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Simple Summary: Our findings confirm the role of developmental aspects in extracranial germ cell tumors (eGCTs). Strong associations between syndromes or congenital anomalies and eGCTs may hint at the need for research to identify potential causes and mechanisms. Strong effects were observed for Swyer and Currarino syndrome. The strengths of the associations emphasize the need for further elaboration on presently discussed pathophysiological mechanisms. For other suggested risk factors such as Klinefelter, Turner, and Down syndrome, the strength of risk appears to be substantially low and may be missed because of diagnostic bias for the first two or lack of power for the latter. A number of further syndromes were identified in single cases. Most of these pertain to girls. GCTs are developmental tumors and are likely to reflect ontogenetic and teratogenetic determinants. The objective of this study was to identify syndromes with or without congenital anomalies and non-syndromic defects as potential risk factors. Patients with extracranial GCTs (eGCTs) registered in MAKEI 96/MAHO 98 between 1996 and 2017 were included. According to Teilum's holistic concept, malignant and benign teratomas were registered. We used a case–control study design with Orphanet as a reference group for syndromic defects and the Mainz birth registry (EUROCAT) for congenital anomalies at birth. Co-occurring genetic syndromes and/or congenital anomalies were assessed accordingly. Odds ratios and 95% confidence intervals were calculated and p-values for Fisher's exact test with Bonferroni correction if needed. A strong association was confirmed for Swyer (OR 338.6, 95% CI 43.7–2623.6) and Currarino syndrome (OR 34.2, 95% CI 13.2–88.6). We additionally found 16 isolated cases of eGCT with a wide range of syndromes. However, these were not found to be significantly associated following Bonferroni correction. Most of these cases pertained to girls. Regarding non-syndromic defects, no association with eGCTs could be identified. In our study, we confirmed a strong association for Swyer and Currarino syndromes with additional congenital anomalies. [ABSTRACT FROM AUTHOR]

Simple Summary: The treatment options for children with recurrent medulloblastoma are often limited due to extensive previously received treatments after initial diagnosis. Especially, repeated radiotherapy is associated with significant side-effects. In this study, we study the impact on survival of repeated radiotherapy at recurrence for patients with previous irradiation, as well as first irradiation at recurrence when no previous radiotherapy was applied. We find that repeated radiotherapy provides a short-time benefit in terms of survival, but survival ten years after recurrence is not significantly improved. At the same time, we find that applying radiotherapy at recurrence when patients received no previous irradiation did significantly improve survival, both short and long term. Background: Radiotherapy (RT) involving craniospinal irradiation (CSI) is important in the initial treatment of medulloblastoma. At recurrence, the re-irradiation options are limited and associated with severe side-effects. Methods: For pre-irradiated patients, patients with re-irradiation (RT2) were matched by sex, histology, time to recurrence, disease status and treatment at recurrence to patients without RT2. Results: A total of 42 pre-irradiated patients with RT2 were matched to 42 pre-irradiated controls without RT2. RT2 improved the median PFS [21.0 (CI: 15.7–28.7) vs. 12.0 (CI: 8.1–21.0) months] and OS [31.5 (CI: 27.6–64.8) vs. 20.0 (CI: 14.0–36.7) months]. Concerning long-term survival after ten years, RT2 only lead to small improvements in OS [8% (CI: 1.4–45.3) vs. 0%]. RT2 improved survival most without (re)-resection [PFS: 17.5 (CI: 9.7–41.5) vs. 8.0 (CI: 6.6–12.2)/OS: 31.5 (CI: 27.6–NA) vs. 13.3 (CI: 8.1–20.1) months]. In the RT-naïve patients, CSI at recurrence improved their median PFS [25.0 (CI: 16.8–60.6) vs. 6.6 (CI: 1.5–NA) months] and OS [40.2 (CI: 18.7–NA) vs. 12.4 (CI: 4.4–NA) months]. Conclusions: RT2 could improve the median survival in a matched cohort but offered little benefit regarding long-term survival. In RT-naïve patients, CSI greatly improved their median and long-term survival. [ABSTRACT FROM AUTHOR]

Simple Summary: The aim of this study was to retrospectively analyze the characteristics and treatment outcomes of adolescents with AML compared to children and infants treated, according to the two consecutive BFM protocols. It showed that overall survival did not differ significantly between adolescents and children aged 1 to 15 years. However, relapse-free survival was shorter in adolescents compared to younger children, and treatment-related mortality tended to be higher. High-risk genetics and a leukocyte count above 100,000/μL at diagnosis, rather than age above 15 years, proved to be unfavorable prognostic factors for the treatment outcome. Background: The reports of studies that compare the survival of adolescents and young adults with younger children with acute myeloid leukemia (AML) are contradictory. Patients and Methods: We retrospectively analyzed 220 AML patients aged 0–18 years treated in pediatric oncologic centers in Poland from 2015 to 2022. The evaluated group included 31 infants (below 1 year), 91 younger children (1–9.9 years), 59 older children (10–14.9 years), and 39 adolescents (15–18 years). Results: A 5-year overall survival for adolescents was not significantly inferior compared to younger and older children (74.3 ± 7.6% vs. 80.5 ± 4.4% vs. 77.9 ± 5.1, p = 0.243). However, relapse-free survival was lower in adolescents compared to younger children (76.5 ± 7.8% vs. 65.7 ± 9.0%, p = 0.049), and treatment-related mortality tended to be higher (10.3% vs. 4.4%, p = 0.569). In the univariate analysis, high-risk genetics [HR, 2.0 (95% CI 1.1–3.6; p = 0.014)] and a leukocyte count at diagnosis above 100,000/μL [HR, 2.4 (95% CI 1.3–4.6; p = 0.004)] were found to be unfavorable prognostic factors for survival. Conclusions: Although we have not found that age over 15 years is an unfavorable factor for overall survival, the optimal approach to therapy in adolescents, as in other age groups, is to adjust the intensity of therapy to individual genetic risk and introduce targeted therapies when indicated. [ABSTRACT FROM AUTHOR]

Simple Summary: A few large series of cases of extracranial germ cell tumors (GCTs) are reported in Asian children. We present a retrospective analysis of extensive scale data of pediatric extracranial GCTs from multiple centers in China. The pathological subtypes and primary sites of tumors showed a preference for occurrence at different ages. For example, sacrococcygeal tumors mostly occur in infants, while mediastinal tumors are common in adolescents. In the context of treatment strategies including platinum-based various chemotherapy regimens, the 5-year overall survival rate and event-free survival rates were 94.13% and 82.33%, respectively. There is no difference in overall survival rate among different chemotherapy regimens for children. The independent clinical factors associated with poor prognosis were that the primary tumor is located in the mediastinum and alpha-fetoprotein levels greater than 10,000 ng/L. In conclusion, the incidence rate and clinical features of extracranial GCTs in children in China are similar to those reported in Europe and the United States. The age distribution of various pathological types and primary sites reflect the characteristics of tumor cell origin of primordial germ cell (PGC) mismigration. For the malignant germ cell tumor with the primary site of mediastinum, more effective treatment regiments should be explored. Objective: The aim was to describe the clinical features of extracranial germ cell tumors (GCTs) in pediatrics and study the clinical risk factors related to survival for malignant germ cell tumors (MGCTs) in order to optimize therapeutic options. Methods: The clinical data of children with extracranial GCTs in three children's medical centers in Shanghai were retrospectively analyzed. Results: In total, 1007 cases of extracranial GCTs diagnosed between 2010 and 2019 were included in this study, including teratomas (TERs) 706 (70.11%) and MGCTs 301 (29.89%). There were twice as many TER cases as MGCT cases. Approximately 50% of children with GCTs were <3 years old (43.39% for TERs, 67.13% for MGCTs). GCTs in children of different ages show differences in tumor anatomical locations and pathological subtypes. The 5-year event-free survival (EFS) and overall survival (OS) of all patients with MGCTs were 82.33% (95% CI, 77.32%, 86.62%) and 94.13% (95% CI, 90.02%, 96.69%), respectively. The multivariate Cox regression analysis identified a primary site in the mediastinum and alpha fetoprotein (AFP) levels ≥10,000 ng/mL as independent adverse prognostic factors (p < 0.0.0001, χ2 = 23.6638, p = 0.0225, χ2 = 5.2072.). There were no significant differences in OS among children receiving various chemotherapy regimens, such as the BEP, PEB, JEB and other regimens (VBP/VIP and AVCP/IEV) (p < 0.05). Conclusions: The clinical features of GCTs in Chinese pediatrics are similar to those reported in children in Europe and America. The age distribution of pathological types and primary sites in GCTs reflect the developmental origin of type I and type II GCTs transformed from mismigration primordial germ cells (PGCs). Optimizing the current platinum-based chemotherapy regimens and exploring the treatment strategies for MGCTs of the mediastinum are future research directions. [ABSTRACT FROM AUTHOR]

Simple Summary: Medulloblastoma is one of the most common malignant brain tumor types and comprises the molecular groups WNT-MB, SHH-MB TP53-wildtype, SHH-MB TP53-mutant and non-WNT/non-SHH MB. Developmental gene expression data suggest that these molecular groups arise from different sites of origin in the developing brain. Therefore, we hypothesized that intraoperative observation could enable the neurosurgeon to predict the molecular group during surgery and opt for a less aggressive resection in molecular groups with favorable prognosis to preserve neurological function. We reviewed the intraoperative reports, surgical videos and information on the molecular group of 58 patients who were operated at our institution from 1996 to 2020. Our data demonstrate that the correct prediction of the molecular group based on the intraoperatively observed site of origin was limited. Based on our results, we conclude that maximal safe resection should remain the aim of surgery irrespective of the observed site of origin. Developmental gene expression data from medulloblastoma (MB) suggest that WNT-MB originates from the region of the embryonic lower rhombic lip (LRL), whereas SHH-MB and non-WNT/non-SHH MB arise from cerebellar precursor matrix regions. This study aimed to analyze detailed intraoperative data with regard to the site of origin (STO) and compare these findings with the hypothesized regions of origin associated with the molecular group. A review of the institutional database identified 58 out of 72 pediatric patients who were operated for an MB at our department between 1996 and 2020 that had a detailed operative report and a surgical video as well as clinical and genetic classification data available for analysis. The STO was assessed based on intraoperative findings. Using the intraoperatively defined STO, "correct" prediction of molecular groups was feasible in 20% of WNT-MB, 60% of SHH-MB and 71% of non-WNT/non-SHH MB. The positive predictive values of the neurosurgical inspection to detect the molecular group were 0.21 (95% CI 0.08–0.48) for WNT-MB, 0.86 (95% CI 0.49–0.97) for SHH-MB and 0.73 (95% CI 0.57–0.85) for non-WNT/non-SHH MB. The present study demonstrated a limited predictive value of the intraoperatively observed STO for the prediction of the molecular group of MB. [ABSTRACT FROM AUTHOR]

Simple Summary: After the Fukushima nuclear power plant accident in Japan on 11 March 2011, thyroid ultrasound examinations (TUEs) were conducted as part of the Fukushima health management survey (FHMS) by the Fukushima Medical University (FMU) on all residents aged ≤18 years at the time of the accident. The results showed a dozens-fold increase in thyroid cancer detection (97% papillary thyroid cancer, PTC) compared with the expected incidence from the cancer registry. More than 350 thyroid cancer patients endured poor health, being unable to disclose that they had PTC surgery due to the official stance that the nuclear accident caused no health effects. Without any international recognition of at least one adverse health effect of radiation exposure, the situation experienced by patients in Fukushima might be experienced by people exposed in the next nuclear accident. Young patients should be able to undergo appropriate operations and receive the most efficient treatments with sympathy and support from both government and society. The FMU and the United Nations Scientific Committee on the Effects of Atomic Radiation (UNSCEAR) concluded that the high incidence of thyroid cancer after the Fukushima nuclear accident was not the result of radiation exposure, but rather might have been overdiagnosis based on the low thyroid dose estimated in the UNSCEAR 2020/2021 report. In this study, the origin of increased PTC in Fukushima was examined based on the thyroid dose estimated by UNSCEAR. The dose–response relationship of the incidence rate per person-years (PY) was analyzed for four areas in Fukushima prefecture via regression analysis. The linear response of the annual incidence rates to thyroid dose in the first six years showed that the dominant origin of childhood thyroid cancer was radiation exposure. Excess absolute risk (EAR) proportionally increased with thyroid dose, with an EAR/104 PY Gy of 143 (95%CI: 122, 165) in the second TUE (p < 0.001), which is approximately 50–100 times higher than the EAR/104 PY Gy ≒ 2.3 observed after the Chernobyl accident. This suggests an underestimation of the thyroid dose by UNSCEAR of approximately 1/50~1/100 compared with the thyroid dose for Chernobyl. The increased childhood thyroid cancer in Fukushima was found to arise from radioactive iodine exposure, which was comparable to that in Chernobyl. [ABSTRACT FROM AUTHOR]

Simple Summary: Limited effective therapies exist for the treatment of neurofibromatosis type 1 (NF1)-associated plexiform neurofibroma (PN). The aim of our prospective clinical trial was to evaluate the activity and safety of vinblastine and methotrexate (conventional cytotoxic chemotherapies) given on a metronomic schedule in children and young adults with NF1 and PN. Of the 23 participants evaluable for treatment outcomes and toxicities, 14 completed all protocol therapy. There were no participants that discontinued therapy due to dose-limiting toxicities. In addition, there were no participants that demonstrated a partial response. VBL/MTX was well-tolerated but did not result in objective volumetric responses. Limited therapies exist for neurofibromatosis type 1 (NF1)-associated plexiform neurofibroma (PN). For this reason, the activity of vinblastine (VBL) and methotrexate (MTX) was evaluated in children and young adults with NF1 and PN. Patients ≤ 25 years of age with progressive and/or inoperable NF1-PN received VBL 6 mg/m2 and MTX 30 mg/m2 weekly for 26 weeks, followed by every 2 weeks for 26 weeks. Objective response rate was the primary endpoint. Of 25 participants enrolled, 23 were evaluable. The median age of participants was 6.6 years (range 0.3–20.7). The most frequent toxicities were neutropenia and elevation of transaminases. On two-dimensional (2D) imaging, 20 participants (87%) had stable tumor, with a median time to progression of 41.5 months (95% confidence interval 16.9, 64.9). Two of eight participants (25%) with airway involvement demonstrated functional improvements including decreased positive pressure requirements and apnea-hypopnea index. A post hoc three-dimensional (3D) analysis of PN volumes was completed on 15 participants with amenable imaging; 7 participants (46%) had progressive disease on or by the end of therapy. VBL/MTX was well-tolerated but did not result in objective volumetric response. Furthermore, 3D volumetric analysis highlighted the lack of sensitivity of 2D imaging for PN response evaluation. [ABSTRACT FROM AUTHOR]

Simple Summary: Lymphomas related to HIV are generally aggressive and have a poor prognosis, despite the use of effective combined antiretroviral therapy (cART) and effective chemotherapy treatment. This study aimed to evaluate, for the first time, survival and prognostic factors in children and adolescents living with HIV (CLWH) with lymphomas in Rio de Janeiro (RJ), Brazil. Our study population showed reduced overall, event-free, and disease-free survival probabilities. Performance status 4 (PS 4) and low CD4+ T-cell counts were considered poor prognostic factors. This study was designed to improve the quality of HIV-related lymphoma treatment in our population. Lymphomas related to HIV are generally aggressive and have a poor prognosis, despite the use of combined antiretroviral therapy (cART) and effective chemotherapy treatment. To determine survival and prognostic factors in children and adolescents living with HIV (CLWH) in Rio de Janeiro (RJ), Brazil, who developed lymphomas, we performed a retrospective and observational study of vertically infected CLWH aged from 0 to 20 incomplete years during1995 to 2018 at five reference centers for cancer and HIV/AIDS treatment. Of the 25 lymphomas, 19 were AIDS-defining malignancies (ADM) and 6 were non-AIDS-defining malignancies (NADM). The 5-year overall survival (OS) and 5-year event-free survival (EFS) probabilities were both 32.00% (95% CI = 13.72–50.23%), and the 5-year disease-free survival (DFS) probability was 53.30% (95% CI = 28.02–78.58%). In the multivariate Cox regression analysis, performance status 4 (PS 4) was considered a poor prognostic factor for OS (HR 4.85, 95% CI = 1.81–12.97, p = 0.002) and EFS (HR 4.95, 95% CI = 1.84–13.34, p = 0.002). For the DFS, higher CD4+ T-cell counts were considered a better prognostic factor (HR 0.86, 95% CI = 0.76–0.97, p = 0.017) in the multivariate Cox regression analysis. This study demonstrates, for the first time, survival and prognostic factors for CLWH who developed lymphomas in RJ, Brazil. [ABSTRACT FROM AUTHOR]

Simple Summary: In children undergoing allogenic HCT, invasive fungal infections are a significant cause of mortality, for which ECIL-8 have proposed systematic primary prophylaxis. This study evaluates our local strategy of not systematizing it, and reveals a similar IFI incidence and mortality rate. Background: Allogenic hematopoietic stem cell transplantation (a-HCT) remains a therapeutic treatment for many pediatric hematological diseases. The occurrence of invasive fungal infections (IFIs) is a complication for which ECIL-8 recommends primary antifungal prophylaxis. In this study, we evaluated the impact of our local strategy of not systematically administering primary antifungal prophylaxis in children undergoing a-HCT on the occurrence and mortality of IFIs. Methods: We performed a retrospective monocentric study from 2010 to 2020. We retained all proven and probable IFIs diagnosed during the first year post a-HCT. Results: 308 patients were included. Eighteen patients developed twenty IFIs (thirteen proven, seven probable) (6.5%) among which aspergillosis (n = 10, 50%) and candidosis (n = 7, 35%) were the most frequently diagnosed infections. Only 2% of children died because of an IFI, which represents 14% of all deaths. Multivariate analysis found that age > 10 years (OR: 0.29), the use of a therapeutic antiviral treatment (OR: 2.71) and a low neutrophil count reconstitution (OR: 0.93) were significantly associated with the risk of IFI occurrence. There was also a trend of malignant underlying disease and status ≥ CR2 but it was not retained in multivariate analysis. Conclusions: IFI occurrence was not higher in our cohort than what is reported in the literature with the use of systematic antifungal prophylaxis, with a good survival rate nonetheless. Thus, a prophylaxis could be considered for children with a high risk of IFI such as those aged over 10 years. [ABSTRACT FROM AUTHOR]

Simple Summary: The number of pigmented moles is the most important risk factor for melanoma. This "real world" study conducted in 25 Australian childcare centers is the first to show it is possible to prevent a significant proportion of pigmented moles in young Caucasian children by dressing them in UPF 30-50+ clothing that covers at least half their body on a daily basis. Regularly wearing this clothing for 3.5 years was sufficient to prevent almost one-quarter of the pigmented moles that young children developed on their skin. This should, by implication, reduce their risk of developing melanoma in the future. Primary health care providers should stress the importance of garment coverage when recommending sun protection for children and should lobby for all sun-protective clothing standards to assess and report garment coverage, in addition to the transmission of ultraviolet radiation through the fabric (reported as UPF), on clothing labels and packaging for children's clothing, including school uniforms. Numerous pigmented moles are associated with sun exposure and melanomarisk. This cluster randomized controlled trial aimed to determine if sun-protective clothing could prevent a significant proportion of the moles developing in young children (ACTRN12617000621314; Australian New Zealand Clinical Trials Registry. Twenty-five childcare centers in Townsville (19.25° S), Australia, were matched on shade provision and socioeconomic status. One center from each pair was randomized to the intervention arm and the other to the control arm. Children at 13 intervention centers wore study garments and legionnaire hats at childcare and received sun-protective swimwear and hats for home use, while children at the 12 control centers did not. The 1–35-month-old children (334 intervention; 210 control) were examined for moles at baseline (1999–2002) and were re-examined annually for up to 4 years. Both groups were similar at baseline. Children at intervention centers acquired fewer new moles overall (median 12.5 versus 16, p = 0.02; 0.46 versus 0.68 moles/month, p = 0.001) and fewer new moles on clothing-protected skin (6 vs. 8; p = 0.021 adjusted for confounding and cluster sampling) than controls. Intervention children had 24.3% fewer new moles overall (26.5 versus 35) and 31.6% (13 versus 19) fewer moles on clothing-protected skin than controls after 3.5 years. Sunlight's influence on nevogenesis is mitigated when children regularly wear UPF 30-50+ clothing covering half their body, implying that increased clothing cover reduces melanoma risk. Sun-protective clothing standards should mandate reporting of the percentage of garment coverage for childrenswear. [ABSTRACT FROM AUTHOR]

Simple Summary: Ewing's sarcoma is a highly aggressive malignant small round-cell tumor that mainly affects children and adolescents. A raised level of C-reactive protein (CRP) seems to be an indicator of poor prognosis in several cancers. The purpose of the present study was to evaluate the prognostic role of CRP in children with Ewing's sarcoma in relation to previously cited variables, including age, gender, tumor volume, tumor site, chemotherapy-induced necrosis, and other inflammatory biomarkers. The identification of reliable prognostic factors could help to identify high-risk patients, which may require a different treatment and follow up. The purpose of the present study was to evaluate the prognostic role of C-reactive protein (CRP) in children with Ewing's sarcoma. We conducted a retrospective study on 151 children undergoing multimodal treatment for Ewing's sarcoma in the appendicular skeleton from December 1997 to June 2020. Univariate Kaplan-Meier analyses of laboratory biomarkers and clinical parameters showed that CRP and metastatic disease at presentation were poor prognostic factors associated with overall survival and disease recurrence at 5 years (p < 0.05). A multivariate Cox regression model showed that pathological CRP (≥1.0 mg/dL) [HR of 3.67; 95% CI, 1.46 to 10.42] and metastatic disease [HR of 4.27; 95% CI, 1.58 to 11.47] were associated with a higher risk of death at 5 years (p < 0.05). In addition, pathological CRP (≥1.0 mg/dL) [HR of 2.66; 95% CI, 1.23 to 6.01] and metastatic disease [HR of 2.56; 95% CI, 1.13 to 5.55] were associated with a higher risk of disease recurrence at 5 years (p < 0.05). Our findings demonstrated that CRP was associated with the prognosis of children with Ewing's sarcoma. We recommend pre-treatment measurement of the CRP in order to recognize children with Ewing's sarcoma who are at greater risk of death or local recurrence. [ABSTRACT FROM AUTHOR]

Simple Summary: Cervical lymphadenopathy is common in children. A decision model for detecting high-grade lymphoma in children with cervical lymphadenopathy is currently lacking. Most previous studies identified individual predicting factors for lymphoma, a few created multivariate models, but none of these were sufficiently discriminative for application in clinical practice. We have developed a 12-factor diagnostic scoring model with machine learning logistic regression that is highly sensitive and specific in detecting high-grade lymphomas. This diagnostic model facilitates early decision making in children with cervical lymphadenopathy suspected of lymphoma. Its application may enable early referral to a pediatric oncologist in patients with high-grade lymphoma and may reduce the number of referrals in patients with benign lymphadenopathy, thus preventing unnecessary invasive procedures, such as biopsies. While cervical lymphadenopathy is common in children, a decision model for detecting high-grade lymphoma is lacking. Previously reported individual lymphoma-predicting factors and multivariate models were not sufficiently discriminative for clinical application. To develop a diagnostic scoring tool, we collected data from all children with cervical lymphadenopathy referred to our national pediatric oncology center within 30 months (n = 182). Thirty-nine putative lymphoma-predictive factors were investigated. The outcome groups were classical Hodgkin lymphoma (cHL), nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL), non-Hodgkin lymphoma (NHL), other malignancies, and a benign group. We integrated the best univariate predicting factors into a multivariate, machine learning model. Logistic regression allocated each variable a weighing factor. The model was tested in a different patient cohort (n = 60). We report a 12-factor diagnostic model with a sensitivity of 95% (95% CI 89–98%) and a specificity of 88% (95% CI 77–94%) for detecting cHL and NHL. Our 12-factor diagnostic scoring model is highly sensitive and specific in detecting high-grade lymphomas in children with cervical lymphadenopathy. It may enable fast referral to a pediatric oncologist in patients with high-grade lymphoma and may reduce the number of referrals and unnecessary invasive procedures in children with benign lymphadenopathy. [ABSTRACT FROM AUTHOR]

Simple Summary: Children treated for hemato-oncological diseases are at risk of muscle deterioration, such as loss of muscle mass and muscle weakness, with consequent impaired physical functioning. An easy screening tool will facilitate the early identification of children at risk and will support clinical decision making. We investigated the accuracy of an easy screening tool: the pediatric SARC-F (PED-SARC-F), for identifying functional sarcopenia in pediatric hemato-oncology patients. Functional sarcopenia indicates low muscle strength combined with low physical performance. We showed that the PED-SARC-F has a 90% accuracy in identifying pediatric hemato-oncology patients with functional sarcopenia. A PED-SARC-F cut-off point of ≥5 had the highest specificity (91%) and limits unnecessary assessments in patients who are not at risk of sarcopenia. This tool can be used to identify children that need a physiotherapy assessment and further interventions to prevent physical deterioration during and shortly after treatment for a hemato-oncology disease. Sarcopenia in pediatric hemato-oncology patients is undesirable because of the consequences it may have for treatment continuation and outcome, physical abilities and participation in daily life. An easy-to-use screening tool for sarcopenia will facilitate the identification of children at risk who need interventions to prevent serious physical deterioration. In the elderly, the use of the SARC-F score as a case-finding tool for sarcopenia is recommended. The aim of this cross-sectional study was to investigate the accuracy of the pediatric SARC-F (PED-SARC-F) for identifying sarcopenia in pediatric hemato-oncology patients, including the determination of a cut-off point for clinical use. Patients 3–20 years of age, under active treatment or within 12 months after treatment cessation were eligible. Patients had a physiotherapy assessment including a PED-SARC-F (0–10) and measurements of muscle strength (handheld dynamometry), physical performance (various tests) and/or muscle mass (bio-impedance analysis), as part of the standard of care. Spearman's correlation coefficient (rs) between the PED-SARC-F and physiotherapy outcomes were calculated. Structural sarcopenia was defined as low appendicular skeletal muscle mass (ASMM) in combination with low muscle strength and/or low physical performance. Functional sarcopenia indicated low muscle strength combined with low physical performance. Multiple logistic regression models were estimated to study the associations between the PED-SARC-F and structural/functional sarcopenia. To evaluate which cut-off point provides the most accurate classification, the area under the receiver operating characteristic curve (AUCs), sensitivity and specificity per point were calculated. In total, 215 assessments were included, 62% were performed in boys and the median age was 12.9 years (interquartile range: 8.5–15.8). The PED-SARC-F scores correlated moderately with the measurements of muscle strength (rs = −0.37 to −0.47, p < 0.001) and physical performance (rs = −0.45 to −0.66, p < 0.001), and weakly with ASMM (rs = −0.27, p < 0.001). The PED-SARC-F had an AUC of 0.90 (95% confidence interval (CI) = 0.84–0.95) for functional sarcopenia and 0.79 (95% CI = 0.68–0.90) for structural sarcopenia. A cut-off point of ≥5 had the highest specificity of 96% and a sensitivity of 74%. In conclusion, we adapted the SARC-F to a pediatric version, confirmed its excellent diagnostic accuracy for identifying functional sarcopenia and defined a clinically useful cut-off point in pediatric hemato-oncology patients. [ABSTRACT FROM AUTHOR]

Simple Summary: Around 30% of children with optic pathway glioma (OPG) require next order systemic anticancer therapy (SAT) in case of progression. Bevacizumab (BVZ) is considered an effective subsequent SAT for pediatric low grade glioma. This retrospective nationwide multicentre study evaluated the effect of treatment with BVZ of 33 children with OPG. A new finding is that visual acuity stabilised (74.4%) or improved (20.5%) after treatment in 39 analysed eyes, visual field stabilised in 15.4% and improved in 73.1% of 25 eyes. Progression free survival from start of treatment decreased from 70.9% at 18 months to 38.0% at 36 months. Reversible severe toxicity was observed in five of 33 patients (15.2%). Our results suggest that the majority of patients with OPG treated with BVZ temporarily stabilize, however most show progression at a later time point. Visual functions, especially visual field, improve in a high percentage of patients. BVZ treatment is suggested to be a useful successive SAT. Backgrounds: Bevacizumab (BVZ) is used as a subsequent line of treatment for pediatric optic pathway glioma (OPG) in the case of progression. Data on the treatment effect concerning tumor progression and visual function are scarce and nationwide studies are lacking. Methods: We performed a retrospective, nationwide, multicentre cohort study including all pediatric patients with OPG treated with BVZ in the Netherlands (2009–2021). Progression-free survival, change in visual acuity and visual field, MRI-based radiologic response, and toxicity were evaluated. Results: In total, 33 pediatric patients with OPG were treated with BVZ (median 12 months). Visual acuity improved in 20.5%, remained stable in 74.4%, and decreased in 5.1% of 39 of all analysed eyes. The monocular visual field improved in 73.1%, remained stable in 15.4%, and decreased in 7.7% of 25 analysed eyes. Radiologic response at the end of therapy showed a partial response in 7 patients (21.9%), minor response in 7 (21.9%), stable disease in 15 (46.9%), and progressive disease in 3 (9.3%). Progression-free survival at 18 and 36 months after the start of BVZ reduced from 70.9% to 38.0%. Toxicity (≥grade 3 CTCAE) during treatment was observed in five patients (15.2%). Conclusion: Treatment of BVZ in pediatric patients with OPG revealed stabilisation in the majority of patients, but was followed by progression at a later time point in more than 60% of patients. This profile seems relatively acceptable given the benefits of visual field improvement in more than 70% of analysed eyes and visual acuity improvement in more than 20% of eyes at the cessation of BVZ. [ABSTRACT FROM AUTHOR]

Simple Summary: Diffuse intrinsic pontine gliomas in children are rare, highly malignant infiltrating tumors in a location precluding surgical resection. The absence of non-invasive correlates of response and disease progression in these tumors invites the exploration of imaging biomarkers. Magnetic resonance spectroscopy is an advanced imaging technique for measuring cell metabolites. This study evaluated whether measurements of in vivo cell metabolites using magnetic resonance spectroscopy may serve as biomarkers of response to therapy, including progression. Single-voxel magnetic resonance spectra were serially acquired in two cohorts of patients with these tumors treated with radiation therapy with or without concurrent chemotherapy and prior to progression: 14 participants were enrolled in a clinical trial of adjuvant glioma-associated antigen peptide vaccines and 32 patients were enrolled who did not receive adjuvant vaccine therapy. In the vaccine cohort, an elevated myo-inositol/choline ratio after 2–3 doses was associated with longer survival. Scans performed up to 6 months before death showed a terminal decline in the myo-inositol/choline ratio. Higher myo-inositol/choline ratios following radiation therapy, consistent with less proliferate tumors and decreased cell turnover, were associated with longer survival, suggesting that this ratio can serve as a biomarker of prognosis following radiation therapy. Purpose: Diffuse intrinsic pontine gliomas (DIPG) are highly aggressive tumors with no currently available curative therapy. This study evaluated whether measurements of in vivo cell metabolites using magnetic resonance spectroscopy (MRS) may serve as biomarkers of response to therapy, including progression. Methods: Single-voxel MR spectra were serially acquired in two cohorts of patients with DIPG treated with radiation therapy (RT) with or without concurrent chemotherapy and prior to progression: 14 participants were enrolled in a clinical trial of adjuvant glioma-associated antigen peptide vaccines and 32 patients were enrolled who did not receive adjuvant vaccine therapy. Spearman correlations measured overall survival associations with absolute metabolite concentrations of myo-inositol (mI), creatine (Cr), and n-acetyl-aspartate (NAA) and their ratios relative to choline (Cho) during three specified time periods following completion of RT. Linear mixed-effects regression models evaluated the longitudinal associations between metabolite ratios and time from death (terminal decline). Results: Overall survival was not associated with metabolite ratios obtained shortly after RT (1.9–3.8 months post-diagnosis) in either cohort. In the vaccine cohort, an elevated mI/Cho ratio after 2–3 doses (3.9–5.2 months post-diagnosis) was associated with longer survival (rho = 0.92, 95% CI 0.67–0.98). Scans performed up to 6 months before death showed a terminal decline in the mI/Cho ratio, with an average of 0.37 ratio/month in vaccine patients (95% CI 0.11–0.63) and 0.26 (0.04–0.48) in the non-vaccine cohort. Conclusion: Higher mI/Cho ratios following RT, consistent with less proliferate tumors and decreased cell turnover, were associated with longer survival, suggesting that this ratio can serve as a biomarker of prognosis following RT. This finding was seen in both cohorts, although the association with OS was detected earlier in the vaccine cohort. Increased mI/Cho (possibly reflecting immune-effector cell influx into the tumor as a mechanism of tumor response) requires further study. [ABSTRACT FROM AUTHOR]

Simple Summary: Previously published data suggest anesthesiologic interventions during the perioperative period might play a major role in determining patient outcome after tumor surgery. However, only scarce data are available regarding this question in pediatric patients. This retrospective, multicenter study aimed to assess such a potential effect in pediatric patients undergoing cancer surgery for nephroblastoma. Data from 65 patients were analyzed. Intraoperative administration of erythrocyte concentrates was associated with a reduction in recurrence-free survival. The use of regional anesthesia or the choice of anesthetic had no effect. However, regional anesthesia was associated with fewer ICU transfers, a shortened hospital stay and a decreased postoperative neutrophil-to-lymphocyte ratio. The current study provides the first evidence for a possible association between anesthesia and outcome after pediatric cancer surgery. Children undergoing tumor surgery might therefore benefit from an optimized anesthetic regimen—including the use of regional anesthesia—and more restrictive blood transfusion management. Background: Recent data suggest that anesthesiologic interventions—e.g., the choice of the anesthetic regimen or the administration of blood products—might play a major role in determining outcome after tumor surgery. In contrast to adult patients, only limited data are available regarding the potential association of anesthesia and outcome in pediatric cancer patients. Methods: A retrospective multicenter study assessing data from pediatric patients (0–18 years of age) undergoing surgery for nephroblastoma between 2004 and 2018 was conducted at three academic centers in Europe. Overall and recurrence-free survival were the primary outcomes of the study and were evaluated for a potential impact of intraoperative administration of erythrocyte concentrates, the use of regional anesthesia and the choice of the anesthetic regimen. The length of stay on the intensive care unit, the time to hospital discharge after surgery and blood neutrophil-to-lymphocyte ratio were defined as secondary outcomes. Results: In total, data from 65 patients were analyzed. Intraoperative administration of erythrocyte concentrates was associated with a reduction in recurrence-free survival (hazard ratio (HR) 7.59, 95% confidence interval (CI) 1.36–42.2, p = 0.004), whereas overall survival (HR 5.37, 95% CI 0.42–68.4, p = 0.124) was not affected. The use of regional anesthesia and the choice of anesthetic used for maintenance of anesthesia did not demonstrate an effect on the primary outcomes. It was, however, associated with fewer ICU transfers, a shortened time to discharge and a decreased postoperative neutrophil-to-lymphocyte ratio. Conclusions: The current study provides the first evidence for a possible association between blood transfusion as well as anesthesiologic interventions and outcome after pediatric cancer surgery. [ABSTRACT FROM AUTHOR]

Simple Summary: We assessed quality of life in patients participating in Australia's national clinical trial of precision medicine for children with high-risk cancer. Quality of life measures aim to capture an individuals' perceptions of physical, psychological, and social aspects of health. Knowledge of patient quality of life can help clinicians and parents make decisions in a setting where survival time must be weighed against patients' experiences of illness and treatment. We found that most patients experienced compromised quality of life at the time of trial enrolment, typically in multiple domains. In patients whom we were able to follow-up after receipt of trial sequencing results, this did not change. We found an association between the outcomes of trial testing and patient quality of life which warrants unpacking in future research. Integrating collection of patient quality of life data into clinical processes would provide a more complete picture. Precision medicine is changing the treatment of childhood cancer globally, however little is known about quality of life (QoL) in children and adolescents participating in precision medicine trials. We examined QoL among patients enrolled in PRISM, the Zero Childhood Cancer Program's precision medicine trial for high-risk childhood cancer. We assessed patient QoL via self-report (aged 12–17 years) and parent-proxy (aged 4–17 years) completion of the EQ-5D-Y. We analysed data using descriptive statistics and regression models. Patients (n = 23) and parents (n = 136) provided data after trial enrolment and following receipt of trial results and treatment recommendations (n = 8 patients, n = 84 parents). At enrolment, most patients were experiencing at least some difficulty across more than one QoL domain (81% patient self-report, 83% parent report). We did not find strong evidence of a change in QoL between timepoints, or of demographic or disease factors that predicted parent-reported patient QoL (EQ-VAS) at enrolment. There was strong evidence that receiving a treatment recommendation but not a change in cancer therapy was associated with poorer parent-reported patient QoL (EQ-VAS; Mdiff = −22.5, 95% CI: −36.5 to −8.5, p = 0.006). Future research needs to better understand the relationship between treatment decisions and QoL and would benefit from integrating assessment of QoL into routine clinical care. [ABSTRACT FROM AUTHOR]

Simple Summary: Despite significant survival improvements for adolescents and young adults (AYAs) with cancer overall, several subsets of AYAs lag behind. This is especially true for AYAs diagnosed with metastatic disease, where, for many types of cancer, fewer than 20% of patients are alive 5 years later. Which sociodemographic subgroups of AYAs are at highest risk for presenting with metastatic disease is not well understood. In this study using United States Surveillance, Epidemiology, and End Results Program data, we found significantly increased risk of metastatic disease across many cancer sites for non-Hispanic Blacks, males, and low socioeconomic status AYAs. In particular, metastatic melanoma was striking for demonstrating multiple sociodemographic disparities. Results of this study shed light on the relative roles of age, race/ethnicity, sex, and socioeconomic status in metastatic disease presentation. These will inform future, cancer-specific research to elucidate biological, social, and environmental mechanisms underlying these associations with metastatic disease. Having metastatic disease at diagnosis poses the great risk of death among AYAs with cancer from all sociodemographic subgroups. This "landscape" study utilized United States Surveillance, Epidemiology, and End Results Program data from 2000–2016 to identify subgroups of AYAs at highest risk for presenting with metastases across twelve cancer sites having a poor-prognosis (5-year survival <50% with metastases). Adjusted odds ratios for risk of metastatic disease presentation were compared for AYAs in aggregate and by sociodemographic subgroup (race/ethnicity, sex, socioeconomic status [SES]). In general, AYAs who were male, racial/ethnic minorities, or low SES were at consistently greatest risk of metastases. Strikingly, having metastatic melanoma was independently associated with multiple AYA sociodemographic subgroups, including males (aOR 3.11 [95% CI 2.64–3.66]), non-Hispanic Blacks (4.04 [2.32–7.04]), Asian Pacific Islanders (2.99 [1.75–5.12]), Hispanics (2.37 [1.85–3.04]), and low SES (2.30 [1.89–2.80]). Non-Hispanic Blacks were more likely to present with metastatic cancer in all sites, except for bone, rhabdomyosarcoma, and stomach. Low SES AYAs are more likely to present with metastatic melanoma, bone tumors, soft tissue sarcomas, breast, cervical, lung, and stomach carcinomas. Building on these results, future cancer-specific studies should investigate the connection between sociodemographic risk factors and biological drivers of metastases. This line of research has potential to inform targeted public health and screening efforts to facilitate risk reduction and earlier detection of these deadly diseases. [ABSTRACT FROM AUTHOR]

Simple Summary: The most frequent brain tumors in children are solid tumors. A significant fraction of pediatric brain tumors is represented by gliomas, which are heterogeneous. Diffusion kurtosis imaging metrics (MK, AK, RK, FA, and ADC) have shown promising results for glioma grading in adult patients; however, it is unclear whether this technique is accurate for diagnosing high grade pediatric gliomas and if it is correlated with patient survival. In our study, we performed a retrospective whole-tumor analysis on 59 children affected by gliomas and tested (1) if DKI metrics are accurate for grading pediatric gliomas and (2) if DKI metrics are correlated with patient overall survival and progression-free survival. Purpose: To develop a predictive grading model based on diffusion kurtosis imaging (DKI) metrics in children affected by gliomas, and to investigate the clinical impact of the predictive model by correlating with overall survival and progression-free survival. Materials and methods: 59 patients with a histological diagnosis of glioma were retrospectively studied (33 M, 26 F, median age 7.2 years). Patients were studied on a 3T scanner with a standardized MR protocol, including conventional and DKI sequences. Mean kurtosis (MK), axial kurtosis (AK), radial kurtosis (RK), fractional anisotropy (FA), and apparent diffusion coefficient (ADC) maps were obtained. Whole tumour volumes (VOIs) were segmented semi-automatically. Mean DKI values were calculated for each metric. The quantitative values from DKI-derived metrics were used to develop a predictive grading model to develop a probability prediction of a high-grade glioma (pHGG). Three models were tested: DTI-based, DKI-based, and combined (DTI and DKI). The grading accuracy of the resulting probabilities was tested with a receiver operating characteristics (ROC) analysis for each model. In order to account for dataset imbalances between pLGG and pHGG, we applied a random synthetic minority oversampling technique (SMOTE) analysis. Lastly, the most accurate model predictions were correlated with progression-free survival (PFS) and overall survival (OS) using the Kaplan–Meier method. Results: The cohort included 46 patients with pLGG and 13 patients with pHGG. The developed model predictions yielded an AUC of 0.859 (95%CI: 0.752–0.966) for the DTI model, of 0.939 (95%CI: 0.879–1) for the DKI model, and of 0.946 (95%CI: 0.890–1) for the combined model, including input from both DTI and DKI metrics, which resulted in the most accurate model. Sample estimation with the random SMOTE analysis yielded an AUC of 0.98 on the testing set. Model predictions from the combined model were significantly correlated with PFS (25.2 months for pHGG vs. 40.0 months for pLGG, p < 0.001) and OS (28.9 months for pHGG vs. 44.9 months for pLGG, p < 0.001). Conclusions: a DKI-based predictive model was highly accurate for pediatric glioma grading. The combined model, derived from both DTI and DKI metrics, proved that DKI-based model predictions of tumour grade were significantly correlated with progression-free survival and overall survival. [ABSTRACT FROM AUTHOR]

Simple Summary: Due to previous cancer and its treatments, long-term childhood cancer survivors (CCS) are at risk of developing medical comorbidities, as well as socioeconomic vulnerability. Above all, work placement, financial independence, and job satisfaction can represent burdensome areas for some CCS. Regarding this topic, it is important to consider the variety of country-specific educational and vocational systems. The aim of this study is to provide a description of the occupational status of CCS in the Italian socio-economic scenery and to evaluate the association between late effects and unemployment and late effects and job satisfaction. Our data contribute to the description of the different country scenery of work placement for CCS in Europe and agree with previous literature on the impact of severe late effects on occupation. Future research in this field can be focused on interventions to improve CCS in obtaining jobs suitable for their health. Late effects of cancer and its treatments during childhood or adolescence can impact work placement and increase the risk of unemployment. The aim of this study is to describe the work placement and the perceived job and economic satisfaction of long-term childhood cancer survivors (CCS). Jobs have been categorized according to the International Standard Classification of Occupations version 08 (ISCO-08), and satisfaction has been evaluated through the Satisfaction Profile (SAT-P). Out of 240 CCS (female = 98) included: 53 were students, 46 were unemployed and 141 were employed. Within unemployed survivors, 89.13% were affected by late effects (n = 41). The presence of at least one severe late effect was significantly associated with the probability of unemployment (OR 3.21; 95% CI 1.13–9.12, p < 0.050), and having any late effect was inversely related to the level of satisfaction of the financial situation of unemployed CCS (b −35.47; 95% CI −59.19, −11.74, p = 0.004). Our results showed that being a survivor with severe comorbidities has a significantly negative impact on occupation and worsens the perception of satisfaction of economic situations. Routinary follow-up care of CCS should include the surveillance of socioeconomic development and provide interventions, helping them to reach jobs suitable for their health. [ABSTRACT FROM AUTHOR]

Simple Summary: Survivors of childhood cancer have an increased risk to experience symptoms of severe and persistent fatigue. We studied how fatigue might affect the health-related quality of life of these survivors. Questionnaire items asking about a broad range of daily life aspects were compared between fatigued survivors, survivors without fatigue and the general Dutch population. A total of eleven aspects were studied which were all negatively affected by fatigue, with the largest impact seen for Vitality (how much energy does a person have), General Health (perception of current and future health) and Role Limitations (work-related activities). Results show the negative impact fatigue can have on the daily lives of survivors and why it is important to treat fatigue adequately. Background: Early detection and management of late effects of treatment and their impact on health-related quality of life (HRQOL) has become a key goal of childhood cancer survivorship care. One of the most prevalent late effects is chronic fatigue (CF). The current study aimed to investigate the association between CF and HRQOL in a nationwide cohort of CCS. Methods: Participants were included from the Dutch Childhood Cancer Survivor Study (DCCSS) LATER cohort, a nationwide cohort of CCS. Participants completed the Checklist Individual Strength (CIS) to indicate CF (CIS fatigue severity subscale ≥ 35 and duration of symptoms ≥6 months) and the Short Form-36 (SF-36) and TNO (Netherlands Organization for Applied Scientific Research) and AZL (Leiden University Medical Centre) Adult's Health-Related Quality of Life questionnaire (TAAQOL) as measures for HRQOL. Differences in mean HRQOL domain scores between CF and non-CF participants were investigated using independent samples t-tests and ANCOVA to adjust for age and sex. The association between CF and impaired HRQOL (scoring ≥ 2 SD below the population norm) was investigated using logistic regression analyses, adjusting for confounders. Results: A total of 1695 participants were included in the study. Mean HRQOL domain scores were significantly lower in participants with CF. In addition, CF was associated with impaired HRQOL on all of the domains (except physical functioning) with adjusted odds ratios ranging from 2.1 (95% CI 1.3–3.4; sexuality domain) to 30.4 (95% CI 16.4–56.2; vitality domain). Conclusions: CF is associated with impaired HRQOL, urging for the screening and regular monitoring of fatigue, and developing possible preventative programs and interventions. [ABSTRACT FROM AUTHOR]

Simple Summary: Younger age has been associated with better overall survival in Ewing sarcoma, especially under the age of 10. Our study aimed at describing long-term outcomes of a cohort of 60 patients aged 0–10 with Ewing sarcoma, treated with chemotherapy, surgery and/or radiotherapy. Overall survival of these youngest patients with ES was very good. After 10 years, 81% of patients were still alive, 89% did not have a local recurrence and 81% did not have distant metastasis (in lungs and/or bone). Limb salvage surgery was achieved in >90% of patients. Wide resection margin was the only factor significantly associated with better survival, but age < 6 years, smaller tumors, no metastases at diagnosis and treatment after 2000 also seemed to result in better overall survival. (1) Background: Younger age has been associated with better overall survival (OS) in Ewing sarcoma (ES), especially under the age of 10. The favorable survival in younger patients underlines the need for minimizing treatment burden and late sequelae. Our study aimed at describing clinical characteristics, treatment and outcome of a cohort of ES patients aged 0–10. (2) Methods: In this retrospective multicenter study, all consecutive ES patients aged 0–10, treated in four sarcoma centers in the Netherlands (n = 33) and one in Spain (n = 27) between 1982 and 2008, with a minimum follow-up of 10 years, were included. OS, local recurrence-free survival (LRFS) and distant metastasis-free survival (DMFS) were calculated. Potential factors of influence on OS (risk and protective factors) were analyzed. (3) Results: 60 patients with median follow-up 13.03 years were included. All patients were treated with chemotherapy in combination with local treatment, being surgery alone in 30 (50%) patients, radiotherapy (RT) alone in 12 (20%) patients or surgery plus RT in 18 (30%) patients (12 pre- and 6 postoperative). Limb salvage was achieved in 93% of patients. The 10-OS, -LRFS and -DMFS are 81% (95% CI: 71–91%), 89% (95% CI: 85–93%) and 81% (95% CI: 71–91%), respectively. Six patients developed LR, of which two developed subsequent DM; all had axial ES (pelvis, spine or chest wall), and these patients all died. Ten patients developed DM; eight died due to progressive disease, and two are currently in remission, both with pulmonary metastasis only. Negative or wide resection margin was significantly associated with better OS. Age < 6 years, tumor volume < 200 mL, absence of metastatic disease and treatment after 2000 showed trends towards better OS. Two patients developed secondary malignancy; both had chemotherapy combined with definitive RT for local treatment. (4) Conclusions: Overall survival of these youngest patients with ES was very good. Limb salvage surgery was achieved in >90% of patients. Wide resection margin was the only factor significantly associated with better survival. [ABSTRACT FROM AUTHOR]

Simple Summary: Blinatumomab, a bispecific T-cell engager, binding T-cell CD3 and B-cell CD19 antigens, has remarkably enlarged the treatment options for patients with relapsed/refractory B-cell precursor acute lymphoblastic leukemia (r/r BCP-ALL). The aim of our study was to retrospectively assess the safety and efficacy profile of blinatumomab in 39 r/r ALL children treated in seven AIEOP centers in a compassionate or off-label program. This report is among the largest multicentric real-life retrospective analyses on blinatumomab in pediatric r/r BCP ALL. Blinatumomab showed a tolerable safety profile (34.8% of adverse events ≥grade 3, no cytokine release syndrome and no associated toxic deaths) and proved to be very effective (complete remission rate 46% in the 13 patients with ≥5% blasts and 81% PCR/FC MRD negativity in the 26 patients with <5% blasts) in this group of patients affected by r/r BCP-ALL already treated in the frame of very intensive front-line and relapsed protocols. Five-year event-free survival in pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL) currently exceeds 80–85%. However, 15–20% of patients still experience a relapsed/refractory disease. From 1 January 2015 to 31 December 2020, thirty-nine patients, 0–21 years old with r/r BCP-ALL were treated with blinatumomab with the aim of inducing remission (n = 13) or reducing MRD levels (n = 26) in the frame of different multiagent chemotherapy schedules, in seven AIEOP centers. Patients were treated in compassionate and/or off-label settings and were not enrolled in any controlled clinical trials. Treatment was well tolerated; 22 (56.4%) patients reported adverse events (AE) on a total of 46 events registered, of which 27 (58.7%) were ≤2 grade according to CTCAE. Neurological AEs were 18 (39.1%); only two patients required transient blinatumomab discontinuation. Complete remission (CR) rate was 46% for the 13 patients treated with ≥5% blasts and 81% PCR/FC MRD negativity in the 26 patients with blasts < 5%. Median relapse-free survival was 33.4 months (95% CI; 7.5–59.3); median overall survival was not reached over a mean follow-up of 16 months. In our study, as in other real-life experiences, blinatumomab proved to be effective and well-tolerated, able to induce a high rate of CR and MRD negativity. [ABSTRACT FROM AUTHOR]

Simple Summary: Maternal thyroid disease, especially hypothyroidism, is known to affect pregnancy and its outcome. We evaluated the risk of childhood cancer in the offspring following exposure to maternal thyroid disease in a case-control setting using registry data. In our study, maternal hypothyroidism was associated with an increased risk of lymphoma in the offspring. The association remained stable when possible familial cancers were excluded. Maternal thyroid disease, especially hypothyroidism, affects pregnancy and its outcome. In-utero exposure to autoimmune thyroid disease has been reported to associate with childhood ALL in the offspring. We evaluated the risk of childhood cancer in the offspring following exposure to maternal thyroid disease in a case-control setting using registry data. All patients with their first cancer diagnosis below the age of 20 years were identified from the Finnish Cancer Registry (n = 2037) and matched for sex and birth year at a 1:5 ratio to population controls identified from the Medical Birth Registry (n = 10,185). We collected national information on maternal thyroid disease from the Medical Birth Registry, Care Register for Health Care, Register for Reimbursed Drug Purchases and Register of Special Reimbursements. We used conditional logistic regression to analyze childhood cancer risk in the offspring. The adjusted OR for any childhood cancer was 1.41 (95%, CI 1.00–2.00) comparing the offspring of mothers with hypothyroidism and those with normal thyroid function. The risk of lymphomas was increased (adjusted OR for maternal hypothyroidism 3.66, 95%, CI 1.29–10.38). The results remained stable when mothers with cancer history were excluded from the analyses. Maternal hypothyroidism appears to be associated with an increased risk for childhood lymphoma in the offspring. The association exists even after excluding possible familial cancers. [ABSTRACT FROM AUTHOR]

Simple Summary: Thyroid cancer is a rare disease in childhood; however, its incidence is rising. Thyroid cancer consists of three main types: Papillary thyroid cancer (PTC), follicular thyroid cancer (FTC), and medullary thyroid cancer (MTC). The aim of our retrospective study was to investigate the incidence and survival trends of these three thyroid cancer types in Dutch children, adolescents, and young adults over a 30-year life span. In total, 839 patients aged 0–24 years had been diagnosed with thyroid cancer between 1990 and 2019. The incidence of PTC increased significantly over time, the incidence of FTC showed a stable trend, while the incidence of MTC decreased significantly. Overall, the 10-year survival rates over the last decades were high (>95%) for PTC, FTC, and MTC in young individuals. Thyroid cancer is the most common endocrine malignancy in children. A rising incidence has been reported worldwide. Possible explanations include the increased use of enhanced imaging (leading to incidentalomas) and an increased prevalence of risk factors. We aimed to evaluate the incidence and survival trends of thyroid cancer in Dutch children, adolescents, and young adults (0–24 years) between 1990 and 2019. The age-standardized incidence rates of differentiated thyroid cancer (DTC, including papillary and follicular thyroid cancer (PTC and FTC, respectively)) and medullary thyroid cancer (MTC), the average annual percentage changes (AAPC) in incidence rates, and 10-year overall survival (OS) were calculated based on data obtained from the nationwide cancer registry (Netherlands Cancer Registry). A total of 839 patients aged 0–24 years had been diagnosed with thyroid carcinoma (PTC: 594 (71%), FTC: 128 (15%), MTC: 114 (14%)) between 1990 and 2019. The incidence of PTC increased significantly over time (AAPC +3.6%; 95%CI +2.3 to +4.8), the incidence rate of FTC showed a stable trend ((AAPC −1.1%; 95%CI −3.4 to +1.1), while the incidence of MTC decreased significantly (AAPC: −4.4% (95%CI −7.3 to −1.5). The 10-year OS was 99.5% (1990–1999) and 98.6% (2000–2009) in patients with DTC and 92.4% (1990–1999) and 96.0% (2000–2009) in patients with MTC. In this nationwide study, a rising incidence of PTC and decreasing incidence of MTC were observed. For both groups, in spite of the high proportion of patients with lymph node involvement at diagnosis for DTC and the limited treatment options for MTC, 10-year OS was high. [ABSTRACT FROM AUTHOR]

Simple Summary: The treatment of osteosarcoma and Ewing sarcoma, the two major types of malignant bone tumors in children, has progressed considerably during the last decades, with more patients becoming long-term survivors. This improvement has resulted in an increasing number of patients with long-term adverse health consequences from the life-saving treatment. The aim of this study was to provide a detailed, comprehensive overview of somatic diseases that require hospitalization in long-term survivors of osteosarcoma and Ewing sarcoma. This study contributes new insights into the risk of somatic late effects in survivors of osteosarcoma and Ewing sarcoma which are urgently requested by pediatric oncologists, researchers, and by survivors and their families. The study provides an essential basis for the development of preventive intervention strategies and for optimal patient counseling and follow-up care, which all contribute to improving the health and quality of life in survivors. Survivors of malignant bone tumors in childhood are at risk of long-term adverse health effects. We comprehensively reviewed cases of somatic diseases that required a hospital contact in survivors of osteosarcoma and Ewing sarcoma. In a population-based cohort study, 620 five-year survivors of osteosarcoma (n = 440) or Ewing sarcoma (n = 180), diagnosed before the age of 20 years in Denmark, Finland, Iceland, and Sweden during 1943–2008, were followed in the national hospital registers. Overall rates of hospital contacts for any somatic disease and for 12 main diagnostic groups and 120 specific disease categories were compared with those in a matched comparison cohort (n = 3049) randomly selected from the national population registers. The rate of hospital contact for any somatic disease was 80% higher in survivors of malignant bone tumors than in comparisons and remained elevated up to 30 years after diagnosis. The rate of hospital contacts was higher after Ewing sarcoma (rate ratio (RR) 2.24; 95% confidence interval (CI) 1.76–2.85) than after osteosarcoma (RR 1.67; 95% CI 1.41–1.98). Elevated rates were observed for 11 main diagnostic groups, including infections, second malignant neoplasms, and diseases of the skin, bones, and circulatory, digestive, endocrine, and urinary systems. Survivors of malignant bone tumors in childhood are at increased risk of somatic diseases many years after diagnosis. This comprehensive study contributes new insight into the risk of late effects in survivors of osteosarcoma and Ewing sarcoma, which is an essential basis for optimal patient counseling and follow-up care. [ABSTRACT FROM AUTHOR]

Simple Summary: Cachexia is a major cause of mortality in cancer patients and is characterized by a continuous skeletal muscle loss. Muscle depletion assessed by computed tomography (CT) is a predictive marker in solid tumors but has never been assessed in non-Hodgkin's lymphoma. Despite software improvements, its measurement remains highly time-consuming and cannot be performed in clinical practice. We report the development of a CT segmentation algorithm based on convolutional neural networks. It automates the extraction of anthropometric data from pretherapeutic CT to assess precise body composition of young diffuse large B cell lymphoma (DLBCL) patients at the time of diagnosis. In this population, muscle hypodensity appears to be an independent risk factor for mortality, and can be estimated at diagnosis with this new tool. Background. Muscle depletion (MD) assessed by computed tomography (CT) has been shown to be a predictive marker in solid tumors, but has not been assessed in non-Hodgkin's lymphomas. Despite software improvements, MD measurement remains highly time-consuming and cannot be used in clinical practice. Methods. This study reports the development of a Deep-Learning automatic segmentation algorithm (DLASA) to measure MD, and investigate its predictive value in a cohort of 656 diffuse large B cell lymphoma (DLBCL) patients included in the GAINED phase III prospective trial (NCT01659099). Results. After training on a series of 190 patients, the DLASA achieved a Dice coefficient of 0.97 ± 0.03. In the cohort, the median skeletal muscle index was 50.2 cm2/m2 and median muscle attenuation (MA) was 36.1 Hounsfield units (HU). No impact of sarcopenia was found on either progression free survival (PFS) or overall survival (OS). Muscular hypodensity, defined as MA below the tenth percentile according to sex, was associated with a lower OS and PFS, respectively (HR = 2.80 (95% CI 1.58–4.95), p < 0.001, and HR = 2.22 (95% CI 1.43–3.45), p < 0.001). Muscular hypodensity appears to be an independent risk factor for mortality in DLBCL and because of DLASA can be estimated in routine practice. [ABSTRACT FROM AUTHOR]

Simple Summary: About 50% of adults with chronic myeloid leukemia (CML) in sustained deep molecular response (DMR) to tyrosine kinase inhibitors (TKI) could discontinue the treatment permanently without molecular relapse. Recommendations regarding discontinuation apply only for adults because childhood CML is a very rare disease and represents a separate entity. The aim of our retrospective study was to assess within the International Registry of Childhood CML, the rate of children remaining in molecular response after discontinuation of imatinib in a context of DMR defined as BCR-ABL1/ABL1 < 0.01% (MR4) for at least two years. Eighteen patients less than 18 years old at diagnosis of CML exhibiting a sustained DMR followed by imatinib discontinuation were identified. After discontinuation, the molecular free remission rate was 61%, 56% and 56% at 6, 12 and 36 months, respectively. Our findings represent the basis of recommendation regarding discontinuation for physicians involved in the pediatric CML field. Within the International Registry of Childhood Chronic Myeloid Leukemia (CML), we identified 18 patients less than 18 years old at diagnosis of CML who were in the chronic phase and exhibiting a sustained deep molecular response (DMR) to imatinib defined as BCR-ABL1/ABL1 < 0.01% (MR4) for at least two years followed by discontinuation of imatinib. Before discontinuation, the median duration of imatinib was 73.2 months (range, 32–109) and the median duration of MR4 was 46.2 months (range, 23.9–98.6). Seven patients experienced loss of major molecular response (MMR) 4.1 months (range, 1.9–6.4) after stopping and so restarted imatinib. The median molecular follow-up after discontinuation was 51 months (range, 6–100) for the nine patients without molecular relapse. The molecular free remission rate was 61% (95% CI, 38–83%), 56% (95% CI, 33–79%) and 56% (95% CI, 33–79%) at 6, 12 and 36 months, respectively. Six of the seven children who experienced molecular relapse after discontinuation regained DMR (median, 4.7 months; range, 2.5–18) after restarting imatinib. No withdrawal syndrome was observed. In univariate analysis, age, sex, Sokal and ELTS scores, imatinib treatment and DMR durations before discontinuation had no influence on treatment free remission. These data suggest that imatinib can be safely discontinued in children with sustained MR4 for at least two years. [ABSTRACT FROM AUTHOR]

Simple Summary: Acute myeloid leukemia in children remains a difficult disease to cure despite intensive therapies that push the limits of tolerability. Though the intent of initial therapy should be the prevention of relapse, about 30% of all patients experience a relapse. Hence, relapse therapy remains critically important for survival. This retrospective analysis of two large international study groups (COG and BFM) was undertaken to describe the current survival, response rates and clinical features that predict outcomes. We demonstrate that children with relapsed AML may be cured with cytotoxic therapy followed by HSCT. High-risk features at initial diagnosis and early relapse remain prognostic for post-relapse survival. Current response criteria are not aligned with the standards of care for children, nor are the count recovery thresholds meaningful for prognosis in children with relapsed AML. Our data provide a new baseline for future treatment planning and will allow an updated stratification in upcoming studies. Post-relapse therapy remains critical for survival in children with acute myeloid leukemia (AML). We evaluated survival, response and prognostic variables following relapse in independent cooperative group studies conducted by COG and the population-based AML-BFM study group. BFM included 197 patients who relapsed after closure of the last I-BFM relapse trial until 2017, while COG included 852 patients who relapsed on the last Phase 3 trials (AAML0531, AAML1031). Overall survival at 5 years (OS) was 42 ± 4% (BFM) and 35 ± 2% (COG). Initial high-risk features (BFM 32 ± 6%, COG 26 ± 4%) and short time to relapse (BFM 29 ± 4%, COG 25 ± 2%) predicted diminished survival. In the BFM dataset, there was no difference in OS for patients who had a complete remission with full hematopoietic recovery (CR) following post-relapse re-induction compared to those with partial neutrophil and platelet recovery (CRp and CRi) only (52 ± 7% vs. 63 ± 10%, p = 0.39). Among 90 patients alive at last follow-up, 87 had received a post-relapse hematopoietic stem cell transplant (HSCT). OS for patients with post-relapse HSCT was 54 ± 4%. In conclusion, initial high-risk features and early relapse remain prognostic. Response assessment with full hematopoietic recovery following initial relapse therapy does not predict survival. These data indicate the need for post-relapse risk stratification in future studies of relapse therapies. [ABSTRACT FROM AUTHOR]

Simple Summary: Most children infected with HIV live in Sub-Sahara Africa (SSA). These children are at risk of cancers related to HIV infection, but the degree of this risk and how it is influenced by antiretroviral therapy (ART) is unknown. In this study, we determined the subtypes, incidence, and risk factors of cancers in children with HIV in SSA and receiving ART with the goal of learning how we may prevent these cancers. We found that Kaposi sarcoma and lymphoma are the most common, comprising about 77% and 19% of cancers in these children, respectively. For every 100,000 person-years, 47.6 children developed cancer. Waiting to start ART until after 2 years old and having had severe immunosuppression were the two biggest risk factors for cancer that we identified. The findings justify the recommendations to start children on ART as soon as they are diagnosed with HIV regardless of their CD4 immune status. Approximately 91% of the world's children living with HIV (CLWH) are in sub-Saharan Africa (SSA). Living with HIV confers a risk of developing HIV-associated cancers. To determine the incidence and risk factors for cancer among CLWH, we conducted a nested case-control study of children 0–18 years from 2004–2014 at five centers in four SSA countries. Incident cases of cancer and HIV were frequency-matched to controls with HIV and no cancer. We calculated the incidence density by cancer type, logistic regression, and relative risk to evaluate risk factors of cancer. The adjusted incidence density of all cancers, Kaposi sarcoma, and lymphoma were 47.6, 36.6, and 8.94 per 100,000 person-years, respectively. Delayed ART until after 2 years of age was associated with cancer (OR = 2.71, 95% CI 1.51, 4.89) even after adjusting for World Health Organization clinical stage at the time of enrolment for HIV care (OR = 2.85, 95% CI 1.57, 5.13). The relative risk of cancer associated with severe CD4 suppression was 6.19 (p = 0.0002), 2.33 (p = 0.0042), and 1.77 (p = 0.0305) at 1, 5, and 10 years of ART, respectively. The study demonstrates the high risk of cancers in CLWH and the potential benefit of reducing this risk by the early initiation of ART. [ABSTRACT FROM AUTHOR]

Simple Summary: Despite progress in the biology and upfront treatment of childhood medulloblastoma, relapse is almost universally fatal. No standardized treatment has so far been established for these patients. By determining which characteristics are prognostic after relapse, treatment strategies may be optimized for each of these children. We demonstrated that molecular subgroup at diagnosis is a relevant prognostic factor of outcome after relapse. Moreover, we showed that time to relapse and the use of salvage radiotherapy at relapse might have a potential impact on post-relapse survival. Our data suggest that ongoing efforts toward a better understanding of the biology, timing and type of relapse would be important to understand the determinants of tumor behavior at relapse. This could help us address more specific questions on the best surveillance strategies after completion of the treatment and the introduction of risk-stratified second-line treatment strategies. Given the very poor prognosis for children with recurrent medulloblastoma, we aimed to identify prognostic factors for survival post-relapse in children with childhood medulloblastoma. We retrospectively collected clinico-biological data at diagnosis and main clinical characteristics at relapse of children newly diagnosed with a medulloblastoma between 2007 and 2017 at Gustave Roussy and Necker Hospital. At a median follow-up of 6.6 years (range, 0.4–12.3 years), relapse occurred in 48 out 155 patients (31%). The median time from diagnosis to relapse was 14.3 months (range, 1.2–87.2 months). Relapse was local in 9, metastatic in 22 and combined (local and metastatic) in 17 patients. Second-line treatment consisted of chemotherapy in 31 cases, radiotherapy in 9, SHH-inhibitor in four and no treatment in the remaining four. The 1-year overall survival rate post-relapse was 44.8% (CI 95%, 31.5% to 59.0%). While molecular subgrouping at diagnosis was significantly associated with survival post-relapse, the use of radiotherapy at relapse and time to first relapse (>12 months) might also have a potential impact on post-relapse survival. [ABSTRACT FROM AUTHOR]

Simple Summary: The use of hematopoietic stem cell transplantation (HSCT), particularly among children, has increased over the last decades. However, it is frequently associated with a high risk of morbidity and mortality, and HSCT-related adverse effects can potentially impair survivors' health status. We aimed to assess the effects on major clinical outcomes of a supervised exercise intervention performed by children with cancer during hospitalization for HSCT. The main finding of this prospective study in a quite large cohort of pediatric HSCT recipients (n = 118, aged 4–18 years) is that a moderate intensity supervised exercise program (aerobic + resistance exercises) performed from the beginning of the conditioning phase for HSCT until the end of the neutropenic phase is safe and well tolerated and tends to decrease risk of infections after allogeneic HSCT, as compared with not performing the program. We assessed the clinical effects of a supervised exercise (aerobic + resistance) intervention performed during inpatient hospitalization for pediatric hematopoietic stem cell transplantation (HSCT). Patients were placed in an exercise (n = 65 (47 and 18 with allogeneic (allo-) and autologous (auto-) HSCT, respectively)) or a control (n = 53 (39 and 14)) group. Exercise interventions were performed in isolated hospital patient rooms. Patients were followed-up from the beginning of the conditioning phase up to 6 years. We assessed survival, risk of graft-versus-host disease (GvHD) or graft failure (primary outcomes), and engraftment kinetics, supportive care, toxicity profile, and immune reconstitution for auto-HSCT and allo-HSCT. The exercise intervention was safe and did not affect the risk of mortality, acute/chronic GvHD, or graft failure (all p > 0.05). No between-group differences (p > 0.05) were found for the remainder of clinical endpoints, except for a reduced number of total and viral infections in the exercise group after allo-HSCT (unadjusted p = 0.005 for both total and viral infections, and adjusted p = 0.023 and 0.083, respectively). In conclusion, exercise performed during inpatient hospitalization for pediatric HSCT is safe and well tolerated during both auto and allo-HSCT and tends to decrease the risk of infection after allo-HSCT. These findings provide additional support to the notion that a multidisciplinary approach (i.e., including the work of exercise specialists) is suitable in the management of children undergoing HSCT. Further studies are needed to determine whether applying a different training stimulus (notably, higher exercise intensities) exerts positive effects on HSCT prognosis in these patients. [ABSTRACT FROM AUTHOR]

The TP53 R337H mutation is associated with increased incidence of pediatric adrenocortical tumor (ACT). The different environmental conditions where R337H carriers live have not been systematically analyzed. Here, the R337H frequencies, ACT incidences, and R337H penetrance for ACT were calculated using the 2006 cohort with 4165 R337H carriers living in Paraná state (PR) subregions. The effectiveness of a second surveillance for R337H probands selected from 42,438 tested newborns in PR (2016 cohort) was tested to detect early stage I tumor among educated families without periodical exams. Estimation of R337H frequencies and ACT incidence in Santa Catarina state (SC) used data from 50,115 tested newborns without surveillance, ACT cases from a SC hospital, and a public cancer registry. R337H carrier frequencies in the population were 0.245% (SC) and 0.306% (PR), and 87% and 95% in ACTs, respectively. The ACT incidence was calculated as ~6.4/million children younger than 10 years per year in PR (95% CI: 5.28; 7.65) and 4.15/million in SC (CI 95%: 2.95; 5.67). The ACT penetrance in PR for probands followed from birth to 12 years was 3.9%. R337H carriers living in an agricultural subregion (C1) had a lower risk of developing pediatric ACT than those living in industrial and large urban subregion (relative risk = 2.4). One small ACT (21g) without recurrence (1/112) was detected by the parents in the 2016 cohort. ACT incidence follows R337H frequency in each population, but remarkably environmental factors modify these rates. [ABSTRACT FROM AUTHOR]

This study aimed to evaluate the prognostic value of variables used in the 2017 PRE-Treatment EXTent of tumor (PRETEXT) system and the Children's Hepatic tumors International Collaboration-Hepatoblastoma Stratification (CHIC-HS) system in pediatric patients with hepatoblastoma. A retrospective analysis of data from the pediatric hepatoblastoma registry of a tertiary referral center was conducted to evaluate the clinical and imaging variables (annotation factors) of the PRETEXT staging system. The primary outcome was event-free survival (EFS). Data from 84 patients (mean age: 2.9 ± 3.5 years) identified between 1998 and 2017 were included. Univariable Cox proportional hazards analysis revealed that PRETEXT annotation factors P (portal vein involvement), F (multifocality of tumor), and M (distant metastasis) showed a significant negative association with EFS. Multivariable Cox proportional hazard analysis showed that factor F was the strongest predictor (HR (hazard ratio), 2.908; 95% CI (confidence interval), 1.061–7.972; p = 0.038), whereas factor M showed borderline significance (HR, 2.416; 95% CI, 0.918–6.354; p = 0.074). The prediction model based on F and M (F + M) showed good performance to predict EFS (C-statistic, 0.734; 95% CI, 0.612–0.854). In conclusion, the PRETEXT annotation factor F was the strongest predictor of EFS, and the F + M model showed good performance to predict EFS in pediatric patients with hepatoblastoma. [ABSTRACT FROM AUTHOR]