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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.

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.

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

Oestrogen receptor α (ERα) is responsible for activation of gene transcription, while oestrogen receptor β (ERβ) serves as a negative regulator of ERα function. Since ER status is a prognostic and predictive factor in some cancers, we analysed the immunohistochemical expression of ERα and ERβ in Reed-Sternberg (RS) cells in paraffin-embedded lymph node specimens from 27 children with classical Hodgkin lymphoma (HL) in relation to histological type, clinical stage, age, and gender. Percentage of RS cells with positive nuclear reaction for the presence of ERα and/or ERβ was assessed. ERα positive RS cells were present in 11% (3/27) of lymph nodes (range 1-8%, mean 0.4%) whereas ERβ positive RS cells were detected in 96% (26/27) of lymph nodes (range 1-97.5%, mean 61.8%). The highest percentage of ERβ positive RS cells was observed in patients with the most advanced (IVB) disease as compared to patients with lower stages (90.3% vs. 56.9% respectively, p = 0.004). To the best of our knowledge this is the first report on the expression of ERβ in RS cells in children. We conclude that RS cells in classical HL in children seem to be mainly ERβ positive and ERα negative.

Nuclear factor ĸB (NF-ĸB) is a transcription regulator of proliferation and cell death. Increased activation of NF-ĸB may be responsible for treatment failure in children with acute lymphoblastic leukaemia (ALL). This study aimed to assess changes in NF-ĸB activation in peripheral blood mononuclear cells prior to and after 6 and 12 h of prednisone administration in relation to age, initial WBC count at diagnosis and early treatment response in childhood ALL. The study comprised 55 children with de novo ALL. Cells were stained with mouse anti-NF-ĸB (p65) antibody followed by goat anti-mouse antibody conjugated with FITC and measured by laser scanning cytometer. The nuclear/cytoplasmic (N/C) ratio of NF-ĸB reflecting activation of NF-ĸB was decreased 12 h after treatment in the standard risk group patients, whereas it remained statistically unchanged in the non-standard risk group patients. Changes in the N/C ratio of NF-ĸB were not associated with age and early treatment response; however, in children with an initial WBC count higher than 20 000/μl at diagnosis, this ratio was increased after 6 and 12 h from prednisone administration. The association of higher activation of NF-ĸB with an elevated initial WBC count suggests that activation of NF-ĸB may be responsible for treatment failure in children with ALL.

Ineffective apoptosis is one of main causes of a treatment failure in childhood acute lymphoblastic leukemia (ALL). p53 plays a crucial role in triggering apoptosis of ALL in response to prednisone treatment. MDM2 is the endogenous inhibitor of apoptosis that downregulates the functional activity of p53 protein. This study is aimed to evaluate changes in MDM2 and p53 expression in peripheral blood mononuclear cells collected from children with ALL prior to and after 6 and 12 h of prednisone administration in relation to early treatment response. The study comprised 35 children with newly diagnosed ALL, subdivided into good (n = 24) and poor (n = 11) early treatment responders. MDM2 - associated APC fluorescence and p53 - associated FITC fluorescence were measured by the laser scanning cytometer. In the group of poor responders, p53 and MDM2 fluorescence were significantly higher than in the group of good responders. In the group of good early treatment responders, a statistically significant rise of p53 fluorescence measured in the nucleus and in the cytoplasm 12 h after prednisone administration as well as increase in MDM2 fluorescence measured in the cytoplasm 6 and 12 h after prednisone administration were seen. These data suggest that pretreatment overexpression of MDM2 protein may contribute to poor early treatment response.

Objectives and aims of the study: The MLL oncogene on chromosome 11q23 undergoes various translocations in acute leukemias. MLL gene rearrangements are associated with worse outcome in infant acute lymphoblastic leukemia (ALL), while t(4;11) is a high-risk factor in children with ALL > 1 year of age. The prognostic value of MLL gene rearrangements in acute myeloid leukemia (AML) remains to be determined. In this study, we aimed at comprehensive analysis of the incidence and spectrum of MLL gene rearrangements in a large cohort of pediatric acute leukemias in Poland. Material and Methods: The study group comprised 355 children including 271 patients with de novo ALL, 24 children with relapsed ALL, 56 children with AML, three children with relapsed AML and a patient with acute bi-lineage leukemia. The presence of MLL rearrangements was determined with split-signal fluorescent in situ hybridization (FISH). Partner genes rearranged to MLL locus were identified with long-distance inverse PCR at the genomic DNA level. Results: MLL rearrangements were found in 18 patients with de novo ALL, 12 infants and six children > 1 year of age (6.6%). They included 12 t(4;11) with MLL-AFF1 fusion, two t(11;19) with MLL-MLLT1 fusion, one t(9;11) with MLL-MLLT3 fusion and one t(10;11) translocation with two gene fusions MLL-MLLT10 and PIWIL4-MLL. MLL rearrangements were also present in two patients with relapsed ALL. MLL rearrangement characterized 11 patients with de novo AML [four t(9;11) with MLL-MLLT3 fusion, one t(11;19) with MLL-ELL fusion, one (1;11) with MLL-EPS15 fusion, and a single t(1;11;17)] and one patient with secondary AML after ALL treatment [t(11;19)], which comprises 22% of all AML patients. This incidence is higher than usually described in literature (approximately 10–15%). Interestingly, in patient with t(1;11;17) two in-frame gene fusions were identified: MLL-MLLT11 and MYO18A-MLL, with the latter previously not reported. MLL gene rearrangement [t(9;11)], was also found in one of three relapsed AML cases. In a patient with acute bi-lineage leukemia both lymphoblasts and myeloblasts displayed t(4;11) translocation. Interestingly MLL-AFF1 fusion in this patient was accompanied by the fusion of the distal part of MLL to KIAA0999 gene on chromosome 11q23.3. Conclusions: In ALL patients MLL gene rearrangements are most frequent in infants (80% of cases) and very infrequent in older children (< 2%). Application of split-signal FISH as a screening for MLL gene rearrangements revealed unprecedentedly high incidence of these aberrations in childhood AML. Molecular analysis of MLL gene fusions and breakpoints shows several different mechanisms leading to these chromosome aberrations.