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A significant proportion of events in paediatric acute myeloid leukaemia (AML) are caused by resistant disease (RD). We investigated clinical and biological characteristics in 66 patients with RD from 1013 children with AML registered and treated according to the NOPHO-AML 93, NOPHO-AML 2004, DB AML-01 and NOPHO-DBH AML 2012 protocols. Risk factors for RD were age10 years or older and a white-blood-cell count (WBC) of 100 × 10 9 /L or more at diagnosis. The five-year overall survival (OS) was 38% (95% confidence interval [CI]: 28%-52%). Of the 63 children that received salvage therapy with chemotherapy, 59% (N = 37) achieved complete remission (CR) with OS 57% (95% CI: 42%-75%) compared to 12% (95% CI: 4%-35%) for children that did not achieve CR. Giving more than two salvage chemotherapy courses did not increase CR rates. OS for all 43 patients receiving allogeneic haematopoietic stem cell transplantation (HSCT) was 49% (95% CI: 36%-66%). Those achieving CR and proceeding to HSCT had an OS of 56% (95% CI: 41%-77%, N = 30). This study showed that almost 40% of children with primary resistant AML can be cured with salvage therapy followed by HSCT. Children that did not achieve CR after two salvage courses with chemotherapy did not benefit from additional chemotherapy.

In areas with suboptimal resources, blood transfusion may not be feasible even when mandatory for severely anemic children with a life-threatening disease. We evaluated how much not having received a transfusion affected the survival in 171 children with an admission blood hemoglobin level of < 6 g/dL and bacterial meningitis in Luanda, Angola. Of these children, 75% (128 of 171) had received a blood transfusion during hospitalization, but 25% (43 of 171) had not. Within the first week, 33% of patients (40 of 121) with transfusion and 50% (25 of 50) without a transfusion died (P = 0.04). Early transfusion (days 1–2 of hospitalization) prolonged the time of survival from a median of 132 hours [interquartile range (IQR), 15–168] to 168 hours (IQR, 69–168; P = 0.004), and had odds of 0.49 (95% CI, 0.25–0.97; P = 0.040) for death compared with no transfusion. The effect of transfusion/no transfusion at any time during hospitalization on mortality within 30 days, and prolongation of the time of survival were similar to early transfusion but showed even clearer benefits. Our results emphasize the value of timely transfusion in facilities that care for severely anemic children with severe infections to maximize their chances of survival.

Allogeneic hematopoietic stem cell transplantation (HSCT) provides patients with severe hematologic disease a well-established potential for curation. Incorporation of germline analyses in the workup of HSCT patients is not a common practice. Recognizing rare harmful germline variants may however affect patients’ pre-transplantation care, choice of the stem cell donor, and complication risks. We analyzed a population-based series of germline exome data of 432 patients who had undergone HSCT. Our aim was to identify clinically relevant variants that may challenge the outcome of the HSCT. We focused on genes predisposing to hematological diseases, or solid tumors, and genes included in the American College of Medical Genetics secondary findings list v3.0. As population-specific controls, we used GnomAD non-cancer Finns (n = 10,816). We identified in our population-based analysis rare harmful germline variants in disease-predisposing or actionable toxicity-increasing genes in 17.8% of adult and pediatric patients that have undergone HSCT (15.1% and 22.9%, respectively). More than half of the patients with a family member as a donor had not received genetic diagnosis prior to the HSCT. Our results encourage clinicians to incorporate germline genetic testing in the HSCT protocol in the future in order to reach optimal long-term outcome for the patients.

Myeloproliferative disease; Paediatrics Enfermedad mieloproliferativa; Pediatría Malaltia mieloproliferativa; Pediatria Open Access funding enabled and organized by Projekt DEAL.

Endocrine complications are a common late effect after childhood cancer. Our study assessed the prevalence and predictors of premature ovarian insufficiency (POI) and prospects of pregnancy in young female survivors. This nationwide study combined registry and survey data for female childhood cancer survivors aged 19 to 40 years, identified through the National Quality Registry for Childhood Cancer in Sweden. Of 1989 approached young women, 1333 (67%) participated by completing a survey. Median age at diagnosis 1981 to 2017 was 6 (range 0-17) and at study 28 (19-40) years. There were two indicators of POI, induced puberty reported in 5.3% and estrogen replacement therapy (ERT) in 9.3% at assessment. In separate logistic regression analyses (P

STUDY QUESTIONWhat is the impact of cancer or hematological disorders on germ cells in pediatric male patients?SUMMARY ANSWERSpermatogonial quantity is reduced in testes of prepubertal boys diagnosed with cancer or severe hematological disorder compared to healthy controls and this reduction is disease and age dependent: patients with central nervous system cancer (CNS tumors) and hematological disorders, as well as boys WHAT IS KNOWN ALREADYFertility preservation in pediatric male patients is considered based on the gonadotoxicity of selected treatments. Although treatment effects on germ cells have been extensively investigated, limited data are available on the effect of the disease on the prepubertal male gonad. Of the few studies investigating the effects of cancer or hematologic disorders on testicular function and germ cell quantity in prepuberty, the results are inconsistent. However, recent studies suggested impairments before the initiation of known gonadotoxic therapy. Understanding which diseases and at what age affect the germ cell pool in pediatric patients before treatment is critical to optimize strategies and counseling for fertility preservation.STUDY DESIGN, SIZE, DURATIONThis multicenter retrospective cohort study included 101 boys aged PARTICIPANTS/MATERIALS, SETTING, METHODSIn addition to clinical data, we analyzed measurements of testicular volume and performed histological staining on testicular biopsies obtained before treatment, at cryopreservation, to evaluate number of spermatogonia per tubular cross-section, tubular fertility index, and the most advanced germ cell type prior to chemo-/radiotherapy. The controls were data simulations with summary statistics from original studies reporting healthy prepubertal boys’ testes characteristics.MAIN RESULTS AND THE ROLE OF CHANCEPrepubertal patients with childhood cancer or hematological disorders were more likely to have significantly reduced spermatogonial quantity compared to healthy controls (48.5% versus 31.0% prevalence, respectively). The prevalence of patients with reduced spermatogonial quantity was highest in the CNS tumor (56.7%) and the hematological disorder (55.6%) groups, including patients with hydroxyurea pre-treated sickle cell disease (58.3%) and patients not exposed to hydroxyurea (50%). Disease also adversely impacted spermatogonial distribution and differentiation. Irrespective of disease, we observed the highest spermatogonial quantity reduction in patients LIMITATIONS, REASONS FOR CAUTIONFor ethical reasons, we could not collect spermatogonial quantity data in healthy prepubertal boys as controls and thus deployed statistical simulation on data from literature. Also, our results should be interpreted considering low patient numbers per (sub)group.WIDER IMPLICATIONS OF THE FINDINGSCancers, especially CNS tumors, and severe hematological disorders can affect spermatogonial quantity in prepubertal boys before treatment. Consequently, these patients may have a higher risk of depleted spermatogonia following therapies, resulting in persistent infertility. Therefore, patient counseling prior to disease treatment and timing of fertility preservation should not only be based on treatment regimes, but also on diagnoses and age.STUDY FUNDING/COMPETING INTEREST(S)This study was supported by Marie Curie Initial Training Network (ITN) (EU-FP7-PEOPLE-2013-ITN) funded by European Commision grant no. 603568; ZonMW Translational Adult stem cell research (TAS) grant no. 116003002. No competing interests.TRIAL REGISTRATION NUMBERN/A.

Despite improvement of current treatment strategies and novel targeted drugs, relapse and treatment resistance largely determine the outcome for acute myeloid leukemia (AML) patients. To identify the underlying molecular characteristics, numerous studies have been aimed to decipher the genomic- and transcriptomic landscape of AML. Nevertheless, further molecular changes allowing malignant cells to escape treatment remain to be elucidated. Mass spectrometry is a powerful tool enabling detailed insights into proteomic changes that could explain AML relapse and resistance. Here, we investigated AML samples from 47 adult and 22 pediatric patients at serial time-points during disease progression using mass spectrometry-based in-depth proteomics. We show that the proteomic profile at relapse is enriched for mitochondrial ribosomal proteins and subunits of the respiratory chain complex, indicative of reprogrammed energy metabolism from diagnosis to relapse. Further, higher levels of granzymes and lower levels of the anti-inflammatory protein CR1/CD35 suggest an inflammatory signature promoting disease progression. Finally, through a proteogenomic approach, we detected novel peptides, which present a promising repertoire in the search for biomarkers and tumor-specific druggable targets. Altogether, this study highlights the importance of proteomic studies in holistic approaches to improve treatment and survival of AML patients. Title in the list of papers of Svea Stratmann thesis: Proteogenomic analysis of relapsed acute myeloid leukemia in adults and childrenAuthors in the list of papers of Svea Stramann: S. Stratmann, M. Vesterlund, H.M. Umer, A. Skaftason, M. Krogh Herlin, C. Sundström, A. Eriksson, M. Höglund, J. Palle, J. Abrahamson, K. Jahnukainen, M. Cheng Munthe-Kaas, B. Zeller, K. Pokrovskaja Tamm, L. Cavelier, J. Lehtiö, L. Holmfeld

Children with Down syndrome (DS) are at a significantly higher risk of developing acute myeloid leukemia, also termed myeloid leukemia associated with DS (ML-DS). In contrast to the highly favorable prognosis of primary ML-DS, the limited data that are available for children who relapse or who have refractory ML-DS (r/r ML-DS) suggest a dismal prognosis. There are few clinical trials and no standardized treatment approach for this population. We conducted a retrospective analysis of international study groups and pediatric oncology centers and identified 62 patients who received treatment with curative intent for r/r ML-DS between 2000-2021. Median time from diagnosis to relapse was 6.8 (range 1.1 - 45.5) months. Three-year event-free (EFS) and overall survival (OS) were 20.9±5.3% and 22.1±5.4%, respectively. Survival was associated with receipt of hematopoietic stem cell transplantation (HSCT) (HR 0.28), duration of first complete remission (CR1) (HR 0.31 for > 12 months) and attainment of remission after relapse (HR 4.03). Patients who achieved CR prior to HSCT, had an improved OS and EFS of 56.0±11.8% and 50.5±11.9% respectively, compared to those who underwent HSCT without CR (3-year OS and EFS of 10.0±9.5%). Treatment failure after HSCT was predominantly due to disease recurrence (52%) followed by treatment related mortality (10%). The prognosis of r/r ML-DS remains dismal even in the current treatment period and serve as a reference point for current prognostication and future interventional studies. Clinical trials aimed at improving the survival of patients with r/r ML-DS are needed.

Biallelic germline ERCC6L2 variants strongly predispose to bone marrow failure (BMF) and myeloid malignancies characterized by somatic TP53-mutated clones and erythroid predominance. We present a series of 52 subjects (35 families) with ERCC6L2 biallelic germline variants collected retrospectively in 11 centers globally, including follow-up of 1165 person-years. At initial investigations, 32 individuals were diagnosed with BMF and 15 with a hematological malignancy (HM). Subjects presented with 19 different variants across ERCC6L2, and we identified a founder mutation c.1424delT in the Finnish patients. The median age of subjects at baseline was 18 years (range 2-65). Changes in complete blood count (CBC) were mild despite severe bone marrow hypoplasia and somatic TP53 mutations, with no significant difference between subjects with or without (HM). Signs of a progressive disease were increasing TP53 variant allele frequency, dysplasia in megakaryocytes and/or erythroid lineage, and erythroid predominance in bone marrow morphology. The median age at onset of HM was 37.0 years (95% CI: 31.5-42.5; range 12-65). Overall survival (OS) at 3 years was 95% (95% CI: 85-100) and 19% (95% CI: 0-39) for patients with BMF and HM, respectively. Patients with myelodysplastic syndrome or acute myeloid leukemia with mutated TP53 undergoing hematopoietic stem cell transplantation had a poor outcome: 3-year OS is 28% (95% CI: 0-61). Our results demonstrate the importance of early recognition and active surveillance of patients with biallelic germline ERCC6L2 variants.

Treatment-related mortality and morbidity remain a challenge in hematopoietic stem cell transplantation (HSCT). In this retrospective, single-center study, we analyzed endothelial damage as a potential, common denominator and mechanism for the adverse effects. We evaluated the prevalence of key vascular complications and graft-versus-host disease among 122 pediatric patients with an allogeneic HSCT between 2001 and 2013. The spectrum and frequency of acute adverse events emerging ≤100 days post transplant were graded according to the CTCAE 4.03 and analyzed. We identified a total of 19/122 (15.6%) patients with vascular complications, fulfilling the criteria of capillary leak syndrome, veno-occlusive disease/sinusoidal obstruction syndrome or thrombotic microangiopathy. The patients had a poorer overall survival (77% versus 26%, p p = 0.023), thrombocytopenia (p = 0.001), gastrointestinal bleeding (p p p p = 0.027). These endotheliopathy-related adverse events appeared early post HSCT, varied in their clinical phenotype and predicted a poor outcome. An unrelated donor but not previous exposure to leukemia or irradiation-based conditioning was identified as a risk factor for vascular complications and endotheliopathy.

Human primordial germ cells (hPGCs), the precursors of sperm and eggs, are specified during weeks 2-3 after fertilization. Few studies on ex vivo and in vitro cultured human embryos reported plausible hPGCs on embryonic day (E) 12-13 and in an E16-17 gastrulating embryo. In vitro, hPGC-like cells (hPGCLCs) can be specified from the intermediary pluripotent stage or peri-gastrulation precursors. Here, we explore the broad spectrum of hPGCLC precursors and how different precursors impact hPGCLC development. We show that resetting precursors can give rise to hPGCLCs (rhPGCLCs) in response to BMP. Strikingly, rhPGCLCs co-cultured with human hindgut organoids progress at a pace reminiscent of in vivo hPGC devel-opment, unlike those derived from peri-gastrulation precursors. Moreover, rhPGCLC specification depends on both EOMES and TBXT, not just on EOMES as for peri-gastrulation hPGCLCs. Importantly, our study pro-vides the foundation for developing efficient in vitro models of human gametogenesis.

Objective: To determine the prevalence of sexual dysfunction and to identify the factors associated with sexual dysfunction in young adult childhood cancer survivors. Methods: All survivors of childhood cancer (aged 19-40 years) in Sweden were invited to this population-based study, and 2546 men and women (59%) participated. Sexual function was examined with the PROMIS Sexual Function and Satisfaction Measure. Logistic regression was used to assess the differences between survivors and a general population sample (n = 819) and to identify the factors associated with sexual dysfunction in survivors. Results: Sexual dysfunction in at least one domain was reported by 57% of female and 35% of male survivors. Among females, dysfunction was most common for Sexual interest (36%), Orgasm -ability (32%) and Vulvar discomfort -labial (19%). Among males, dysfunction was most common for the domains satisfaction with sex life (20%), Sexual interest (14%) and Erectile function ( 9%). Compared with the general population, male survivors more frequently reported sexual dysfunction in >2 domains (OR = 1.67, 95% CI: 1.03-2.71), with an increased likelihood of dysfunction regarding Orgasm -ability (OR = 1.82; 95% CI: 1.01-3.28) and Erectile function (OR = 2.30; 95% CI: 1.18-4.49). Female survivors reported more dysfunction regarding Orgasm pleasure (9% versus 5%, OR Z 1.86; 95% CI: 1.11-3.13). A more intensive cancer treatment, emotional distress and body image disturbance were associated with sexual dysfunction in survivors. Conclusions: The findings underscore the need for routine assessment of sexual health in follow-up care of childhood cancer survivors and highlight that those treated with more intensive cancer treatment and who experience concurrent psychological concerns may benefit from targeted screening and interventions. 2021 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Publisher Copyright: Copyright © 2022 The Author(s). Sickle cell disease (SCD) was found in 10% of children with bacterial meningitis (BM) in Luanda, 5-fold more than in the general population. BM children with SCD versus BM children without SCD had higher inflammatory markers, more often had pneumococcal meningitis (71% vs. 39%), and either died (39% vs. 22%) or had a longer hospital stay (15 vs. 11 days).

Patients with childhood, adolescent, and young adult cancer who will be treated with gonadotoxic therapies are at increased risk for infertility. Many patients and their families desire biological children but effective communication about treatment-related infertility risk and procedures for fertility preservation does not always happen. The PanCareLIFE Consortium and the International Late Effects of Childhood Cancer Guideline Harmonization Group reviewed the literature and developed a clinical practice guideline that provides recommendations for ongoing communication methods for fertility preservation for patients who were diagnosed with childhood, adolescent, and young adult cancer at age 25 years or younger and their families. Moreover, the guideline panel formulated considerations of the ethical implications that are associated with these procedures. Grading of Recommendations Assessment, Development and Evaluation methodology was used to grade the evidence and recommendations. In this clinical practice guideline, existing evidence and international expertise are combined to develop transparent recommendations that are easy to use to facilitate ongoing communication between health-care providers and patients with childhood, adolescent, and young adult cancer who might be at high risk for fertility impairment and their families.

Changes in body composition related to metabolic syndrome are frequent among survivors of haematopoietic stem cell transplantation (HSCT), but insights into predisposing factors are incomplete, and it is unknown to what degree these changes persist at long term. We cross-sectionally investigated body composition by dual-energy X-ray absorptiometry in 98 male survivors of paediatric allogeneic HSCT. Median (range) age at follow-up was 28.1 (18.5-47.0) years and median (range) time from transplant was 18.3 (7.7-34.6) years. Lean Body Mass Index and Skeletal Muscle Mass Index were lower in patients compared to the reference population (mean (SD) standard deviation score (SDS) -1.29 (0.99), p < 0.001 and -1.20 (1.03), p < 0.001). Fat Mass Index was comparable to the reference population, but android/gynoid (AG) fat ratio SDS was higher (mean (SD) 0.46 (1.28), p < 0.001). These changes were found in patients treated with total body irradiation (TBI) as well as non-TBI regimens, although most pronounced in the former. Further, low lean mass was associated with chronic graft-versus-host disease, while high AG ratio was associated with lower testosterone levels. Since the combination of low lean mass and high AG ratio increases the risk of cardio-metabolic disease, these health issues should be monitored at long-term clinical follow-up after paediatric HSCT.

Male gonadal dysfunction is a frequent late effect after pediatric hematopoietic stem cell transplantation (HSCT), but detailed insight into patterns of male gonadal function at long-term is limited by retrospective studies without semen sample data. In this study, we investigated the risk of azoospermia and testosterone deficiency, the diagnostic value of markers of spermatogenesis, and paternity at long-term follow-up after pediatric allogeneic HSCT. All male HSCT survivors age ≥18 years, transplanted in Denmark or Finland between 1980 and 2010, were invited to participate in this cross-sectional study. Examinations included a semen sample, measurements of reproductive hormones and testicular volume, and screening for chronic graft-versus-host disease (GVHD). Cumulative (pre-HSCT plus HSCT) treatment doses were calculated. Of 181 eligible patients, 98 participated, at a median 18 years (range, 8 to 35 years) after undergoing HSCT. Sperm was found in 30 patients, azoospermia in 42, and azoospermia during testosterone substitution in 24. A higher cumulative testicular irradiation dose was associated with increased risk of azoospermia and testosterone substitution (odds ratio [OR] per +1 Gy, 1.27; 95% confidence interval [CI], 1.14 to 1.46 [P 12 Gy had azoospermia, and all but 1 patient treated with >16 Gy needed testosterone substitution. In patients treated with chemotherapy only (n = 23), a higher cumulative cyclophosphamide equivalent dose was associated with an increased risk of azoospermia (OR per +1 g/m2, 1.34; 95% CI, 1.01 to 2.15; P = .037). Prepubertal stage at HSCT was a risk factor for testosterone substitution (OR, 15.31; 95% CI, 2.39 to 315; P = .017), whereas chronic GVHD was unrelated to gonadal dysfunction. Inhibin B was the best surrogate marker of azoospermia (area under the curve, .91; 95% CI, .85 to .98; 90% sensitivity and 83% specificity) compared with follicle-stimulating hormone and testicular volume. Of 24 males who had attempted to conceive, 6 had fathered children. In conclusion, the risk of male gonadal dysfunction after pediatric HSCT is high and depends primarily on the cumulative testicular irradiation dose and pubertal stage at transplantation. Our findings support the need for fertility preservation before HSCT, as well as for prolonged follow-up of pediatric HSCT recipients into adulthood.

Background Data on adult sexual functioning after kidney transplantation (KTx) during childhood or adolescence are scarce. Aim To assess the long-term sexual and psychosocial quality of life after pediatric KTx. Methods 29 young men (median age 27.1 years) were examined 18.7 years (median) after KTx. 56 age-matched healthy men (median age 30.0 years) served as controls. Outcome We studied the influence of sociodemographics, previous renal replacement therapy, current reproductive hormonal serum levels, testicular size, and data on several validated mental and physical questionnaires on participants' Derogatis Interview for Sexual Functioning self-report scores. Results The KTx recipients had significantly poorer sexual functioning than their healthy peers. KTx men had less frequent sexual activity with a partner (P = .03) and poorer orgasms (P = .002) than the controls but no erectile dysfunction (P = .5). Clinical implications Depressive symptoms, relationship status, and longer dialysis duration predicted poor adult sexual functioning in KTx recipients, whereas age at transplantation or at the time of the study did not. Strengths & Limitations This study contributes extended follow-up data to the very scarce literature on adult sexual functioning in pediatric KTx recipients. Relatively small population and low participation rate limit the comprehensive data interpretation in a population-based cohort of male KTx recipients. Conclusion Sexual functioning is often impaired in young men after pediatric KTx, emphasizing the need for long-term monitoring of sexual health and sexuality as important dimensions of quality of life.

The increasing cure rate of cancer has led to a vast population of survivors having to face the late adverse effects of oncological treatments, with fertility impairment being one of the most sensitive issues for patients. Different options to preserve the fertility of adult patients are routinely used in clinical practice. However, fertility preservation strategies for prepubertal patients at risk of infertility are limited to the cryopreservation of immature gonadal tissue. In recent decades, many research efforts have been focused on the future use of cryopreserved gonadal tissue. This review discusses the common status of fertility preservation measures for pediatric patients undergoing gonadotoxic treatment, focusing especially on the challenges that remain to be solved in order to implement this fundamental service.

Objective: To normalize age-dependent effects on standardized measures of spermatogonial quantity such as the number of spermatogonia per tubular cross-section (S/T) or fertility index. Design: Published quantitative histologic data on human spermatogonial numbers were used to create Z-scores for reference means and tested on archived testicular tissue samples. Setting: Retrospective cohort study. Patient(s): The sample cohort comprised testicular samples from 24 boys with cancer diagnosis and 10 with Klinefelter syndrome, as part of the fertility preservation programs NORDFERTIL and Androprotect, as well as archived histologic samples from 35 prepubertal boys with acute lymphoblastic leukemia and 20 testicular biobank samples. Intervention(s): None. Main Outcome Measure(s): Z-score values for S/T and fertility index on the basis of morphology and germ cell-specific markers (MAGEA4 and/or DDX4) were calculated, and the impact of cancer therapy exposure and genetic disorders on Z-score values was evaluated. Result(s): The Z-scores for S/T values in the nontreated samples (-2.08 +/- 2.20, n = 28) and samples treated with nonalkylating agents (-1.90 +/- 2.60, n = 25) were comparable within +/- 3 standard deviations of the reference mean value but differed significantly from samples exposed to alkylating agents (-12.14 +/- 9.20, n = 22) and from patients with Klinefelter syndrome (-11.56 +/- 4.89, n = 8). The Z-scores for S/T were correlated with increasing cumulative exposure to alkylating agents (r = -0.7020). Conclusion(s): The Z-score values for S/T allow for the quantification of genetic and cancer treatment-related effects on testicular tissue stored for fertility preservation, facilitating their use for patient counseling. (C) 2021 by American Society for Reproductive Medicine.

Male gonadal dysfunction is a frequent late effect after pediatric hematopoietic stem cell transplantation (HSCT) that can lead to disturbances in pubertal development, sexual dysfunction, and infertility. However, no systematic review exists regarding prevalence and risk factors in relation to different treatment regimens. We aimed to systematically evaluate the current evidence regarding the prevalence of male gonadal dysfunction after pediatric HSCT, related risk factors, and the diagnostic value of surrogate markers of spermatogenesis in this patient group. We searched PubMed and Embase using a combination of text words and subject terms. The eligibility screening was conducted using predefined criteria. Data were extracted corresponding to the Leydig cell compartment involved in testosterone production and the germ cell compartment involved in spermatogenesis, respectively. Subsequently, data synthesis was performed. Of 2369 identified records, 25 studies were eligible. The studies were heterogeneous in terms of included diagnoses, gonadotoxic therapy, follow-up time, and definitions of gonadal dysfunction. The data synthesis revealed a preserved Leydig cell function in patients treated with non-total body irradiation (TBI) regimens, whereas the evidence regarding the impact of TBI conditioning on Leydig cell function was conflicting. Based on surrogate markers of spermatogenesis and only limited data on semen quality, the germ cell compartment was affected in half of the patients treated with non-TBI regimens and in nearly all patients treated with TBI conditioning. Testicular irradiation as part of front-line therapy before referral to HSCT led to complete Leydig cell failure and germ cell failure. Evidence regarding the impact of diagnosis, pubertal stage at HSCT, and chronic graft-versus-host disease is limited, as is the evidence of the diagnostic value of surrogate markers of spermatogenesis. Testicular irradiation as part of front-line therapy and TBI conditioning are the main risk factors associated with male gonadal dysfunction after pediatric HSCT; however, impaired spermatogenesis is also observed in half of the patients treated with non-TBI regimens. Methodological shortcomings limit existing evidence, and future studies should include semen quality analyses, follow-up into late adulthood, and evaluation of the cumulative exposure to gonadotoxic therapy.

Pediatric acute myeloid leukemia (AML) is a heterogeneous disease composed of clinically relevant subtypes defined by recurrent cytogenetic aberrations. The majority of the aberrations used in risk grouping for treatment decisions are extensively studied, but still a large proportion of pediatric AML patients remain cytogenetically undefined and would therefore benefit from additional molecular investigation. As aberrant epigenetic regulation has been widely observed during leukemogenesis, we hypothesized that DNA methylation signatures could be used to predict molecular subtypes and identify signatures with prognostic impact in AML. To study genome-wide DNA methylation, we analyzed 123 diagnostic and 19 relapse AML samples on Illumina 450k DNA methylation arrays. We designed and validated DNA methylation-based classifiers for AML cytogenetic subtype, resulting in an overall test accuracy of 91%. Furthermore, we identified methylation signatures associated with outcome in t(8, 21)/RUNX1-RUNX1T1, normal karyotype, and MLL/KMT2A-rearranged subgroups (p &lt, 0.01). Overall, these results further underscore the clinical value of DNA methylation analysis in AML.

Chemotherapy may result in ovarian atrophy, a depletion of the primordial follicle pool, diminished ovarian weight, cortical and stromal fibrosis. Imatinib mesylate is an anticancer agent that inhibits competitively several receptor tyrosine kinases (RTKs). RTKs play important roles in cell metabolism, proliferation, and apoptosis. In clinic, imatinib mesylate is also known as an anti-fibrotic medicine. In the present study, the impact of imatinib on the ovarian tissue was investigated by assessing ovarian tissue fibrosis in postnatal rat administered with or without imatinib for three days. Fibrosis in the ovarian tissue was determined by histology (Picrosirius and Masson's trichrome staining) and the protein expression of vimentin and alpha-smooth muscle actin (alpha-SMA). Furthermore, mRNA expression of Forkhead box transcription factor O1 and O3 (FOXO1 and FOXO3), which are markers of cell proliferation was quantified. A short-term exposure to imatinib showed to increase tissue fibrosis in ovaries. This was observed by Masson's trichrome staining. Exposure to imatinib led also to a down-regulation of vimentin protein expression and up-regulation mRNA expression of FOXO3. This may indicate a role of FOXO3 in ovarian tissue fibrosis in postnatal rat ovaries.