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Mature ovarian dermoid cysts (ODCs) are the most common benign ovarian tumors diagnosed in children. However, there is minimal data on management of ODCs in premenarchal patients. This study assesses characteristics associated with expectant (EM) vs surgical (SM) management in premenarchal patients and the growth rate of ODCs in EM patients at a single institution. Forty-four premenarchal patients, either post-surgical with pathologically-confirmed ODC or having radiologic findings consistent with ODCs, were included. Data collected included demographics, cyst characteristics, imaging findings, presence of symptoms, surgical procedure performed, and ovarian torsion occurrence. Patient age at diagnosis was similar between groups (SM: 8.8 vs EM: 8.0, P =.55). At presentation, 36 patients (82%) underwent SM and 8 (18%) underwent EM. There was a significant difference in cyst size between groups (SM: 8.9 cm vs EM: 3.6 cm, P =.004). Of SM patients, 30% underwent oophorectomy vs cystectomy, with a significant difference in ODC size between procedures (11.8 cm vs 7.7 cm, P =.016). Of EM patients, 75% had at least one and 60% had three follow-up ultrasounds, with average follow-up timeframes of 3.7 and 27 months respectively. Average yearly ODC growth rate for the latter group was 0.8 cm. The average yearly growth rate of ODCs in premenarchal patients within our institution was slower than in older cohorts, and both age and cyst size played significant roles in determining surgical procedure. Continued study on EM in premenarchal ODCs will help define parameters for recommending SM vs EM in this population. [ABSTRACT FROM AUTHOR]

Anatomical models have key applications in radiotherapy, notably to help understand the relationship between radiation dose and risk of developing side effects. This review analyses whether age-specific computational phantoms, developed from healthy subjects and paediatric cancer patient data, are adequate to model a paediatric population. The phantoms used in the study were International Commission on Radiological Protection (ICRP), 4D extended cardiac torso (XCAT) and Radiotherapy Paediatric Atlas (RT-PAL), which were also compared to literature data. Organ volume data for 19 organs was collected for all phantoms and literature. ICRP was treated as the reference for comparison, and percentage difference (P.D) for the other phantoms were calculated relative to ICRP. Overall comparisons were made for each age category (1, 5, 10, 15) and each organ. Statistical analysis was performed using Microsoft Excel (version 16.59). The smallest P.D to ICRP was for Literature (-17.4%), closely followed by XCAT (26.6%). The largest was for RT-PAL (88.1%). The rectum had the largest average P.D (1,049.2%) and the large bowel had the smallest (2.0%). The P.D was 122.6% at age 1 but this decreased to 43.5% by age 15. Linear regression analysis showed a correlation between organ volume and age to be the strongest for ICRP (R2 = 0.943) and weakest for XCAT (R2 = 0.676). The phantoms are similar enough to ICRP for potential use in modelling paediatric populations. ICRP and XCAT could be used to model a healthy population, whereas RT-PAL could be used for a population undergoing/after radiotherapy. [ABSTRACT FROM AUTHOR]

The article delves into the intricacies of administering anesthesia to children diagnosed with cancer. It delves into the challenges and considerations surrounding adjuvant chemotherapy, which is often part of cancer treatment protocols for children. It discusses strategies and guidelines aimed at effectively managing this complication, ensuring the best possible outcomes for children undergoing cancer therapy.

To investigate the incidence rate of primary brain tumors (PBTs) among Palestinian children over a 6-year interval. This study also aimed to identify the predominant histopathologic types identified in these children. This retrospective epidemiologic study focused on PBTs in children (<15 years) in Palestine. The data were collected from the registry system at Al-Makassed Hospital in Jerusalem, a prominent referral institution in Palestine and the largest center for PBTs in the region, over a 6 years period from 2018 to 2023. The incidence rate of PBTs in children (<15 years) was 1.33 per 100,000 person-years, with a 5% mortality rate. Pilocytic astrocytoma was the most common type (24%), followed by medulloblastoma (15.2%) and glioblastoma (6.3%). About one half of the tumors in children were malignant. Headaches were the most common first sign or symptom. About 20% of brain tumors in children were situated within the ventricles, making it the most prevalent location of these tumors, followed by the cerebellum (15.19%) and frontal lobe (11.39%). This is the first national study in Palestine investigating PBTs in children. The crude incidence rate of primary brain tumors among Palestinian children was lower than the incidence rate in many countries around the world. It is recommended that more research be done on the epidemiology and distribution of PBTs in children in Palestine. [ABSTRACT FROM AUTHOR]

Reirradiation is increasingly used in children and adolescents/young adults (AYA) with recurrent primary central nervous system tumors. The Pediatric Normal Tissue Effects in the Clinic (PENTEC) reirradiation task force aimed to quantify risks of brain and brain stem necrosis after reirradiation. A systematic literature search using the PubMed and Cochrane databases for peer-reviewed articles from 1975 to 2021 identified 92 studies on reirradiation for recurrent tumors in children/AYA. Seventeen studies representing 449 patients who reported brain and brain stem necrosis after reirradiation contained sufficient data for analysis. While all 17 studies described techniques and doses used for reirradiation, they lacked essential details on clinically significant dose-volume metrics necessary for dose-response modeling on late effects. We, therefore, estimated incidences of necrosis with an exact 95% CI and qualitatively described data. Results from multiple studies were pooled by taking the weighted average of the reported crude rates from individual studies. Treated cancers included ependymoma (n = 279 patients; 7 studies), medulloblastoma (n = 98 patients; 6 studies), any CNS tumors (n = 62 patients; 3 studies), and supratentorial high-grade gliomas (n = 10 patients; 1 study). The median interval between initial and reirradiation was 2.3 years (range, 1.2-4.75 years). The median cumulative prescription dose in equivalent dose in 2-Gy fractions (EQD2 2 ; assuming α/β value = 2 Gy) was 103.8 Gy (range, 55.8-141.3 Gy). Among 449 reirradiated children/AYA, 22 (4.9%; 95% CI, 3.1%-7.3%) developed brain necrosis and 14 (3.1%; 95% CI, 1.7%-5.2%) developed brain stem necrosis with a weighted median follow-up of 1.6 years (range, 0.5-7.4 years). The median cumulative prescription EQD2 2 was 111.4 Gy (range, 55.8-141.3 Gy) for development of any necrosis, 107.7 Gy (range, 55.8-141.3 Gy) for brain necrosis, and 112.1 Gy (range, 100.2-117 Gy) for brain stem necrosis. The median latent period between reirradiation and the development of necrosis was 5.7 months (range, 4.3-24 months). Though there were more events among children/AYA undergoing hypofractionated versus conventionally fractionated reirradiation, the differences were not statistically significant (P =.46). Existing reports suggest that in children/AYA with recurrent brain tumors, reirradiation with a total EQD2 2 of about 112 Gy is associated with an approximate 5% to 7% incidence of brain/brain stem necrosis after a median follow-up of 1.6 years (with the initial course of radiation therapy being given with conventional prescription doses of ≤2 Gy per fraction and the second course with variable fractionations). We recommend a uniform approach for reporting dosimetric endpoints to derive robust predictive models of late toxicities following reirradiation. [ABSTRACT FROM AUTHOR]

The success and safety of modern radiotherapy relies on accurate contouring. Understanding the time taken to complete radiotherapy contours is critical to informing workforce planning and, in the context of a workforce shortfall, advocating for investment in technology and multi-professional skills mix. We aimed to quantify the time taken to delineate target volumes for radical radiotherapy. The Royal College of Radiologists circulated two electronic surveys via email to all clinical oncology consultants in the UK. The individual case survey requested anonymous data regarding the next five patients contoured for radical radiotherapy. The second survey collected data on respondents' usual practice in radiotherapy contouring. The median time to contour one radiotherapy case was 85 minutes (IQR = 50–131 minutes). Marked variability between and within tumour sites was evident: paediatric cancers took the most time (median = 210 minutes, IQR = 87.5 minutes), followed by head and neck and gynaecological cancers (median = 120 minutes, IQR = 71 and 72.5 minutes respectively). Breast cancer contouring required the least time (median = 43 minutes, IQR = 60 minutes). Radiotherapy technique, inclusion of nodes and 4D CT planning were associated with longer contouring times. A non-medical professional was involved in contouring in 65% of cases, but clinical oncology consultants were involved in target volume delineation in 90% of cases, and OARs in 74%. Peer review took place in 46% of cases with 56% of consultants reporting no time for peer review in their job plan. Contouring for radical radiotherapy is complex and time-consuming, and despite increasing involvement of non-medical professionals, clinical oncology consultants remain the primary practitioners. Peer review practice is variable and time is often a limiting factor. Many factors influence the time required for contouring, and departments should take these factors and the need for peer-review into account when developing job plans. • Contouring for radical radiotherapy requires considerable consultant time. • Time needed for contouring varies considerably, and is affected by patient, tumour and treatment related factors. • As more advanced treatment techniques become more commonplace, complexity and time requirements are certain to increase. • Despite involvement of non-medical professionals, clinical oncology consultants remain the primary contouring practitioners. • Time constraints are a major factor limiting peer review practice. [ABSTRACT FROM AUTHOR]

Posterior fossa tumours (PFTs), which account for two-thirds of paediatric brain tumours, are successfully treated in about 70% of patients, but most survivors experience long-term cognitive impairment. We evaluated arterial spin labelling (ASL), a common, non-invasive magnetic resonance imaging (MRI) technique, as a biomarker of cognitive impairment in a paediatric PFT survivor population. Sixty participants were prospectively analysed. PFT survivors were at least 5 years post-treatment and had been treated as appropriate for their age and type of tumour. Group 1 had received radiotherapy and Group 2 had not. Group 3 were healthy controls matched to Group 1 for age, sex and handedness. All participants underwent cognitive assessment and multimodal MRI, including an ASL perfusion sequence. We used semi-quantitative ASL methods to assess differences in mean perfusion in the thalamus, caudate, putamen and hippocampus. Statistically, no significant associations between cognitive data and radiation doses were identified. Compared with healthy controls, Group 1 patients had significantly lower overall mean perfusion values (20–30% lower, depending on the cerebral structure) and Group 2 had slightly lower mean perfusion values (5–10% lower). Perfusion values did not correlate with total prescribed irradiation doses nor with doses received by different cerebral structures. Episodic and semantic memory test scores were significantly lower in Group 1 and correlated with lower mean absolute perfusion values in the hippocampus (P < 0.04). These preliminary results indicate that radiotherapy affects the perfusion of specific cerebral structures and identify perfusion as a potential biomarker of hippocampus-dependent memory deficit. • A semi-quantitative ASL method was used to quantify cognitive loss in PFT survivors. • Radiotherapy induced long-term overall cerebral semi-quantitative hypoperfusion in a paediatric PFT population. • Perfusion values tend to correlate significantly with the mean radiation dose received by the left hippocampus but not other brain structures examined. • A decrease in hippocampal perfusion is therefore a potential marker of memory impairment in irradiated children. [ABSTRACT FROM AUTHOR]

We sought to analyze the evolution of hydrocephalus and enumerate its predictive factors in posterior fossa tumors in children and adults. We also validated the modified Canadian Preoperative Prediction Rule for Hydrocephalus (mCPPRH) and Frankfurt grading systems as tools to predict cerebrospinal fluid (CSF) diversion in children and adults, respectively. A retrospective review of patients with posterior fossa tumors operated between 2012 and 2019 was performed. Clinical, radiologic, and operative data were obtained. Validation was performed for both scores via receiver operating characteristic (ROC) curves and evaluation of the area under the curve (AUC). We included 116 children and 343 adults in the study. Of the adults, 141 patients had intraaxial tumors and 172 had extraaxial tumors. The insertion of external ventricular drain (EVD), its duration, papilledema was noted to have significant influence on the need for permanent CSF diversion (P < 0.05) in children. The ROC for mCPPRH score was 0.659 (0.501–0.816), Age- 0.496 (0.334–0.658) and Evans index- 0.788 (0.654–0.922). In adults- Intraaxial tumours Age, Frankfurt score, duration of EVD, Diagnosis, Extent of resection and periventricular capping significant predictors and ROC age AUC 0.300 (0.193–0.407), Evans index 0.939 (0.888–0.990), and Frankfurt score 0.908 (0.853–0.964) (P < 0.05), whereas in extraaxial tumors Frankfurt grading, sex, duration of EVD, presence of perilesional edema and extent of resection (P < 0.05) ROC age AUC 0.439 (0.344–0.534), Evans index 0.941 (0.906–0.977), and Frankfurt score 0.847 (0.782–0.912). This is the first external validation study for the 2 predictive systems in use. mCPPRH demonstrated poor predictive accuracy, and Frankfurt grading system demonstrated good accuracy. EVD insertion and its duration was significantly predictive of the need for permanent CSF diversion. [ABSTRACT FROM AUTHOR]

Though rhabdomyosarcoma is the most common soft-tissue tumor diagnosed in children there are no reported cases of prenatally detected prostatic embryonal rhabdomyosarcoma. This report demonstrates the first reported case of this phenomenon and its subsequent workup, diagnosis, and treatment. [ABSTRACT FROM AUTHOR]

Ependymomas are the third most common brain tumors in children. The current standard of care for curative intent treatment is maximal safe resection followed by adjuvant radiotherapy. Controversy in the literature still exists over optimal radiotherapy dose. The most important prognostic factor for these tumors is the extent of resection followed by the addition of adjuvant radiotherapy. We completed a systematic review and meta-analysis of the available literature to determine the optimal radiotherapy dose regarding outcomes, including local control (LC), event-free survival (EFS), and overall survival (OS) in pediatric patients (≤22y). We searched MEDLINE (PubMed), Cochrane Database of Systematic Reviews, and Web of Science from inception to January 2024. We included cohort studies that compared adjuvant radiotherapy doses of ≤54Gy to >54Gy in pediatric patients (≤22y) with non-metastatic intracranial ependymomas treated with curative intent therapy. We assessed the risk of bias using the Newcastle-Ottawa Quality Assessment Scale of Cohort Studies. We quantitatively pooled studies using a random effects meta-analysis for hazard ratios (HR), 95% confidence intervals (CI), and statistical heterogeneity via I2. When HRs were unavailable, we transformed 3-year risks using established methods. We narratively summarized qualitative outcomes. Seven cohort studies met our inclusion criteria, covering a combined 1321 pediatric patients. Studies included a range of doses from 45-66.6Gy. Compared with patients receiving adjuvant radiotherapy dose of >54Gy, we found no difference in LC for those receiving ≤54Gy (HR = 0.83, 95% CI = 0.56-1.24, I2 = 49.1%), in EFS (HR = 1.02, 95% CI = 0.95-1.09, I2 = 0.00%), and OS (HR = 0.99, 95% CI = 0.82-1.20, I2 = 37.5%). Three studies methodically placed younger children in the lower dose cohorts due to concerns of late-effects of therapy. Two studies reported on the extent of resection by radiotherapy dose, with neither study reporting a statistical difference in LC, EFS, or OS, though the number of patients included in each study analysis was small (n≤30). Five studies reported on late effects, with brainstem radionecrosis, radiation-induced vasculopathy, and secondary tumors being the most frequently reported toxicities. Toxicities were not reported in relation to the specific doses of radiotherapy received. Overall study quality was high, though lower scores were consistently seen in the comparability of cohorts. We found no difference in LC, EFS, or OS for those treated with ≤54Gy compared to >54Gy. Many of the children who were in the lower dose cohorts were younger in age, a group with historically worse outcomes, which may artificially increase rates of relapse, events, and mortality. There was insufficient data to complete a subgroup meta-analysis on radiotherapy dosing based on the extent of resection or molecular subgroups, an important question for future research. [ABSTRACT FROM AUTHOR]

The indication for performing biopsies in patients with diffuse lesions in the brain stem is controversial. The possible risks associated with the technically challenging interventions must be balanced against clarifying the diagnosis and the possible therapeutic options. We reviewed the feasibility, risk profile, and diagnostic yield of different biopsy techniques in a pediatric cohort. We retrospectively included all patients aged <18 years who had undergone biopsy of the caudal brainstem region (pons, medulla oblongata) at our pediatric neurosurgical center from 2009 to 2022. We identified 27 children. Biopsies were performed using frameless stereotactic (Varioguide; n = 12), robotic-assisted (Autoguide; n = 4), endoscopic (n = 3), and open biopsy (n = 8) techniques. Intervention-related mortality was not observed. Three patients experienced a transient postoperative neurological deficit. No patient experienced intervention-related permanent morbidity. Biopsy yielded the histopathological diagnosis in all 27 cases. Molecular analysis was feasible for 97% of the cases. The most common diagnosis was H3K27M-mutated diffuse midline glioma (60%). Low-grade gliomas were identified in 14% of patients. Overall survival was 62.5% after 24 months of follow-up. Biopsies of the caudal brainstem in children were feasible and safe in the presented setup. The amount of tumor material acquired allowing for an integrated diagnosis and was obtained at reasonable risk. The selection of the surgical technique depends on the tumor location and growth pattern. We recommend the performance of brainstem tumor biopsies in children at specialized centers to better understand the biology and enable possible novel therapeutic options. [ABSTRACT FROM AUTHOR]

There is a lack of clinical protocols for re-irradiation in paediatric central nervous system (CNS) tumours. To fill this void, the Swedish Workgroup of Paediatric Radiotherapy (SBRTG) compiled national guidelines on re-irradiation in paediatric CNS tumours (diffuse intrinsic pontine glioma, ependymoma, germinoma and medulloblastoma). These have been in clinical practice since 2019 in all paediatric radiotherapy centres in Sweden. Since the implementation, the guidelines have been complemented with a yearly review on clinical outcome and toxicities in all paediatric patients treated according to the guidelines. This article presents the Swedish national guidelines on re-irradiation in paediatric CNS tumours. • Re-irradiation of CNS tumours in paediatric patients is becoming more common. • Clinical guidelines for re-irradiation of paediatric CNS tumours are lacking. • We present Swedish national guidelines on re-irradiation in paediatric CNS tumours. [ABSTRACT FROM AUTHOR]

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Pediatric pituitary adenomas are rare lesions and account for approximately 3% of all supratentorial tumors in children. There is a paucity of reports on endoscopic transsphenoidal surgery in children. The aim of this study was to assess the early/late outcomes of endoscopic pediatric pituitary adenoma surgery at a high-volume tertiary center, as well as to characterize the factors associated with aggressive growth, including the histopathological features. Between August 1997 and June 2022, a total of 3256 patients underwent endoscopic transsphenoidal surgery for pituitary adenoma at the Department of Neurosurgery and Pituitary Research Center of the Kocaeli University School of Medicine. Of these, 70 (2.1%) pediatric patients (25 males, 45 females) (age ≤18 years) with a pathological diagnosis of pituitary adenoma were retrospectively reviewed. The mean age of patients was 15.5 ± 2.3 years. Among the hormone-secreting adenomas, 19 (34.5%) were adrenocorticotrophic hormone secreting, 13 (23.6%) were growth hormone secreting, 19 (34.5%) were prolactin secreting, and 4 (7.2%) were both growth hormone-prolactin secreting. Gross total resection was achieved in 93.3% of nonfunctional tumors. The early/late surgical remission rates for hormone-secreting adenomas were 61.5%/46.1% (mean follow-up: 63.7 ± 49.3 months) for acromegaly, 78.9%/68.4% (47.8 ± 51.0 months) for Cushing disease, 57.8%/31.5% (72.2 ± 59.5 months) for prolactinoma, and 25%/25% (35.2 ± 31.4 months) for growth hormone-prolactin–secreting adenomas. Five sparsely granulated corticotroph tumors, 5 sparsely granulated somatotroph tumors, and 11 densely granulated lactotroph tumors were classified as aggressive histopathological subtypes. The unique characteristics of the pediatric population and the aggressiveness of the disease in this population pose considerable therapeutic challenges. To increase treatment success, current adjuvant therapies that are appropriate for the morphological and biological characteristics of the tumor are required in addition to surgical treatment. [ABSTRACT FROM AUTHOR]

Adjuvant radiotherapy is an integral component in the management of soft-tissue sarcomas. Brachytherapy is a very convenient and conformal way of delivering adjuvant radiotherapy in such tumours, which spares the surrounding normal tissue. Randomised studies have established the efficacy of brachytherapy in the adjuvant setting, with a 5-year local control of 80–85%. High dose rate, low dose rate and pulsed dose rate have shown equivalent local control, but high dose rate has gained popularity owing to patient convenience, radiation safety and flexibility in dose optimisation. Freehand insertion perioperative brachytherapy (intraoperative placement and postoperative treatment) is the most commonly used technique in soft-tissue sarcomas, with intraoperative radiotherapy and radioactive seed placement being the less commonly used techniques. Brachytherapy can be used as monotherapy or in combination with external beam radiotherapy, such as in cases of close/positive margins for safe dose escalation. Although the quantum of side-effects with external beam radiotherapy has considerably reduced with the evolution of technology and the introduction of intensity modulation (intensity-modulated radiotherapy), brachytherapy still scores better in terms of dose conformality, especially in recurrent tumours (previously irradiated) and when used to treat paediatric and geriatric patients. • Brachytherapy allows effective disease control and organ and function preservation for soft tissue sarcomas in adult and paediatric age groups. • Appropriate selection of patient and brachytherapy technique are critical in achieving optimal outcomes. • Brachytherapy is particularly useful in children as it allows reduction in volumes of immature normal tissue irradiated. [ABSTRACT FROM AUTHOR]

Immunosuppression of varying degree is present in children with cancer. This can range from mild to severe. Cancer itself, particularly leukaemia and lymphoma, can cause suppression of cellular and humoral immune function. However, cytotoxic antineoplastic therapy is the main contributor. Immune alteration is reflected by decreases in neutrophils, lymphocytes, immunoglobulin levels, and specific antibodies against previous vaccinations and infections. Immune recovery post-treatment occurs in a differential manner, with innate immune function recovering before adaptive immune function, and with B-cell function recovering faster than T-cell function. As a result of these changes children with cancer, and particularly those who are also haematopoietic stem cell transplant (HSCT) recipients, have an acquired immune deficiency, and are at increased risk of significant morbidity and mortality from infections. It is therefore important to ensure that such children are maximally protected against vaccine-preventable diseases. This can be achieved by optimising the vaccination strategy in children during immunosuppressive cancer treatment and after completion of treatment. Vaccination should be routine practice for all children treated for cancer. The vaccination strategy should not only include the patient, but also the household members and healthcare contacts of the patient. [ABSTRACT FROM AUTHOR]

This phase I/expansion study assessed the safety, pharmacokinetics and preliminary antitumor activity of afatinib in paediatric patients with cancer. The dose-finding part enroled patients (2–<18 years) with recurrent/refractory tumours. Patients received 18 or 23 mg/m2/d afatinib orally (tablet or solution) in 28-d cycles. In the maximum tolerated dose (MTD) expansion, eligible patients (1–<18 years) had tumours fulfilling ≥2 of the following criteria in the pre-screening: EGFR amplification; HER2 amplification; EGFR membrane staining (H-score>150); HER2 membrane staining (H-score>0). The primary end-points were dose-limiting toxicities (DLTs), afatinib exposure, and objective response. Of 564 patients pre-screened, 536 patients had biomarker data and 63 (12%) fulfilled ≥2 EGFR/HER2 criteria required for inclusion in the expansion part. A total of 56 patients were treated (17 in the dose-finding and 39 in the expansion part). DLTs were observed in one of six MTD-evaluable patients receiving 18 mg/m²/d and in two of five MTD-evaluable patients receiving 23 mg/m²/d; 18 mg/m²/d was defined as the MTD. There were no new safety signals. Pharmacokinetics confirmed exposure consistent with the approved dose in adults. One partial response (−81% per Response Assessment in Neuro-Oncology) was observed in a patient with a glioneuronal tumour harbouring a CLIP2::EGFR fusion; unconfirmed partial responses were observed in two patients. In total, 25% of patients experienced objective response or stable disease (95% confidence interval: 14–38). Targetable EGFR/HER2 drivers are rare in paediatric cancers. Treatment with afatinib led to a durable response (>3 years) in one patient with a glioneuronal tumour with CLIP2::EGFR fusion. • 12% of 536 paediatric patients screened had ≥2 potential ErbB-activation markers. • 56 paediatric patients with ErbB-dysregulated tumours received afatinib. • MTD in children was 18 mg/m²/d; PK and safety were equivalent to adults. • Objective response observed in one patient (>3 years), with a CLIP2::EGFR fusion. • EGFR gene fusion or driver mutations are rare in paediatric cancer but are sensitive to afatinib. [ABSTRACT FROM AUTHOR]

Infantile hepatic hemangioma (IHH) is the most common benign liver tumor in children, and multifocal and diffuse tumors often become life-threatening, necessitating therapy. Propranolol is now considered the first choice of therapy with ample data in Caucasian children. We present a series of nine Indian children with multifocal (n = 5) and diffuse (n = 4) IHH treated with propranolol monotherapy. This was a retrospective clinical data-based single-center study. Propranolol was used at a median dose of 3.2 mg/kg/day (range 3–3.3 mg/kg/day) for a median duration of 12 months (range 6–32 months). The presentations of IHH (either in isolation or combination) were hypothyroidism in six patients (diagnosed by elevated serum TSH levels), heart failure in three (diagnosed based on clinical and echocardiographic features), and imaging evidence of macrovascular shunting in two patients. A good response to propranolol monotherapy (with a median dose of 3.2 mg/kg/day for a median duration of 12 months) was observed in eight patients, with a poor response in one. One patient experienced recurrence but responded adequately to propranolol retreatment. Our data reiterate the excellent response (88.9% responded) and safety profile with propranolol monotherapy in complicated IHH and strengthen the data in Asian (Indian) children. It includes the maximum proportion of complicated IHH treated with propranolol in East and South Asia, and the largest series from India. [Display omitted] [ABSTRACT FROM AUTHOR]

Neuroblastoma (NB) is one of the most common extracranial solid tumors in children. MYCN gene amplification is highly associated with poor prognosis in high-risk NB patients. In non-MYCN-amplified high-risk NB patients, the expression of c-MYC (MYCC) and its target genes is highly elevated. USP28 as a deubiquitinase is known to regulate the stability of MYCC. We show here USP28 also regulates the stability of MYCN. Genetic depletion or pharmacologic inhibition of the deubiquitinase strongly destabilizes MYCN and stops the growth of NB cells that overexpress MYCN. In addition, MYCC could be similarly destabilized in non-MYCN NB cells by compromising USP28 function. Our results strongly suggest USP28 as a therapeutic target for NB with or without MYCN amplification/overexpression. [ABSTRACT FROM AUTHOR]

Cerebellar mutism syndrome (CMS) is a well-known complication after posterior fossa tumor surgery in pediatric patients. We evaluated the incidence of CMS in our institute and analyzed its association with multiple risk factors, such as tumor entity, surgical approach, and hydrocephalus. All pediatric patients who had undergone intra-axial tumor resection in the posterior fossa between January 2010 and March 2021 were included in the retrospective analysis. Various data points, including demographic, tumor-associated, clinical, radiological, surgery-associated, complications, and follow-up data, were collected and statistically evaluated for an association with CMS. A total of 63 surgeries in 60 patients were included. The median patient age was 8 years. Pilocytic astrocytoma was the most common tumor type (50%), followed by medulloblastoma (28%) and ependymomas (10%). Complete, subtotal, and partial resection was achieved in 67%, 23%, and 10%, respectively. A telovelar approach had been used the most often (43%) compared with a transvermian approach (8%). Of the 60 children, 10 (17%) had developed CMS and showed marked improvement but with residual deficits. The significant risk factors were a transvermian approach (P = 0.03), vermian splitting when added to another approach (P = 0.002), an initial presentation with acute hydrocephalus (P = 0.02), and hydrocephalus present after tumor surgery (P = 0.004). Our CMS rate is comparable to those described in the literature. Despite the limitations of the retrospective study design, we found that CMS was not only associated with a transvermian approach but was also associated with a telovelar approach, although to a lesser extent. Acute hydrocephalus at the initial presentation necessitating urgent management was significantly associated with a greater incidence of CMS. [ABSTRACT FROM AUTHOR]

Determination of optic nerve sheath diameter (ONSD) with transbulbar sonography has become an easily accessible and time-effective tool in the assessment of increased intracranial pressure. The aim of our study was to evaluate the usefulness of transbulbar sonography in the initial diagnosis and in follow-up examinations of children and adolescents with the diagnosis of pseudotumor cerebri syndrome (PTCS). We retrospectively reviewed imaging results of 24 patients aged 0.75–17 years with PTCS. Serial transbulbar sonography examinations were performed between 2011 and 2021. Sonographic evaluation included the ONSD, papilledema and subarachnoid space. 240 sonographic measurements taken at 108 time points in 17 patients met the inclusion criteria. All patients underwent serial lumbar punctures and routine fundoscopy in close relation to transbulbar sonography. We found that ONSD values remained high in all patients. The longest follow-up period was dated 2498 days (6.84 years) after initial diagnosis. Papilledema resolved in close correlation to fundoscopy normalization. In 16/17 patients the subarachnoid space remained cystic in appearance. These findings were independent of clinical symptoms and lumbar puncture opening pressure. We conclude that transbulbar sonography is a useful diagnostic tool in the initial diagnostic workup of children with PTCS. On follow-up however ONSD values and the cystic transformation of the subarachnoid space remained pathologic in the majority of cases while papilledema resolved parallel to fundoscopy findings. Serial measurements of ONSD are therefore of limited value in the follow-up of patients with PTCS and cannot be considered a reliable tool in subsequent therapeutic decisions. • Transbulbar sonography is useful for diagnosis of pediatric pseudotumor cerebri. • On follow-up optic nerve sheath diameter and subarachnoid space remain enlarged. • Sonographic papillary changes normalize parallel to fundoscopy findings. • Serial ONSD measurements are of limited value. • ONSD measures in follow-up are not a reliable tool for subsequent therapy decisions. [ABSTRACT FROM AUTHOR]

The use of the Alexis wound protector-retractor (AWPR) could further improve the laparoscopic techniques for safely removing huge ovarian tumors in children. A 15-year-old patient presented to our emergency department with a history of weeks of persistent abdominal pain. Clinical examination and magnetic resonance imaging demonstrated a 25 × 21 × 21 cm cystic mass arising from the left ovary. An en block unilateral oophorectomy and salpingectomy with the use of a medium-sized AWPR was performed without complications. The patient was discharged on the second postoperative day. The AWPR is a safe and effective tool in treating such children and adolescents with huge ovarian tumors, preserving fertility, minimizing the postoperative pain and hospital stay, and providing an excellent cosmetic outcome. [ABSTRACT FROM AUTHOR]

Lynch syndrome (LS) is an autosomal dominant genetic disorder defined by germline mutations in one of four mismatch repair genes including PMS2, MLH2, MSH1, MSH2, or deletion in the EPCAM gene.1 The most common urologic manifestation of LS is upper tract urothelial carcinoma, which occurs in up to 20% of patients with LS.2 While data are scarce, there is growing evidence of an increased relative risk of bladder malignancy in patients with LS.3,4 Bladder tumors in children are a rare entity and the link between pediatric bladder tumors and LS has not been previously reported to our knowledge. [ABSTRACT FROM AUTHOR]

Cancer (CA) among adolescents and young adults (AYA) presents with unique biological characteristics and histological distributions that differ from children or older adults. CA incidence among AYA (15-39 years) is on the rise despite stable rates among other patient populations, and current literature lacks a consensus as to the etiology behind this trend. Behaviors and characteristics such as tobacco use, alcohol consumption, obesity, diet quality, and sedentary lifestyles have been linked to increased CA risk. To determine if AYA engage in these behaviors at a higher rate compared to previous years, increasing their risk for CA. This descriptive, cross-sectional study collected data between 2005-2023 from a convenience sample of undergraduate students ages 18-24 years enrolled in an entry-level, general education nutrition course at a large, northeastern university. Alcohol/tobacco/vape use, and self/family medical history were self-reported through an online survey. Dietary intake was assessed via 3-day food records and online nutrient analysis software. Daily activity level (steps/day) was measured via research-grade pedometers. Height and weight were measured in duplicate after an overnight fast by research assistants. Most of the final sample (n=11600) were female (68.7%) and reported self or family history of CA (69.3%). Average BMI was 23.6±3.7 kg/m2, and 6.1% of students met criteria for obesity (≥30 kg/m2). Over half (57.9%) reported binge drinking within the past 30 days. While a low proportion of students reported smoking cigarettes (6.5%), almost one in four (23.3%) of students reported using an electronic vape daily or almost daily. A low proportion of students met recommendations for fruit (21.6%), vegetable (22.3%) and fiber intake (16%). Most students (74.3%) were categorized as somewhat active, and 11.4% were sedentary-low active. While most students reported family or self-history of CA, many also reported behaviors link to increased cancer risk including binge drinking, vaping, and poor dietary quality. This data has the potential to inform interventions targeting AYA aiming to reduce CA risk. NIFA [ABSTRACT FROM AUTHOR]

Vaginal yolk sac tumors are rare pediatric malignant tumors and the most common form of vaginal germ-cell tumors in children. They are almost exclusively found in females under 3 years of age. Treatment involves local excision either with or without chemotherapy. Herein, we describe a case of a 3-year-old girl with vaginal Yolk sac tumor, who underwent buccal mucosa vaginoplasty through an anterior sagittal transrectal approach , as an effective oncological procedure, with preservation of reproductive function. [ABSTRACT FROM AUTHOR]

Precision oncology requires diagnostic accuracy and robust detection of actionable alterations. The Pediatric Targeted Therapy (PTT) 2.0 program aims at improving diagnostic accuracy by addition of molecular analyses to the existing histological diagnosis and detection of actionable alterations for relapsed paediatric oncology patients, in cases with limited availability of tumour material. Paediatric patients diagnosed with relapse or progression of a central nervous system tumour (n = 178), a sarcoma (n = 41) or another solid tumour (n = 44) were included. DNA methylation array, targeted gene panel sequencing on tumour and blood (130 genes), RNA sequencing in selected cases and a pathway-specific immunohistochemistry (IHC) panel were performed using limited formalin-fixed paraffin embedded tissue from any disease episode available. The clinical impact of reported findings was assessed by a serial questionnaire-based follow-up. Integrated molecular diagnostics resulted in refined or changed diagnosis in 117/263 (44%) tumours. Actionable targets were detected in 155/263 (59%) cases. Constitutional DNA variants with clinical relevance were identified in 16/240 (7%) of patients, half of which were previously unknown. Clinical follow-up showed that 26/263 (10%) of patients received mechanism-of-action based treatment matched to the molecular findings. Next-generation diagnostics adds robust and relevant information on diagnosis, actionable alterations and cancer predisposition syndromes even when tissue from the current disease episode is limited. [Display omitted] • International molecular diagnostics study for recurrent paediatric oncology patients. • Robust molecular diagnostics on limited paraffin-embedded tumour material. • Clinically feasible turn-around time and impact on clinical decision making. • Refined and re-classified diagnoses, detection of targetable molecular alterations. • Identification of constitutional DNA variants. [ABSTRACT FROM AUTHOR]

This study systematically reviewed the literature to investigate the value of secondary surgery for children with a high-risk neuroendocrine tumor (NET) of appendix. A systematic search was performed in PubMed, Embase and Web of Science. All randomized controlled trials, cohort studies, and case series reporting on the management and outcomes of patients (<20 years) with a histopathologically proven NET of the appendix were eligible for inclusion. Two authors independently selected eligible articles, assessed risk of bias, and extracted data. The outcomes of patients with a high-risk NET treated with secondary surgery were compared to those treated without secondary surgery. Primary outcomes were recurrence rate and disease-free survival. The literature search yielded 667 articles, of which 29 were included. These studies reported on 1112 patients, of whom 145 (13%) had high-risk NET. Heterogeneity between studies was large and risk of bias was serious in 26 and moderate in three studies. Secondary surgery after primary appendectomy was performed in 64 of 145 patients (44%). Length of follow-up ranged between 0 and 612 months. In both treatment groups no recurrences were reported, and thus disease-free survival was 100%. Based on current literature, the value of secondary surgery for pediatric high-risk NET of the appendix may be questioned. However, evidence is scarce, of low-quality, and heterogeneity between studies is large. Large international studies with adequate follow-up are needed to generate high-quality evidence on this topic. [ABSTRACT FROM AUTHOR]

• Tenovin-6 inhibits the proliferation, invasion, and migration of SHH type medulloblastoma (SHH-MB) cells. • Tenovin-6 induces apoptosis in SHH-MB cells. • Tenovin-6 inhibits autophagy in SHH-MB, not primarily through P53, SIRT1, and ubiquitin proteasome pathways. • Tenovin-6 blocks autophagic flux in SHH-MB. • Tenovin-6 may affect SHH-MB proliferation and autophagosome production via the EGFR-PI3K-AKT pathway. Medulloblastoma (MB) is the most common malignant brain tumor in children. Within MB, tumors driven by the Sonic Hedgehog (SHH) pathway represent the most heterogeneous subtype, known as SHH subtype medulloblastoma (SHH-MB). Tenovin-6, a recognized p53 activator, has been demonstrated to inhibit autophagy and modulate sirtuin activity, underscoring its potential as a novel therapeutic agent across various malignancies. However, its efficacy in treating SHH-MB remains unexplored. This study aims to investigate the inhibitory effects of tenovin-6 on SHH-MB and elucidate its underlying signaling pathways. We assessed the impact of tenovin-6 on cell proliferation through the CCK-8 and colony formation assays. The scratch and transwell invasion assays were utilized to evaluate the drug's effects on metastasis. Apoptosis and reactive oxygen species (ROS) levels were measured using flow cytometry. Potential signaling pathways were identified via transcriptomics and quantitative PCR (qPCR). Our in vivo studies involved a mouse xenograft model to explore tenovin-6′s anticancer efficacy against SHH-MB. The findings indicate that tenovin-6 not only inhibits cell proliferation and metastasis in SHH-MB cell lines but also promotes apoptosis, which is closely linked to its proliferation-inhibiting properties. Additionally, animal experiments confirmed that tenovin-6 suppresses MB growth in vivo. We discovered that tenovin-6 reduces intracellular ROS levels and inhibits autophagy in SHH-MB by disrupting the fusion of autophagosomes with lysosomes, likely through inducing autophagosome formation. [ABSTRACT FROM AUTHOR]

Osteosarcoma is the most common malignant bone tumor in children and adolescents during rapid bone growth. Traditional chemotherapy has markedly improved patient outcomes but suffers from nonspecific side effects due to nonspecific drug distribution, highlighting the need for targeted therapies. Methotrexate, although effective, poses toxicity concerns and prompts exploration into advanced drug delivery systems like nanoparticles. Here, we developed a novel method of synthesizing gold nanoparticles using bromelain (G-BNPs) as a reducing and capping agent, and we conjugated G-BNPs with methotrexate (G-B-MNPs) via 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide/N-hydroxysuccinimide (EDC/NHS) as crosslinker. Our meticulous characterization, which included UV–visible spectroscopy, Transmission electron microscopy (TEM), Dynamic light scattering (DLS), Zeta potential, and Fourier-transform infrared spectroscopy (FTIR) analyses confirmed the successful fabrication and drug conjugation of the G-BNPs. We then evaluated the cytotoxicity of the G-BNPs (sized ∼ 21 nm) and G-B-MNPs (sized ∼ 24 nm) on the osteosarcoma cell lines, Saos-2 and MG-63, as well as the non-cancerous primary osteoblast cells. Our findings revealed that G-B-MNPs significantly increased the cytotoxic impact on osteosarcoma cells compared to methotrexate alone while showing minimal toxicity toward primary osteoblast cells. Importantly, using 4',6-diamidino-2-phenylindole(DAPI), we demonstrated that G-B-MNPs were delivered directly into the nucleus of the cells without encountering lysosomes. G-B-MNPs can be considered a potential drug delivery method for osteosarcoma treatment by improving effectiveness and reducing adverse effects, thereby enhancing patient prognosis. [Display omitted] • A novel biogenic method was developed to produce highly stable bromelain encapsulated GNPs (G-BNPs). • These particles were bioconjugated to a chemotherapeutic drug, Methotrexate (G-B-MNPs). • G-B-MNPs were found to be highly specific and potent against osteosarcoma cells (MG-63 & Saos-2). • G-B-MNPs reduced the effective concentration of methotrexate 4–6 times while not affecting primary osteoblasts significantly. [ABSTRACT FROM AUTHOR]

The incidence of early-onset cancers in adolescents and young adults (AYA) has been increasing worldwide since the 1990s. In Italy, a significant increased rate of 1.6 % per year has been reported for early-onset cancers among females between 2008 and 2016. This is mainly attributable to melanoma, thyroid, breast and endometrial cancer. The aim of our work was to describe temporal trends of the main established lifestyle risk factors (tobacco use, alcohol consumption, obesity, physical inactivity, dietary westernization and reproductive factors) over the last 20 years in the Italian AYA population. Available data on behavioural risk factors, individual and household daily life have been obtained and elaborated from PASSI, ISTAT and Eurostat reports. Lowering age of smoking initiation, an increase in alcohol drinkers among young females, and an obesity and overweight epidemic, particularly among children and adolescents as a result of physical inactivity and dietary habits, may be contributing factors behind this cancer epidemic, especially among females. In-depth investigations are needed to understand the exact role of each contributing factor, the effects of exposure to nicotine-containing products and environmental factors such as endocrine disruptors that could play a role in this phenomenon. • The incidence of early-onset cancers has been increasing worldwide since the 1990s. • An increased rate of early-onset breast and endometrial cancer has been reported in Italy. • Changes in lifestyle risk factors are contributing to this cancer epidemic. • The area of most concern is overweight and obesity among children and adolescents. • In-depth investigations are needed to understand the role of each contributing factor. [ABSTRACT FROM AUTHOR]

Data on the efficacy and safety of anti PD-1 antibodies in children and adolescents (CA) with melanoma are lacking. The aim of this study was to determine outcomes of CA melanoma patients receiving anti PD-1 antibodies. Melanoma patients ≤18 years treated with anti PD-1 were retrospectively retrieved from 15 academic centers. Information on histopathological diagnosis, surgical treatment, systemic therapy, objective response rate (ORR), safety profile was collected. Progression-free survival (PFS) and overall survival (OS) were assessed by Kaplan-Meier method. Between April 2016 and March 2024, 99 patients treated with systemic therapy were retrieved, 81 treated with anti PD-1 therapy. Median age was 14 years (range 2–18 years), 37 pts were ≤12 yrs. Overall, 38 CA patients received anti PD-1 in adjuvant setting, and the 3-year PFS and OS were 70.6 % and 81.1 %, respectively. Two patients received anti-PD-1 based neoadjuvant treatment, both had a pathologic complete response and remain disease free. Fifty-six received a systemic therapy for advanced disease and among them, 43 received anti PD-1-based therapy for advanced disease in 1st line, while 12 and 5 pts received a 2nd and 3rd line, respectively. Among patients receiving a 1st line therapy with anti PD-1 monotherapy the ORR was 25 %, and the 3-year OS was 34 %. Toxicities were consistent with previous studies in adult melanoma patients. Our study provides the first evidence of efficacy of anti PD-1 in CA melanoma patients and supports the use of anti PD-1 therapy in pts ≤18 years, included those <12 years. [ABSTRACT FROM AUTHOR]

Diffuse midline glioma (DMG) is the most aggressive primary brain tumor in children. The only approved standard of care is radiation therapy (RT). Studies examining the role of other systemic agents have failed to demonstrate a survival benefit, partially due to tumor extension into areas of the brain where the blood-brain barrier (BBB) remains intact. As our laboratory has recently determined active NAD(P)H Quinone Dehydrogenase 1 (NQO1) expression in patient-derived DMG tumor samples, and RT has been shown to induce NQO1 expression, we sought to investigate the NQO1 bioactivatable ROS inducing agent, Napabucasin, as a potential radiosensitizer in DMG. Furthermore, we explore the safety and feasibility of convection-enhanced drug delivery (CED) to overcome limitations of the BBB. Using two DMG cell lines, we performed clonogenic survival assays with increasing doses of RT with and without Napabucasin. We then created subcutaneous xenograft mouse models, treating with (1) vehicle control, (2) Napabucasin 10mg/kg via intraperitoneal injection, (3) 2 Gy of RT daily, or (4) combination treatment with RT and Napabucasin. Flank tumor measurements were obtained weekly using ultrasound imaging. For our syngeneic orthotopic DMG mouse model, we implanted 7-day osmotic infusion pumps containing either vehicle or 80uM Napabucasin. Mice then underwent a second randomization with or without daily RT for 5 days. Weekly MRIs and daily weights were obtained to measure local control and overall survival (OS), respectively. We identified a robust radiosensitizing effect with Napabucasin using in vitro clonogenic survival assays (Bliss synergy score 16.6). In subcutaneous flank models, combination treatment led to a statistically significant decrease in tumor volume post-treatment completion when compared to any monotherapy (P < 0.05). In our syngeneic orthotopic DMG mouse model, RT after osmotic pump implantation in the brainstem did not lead to significant morbidity or mortality. Combination RT and CED of Napabucasin led to a significant OS benefit when compared to monotherapy (median OS 46 days with combination treatment, 33 days with RT monotherapy, and 26 days with Napabucasin monotherapy, P < 0.001). In this study, we identify Napabucasin as a promising radiosensitizer in DMG. Furthermore, this is the first preclinical study showing safety/efficacy of CED with concurrent RT in DMG. As RT is the cornerstone of DMG care, identifying novel radiosensitizing techniques in this devastating disease is paramount to clinical success. [ABSTRACT FROM AUTHOR]

Childhood cancer incidence is on the rise and are most often underreported. However, children are vulnerable to suffer most from the adverse consequences. There is limited information geographical distribution, histological types and clinical presentation of pediatric malignancies at Bugando Medical Center (BMC), in MWANZA, Tanzania. Retrospective hospital-based study was conducted among pediatrics cancer patients attending BMC from May to July 2023 using a cancer registry from 2018 to 2023. A checklist was used to collect socio-demographic, clinical laboratory data from hard copies and and electronic patients' files. Analysis was done using STATA version 15.0 software according to the study objectives. A total of 199 patients were enrolled with median age (IQR) of study population was 7.7 (4.3 – 11.3) years. The majority of the participants were male 115(57.8%). Most of the patients were from Mwanza region 47(23.6%) followed by Mara region 40(20.1%). The most common histological types of pediatric malignancies were nephroblastoma, 31 (15.6%); rhabdomyosarcoma, 30 (15.1%), and retinoblastoma, 28 (14.1%). Approximately 70 (35.5%) had complete remission, 48 (24.2%) were lost to follow up and 20(10.1%). The deaths were more in Katavi, Tabora and Simiyu; and also deaths were more in Non-Hodgkin's lymphoma, Acute lymphocytic leukemia and Retinoblastoma, although the differences were not statistically significant for the association between deaths with region and histological types (p-values = 0.332 and 0.065, respectively). Pediatric malignancies are commonly in the Mwanza and Mara regions with the most common histological types being nephroblastoma. Approximately 1 in 10 of children with pediatric malignancy died, with death occurring mostly in the Katavi, Tabora and Simiyu. Targeted outreach screening programs from BMC are recommended to be focused in the two regions with the highest burden, and three regions with high mortality. [ABSTRACT FROM AUTHOR]

The need for innovative paediatric cancer care models that minimise the reliance on anaesthesia and sedation during treatment has never been more critical. The HEROCARE (Holistic Empowerment in Radiation Oncology) project, developed at the Hong Kong Polytechnic University, pioneers an advanced framework that emphasises personalised preparations and experiential learning for patients, undergraduate radiography students and healthcare providers, particularly radiation therapists. This presentation outlines the transformative impact of the HEROCARE model in paediatric radiotherapy, detailing its dual benefits in enhancing treatment efficacy and educational outcomes. It highlights the model's role in fostering empathy and compassion among practitioners, crucial for patient-centred care. The HEROCARE model integrates immersive simulations and interdisciplinary workshops to prepare children and their carers for the radiotherapy course, significantly reducing the need for sedation/anaesthesia. This model serves as a practical training ground for radiation therapy students and practising therapists, emphasising hands-on engagement, empathetic patient and carer interactions. This model, incorporating real-world clinical scenarios into education, enhances students' professional skills, communication abilities, and emotional intelligence. The implementation of HEROCARE has led to remarkable improvements in treatment outcomes, including a substantial reduction in sedation/anaesthesia use, shorter treatment times, and increased patient comfort and compliance. Simultaneously, the project enriches the training of future radiation therapists by providing them with comprehensive insights into patient-centred approaches and interdisciplinary collaboration. Feedback from participants indicates enhanced understanding of the emotional and physical needs of paediatric patients, better communication with children and families, and greater confidence in managing complex clinical situations without sedation. Building on its success in paediatric settings, the HEROCARE framework is proposed as a model for continuing professional development in radiation therapy. The model's adaptability for advanced practice professionals helps in refining their skills in empathetic patient care, complex decision-making, and collaborative practice. This initiative not only exemplifies the integration of service and education but also sets a visionary standard for developing cancer treatment protocols that are both effective and compassionate. The HEROCARE project not only revolutionises paediatric radiotherapy by improving clinical outcomes and reducing dependency on sedation/anaesthesia but also significantly advances radiation therapy education. By bridging the gap between clinical practice and academic training, HEROCARE cultivates a new generation of radiation therapists who are not only technically proficient but also deeply empathetic and patient-focused. This model promises to redefine professional standards in cancer care, underscoring the critical role of empathy and compassion in the therapeutic disciplines. With the proven success of the HEROCARE model in paediatric oncology, future initiatives will aim to expand its application across other demographics and medical specialties. This includes adapting the model for adult patients and integrating it into broader oncology and radiology training programmes to enhance the scope and impact of this pioneering approach. [ABSTRACT FROM AUTHOR]

As the mitogen-activated protein kinase (MAPK) signalling pathway is activated in many paediatric cancers, it is an important therapeutic target. Currently, a range of targeted MAPK pathway inhibitors are being developed in adults. However, MAPK signals through many cascades and feedback loops and perturbing the MAPK pathway may have substantial influence on other pathways as well as normal development. In view of these issues, the ninth Paediatric Strategy Forum focused on MAPK inhibitors. Development of MAPK pathway inhibitors to date has been predominantly driven by adult indications such as malignant melanoma. However, these inhibitors may also target unmet needs in paediatric low-grade gliomas, high-grade gliomas, Langerhans cell histiocytosis, juvenile myelomonocytic leukaemia and several other paediatric conditions. Although MAPK inhibitors have demonstrated activity in paediatric cancer, the response rates and duration of responses needs improvement and better documentation. The rapid development and evaluation of combination approaches, based on a deep understanding of biology, is required to optimise responses and to avoid paradoxical tumour growth and other unintended consequences including severe toxicity. Better inhibitors with higher central nervous systempenetration for primary brain tumours and cancers with a propensity for central nervous system metastases need to be studied to determine if they are more effective than agents currently being used, and the optimum duration of therapy with MAPK inhibition needs to be determined. Systematic and coordinated clinical investigations to inform future treatment strategies with MAPK inhibitors, rather than use outside of clinical trials, are needed to fully assess the risks and benefits of these single agents and combination strategies in both front-line and in the refractory/relapse settings. Platform trials could address the investigation of multiple similar products and combinations. Accelerating the introduction of MAPK inhibitors into front-line paediatric studies is a priority, as is ensuring that these studies generate data appropriate for scientific and regulatory purposes. Early discussions with regulators are crucial, particularly if external controls are considered as randomised control trials in small patient populations can be challenging. Functional end-points specific to the populations in which they are studied, such as visual acuity, motor and neuro psychological function are important, as these outcomes are often more reflective of benefit for lower grade tumours (such as paediatric low-grade glioma and plexiform neurofibroma) and should be included in initial study designs for paediatric low-grade glioma. Early prospective discussions and agreements with regulators are necessary. Long-term follow-up of patients receiving MAPK inhibitors is crucial in view of their prolonged administration and the important involvement of this pathway in normal development. Further rational development, with a detailed understanding of biology of this class of products, is crucial to ensure they provide optimal benefit while minimising toxicity to children and adolescents with cancer. • Mitogen-activated protein kinase pathway is an important target in glioma, Langerhans cell histiocytosis, neurofibroma and leukaemia • Mitogen-activated protein kinase inhibitors can address many unmet needs and have demonstrated activity • Combination development and monotherapy optimisation is required • New clinical/functional end-points should be agreed prospectively with regulators • Inclusion in front-line studies and generating regulatory data are priorities [ABSTRACT FROM AUTHOR]

Regulatory decisions on paediatric investigation plans (PIPs) aim at making effective and safe medicines timely available for children with high unmet medical need. At the same time, scientific knowledge progresses continuously leading frequently to the identification of new molecular targets in the therapeutic area of oncology. This, together with further efforts to optimise next generation medicines, results in novel innovative products in development pipelines. In the context of global regulatory development requirements for these growing pipelines of innovative products (e.g. US RACE for children Act), it is an increasing challenge to complete development efforts in paediatric oncology, a therapeutic area of rare and life-threatening diseases with high unmet needs. Regulators recognise feasibility challenges of the regulatory obligations in this context. Here, we explain the EU regulatory decision making strategy applied to paediatric oncology, which aims fostering evidence generation to support developments based on needs and robust science. Because there is a plethora of products under development within given classes of or within cancer types, priorities need to be identified and updated as evidence evolves. This also includes identifying the need for third or fourth generation products to secure focused and accelerated drug development. An agreed PIP, as a plan, is a living document which can be modified in light of new evidence. For this to be successful, input from the various relevant stakeholders, i.e. patients/parents, clinicians and investigators is required. To efficiently obtain this input, the EMA is co-organising with ACCELERATE oncology stakeholder engagement platform meetings. • Regulatory decision-making in the context of product development life cycle. • PIP as a plan, allowing for evidence generation, able to be modified. • Fostering collaborative development environment, not competitive. • Need to identify priorities based on science. • Collaboration among all stakeholders key, as exemplified by ACCELERATE. [ABSTRACT FROM AUTHOR]

iTHER is a Dutch prospective national precision oncology program aiming to define tumour molecular profiles in children and adolescents with primary very high-risk, relapsed, or refractory paediatric tumours. Between April 2017 and April 2021, 302 samples from 253 patients were included. Comprehensive molecular profiling including low-coverage whole genome sequencing (lcWGS), whole exome sequencing (WES), RNA sequencing (RNA-seq), Affymetrix, and/or 850k methylation profiling was successfully performed for 226 samples with at least 20% tumour content. Germline pathogenic variants were identified in 16% of patients (35/219), of which 22 variants were judged causative for a cancer predisposition syndrome. At least one somatic alteration was detected in 204 (90.3%), and 185 (81.9%) were considered druggable, with clinical priority very high (6.1%), high (21.3%), moderate (26.0%), intermediate (36.1%), and borderline (10.5%) priority. iTHER led to revision or refinement of diagnosis in 8 patients (3.5%). Temporal heterogeneity was observed in paired samples of 15 patients, indicating the value of sequential analyses. Of 137 patients with follow-up beyond twelve months, 21 molecularly matched treatments were applied in 19 patients (13.9%), with clinical benefit in few. Most relevant barriers to not applying targeted therapies included poor performance status, as well as limited access to drugs within clinical trial. iTHER demonstrates the feasibility of comprehensive molecular profiling across all ages, tumour types and stages in paediatric cancers, informing of diagnostic, prognostic, and targetable alterations as well as reportable germline variants. Therefore, WES and RNA-seq is nowadays standard clinical care at the Princess Máxima Center for all children with cancer, including patients at primary diagnosis. Improved access to innovative treatments within biology-driven combination trials is required to ultimately improve survival. • Implementing comprehensive molecular profiling into standard of care is feasible. • Temporal heterogeneity is observed, indicating the value of sequential analyses. • Molecularly matched treatments are applied in a minority of patients despite clinical benefit. • Poor performance status & limited access to drugs within trial hamper targeted treatment. • The multidisciplinary tumour board is crucial in translating findings into clinical decision making. [ABSTRACT FROM AUTHOR]

Primary lung carcinoma is an exceptionally rare childhood tumour, as per definition of the European Cooperative Study Group on Paediatric Rare Tumours (EXPeRT), with an incidence of 0.1–0.2/1,000,000 per year. Little is known about the clinical characteristics of children with primary lung carcinoma, a gap which this joint analysis of the EXPeRT group aimed to fill. We performed a retrospective case series of children (aged 0–18 years) with primary lung carcinoma, as collected through the EXPeRT databases between 2000 and 2021. We recorded relevant clinical characteristics including treatment and outcome. Thirty-eight patients were identified with a median age of 12.8 years at diagnosis (range: 0–17). Mucoepidermoid carcinoma (MEC) was the most frequent entity (n = 20), followed by adenocarcinoma (n = 12), squamous cell carcinoma (n = 4), adenosquamous carcinoma (n = 1) and small-cell lung cancer (n = 1). Patients with MEC presented rarely with lymph node metastases (2/20 cases). Overall, 19/20 patients achieved long-lasting remission by surgical resection only. Patients with other histologies often presented in advanced stages (14/18 TNM stage IV). With multimodal treatment, 3-year overall survival was 52% ± 13%. While all patients with squamous cell carcinoma died, the 12 patients with adenocarcinoma had a 3-year overall survival of 64% ± 15%. Primary lung carcinomas rarely occur in children. While the outcome of children with MEC is favourable with surgery alone, patients with other histotypes have a poor prognosis, despite aggressive treatment, highlighting the need to develop new strategies for these children, such as mutation-guided treatment. • Primary lung carcinomas are very rare tumours during childhood. • Patients with mucoepidermoid carcinoma have a favourable outcome after resection. • Patients with other histotypes need new multimodal therapeutic strategies. • ALK inhibition in ALK -altered adenocarcinomas may improve the outcome. • Molecular tumour profiling should be systematically performed at an early stage. [ABSTRACT FROM AUTHOR]

Children with COVID-19 fare much better than adults but less is known about children with both COVID-19 and a cancer diagnosis in terms of clinical outcome and imaging. We describe our experience with a cohort of children with COVID-19 and cancer who have undergone medical imaging. We reviewed imaging and recorded clinical data and separated this group into two subgroups - hematologic and solid malignancies. Our observational data show that 1)children with hematologic malignancies may be at higher risk for complications, including death than, those with solid tumors, 2) that pulmonary imaging in the former group more often shows abnormalities and 3) that presence of pulmonary imaging abnormalities may portend an unfavorable outcome. • Children with hematologic malignancies are at greater risk of morbidity and mortality from COVID-19 than are children with solid tumors. • Children with hematologic malignancies and COVID-19 appear to be more likely to exhibit abnormalities on chest imaging than are children with solid tumors. • Children with hematologic malignancies and COVID-19 who have evidence of pneumonia on chest imaging studies may have worse outcomes than children with solid tumors. [ABSTRACT FROM AUTHOR]

Mature ovarian dermoid cysts (ODCs) are the most common benign ovarian tumor diagnosed in children. However, there is a paucity of data on management of ODCs in premenarchal patients. This study aims to assess characteristics associated with expectant management (EM) vs surgical management (SM) in premenarchal patients, to assess growth rate of ODCs in patients expectantly managed, and to investigate rates of oophorectomy versus cystectomy in patients who had surgery A retrospective chart review was performed in premenarchal patients ages 0-14 years diagnosed with an ODC between 2012 and 2023 at a single institution. Inclusion criteria consisted of either post-surgical patients with pathologically-confirmed ODC or patients with a radiologic finding consistent with an ODC. Data collected included demographics, cyst characteristics, imaging findings, presence of symptoms, and surgical procedure performed. Analysis to assess differences was performed using Chi squared and Fisher's exact tests Forty-four patients met inclusion criteria. Patient age at diagnosis was similar between groups (8.8 vs 8.0, P<.55). Thirty-six patients (82%) underwent SM and eight (18%) underwent EM. Racial and ethnic distribution was similar between groups, and a majority (70%, n=30) were diagnosed by a transabdominal pelvic ultrasound (Table 1). Twenty-two (50%) had imaging findings of calcifications, and 17 (39%) had fat found within the ODC. There was a significant difference in cyst size between SM and EM groups (8.9 cm vs 3.6 cm, P<.01). Eleven (30%) of patients in the SM group underwent oophorectomy vs cystectomy and there was a significant difference in ODC size between procedures (11.8 cm vs 7.7 cm P<.016). Thirty (83%) of SM patients had symptoms at diagnosis, compared to 2 (25%) EM patients (P<.01). Six of eight EM patients (75%) had at least one follow-up ultrasound performed, at an average time frame of 3.67 months from diagnosis, and the average cyst size was stable(3.63 cm. vs 3.67 cm). Three EM patients had four follow-up ultrasounds, the farthest out of which was 44 months after diagnosis—in this timeframe, the ODC grew from 1.6 cm to 4.5 cm. See Figure 1 for details on trajectory of EM patients, 3 (50%) of whom eventually underwent surgery Literature on the trajectory and management of ODCs in premenarchal patients is lacking. Cyst size at presentation differs significantly and appears to be a significant determinant in the decision path for SM vs EM. Continued research on EM with a larger cohort would assist in furthering understanding of ODC growth progression and parameters for recommending SM in asymptomatic individuals [ABSTRACT FROM AUTHOR]

Hepatoblastoma (HB) is the most common paediatric liver tumour, and epigenetic aberrations may be important in HB development. Recently, the Children's Hepatic Tumors International Collaboration-Hepatoblastoma Stratification (CHIC-HS) developed risk stratification based on clinicopathological factors. This study aimed to construct a more accurate model by integrating CHIC-HS with molecular factors based on DNA methylation. HB tumour specimens (N = 132) from patients treated with the Japanese Pediatric Liver Tumors Group-2 protocol were collected and subjected to methylation analysis by bisulfite pyrosequencing. Associations between methylation status and clinicopathological factors, overall survival (OS), and event-free survival (EFS) were retrospectively analysed. We investigated the effectiveness of the evaluation of methylation status in each CHIC-HS risk group and generated a new risk stratification model. Most specimens (82%) were from post-chemotherapy tissue. Hypermethylation in ≥2 of the four genes (RASSF1A , PARP6 , OCIAD2 , and MST1R) was significantly associated with poorer OS and EFS. Multivariate analysis indicated that ≥2 methylated genes was an independent prognostic factor (hazard ratios of 6.014 and 3.684 for OS and EFS, respectively). Two or more methylated genes was also associated with poorer OS in the CHIC-very low (VL)-/low (L)-risk and CHIC-intermediate (I) risk groups (3-year OS rates were 83% vs. 98% and 50% vs. 95%, respectively). The 3-year OS rates of the VL/L, I, and high-risk groups in the new stratification model were 98%, 90%, and 62% (vs. CHIC-HS [96%, 82%, and 65%, respectively]), optimising CHIC-HS. Our proposed stratification system considers individual risk in HB and may improve patient clinical management. • Hepatoblastoma is the most common paediatric liver tumour. • We proposed a risk stratification model integrating CHIC-HS with epigenetic markers. • mCHIC-HS improves CHIC-HS by selecting higher-risk patients from a lower-risk group. • mCHIC-HS is feasible and may improve the clinical management of hepatoblastoma. [ABSTRACT FROM AUTHOR]

The European Society for Paediatric Oncology (SIOPE) Radiation Oncology Working Group presents the QUARTET Project: a centralised quality assurance programme designed to standardise care and improve the quality of radiotherapy and imaging for international clinical trials recruiting children and adolescents with cancer throughout Europe. QUARTET combines the paediatric radiation oncology expertise of SIOPE with the infrastructure and experience of the European Organisation for Research and Treatment of Cancer to deliver radiotherapy quality assurance programmes for large, prospective, international clinical trials. QUARTET-affiliated trials include children and adolescents with brain tumours, neuroblastoma, sarcomas including rhabdomyosarcoma, and renal tumours including Wilms' tumour. With nine prospective clinical trials and two retrospective studies within the active portfolio in March 2022, QUARTET will collect one of the largest repositories of paediatric radiotherapy and imaging data, support the clinical assessment of radiotherapy, and evaluate the role and benefit of radiotherapy quality assurance for this cohort of patients within the context of clinical trials. • High-quality, protocol compliant radiotherapy is essential in clinical trials. • QUARTET is a platform for centralised prospective radiotherapy quality assurance. • QUARTET facilitates a strong collaborative network for paediatric radiation oncology. • QUARTET improves equity in access to paediatric radiotherapy expertise across Europe. • QUARTET supports central review of diagnostic imaging for treatment failure analysis. [ABSTRACT FROM AUTHOR]

Regional lymph node disease (N1) is a component of the risk-based treatment stratification in rhabdomyosarcoma (RMS). The purpose of this study was to determine the contribution of nodal disease to the prognosis of patients with non-metastatic embryonal RMS (ERMS) and analyse their outcome by treatment received. Between 2005 and 2016, 1294 children with ERMS were enrolled in the European paediatric Soft tissue sarcoma Study Group (EpSSG) RMS 2005 protocol, 143 patients with N1. Treatment comprised 9 cycles of ifosfamide, vincristine and dactinomycin. Some patients also received doxorubicin and/or maintenance if enrolled in the randomised studies. Local treatment was planned after 4 cycles of chemotherapy and included surgery to remove macroscopic residual tumour and/or radiotherapy (primary tumour and involved nodes). N1 patients were older and presented with tumours of unfavourable size, invasiveness, site and resectability. Unlike alveolar RMS, nodal involvement was more frequent in the head and neck area and rare in extremity sites. The 5-year event-free and overall survival were 75.5% and 86.3% for patients with N0, and 65.2% and 70.7% for patients with N1, respectively. The nodal involvement and the result of surgery at diagnosis (Intergroup Rhabdomyosarcoma Study group) were independent prognostic factors on multivariate analysis. Considering only patients with N1 ERMS, we were not able to identify any treatment variables which correlated with the outcome. In the case of nodal involvement, patients with ERMS present different characteristics and a better outcome than alveolar RMS. Regional nodal involvement is an independent prognostic factor in ERMS, therefore it is appropriate to include this population in the high-risk category. • Node-positive embryonal and alveolar rhabdomyosarcoma have different characteristics. • Nodal involvement is an independent prognostic factor for embryonal rhabdomyosarcoma. • The role of radiotherapy on nodes did not emerge as determinant for the outcome. [ABSTRACT FROM AUTHOR]

The frequency of Langerhans cell histiocytosis (LCH) and associated malignancies (AM) is greater than statistically expected. Here, we analyze LCH-AM co-occurrence in both children and adults. Between 1991 and 2015, data were collected by regular questionnaires to members of the Histiocyte Society and searches in PubMed and Abstract Books. Patients were grouped by age at LCH diagnosis (≤ and >18 years), and types and timing of AM occurrence were plotted with respect to the LCH diagnosis. For the statistical analysis, only the first AM were considered. A total of 285 LCH-AM in 270 patients were identified, 116 (43%) ≤ 18 years, and 154 (57%) >18 years. In childhood LCH-AM pairs, leukemias and myeloproliferative disorders (n = 58; 50.0%) prevailed over solid tumors (n = 43; 37.1%) and lymphoma (n = 15; 12.9%). In adults, solid tumors were reported in 61 patients (39.6%), lymphoma, and leukemias and myeloproliferative disorders in 56 (36.4%) and 37 (24.0%) patients, respectively. In most children, AM followed LCH (n = 69, 59.5%), whereas in adults, LCH and AM occurred concurrently in 69 patients (44.8%). In children, T-lineage acute lymphoblastic leukemia (ALL) and promyelocytic acute myeloid leukemia (AML) and retinoblastoma were over-represented and thyroid carcinoma in adults. The largest collection of data on LCH-AM to date clearly indicates inherent relationships between specific types of AM and LCH, which may be due to therapy effects, clonal evolution, and germ-line predisposition, respectively. Prospective thorough genetic analysis is warranted and will hopefully shed light on the association of LCH and second neoplasms. • This is the largest case series on the association of LCH with another malignancy. • Associated malignancies can occur before, concurrently or after the LCH diagnosis. • This association between LCH and AM is not due to chance alone. • Possible pathophysiologic mechanisms are proposed. [ABSTRACT FROM AUTHOR]

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Paediatric brain tumours are a major source of cancer-related morbidity and mortality in children. Brain tumours in children vary in their pathology and their outcomes. There is increasing reliance on molecular genetic and epigenetic classification, which may be off-putting to the non-specialist. This review provides an essential overview for care providers outside of neuro-oncology, covering the major types of paediatric brain tumours, including glioma, embryonal tumours, ependymoma, craniopharyngioma, choroid plexus tumours, and germ cell tumours. The review also addresses the recently published 2021 WHO Classification, which will also help update the more experienced in the management of these children. [ABSTRACT FROM AUTHOR]

Neuroblastoma is one of the most common extracranial solid tumors in children. The forkhead transcription factor FOXO3a has been implicated in the progression of a variety of human diseases. Here, we aim to identify the effects of FOXO3a on the malignancy of neuroblastoma. Bioinformatics analysis was employed to identify differentially expressed genes related to neuroblastoma and the downstream regulator of FOXO3a. FOXO3a expression was examined in SH-SY5Y neuroblastoma cells. Interactions between FOXO3a and microRNA-21 (miR-21) were then identified using bioinformatics analysis and dual-luciferase reporter assay. After ectopic expression and depletion experiments in SH-SY5Y cells, cell malignant phenotypes were assessed by cell counting kit-8 and Transwell assays. FOXO3a-overexpressing neuroblastoma cells were xenografted into nude mice to validate the role of FOXO3a in tumor growth. Downregulated expression of FOXO3a was observed in neuroblastoma cells, with a negative correlation between FOXO3a and miR-21 expression. FOXO3a bound to the promoter region of miR-21 to downregulate its expression, resulting in inhibition of SH-SY5Y cell malignant phenotypes. Additionally, miR-21 targeted SPRY2 by binding to the 3′UTR of the mRNA encoding SPRY2, activating the extracellular signal-regulated kinase (ERK) pathway. FOXO3a disrupted the binding of miR-21 to SPRY2 and inactivated ERK to suppress the malignant phenotypes of SH-SY5Y cells as well as tumor growth in vivo. In conclusion, FOXO3a may inhibit the progression of neuroblastoma by suppressing the miR-21 expression and facilitating SPRY2-dependent ERK pathway inactivation. [ABSTRACT FROM AUTHOR]