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Cytokines are responsible for maintaining homeostasis as cell growth, differentiation, migration and apoptosis mediators. They play a pivotal role in immune responses to inflammatory reactions. In oncological diseases, the cross-talk between cells of the immunological system and cells of the tumour microenvironment is led by cytokines. Also, the overproduction of cytokines may change the tumour microenvironment and stimulate tumour development and growth. To test whether pro-inflammatory cytokines or associated with them transcription factor levels are changed in a group of 53 paediatric cancer patients, serum levels of IL-1β, IL-6, TNF-α and NF-κB were assessed and compared to measures in 25 healthy controls. Increased levels of IL-6 were found among patients in active oncological treatment (P=0.002) but not among patients whose treatment was completed. Our data suggest that IL6, but not IL-1β, TNF-α and NF-κB, is elevated as a result of the immune response in the microenvironment around the tumour and in blood cancers, among patients who were not infected at the time of blood collection. Thus, IL6 levels might serve as a potential biomarker of oncohematological diseases.

Nodular Lymphocyte Predominant Hodgkin Lymphoma (NLPHL) is a rare clinical entity. To investigate NLPHL clinical course and treatment a survey was performed within Polish Pediatric Leukaemia/Lymphoma Study Group (PPLLSG) participating centers. A questionnaire was sent to all participating centers and analysis of clinical data was performed. From 2010 to 2019, 19 pediatric patients with confirmed NLPHL were registered in Poland. Median age of patients was 12.2 (5.5 - 17.8) years. NLPHL occurred mainly in males (

The effect of age on the incidence of late sequelae that occur after anticancer treatment in childhood is still not fully elucidated. In this multicenter study of long-term survivors diagnosed before age of three, we investigated the prevalence of late effects many years after treatment.The study group (n = 561) was selected from the Polish National Childhood Cancer Survivors Registry (n = 1761) created in 2007. A survivor was defined as an individual who has survived at least 5 years after completion of anticancer treatment. All children were diagnosed between 1991 and 2016, mean age at diagnosis was 1.82 years (range 0.03-2.99) and median follow up time - 9.85 years (range 5.0-23.6). They were treated in accordance with international protocols approved by the Polish Pediatric Leukemia and Lymphoma Group and Polish Solid Tumor Group. Chemotherapy alone was used in 192 (34.2%), chemotherapy and radiotherapy - 56 (10%), chemotherapy and surgery - 176 (31.4%), chemotherapy, radiotherapy, and surgery - 79 (14.1%), and surgery alone in 58 patients (10.3%).Of all patients enrolled to the study, only 94 (16.8%) had normal function of all organs. Seventy-six (13.5%) children developed dysfunction in one organ, another 83 (14.8%) had symptoms or complaints suggestive of dysfunction in two organs or systems, 88 (15.7%) had abnormalities in three organs, and 220 (39.2%) had at least four or more dysfunctions. In the entire study group, dysfunctions most frequently (20% of cases) involved the following organs/systems: circulatory - 21.8%, urinary - 30.8%, gastrointestinal - 20.8%, immune - 23.5%, vision - 20.7%, hearing - 21.8%, and oral and masticatory dysfunction - 26.9%. We did not find any significant differences in organ dysfunction between children diagnosed under the age of 1 and those diagnosed at the age of 1-3, except for a lower incidence of thyroid abnormalities (p = 0.007) and the higher prevalence of liver dysfunction in youngest patients. In the subset with longer follow-up period (10 years) more frequent thyroid abnormalities (p = 0.019), male (p = 0.002) and female (p = 0.026) gonads dysfunction, as well as musculoskeletal problems (p 0.001) were observed. Among subjects who received radiotherapy compared to those who did not, short stature (p = 0.001), and dysfunction of the following systems/organs - circulatory (p = 0.049), urinary (p = 0.012), thyroid gland (p 0.0001), nervous (p = 0.007), immunological (p = 0.002), liver (p = 0.03), dental or chewing difficulties (p = 0.001), hearing (p = 0.001) and musculoskeletal (p = 0.026) were more frequently reported. When multimodal therapy was applied (chemotherapy, radiotherapy, and surgery) a higher incidence of short stature (p = 0.007), urinary system disorders (p 0.0001), thyroid dysfunction (p 0.0001), hearing loss (p 0.0001), and skin problems (p = 0.031) were observed.This study confirms that radiotherapy and some specific toxicity of cytostatics are the most important factors affecting organ function. Apart from a higher incidence of liver dysfunction in the youngest patients, there were no significant differences in organ and system toxicities between children diagnosed under the age of 1 and those diagnosed at the age of 1-3. We have shown that this group requires systematic, careful and long-term follow-up.

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.

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

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

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.

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.

Amino acids (AAs) play a crucial role in cancer cell metabolism. Levels of 22 plasma AAs at the time of diagnosis and after treatment were established among 39 pediatric cancer patients and 33 healthy children. Glutamic acid levels decreased and tryptophan levels increased during treatment. Cancer patients presented significantly lower levels of glutamine and leucine post-treatment while levels of 12 other AAs were higher comparing to controls. Results suggest that plasma free AA profile may serve as a prognostic biomarker. Electronic supplementary material The online version of this article (doi:10.1007/s00726-020-02910-8) contains supplementary material, which is available to authorized users.

Cancer is one of the major health problems of the modern world. With the development of novel biochemistry and analytical instrumentation, precancer diagnosis has become a major focus of clinical and preclinical research. Finding appropriate biomarkers is crucial to make an early diagnosis, before the disease fully develops. With the improvement of precancer studies, cancer biomarkers prove their usefulness in providing important data on the cancer type and the status of patients’ progression at a very early stage of the disease. Due to the constant evolution of pediatric cancer diagnosis, which includes highly advanced molecular techniques, the authors have decided to focus on selected groups of neoplastic disease and these include brain tumors, neuroblastoma, osteosarcoma and Hodgkin lymphoma.

This paper details the quantitative analysis of neurotransmitters, including dopamine (DA), norepinephrine (NE), epinephrine (E), and serotonin (5-HT), along with their respective precursors and metabolites in children with solid tumors: Wilms' tumor (WT) and neuroblastoma (NB). A panel of neurotransmitters was determined with the use of dispersive liquid-liquid microextraction (DLLME) technique combined with liquid-chromatography mass spectrometry (LC-MS/MS) in plasma samples obtained from a group of pediatric subjects with solid tumors and a control group of healthy children. Next, statistical univariate analysis (t-test) and multivariate analysis (Principal Component Analysis) were performed using chromatographic data. The levels of tyrosine (Tyr) and tryptophan (Trp) (the precursors of analyzed neurotransmitters) as well as 3,4-dihydroxyphenylacetic acid (DOPAC) (a product of metabolism of DA) were significantly higher in the plasma samples obtained from pediatric patients with WT than in the samples taken from the control group. Moreover, statistically significant differences were observed between the levels of 5-HT and homovanillic acid (HVA) in the plasma samples from pediatric patients with solid tumors and the control group. However, elevated levels of these analytes did not facilitate a clear distinction between pediatric patients with WT and those with NB. Nonetheless, the application of advanced statistical tools allowed the healthy controls to be differentiated from the pediatric oncological patients. The identification and quantification of a panel of neurotransmitters as potential prognostic factors in selected childhood malignancies may provide clinically relevant information about ongoing metabolic alterations, and it could potentially serve as an adjunctive strategy in the effective diagnosis and treatment of solid tumors in children.

Aim: Childhood cancer remains one of the main cause of death in the pediatric population. Amino acids (AAs) level alterations in plasma are considered to play a role in carcinogenesis and further course of the disease. Methods: Seventy-seven children with cancer, including 47 with hematological and 30 with solid tumors were enrolled in this study and compared with healthy children. Twenty-two plasma-free AAs were determined by HPLC with fluorometric detection. Results: The results revealed significant decrease in glutamine levels for oncological patients and significant increase in aspartic acid, glutamic acid, asparagine, serine, citrulline, alanine, GABA, tryptophan, methionine, valine, phenylalanine and isoleucine levels in cancer children versus control. Conclusion: Plasma-free AA profile as a biomarker, which combines metabolic and clinical data, as an innovative and interdisciplinary approach, may allow for faster detection of tumor occurrence, and in the future for monitoring patient during treatment, and possible prediction of cancer recurrence.

Anti-cancer treatment in children can deteriorate gonadal function and affect future fertility. We analyzed the hormonal markers of gonadal function in adolescent leukemia survivors, treated in childhood with different levels of aggressiveness. We analyzed hormone levels in 69 adolescents and young adults, leukemia survivors stratified into standard (SR), intermediate (IR), and high (HR) risk groups, and in 80 healthy controls (38 men) at a similar age. We assessed follicular stimulating hormone (FSH), luteinizing hormone (LH), and inhibin B in the whole group, testosterone in males, and E2 and anti-Mullerian hormone (AMH) in females. Males classified into HR group presented, in comparison to control, higher levels of FSH, LH, lower inhibin B, and normal testosterone, whereas in SR and IR group, the hormonal values were comparable to the control. In females, in all risk groups, the levels of FSH, LH, E2, and inhibin B were comparable with the control, but the mean AMH levels were slightly lowered. We did not observe the effect of prophylactic cranial irradiation (12 or 18 Gy) or the time of treatment (before vs. during puberty) on hormone levels. In females, a positive correlation was found between the time interval after the end of treatment and AMH levels. Male leukemia survivors having undergone more intensive chemotherapy show the symptoms of disturbed spermatogenesis and need to be followed-up in the future. Women, irrespective of the risk group, can develop the signs of preterm ovarian insufficiency. They should be informed about the impact of the treatment on gonadal function.

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...

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.

In the last 40 years, considerable progress was made in the treatment of childhood cancer. Nearly 80% of children achieve long-term clinical remission or are permanently cured. This improvement is however not without sacrifice. This is the first Polish study analyzing the general health status and epidemiology of organ late effects in the cohort of Polish childhood and adolescent cancer survivors monitored by doctors and registered in the on-line national database for late effects (N = 1761). This tool collects information on previous therapy and current health status (medical history, physical examination, laboratory tests) of cancer survivors. The survivors are invited to take part in the follow-up examination 5 years after the end of treatment. In the study group, 207 survivors (11.75%) had no complaints; whereas in 1554 cases (88.25%), one or more symptoms/complaints suggesting organ dysfunction were reported. In the whole group, the circulatory problems were most common (31.7%); more than 20% of survivors presented complaints or abnormal function of the urinary tract and had skin, dental, skeletal/muscular problems, or difficulty with chewing. Obesity or short stature alone (21.4%) and a variety of endocrine problems (short stature, obesity, thyroid dysfunction, and gonads toxicity) were present in 323 patients (118 females 15.0% and 205 males 21.0%). Gonadal dysfunction, as the only problem, occurred in 75 girls (9.6%) and 131 boys (13.4%). In our cohort, severe or life-threatening health conditions (3 and 4 grade according to toxicity criteria) were present in low percentage, i.e., 0.2% in the circulatory system, 0.3% in the respiratory tract and, 0.7% in kidney insufficiency. Conclusion: Our findings indicate that many childhood cancer survivors demonstrate numerous complaints, even a short time after treatment, suggesting the importance of regular follow-up examinations in subsequent years. What is Known: • Contemporary studies indicate that a significant number of childhood cancer survivors present different long-term side effects which influence their quality of life. What is New: • This is the first nationwide study performed in the largest cohort of Polish childhood cancer survivors concerning general health status and frequency of organ dysfunction.

This review summarizes the achievement and role of supplemental therapy in prevention of severe complications following anticancer treatment.A promising supplemental therapy agent in the field is glutamine. Glutamine (Gln) is an amino acid that is produced in physiological conditions in human cells. However, in pathological states, glutamine production is often insufficient. In the clinical setting, glutamine has been shown to decrease metabolic side effects resulting from cancer treatment and to improve patient outcome. In clinical trials, the administration of glutamine was shown to benefit specific groups of patients, including oncology patients. The MEDLINE database PubMed search in English using the key words 'glutamine supplementation', 'parenteral and oral glutamine', 'glutamine in cancer' was performed. Only prospective randomized studies on cancer patients between 2005 and 2011 and ongoing researches from the US National Institute of Health trial database and EU Clinical Trials Register were taken into consideration.In the opinion of authors, the optimal dose and route of administration of glutamine needs to be determined in future studies. This review provides an overview of the use of glutamine as supplemental therapy in patients with cancer, including its use in pediatric patients.

Aim of the study: The goal of this study was to evaluate the activities of ery throcyte superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), and the levels of glutathione (GSH) and is chemia-modified albumin (IMA), as po tential markers in different histopatho logic types of pediatric neoplasms. No studies on this subject have been re ported to date. Material and methods: SOD, GSH-Px, GSH, and IMA were measured before on cologic treatment in 129 children with neuroblastoma (NB), soft tissue sarco mas (STS), brain tumors, Hodgkin’s dis ease (HD), and acute leukemias, and in 30 healthy controls. Results: The statistical significance of SOD was observed in patients with brain tumors (median 1840.2 U/g Hb, p= 0.0500). The level of GSH was significantly higher in pa tients with NB (median 6.38 U/g Hb, p= 0.0031) and leukemias (5.16 U/g Hb, p = 0.0200). IMA was statistically sig nificant in cases of STS, NB, and leukemias compared to healthy children ( p = 0.0244, p = 0.0069, and p = = 0.0000, respectively). The activity of GSH-Px was not statistically significant. Conclusions: The antioxidant barrier in all types of pediatric cancers is disturbed. None of the measured parameters was specific enough to represent a reliable marker for any particular histopathologic type of children’s neoplasm.

Background Antioxidant systems in cells maintain the proper homeostasis of reactive oxygen species, which at high concentrations can induce carcinogenesis. The aim of this study was to evaluate the serum levels of ischemia-modified albumin (IMA), erythrocyte superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px) as markers for prognosis in children with neuroblastoma (NB) and soft tissue sarcomas (STS), two cancer types for which reliable prognostic factors are needed. Procedure SOD, GSH-Px, and IMA were measured before and during responses to therapy assessment in 99 children with NB and STS and in 30 healthy controls. Results There were no statistically significant differences in the erythrocyte SOD and GSH-Px activities between the patients with cancer and healthy controls. The levels of IMA in patients with STS and NB were found to be significantly higher than in the controls (P = 0.0013; P = 0.0066, and 0.0164, respectively). Decreased activities of SOD and GSH-Px were found in all patients with poor-responding (PRS) cancers and decreased SOD activity was found in patients with PRS NB. An increase in GSH-Px was observed in patients with good-responding (GR) NB. All patients with GR cancers demonstrated higher SOD and GSH-Px activities than patients with PRS cancers. Conclusions While determining the levels of specific antioxidants as antioxidant-barrier parameters in children with cancer may be valuable in predicting therapeutic responses as well as outcomes, additional studies are required. Pediatr Blood Cancer 2011; 57: 561–568. © 2011 Wiley-Liss, Inc.

Analysis of biogenic amines (BAs) in different human samples provides insight into the mechanisms of various biological processes, including pathological conditions, and thus may be very important in diagnosing and monitoring several neurological disorders and cancerous tumors. In this work, we developed a simple and fast procedure using a digitally controlled microextraction in packed syringe (MEPS) coupled to liquid chromatography mass spectrometry (LC-MS) method for simultaneous determination of biogenic amines, their precursors and metabolites in human plasma and urine samples. The separation of 12 low molecular weight and hydrophilic molecules with a wide range of polarities was achieved with hydrophilic interaction chromatography (HILIC) column without derivatization step in 12 min. MEPS was implemented using the APS sorbent in semi-automated analytical syringe (eVol(®)) and small volume of urine and plasma samples, 5 0µL and 100 μL, respectively. We evaluated important parameters influencing MEPS efficiency, including stationary phase selection, sample pH and volume, number of extraction cycles, and washing and elution volumes. In optimized MEPS conditions, the analytes were eluted by 3 × 50 μL of methanol with 0.1% formic acid. The chromatographic separation of analytes was performed on XBridge Amide™ BEH analytical column (3.0mm × 100 mm, 3.5 µm) using gradient elution with mobile phase consisting of phase A: 10mM ammonium formate buffer in water pH 3.0 and phase B: 10mM ammonium formate buffer in acetonitrile pH 3.0. The LC-HILIC-MS method was validated and, in optimum conditions, presented good linearity in concentration range within 10-2000 ng/mL for all the analytes with a determination coefficient (r(2)) higher than 0.999 for plasma and urine samples. Method recovery ranged within 87.6-104.3% for plasma samples and 84.2-98.6% for urine samples. The developed method utilizing polar APS sorbent along with polar HILIC column was applied for simultaneous bioanalysis of trace amounts of polar endogenous biogenic amines in real human urine and plasma samples.

The first and family names of the authors were interchanged. The correct author names are now correctly presented in this article.

Methemoglobinemia is a rare congenital or acquired disease of increased blood methemoglobin concentration. We documented 2 cases of children suffering from neuroblastoma whose postchemotherapy anemia, leucopenia, and stomatitis were complicated by methemoglobinemia after using a formulary oral gel (7.5% benzocaine, doxycycline, nystatin, glycerin). The complication resulted in hospital treatment. Percutaneous oxygen saturation remained at 85% and 87% despite administration of 100% oxygen through a nonrebreather mask. Arterial blood gas analysis showed an oxygen saturation of 98% and 97%, respectively. Spectroscopic measurement showed methemoglobin concentration of 42% and 35.5%, respectively. After red blood cell transfusion and oral ascorbic acid in case 1 and methylene blue in case 2, the patients' condition improved. Although the benzocaine gel is not in use in several medical systems, it should be considered as a possible reason for methemoglobinemia.

Background Thymomas and thymic carcinomas belong to a group of thymic epithelial tumours arising from the anterior mediastinum and, are extremely rare in children in which no therapeutic guidelines have been established. The aim is to describe paediatric characteristics of these tumours and give some therapeutic indications. Methods Retrospective analysis of clinical data and therapeutic characteristics of paediatric patients less than 18 years with thymic tumours treated between 2000 and 2012 registered in the European Cooperative Study Group for Pediatric Rare Tumors (EXPeRT) database of the cooperating national rare paediatric tumour working groups from France, Italy, Germany and Poland. Results Sixteen children with thymoma, median age 11 years and 20 patients with thymic carcinoma, median age 14 years were enrolled into study. At diagnosis complete primary resection was possible in 11 patients with thymoma and one with thymic carcinoma; resection with microscopic residue was performed in three cases and incomplete resection with macroscopic residue in four patients. Chemotherapy with various regimens was administered to 22 children; 17 of them as neoadjuvant chemotherapy. Eight patients with thymic carcinoma received additional radiotherapy. Seventeen children died (15 thymic carcinoma, two thymoma). Five-year overall survival for patients with thymic carcinoma is 21.0 ± 10.0%. Conclusions This study confirms the possibility to perform European retrospective analysis even in very rare paediatric tumours. Thymic carcinoma is associated with paediatric patients to give a very poor prognosis independently despite multimodal management. Multidisciplinary, multicenter approach and collaboration with adults’ physician are necessary in order to propose homogenous guidelines.

The metabolic differences between normal, healthy cells and neoplastic cells have been exploited by anticancer therapies targeting metabolic pathways. Various studies of malignant processes have demonstrated disturbances in both arginine synthesis and metabolism that enhance or inhibit tumor cell growth. Consequently, there has been an increased interest in the arginine-depleting enzyme arginine deiminase (ADI) as a potential antineoplastic therapy.This review summarizes the literature on the potential anti-cancer therapeutics arginine and ADI, an arginine-catabolizing enzyme. The authors searched the MEDLINE database PubMed using the key words: 'arginine, 'ADI', 'arginine in cancer' and 'ADI and cancer'. The authors evaluate prospective randomized studies on cancer patients between 2004 and 2013 as well as ongoing research found through the US National Institutes of Health trial database.The results of current studies are promising but do not give unequivocal answers and so it is impossible to recommend arginine or its enzyme ADI as a therapeutic. In the opinion of the authors, further identification of arginine-dependent malignant tumors and their metabolism should be investigated. Furthermore, the use of these chemicals, in combination with other chemotherapeutics drugs, should be investigated and indeed may improve the success of arginine-depleting enzymes such as pegylated ADI (ADI-PEG20).

Objective To analyse ovarian Sertoli-Leydig cell tumours (SLCTs) for potential prognostic markers and their use for treatment stratification. Patients Forty-four patients were included. Patients were prospectively reported to the German MAKEI (Maligne Keimzelltumoren) studies ( n =23), French TGM protocols ( n =10), Italian Rare Tumour Project (TREP) registry ( n =6), and the Polish Pediatric Rare Tumour Study group ( n =5). Tumours were classified according to World Health Organisation (WHO) and staged according to International Federation of Gynecological Oncology (FIGO). Results Median age was 13.9 (0.5–17.4) years. All patients underwent resection by tumour enucleation ( n =8), ovariectomy ( n =17), adenectomy isolated ( n =18) or with hysterectomy ( n =1). FIGO-stage: Ia 24pts., Ic 17pts., II/III 3pts. One patient had bilateral tumours. Four patients (stage Ia: 3, stage Ic: 1) developed a metachronous contralateral tumour. Otherwise, all stage Ia patients remained in complete remission. Among 20 patients with incomplete resection or tumour spread (stage Ic–III), eight relapsed, and five patients died. Eleven patients were initially treated with two to sixcycles of cisplatin-based chemotherapy. Of these, seven patients are in continuous remission. Poor histological differentiation was associated with higher relapse rate (5/13) compared to intermediate (3/18) and high differentiation (0/4). Tumours with retiform pattern or heterologous elements showed a high relapse rate, too (5/11). After a median follow-up of 62months, event-free survival is 0.70±0.07, relapse-free survival 0.81±0.06 and overall survival 0.87±0.05. Conclusions Prognosis of SLCTs is determined by stage and histopathologic differentiation. Complete resection with careful avoidance of spillage is a prerequisite of cure. The impact of chemotherapy in incompletely resected and advanced stage tumours remains to be evaluated.

Background Pleuropulmonary blastoma (PPB) is an aggressive embryonal malignancy presenting in early childhood, presumably arising from pleuropulmonary mesenchyme. The European Cooperative Study Group for Paediatric Rare Tumours (EXPeRT) analysed its data on this tumour. Methods This analysis concerns patients aged 0–17 years with histologically-confirmed PPB registered up to 2008 in national databases in Italy, France and the United Kingdom and Poland. Lesions were classified as type I, II or III according to Dehner’s classification. Findings Sixty-five patients were considered (13 type I, 24 type II and 28 type III). Most tumours were large (91% >5 cm) and invaded the parietal pleura (29), mediastinum (10), major vessels (four) or pericardium (three). Regional nodes were involved in two cases, and three had metastases. The median follow-up was 5 years (0.6–22). For type I patients, 5-year progression free survival (PFS) was 83.3% and overall survival 91.7%; six patients received no further treatment after surgery, but two relapsed. All type II/III PPB had chemotherapy (CT) and their 5-year PFS was 42.9% (27.7–57.2). On univariate analysis, favourable prognostic factors were: complete tumour resection at diagnosis ( p = 0.008); and absence of invasiveness ( p = 0.02); for type II/III tumours, type of CT was also a significant factor (patients given doxorubicin fared better, with a 5-year PFS of 70% versus 31.3% [ p = 0.01]). Interpretations Type I PPB patients’ outcome was satisfactory. Complete resection at diagnosis seems important but rarely feasible for type II/III tumours, who benefited from doxorubicin-containing CT regimens. These results will inform the EXPeRT group’s PPB treatment guidelines.

Systemic mastocytosis is a myeloproliferative disorder characterized by growth and accumulation of abnormal mast cells in one or more organs. The symptoms of the disease are due both to the mast cells infiltrating the organs and to the action of its degranulation products. Over 85% of adult patients exhibit point mutations of KIT at position 816 (D816V). Systemic mastocytosis is rare in both adults and children, so treatment is highly individualized; therapy and further treatment is adjusted to each patient's needs. The aim of this study was to present the case of a 14-year old female with systemic mastocytosis and the problems with her treatment. Multidisciplinary management is recommended in systemic mastocytosis.

OBJECTIVE Reactive oxygen species (ROS) play a role in cancerogenesis processing and damage tissues. Furthermore, oncological treatment may impair proper function of the gut barrier. The aim of this study was to measure intestinal permeability in children in clinical remission for solid tumours and to search for a possible relationship between free radicals and the intestinal barrier. No such investigation in children has been reported so far. RESEARCH METHODS AND PROCEDURES The prospective study consisted of 19 paediatric patients with cancer after completion of chemotherapy. 32 healthy children from the outpatients clinics were recruited for measurement of intestinal permeability and antioxidant barrier as a control group. Intestinal permeability was assessed by measurement of urinary lactulose and mannitol after oral challenge. Antioxidant enzymes: superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) in erythrocytes were assessed. Ischemia modified albumin (IMA) concentration was measured in serum. RESULTS Cancer patients excreted less mannitol and more lactulose versus controls. The ratio of lactulose to mannitol was significantly higher in oncological children vs control (mean 0.188 and 0.0453, respectively, p=0.0006,). Significantly higher IMA level in the oncological group vs control was noted (mean 123.8 and 87.3 U/ml, respectively, p=0.0037). No correlation between intestinal permeability and oxidative stress barrier was found. CONCLUSIONS Our data shows that intestinal barrier is damaged in paediatric cancer patients after chemotherapy. IMA is believed to play a protective role in the defence against tissue damage. No correlation was found between these two barriers.

Tumors of the central nervous system (CNS) represent approximately 20% of all pediatric neoplasms. Of these, 4–6% are primary spinal cord tumors. Multiple primary cranio-spinal tumors are often associated with inherited syndromes including neurofibromatosis type 2 (NF2). The principal clinical feature of NF2 is the existence of vestibular schwannomas, meningiomas, and ependymomas; therefore, NF2 is also called MISME (multiple inherited schwannomas, meningiomas, and ependymomas) syndrome. Consequently, a multidisciplinary approach is needed for these patients, and diagnosis and treatment should be performed in an appropriate oncological center with a neurosurgeon, otolaryngologist, neurologist, geneticist, ophthalmologist, pathologist, radiologist, audiologist, and experienced nursing staff. Magnetic resonance imaging of the brain and spinal canal with contrast is the method of choice for diagnosis of CNS tumors. Surgical procedures are often necessary to establish a diagnosis, perform complete or incomplete excision of the tumor mass, and to reduce intracranial pressure. Radiotherapy and chemotherapy are adjuvant treatment options.

The low incidence and the heterogeneity of very rare tumors (VRTs) demand for international cooperation. In 2008, EXPeRT (European Cooperative Study Group for Pediatric Rare Tumors) was founded by national groups from Italy, France, United Kingdom, Poland and Germany. The first aims of EXPeRT were to agree on a uniform definition of VRTs and to develop the currently most relevant scientific questions. Current initiatives include international data exchange, retrospective and prospective studies of specific entities, and the development of harmonized and internationally recognized guidelines. Moreover, EXPeRT established a network for expert consultation to assist in clinical decision in VRTs.

In this study, the levels of ischemia-modified albumin (IMA) in pediatric oncology patients with soft tissue sarcomas (STSs) and neuroblastoma (NB) were analyzed. To date, there have been no studies concerning IMA in these groups of patients. Ninety-nine children with STSs and NB were analyzed from 2006 to 2009, and 30 healthy children were also enrolled in the study. IMA levels were measured throughout treatment in all patients. The levels of IMA in all cancer patients (mean 116.8±39.3 U/ml), in patients with STSs (mean 119.8±27.5 U/ml), and in patients with NB (mean 114.6±36.6 U/ml) were significantly higher than in the control patients (mean 87.3±38.3 U/ml; P=0.0013, 0.0066, and 0.0164, respectively). IMA levels increased before and during the treatment compared with levels in the controls. The determination of IMA levels in pediatric oncology patients with poor prognoses from STSs and NB may play an important role in predicting response to therapy and overall outcome. J. Clin. Lab. Anal. 25:255–258, 2011. © 2011 Wiley-Liss, Inc.

Pancreatoblastoma is a very rare malignant tumour typically occurring in the early years of life. Due to its rarity, standardised diagnostic and therapeutic guidelines are not available for pancreatoblastoma.The newborn cooperative group denominated EXPeRT - European cooperative study group for paediatric rare tumours - combined in a joint analysis of all cases registered between 2000 and 2009 by the national groups of Italy, France, United Kingdom, Poland and Germany.Twenty patients18years old (median age 4years) were analysed: nine had distant metastases at diagnosis. Seventeen patients had tumour resection, at initial or delayed surgery. Eighteen received chemotherapy (response rate 73%), seven received radiotherapy. For the whole series, 5-year event-free survival and overall survival were 58.8% and 79.4%, respectively. Outcome did not correlate with tumour site and size, but was strongly influenced by the feasibility of tumour complete resection.This international study confirms the rarity of the disease, the critical role of surgical resection both as therapy and as a prognostic variable, and the potential efficacy of chemotherapy. The adoption of an intensive multidisciplinary approach is required, as well as the referral to highly experienced centres. Further international cooperation is needed to collect larger series and stimulate biological studies to improve our understanding of the biology and the natural history of PBL.

Antioxidant systems in cells maintain the proper homeostasis of reactive oxygen species, which at high concentrations can induce carcinogenesis. The aim of this study was to evaluate the serum levels of ischemia-modified albumin (IMA), erythrocyte superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px) as markers for prognosis in children with neuroblastoma (NB) and soft tissue sarcomas (STS), two cancer types for which reliable prognostic factors are needed.SOD, GSH-Px, and IMA were measured before and during responses to therapy assessment in 99 children with NB and STS and in 30 healthy controls.There were no statistically significant differences in the erythrocyte SOD and GSH-Px activities between the patients with cancer and healthy controls. The levels of IMA in patients with STS and NB were found to be significantly higher than in the controls (P = 0.0013; P = 0.0066, and 0.0164, respectively). Decreased activities of SOD and GSH-Px were found in all patients with poor-responding (PRS) cancers and decreased SOD activity was found in patients with PRS NB. An increase in GSH-Px was observed in patients with good-responding (GR) NB. All patients with GR cancers demonstrated higher SOD and GSH-Px activities than patients with PRS cancers.While determining the levels of specific antioxidants as antioxidant-barrier parameters in children with cancer may be valuable in predicting therapeutic responses as well as outcomes, additional studies are required.

The occurrence of a second tumour is a severe complication of neoplastic disease and its treatment, and it reduces the patient's chances to survive. The aim of the study was to assess the frequency of a second neoplasm and its clinical course in children treated in Gdańsk in the years 1992-2007.There were 420 children and young adults included in the study. They were treated for malignant tumours in this period in the Department of Paediatrics, Haematology, Oncology and Endocrinology Medical Academy of Gdańsk. The medical records of these patients were analysed.The second neoplasm was diagnosed in 9 patients, aged 9 to 23 years. They were treated for nephroblastoma - 3 cases, soft tissue sarcoma - 2, Ewing's sarcoma - 1, medulloblastoma - 1, retinoblastoma - 1 and neuroblastoma - 1 case. The second neoplasms were: acute non lymphoblastic leukaemia - 2, soft tissue sarcoma - 2, osteosarcoma - 2, chondrosarcoma - 1, renal cell carcinoma - 1 and glioblastoma multiforme - 1 case. Time between the first and second diagnosis was from 3 and 11/12 to 19 years. Treatment failed in 5 out of 9 children treated for osteosarcoma (2/2), chondrosarcoma (1/1), soft tissue sarcoma (1/2) and acute non lymphoblastic leukaemia (1/2). These patients died of progression of neoplastic disease during 2 to 20 months after the diagnosis of the second tumour.The diagnosis of the second tumour worsens the prognosis. It is difficult to define the factors that predispose to the second neoplasm. In 5 cases the second neoplasm occurred in the region which was previously irradiated.

The aim of the study was to analyze the prognostic factors for the outcome in childhood head/neck soft tissue sarcomas (STS) treated in the Department of Paediatrics, Haematology, Oncology and Endocrinology, Medical University of Gdansk between 1992 and 2007.Among 23 children with STS in ten it was located in non-parameningeal region, in eight it was in the parameningeal region, and in five in the orbit. Patients were qualified to particular disease stages according to the current diagnostic and therapeutic protocols (Cooperative Weichtel-sarkom Studie-CWS). The qualifications were based on the results of radiologic examinations (ultrasonography, computed tomography and magnetic resonance of the head and neck region, computed tomography of the chest and abdomen and bone scintigraphy) and also on myelogram smears and cerebrospinal fluid investigation.The longest history concerned the parameningeal (8 months), the shortest the orbital soft tissue sarcomas. Six out of ten patients with non-parameningeal STS were referred to the oncologist with a delay of 6.5 months. This was due to the initially false histopathological diagnosis which excluded the neoplastic process. 82.6% of tumours were diagnosed in advanced, inoperable stages. In 16 children rhabdomyosarcomas (including embryonal subtype - RME in 10, alveolar - RMA in five and undifferentiated in one); in seven non-rhabdomyosarcomas (non-RMS) were found. Good response to chemo- and radiotherapy was observed in 60% of children, mainly with RME. Nine children (mainly with non-parameningeal STS) relapsed. 15 patients are alive (including all with orbital, 6/10 with non-parameningeal and 4/8 with parameningeal STS). Eight children died of disease progression.1. Poor outcome in our patients with non-parameningeal head/neck STS results from false initial diagnosis cansing a delay in referring them to the oncologist. It is essential to give more training to the histopathologists about neoplasms in children. 2. Because complete tumour resection in parameningeal STS is rarely feasible, the prognosis in this group is uncertain despite intense chemo- and radiotherapy. 3. The prognosis in orbital STS is usually good; however, they need mutilating surgery in selected cases not responding to therapy.