Characteristics and treatment results of refractory and relapsed acute myeloid leukaemia in paediatric patients treated in Polish Paediatric Leukaemia/Lymphoma Study Group institutions according to the Protocol Acute Myeloid Leukaemia Berlin-Frankfurt-Munster 2012 and a review of novel treatment possibilities in paediatric acute myeloid leukaemia.

Introduction: This study aimed to present the clinical features and results of treatment of patients diagnosed with refractory or relapsed acute myeloid leukaemia (AML) in Polish Paediatric Leukaemia/Lymphoma Study Group (PPL/LSG) institutions, treated in accordance with the Protocol Acute Myeloid Leukaemia Berlin-Frankfurt-Munster 2012, as their first-line therapy. Material and methods: The outcome data of 10 patients with refractory AML (median age 9.5 years) and 30 with relapsed AML (median age 12 years) were analysed retrospectively. Re-induction was usually based on idarubicin, fludarabine, and cytarabine along with allogeneic haematopoietic stem cell transplant (allo-HSCT) in 5 patients with refractory AML and 7 relapsed AML children. Results: 37.5% (3/8) of refractory AML patients achieved second complete remission second complete remission (CRII). One of ten patients (1/10; 10%) was alive and stayed in complete remission for 34 months after the allo-HSCT. The probability of 3-year event-free survival (pEFS) in this group was 0.125 ±0.11. In the group of relapsed AML patients, the CRII was achieved in 9 patients (34%), and the probability of survival was: pEFS = 0.24 ±0.08; probability overall survival (pOS) = 0.34 ±0.09, with significantly better results achieved in patients who underwent allo-HSCT (pOS = 0.54 ±0.14 vs. 0.08 ±0.08, p < 0.0001). Conclusions: The prognosis of refractory AML and the first AML recurrence in children who were first-line treated in PPL/LSG centres according to Protocol Acute Myeloid Leukaemia Berlin-Frankfurt-Munster 2012 is poor. Failures of re-induction treatment particularly result from difficulties in achieving remission. Allogeneic HSCT improves prognosis in children with refractory and first recurrent AML, under the condition it is performed in complete remission. Novel therapeutic approaches are needed to increase the remission rate and improve the outcomes.

Isolated central nervous system relapses in patients with high-risk neuroblastoma -clinical presentation and prognosis: experience of the Polish Paediatric Solid Tumours Study Group.

Although isolated central nervous system (CNS) relapses are rare, they may become a serious clinical problem in intensively treated patients with high-risk neuroblastoma (NBL). The aim of this study is the presentation and assessment of the incidence and clinical course of isolated CNS relapses. Retrospective analysis involved 848 NBL patients treated from 2001 to 2019 at 8 centres of the Polish Paediatric Solid Tumours Study Group (PPSTSG). Group characteristics at diagnosis, treatment and patterns of relapse were analysed. Observation was completed in December 2020. We analysed 286 high risk patients, including 16 infants. Isolated CNS relapse, defined as the presence of a tumour in brain parenchyma or leptomeningeal involvement, was found in 13 patients (4.5%; 8.4% of all relapses), all of whom were stage 4 at diagnosis. Isolated CNS relapses seem to be more common in young patients with stage 4 MYCN amplified NBL, and in this group they may occur early during first line therapy. The only or the first symptom may be bleeding into the CNS, especially in younger children, even without a clear relapse picture on imaging, or the relapse may be clinically asymptomatic and found during routine screening. Although the incidence of isolated CNS relapses is not statistically significantly higher in patients after immunotherapy, their occurrence should be carefully monitored, especially in intensively treated infants, with potential disruption of the brain-blood barrier.

Recommendations of procedures to follow in the case of ovarian lesions in girls.

This study presents current recommendations of the Polish Association of Pediatric Surgeons (PTChD) regarding diagnostics and treatment of ovarian lesions in girls. They are based on many years of the authors' clinical experience as well as a review of international literature and include practical clinical guidelines. The recommendations were formulated in cooperation with the Polish Association of Pediatric Oncology and Hematology (PTOHD), Polish Pediatric and Adolescent Gynecology Section of the Polish Society of Gynecologists and Obstetricians (PTG) and Polish Pediatric Section of the Polish Society of Radiology (PLTR). Only better understanding of prepubertal ovarian biology and natural history of its pathology may help to introduce efficient and safe diagnostic and therapeutic strategies for girls. The prepared document has been supplemented with treatment algorithms.

Serum heat shock protein 90 as a future predictive biomarker in childhood acute lymphoblastic leukemia.

Heat shock proteins (HSPs) attract the attention of scientists and clinicians due to their potential role as diagnostic and prognostic factors in a variety of cancers. HSP90 is one of the most important and well-known family members, necessary for maintaining intracellular homeostasis. In the extracellular space, it is responsible for the transmission of alarm signals to the immune system. Numerous reports have indicated that the level of intra - and extracellular HSP90 can correlate either with a poorer prognosis or with a better outcome, depending on the type of cancer. Still, little is known why the level of this chaperone is increased in some tumors and decreased in others, reflecting dual role of protein in cell death processes. Currently, there is no database reporting levels of serum HSP90 in children with acute lymphoblastic leukemia (ALL). As such, using enzyme-linked immunosorbent assay (ELISA) method, we aimed to determine this parameter in a group of 21 patients with newly diagnosed ALL. We found decreased protein serum levels in patients at disease presentation and after induction block of chemotherapy in comparison to healthy controls. Furthermore, we observed a negative correlation between HSP90 serum levels and one of the earliest prognostic factors of the treatment response - peripheral blood lymphoblasts on the 8th day of treatment. Our results indicate that HSP90 serum may play an important role in leukemogenesis and could be used as a marker to predict treatment failure in children with ALL.

Expression of BARD1 ß Isoform in Selected Pediatric Tumors.

Currently, many new possible biomarkers and mechanisms are being searched and tested to analyse pathobiology of pediatric tumours for the development of new treatments. One such candidate molecular factor is BARD1 (BRCA1 Associated RING Domain 1)-a tumour-suppressing gene involved in cell cycle control and genome stability, engaged in several types of adult-type tumours. The data on BARD1 significance in childhood cancer is limited. This study determines the expression level of BARD1 and its isoform beta (ß) in three different histogenetic groups of pediatric cancer-neuroblastic tumours, and for the first time in chosen germ cell tumours (GCT), and rhabdomyosarcoma (RMS), using the qPCR method. We found higher expression of beta isoform in tumour compared to healthy tissue with no such changes concerning BARD1 full-length. Additionally, differences in expression of BARD1 ß between histological types of neuroblastic tumours were observed, with higher levels in ganglioneuroblastoma and ganglioneuroma. Furthermore, a higher expression of BARD1 ß characterized yolk sac tumours (GCT type) and RMS when comparing with non-neoplastic tissue. These tumours also showed a high expression of the TERT (Telomerase Reverse Transcriptase) gene. In two RMS cases we found deep decrease of BARD1 ß in post-chemotherapy samples. This work supports the oncogenicity of the beta isoform in pediatric tumours, as well as demonstrates the differences in its expression depending on the histological type of neoplasm, and the level of maturation in neuroblastic tumours.

Results of two consecutive treatment protocols in Polish children with acute lymphoblastic leukemia.

The aim of the study was to retrospectively compare the effectiveness of the ALL IC-BFM 2002 and ALL IC-BFM 2009 protocols and the distribution of risk groups by the two protocols after minimal residual disease (MRD) measurement as well as its impact on survival. We reviewed the medical records of 3248 patients aged 1-18 years with newly diagnosed ALL who were treated in 14 hemato-oncological centers between 2002 and 2018 in Poland. The overall survival (OS) of 1872 children with ALL treated with the ALL IC 2002 protocol was 84% after 3 years, whereas the OS of 1376 children with ALL treated with the ALL IC 2009 protocol was 87% (P < 0.001). The corresponding event-free survival rates were 82% and 84% (P = 0.006). Our study shows that the ALL IC-BFM 2009 protocol improved the results of children with ALL compared to the ALL IC-BFM 2002 protocol in Poland. This analysis confirms that MRD marrow assessment on day 15 of treatment by FCM-MRD is an important predictive factor.

High Frequency of Fusion Gene Transcript Resulting From t(10;11)(p12;q23) Translocation in Pediatric Acute Myeloid Leukemia in Poland.

11q23/MLL rearrangements are frequently detected in pediatric acute myeloid leukemia. The analysis of their clinical significance is difficult because of the multitude of translocation fusion partners and their low frequency. The presence of t(10;11)(p12;q23) translocation was previously identified in pediatric acute myelogenous leukemia (AML). It is considered as the second most common translocation detected in pediatric 11q23/MLL-rearranged (present KMT2A) AML, after t(9;11)(p22;q23). The presence of the above translocation was previously identified as an unfavorable prognostic factor. Since June 2015, the Polish Pediatric Leukemia/Lymphoma Study Group has applied the therapeutic protocol requiring extensive diagnostics of genetic changes in pediatric AML. Until November 2019, molecular genetic studies were performed in 195 children with diagnosed AML to identify carriers of fusion gene transcripts for 28 most common chromosomal translocations in acute leukemia. The fusion gene transcript for translocation t(10;11)(p12;q23) involving MLL gene was detected with unexpectedly high frequency (8.9%) in our research. It was the highest frequency of all detected MLL rearrangements, as well as other detected fusion gene transcripts from chromosomal aberrations characteristic for AML. It seems that chromosomal aberration between chromosomes 10 and 11 can be relatively frequent in some populations. Paying attention to this fact and ensuring proper genetic diagnosis seem to be important for appropriate allocation of patients to risk groups of pediatric AML treatment protocols.

Selected Matrix Metalloproteinases (MMP-2, MMP-7) and Their Inhibitor (TIMP-2) in Adult and Pediatric Cancer.

The tumor microenvironment (TME) consists of numerous biologically relevant elements. One of the most important components of the TME is the extracellular matrix (ECM). The compounds of the ECM create a network that provides structural and biochemical support to surrounding cells. The most important substances involved in the regulation of the ECM degradation process are matrix metalloproteinases (MMPs) and their endogenous inhibitors (tissue inhibitors of metalloproteinases, TIMPs). The disruption of the physiological balance between MMP activation and deactivation could lead to progression of various diseases such as cardiovascular disease, cancer, fibrosis arthritis, chronic tissue ulcers, pathologies of the nervous system (such as stroke and Alzheimer's disease), periodontitis, and atheroma. MMP-TIMP imbalance results in matrix proteolysis associated with various pathological processes such as tumor invasion. The present review discusses the involvement of two MMPs, MMP-2 and MMP-7, in cancer pathogenesis. These two MMPs have been proven in several studies, conducted mostly on adults, to make an important contribution to cancer development and progression. In the current review, several studies that indicate the importance of MMP-TIMP balance determination for the pediatric population are also highlighted. The authors of this review believe that carrying out biochemical and clinical studies focused on metalloproteinases and their inhibitors in tumors in children will be of great relevance for future patient diagnosis, determination of a prognosis, and monitoring of therapy.

Retrospective Analysis of the Treatment Outcome in Myeloid Leukemia of Down Syndrome in Polish Pediatric Leukemia and Lymphoma Study Group From 2005 to 2019.

Background: Children with Down syndrome (DS) have increased risk of myeloid leukemia (ML), but specific treatment protocols ensure excellent outcome. This study was a retrospective analysis of the treatment results and genetic characteristics of ML of DS (ML-DS) in Poland from 2005 to 2019. Methods: All 54 patients with ML-DS registered in the Polish Pediatric Leukemia and Lymphoma Study Group in analyzed period were enrolled to the study. There were 34 children treated with Acute Myeloid Leukemia-Berlin-Frankfurt-Munster 2004 Interim Protocol (group I) and 20 patients treated with ML-DS 2006 Protocol (group II). In the first protocol, there was reduction of the antracyclines doses and intrathecal treatment for ML-DS compared to non-DS patients. In the second protocol, further reduction of the treatment was introduced (omission of etoposide in the last cycle, no maintenance therapy). Results: Probabilities of 5-year overall survival (OS), event-free survival (EFS), and relapse-free survival in the whole analyzed group were 0.85 ± 0.05, 0.83 ± 0.05, and 0.97 ± 0.03, respectively. No significant differences were found between two protocols in the terms of OS and EFS (0.79 ± 0.07 vs. 0.95 ± 0.05, p = 0.14, and 0.76 ± 0.07 vs. 0.95 ± 0.05, p = 0.12, respectively). All deaths were caused by the treatment-related toxicities. Reduction of the treatment-related mortality was noticed (20% in group I and 5% in group II). The only one relapse in the whole cohort occurred in the patient from group I, older than 4 years, without GATA1 gene mutation. He was treated successfully with IdaFLA cycle followed by hematopoietic stem cell transplantation from matched sibling donor. No significant prognostic factor was found in the study group probably due to low number of patients in the subgroups. Conclusions: The study confirms that the reduced intensity protocols are very effective in ML-DS patients. The only cause of deaths was toxicities; however, systematic decrease of the treatment-related mortality was noticed.

Development and validation of a high-performance liquid chromatographic method with a fluorescence detector for the analysis of epirubicin in human urine and plasma, and its application in drug monitoring.

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.

Hedgehog signalling network gene status analysis in paediatric intracranial germ cell tumours.

INTRODUCTION: Germ cell tumours (GCTs) in the children comprise a group of tumours that originate from primordial germ cells but their pathogenesis is not clear. Intracranial GCTs represent a special subset of these paediatric neoplasms. Hedgehog (Hh) pathway gene status in GCTs is generally unexplored, while Hh signalling is involved in germ cell biology. MATERIAL AND METHODS: Comparative genomic profiling analysis with a microarray-comparative genomic hybridization (CGH) + single nucleotide polymorphism (SNP) technique in a group of intracranial paediatric GCTs was performed. The analysis included evaluation of genes being ligands, receptors, regulators, effectors, and targets of Hh signalling. RESULTS: Chromosomal aberrations were found in 62% of examined tumours, showing their heterogeneity. A number of private genomic imbalances were observed, but only a few recurrent ones. The most common numerical changes were trisomies 19, 21 and monosomies 13, 18 while the most frequent structural aberration was gain/amplification of the chromosome 12p. The analysis of the gene status of Hh network elements showed imbalances in a proportion of tumours. PTCH1, GLI2, IHH and ZIC2 gene aberrations occurred most frequently. Moreover, six tumours had various copy gains or losses of several other genes involved in the pathway, including HHIP, GLI1, GLI3, DHH, SHH, SMO, PTCH2, and several genes from the WNT group. Interestingly, four cases showed losses of pathway repressors, with parallel gains of activators in two of them. Correlations with patho-clinical tumour features were not found, most probably due to the heterogeneity of the examined limited group. CONCLUSIONS: Our results show few genomic alterations related to the Hh signalling pathway genes in paediatric intracranial GCTs. Further analysis of Hedgehog pathway alterations can potentially disclose its biological significance and define new prognostic factors and/or therapeutic targets for high-risk patients.

Application of SPME supported by ionic liquids for the determination of biogenic amines by MEKC in clinical practice.

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.

Tumour expressions of hypoxic markers predict the response to neo-adjuvant chemotherapy in children with inoperable rhabdomyosarcoma.

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 factor (VEGF) predict response to neo-adjuvant chemotherapy (naCHT) in children with inoperable rhabdomyosarcoma (RMS). Methods: Immunohistochemical expressions of hypoxia markers were determined semi-quantitatively in tumour tissue microarray of 46 patients with embryonal RMS (RME) and 20 with alveolar (RMA), treated with CWS protocols (1992-2013). Results: In paediatric RME, response to naCHT was influenced significantly by tumour expression of CA IX and GLUT-1. Patients with RMA with low expressions of analysed markers responded well to naCHT, while all poor-responders expressed highly hypoxia markers. Only 5.88% of RMA and 11.11% of RME tumours did not express any of the proteins. In both RME and RMA subgroups, most poor-responders demonstrated simultaneous high expression of ≥3 markers, while most patients expressing ≤2 markers responded well to naCHT. In the whole cohort, co-expression of ≥3 markers, was the only independent factor predicting poor-response to chemotherapy (odds ratio 14.706; 95% CI 1.72-125.75; p = 0.014). Conclusions: Immunohistochemical expression pattern of four endogenous markers of hypoxia, in tumour tissue at diagnosis, emerges as a promising tool to predict response to naCHT in children with inoperable RMS.

Endometrial glial polyp and peritoneal gliomatosis: Neuropathological lesions in gynecological biopsy.

The wide scope of neuropathology is also connected to different systemic pathology findings. Neuroectodermal-type female genital tract lesions are not frequent. This article presents a short review of such entities in gynecological pathology and reports on two rare cases. The first described lesion is an endometrial glial polyp in a young woman. The second is a mature cystic teratoma accompanied by a peritoneal gliomatosis in an adolescent girl. Both presented entities posed diagnostic difficulties from the clinical and pathological perspective. They demanded careful sampling, immunophenotyping, as well as neuropathological consultation.

Infectious complications in children treated for hodgkin and non-hodgkin lymphomas in polish pediatric leukemia/lymphoma study group: incidence, epidemiology and etiology.

The objective of this nation-wide study was to evaluate the epidemiology and profile of bacterial (BI), viral (VI), and invasive fungal disease (IFD) in patients treated for non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HL) between the years 2013-2015. In the analyzed period of time, within the studied group of 328 children diagnosed and treated for lymphomas, at least one infectious complication (IC) was diagnosed i.e. 39.3% children. In these patients there were 350 episodes of IC, therein 80.6% episodes of BI, 11.1% episodes of VI, and 8.3% episodes of IFD. In both groups, NHL and HL patients, a stable level of bacterial infections, with an increase in resistance rates, and increased levels of viral and fungal infections were observed. Profile of BI does not depend on lymphoma type, with predominance of Gram-negative bacteria and higher prevalence of MDR pathogens. The overall survival of lymphoma patients with IC was comparable for different types of infections.

Rosai-Dorfman disease as a rare cause of cervical lymphadenopathy - case report and literature review.

Rosai-Dorfman disease (RDD), also known as sinus histiocytosis with massive lymphadenopathy, is a rare, benign clinical entity of unknown cause. RDD is characterised by the overproduction and accumulation of histiocytes, primarily in the lymph nodes, although it may affect every organ and system. It predominantly affects children and young adults. Typically, patients are in good general condition, with massive cervical lymphadenopathy and fever. In about 40% of cases extranodal localisation of RDD is diagnosed. In laboratory tests the most common abnormalities are increased erythrocyte sedimentation rate (ESR), leukocytosis with neutrophilia, normocytic anaemia, and hypergammaglobulinaemia. Histopathological examination remains the mainstay of diagnosis - lymph nodes have massive sinusoidal dilation, containing histiocytes positive for S-100 and CD68, and negative for CD1a. Most patients do not require treatment as spontaneous remissions are observed. We present a brief review of the literature and the case of a six-year-old boy with cervical lymphadenopathy diagnosed with RDD. So far, the patient has not required systemic treatment and has been kept under observation.

Sonographic Image of Solitary Kidney in Wilms Tumour Survivors.

BACKGROUND/AIMS: This study presents an analysis of the sonographic and laboratory parameters of solitary kidney in Wilms tumour survivors (TWs) and compares these parameters with those of healthy individuals. METHODS: Fifty-three TWs who completed treatment for Wilms tumour and 44 healthy individuals were enrolled. The study protocol consisted of completing a medical history, sonographic examination of the solitary kidney, estimation of glomerular filtration rate (eGFR) by the Schwartz or MDRD formulas, albumin urine excretion and BP measurement. RESULTS: Sonographic signs of kidney damage were observed in 22 (41,5%) TWs. The most frequently detected abnormalities are hyperechoic rings around renal pyramids (28,3% TWs). Hypertrophy of the solitary kidney occurred in 71,7% of cases. The mean volume of the solitary kidney was 77% of the sum of the two kidney volumes in the control group. The median eGFR in the TWs group was 117 with 25Q-105,5, 75Q-130 ml/min/1,73 m2 vs 131,8 with 25Q-124, 75Q-140 ml/min/1,73 m2 in the control group (p=0,000). Six TWs (11,3%) had a value of eGFR below 90 ml/min/1,73 m2. Increased urine albumin excretion (> 30 mg/g) was observed in 7 TWs (13,2%) and in 3 (6,8%) individuals in the control group. CONCLUSION: Ultrasonographic abnormalities in solitary kidney of TWs are frequent. The most frequently detected abnormalities are hyperechoic rings around renal pyramids. Sonographic examination of TWs ought to be performed not only to detect tumour recurrence but also to assess the signs of kidney damage and their progression.

Optimization of LC method for the quantification of doxorubicin in plasma and urine samples in view of pharmacokinetic, biomedical and drug monitoring therapy studies.

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.