the markers' value to predict the outcome was not established. Serum sIL-2Ralpha, beta(2)-M, LDH and ESR may act as markers for diagnostics and used in monitoring of therapy effectiveness in childhood HL. The markers were also increased in subgroups of patients with unfavourable clinical features; however, small sample size of the study did not allow to draw conclusion on their prognostic roles. We were also not able to establish the influence of markers on event free survival and overall survival because all children survived independent of initial clinical characteristics and pretreatment levels of sIL-2Ralpha, beta(2)-M, LDH and ESR.