Malignant Pediatric Tumor Research Articles

Patterns and treatment outcomes of primary bone tumors in children treated at tertiary referral hospital, Ethiopia

BackgroundBone tumors account for approximately 6% of all cancers in children. Malignant bone tumors, commonly occurring in children and adolescents, are associated with high mortality and morbidity. The overall survival of children with primary malignant bone tumors is affected by the stage of disease, time of diagnosis, and treatment response. Despite advanced treatment modalities with chemotherapy, surgery, and radiotherapy, bone tumor is the third leading cause of death in children with malignancy. Patients with metastatic disease at diagnosis have poor outcomes compared to localized disease at presentation. The 5-year Overall Survival and event-free survival in children with primary malignant bone tumors were 85.2% and 69.2%. The study aimed to assess the clinicopathological profile and treatment outcomes of children with primary malignant bone tumors in our setup.Materials and methodsA hospital-based cross-sectional study was conducted on 95 children who met the inclusion criteria through structured questionnaire. The collected data were analyzed using a statistical package for social sciences (SPSS) version 25. P-value < 0.05 was considered to be statistically significant. Kaplan Meier survival estimate was used for overall and event-free survival analysis.ResultsA total of ninety-five patients met the study inclusion criteria and the median age at diagnosis with primary malignant bone tumors was 10 years, with an interquartile range of 8–12 years. The duration of the illness from the onset of symptoms to the oncologic treatment center ranges from three weeks to 2 years with a mean duration of five months. Swelling was the commonest presenting symptom accounting for 95.8% (n = 91). Lower extremity was the commonest primary site of involvement accounting for 55.8% (n = 53) of children with primary malignant bone tumors. Osteosarcoma was the commonest malignant bone tumor constituted 66.3% (n = 63), followed by Ewing sarcoma at 33.7% (n = 32).About 41.2% (n = 39) of children had metastatic disease at presentation and the lung was the commonest site of distant metastasis. The Kaplan Meier survival estimate analysis showed the 1-year and 5-year overall survival probabilities for all pediatric primary malignant bone tumor patients were 65% (95% CI: 0.3–0.56) and 38% (95% CI:0.19–0.47) respectively. The 1-year and 5-year event-free survival probabilities were 55% (95% CI: 0.32–0.73) and 33% (95% CI: 0.10–0.59). The stage of the disease at presentation had a significant association with the outcome (p = 0.023).ConclusionOur study showed the mean duration of the illness from the onset of symptoms to the oncologic treatment center was 5 months ranging from 3 weeks to 2 years. More than one-third of the presented with metastatic disease at presentation. The 1-year and 5-year overall survival (OS) probabilities of children with primary malignant bone tumors were low in our setup compared to other studies.

Abstract 6505: Targeting PINK1 reduces medulloblastoma progression in animal models

Abstract Medulloblastoma is a brain cancer that mainly arises during infancy and childhood. Medulloblastoma is the most common pediatric malignant brain tumor worldwide. It comprises of approximately 20% of all childhood brain tumors and 63% of intracranial embryonic tumors. One of the major effects of proliferating cancer cells is altered mitochondrial metabolism, as well as aberrant metabolism. Medulloblastoma patients suffer severe complications due to intensive and long-term treatments. Thus, we aim to improve applications against medulloblastoma by targeting the PINK1 gene. We hypothesize that PINK1 inactivation slows down medulloblastoma progression. PINK1 is a mitochondrial serine/threonine protein kinase that protects cells by controlling mitochondria quality in response to cellular stress. PINK1 recruits parkin to target damaged mitochondria for degradation through autophagy. In this study, PINK1 has been knocked-out using gene editing technology (CRISPR/Cas9) in two commercial medulloblastoma cell lines (DAOY, and D283 cell lines). We validated PINK1 editing using RT-PCR and Western blot. Then, cell viability was studied in comparison to the control sample. The control sample contained scramble fragments with empty CRISPR/Cas9. We studied apoptosis and performed cell cycle analysis using flow cytometry. Next, orthotopic medulloblastoma mouse model was generated which showed differential survivals comparing the PINK1 knockout group and control. The results showed a low expression of PINK1 within the PINK1 knockout group. In addition, the Western blot showed reductions in PINK1 expression in the knockout group. The knockout group showed more apoptosis (cell death) 40% more than the control. The mouse model showed increased survival of the PINK1 knockout group compared to the control with a p-value of 0.0288 (log-rank). Our analysis shows that survival differences approximately extend human life by one year. We conclude that inhibiting the PINK1 gene in medulloblastoma decreases cell metabolic activities. PINK1 Knockout in medulloblastoma enhances the apoptosis pathways. Engrafted medulloblastoma mouse model treated with PINK1 inhibitor showed superior survival than the control. These results qualify PINK1 to be used as potential therapeutic target for medulloblastoma. The Future work needs additional preclinical studies to investigate the proper dose of PINK1 inhibitor and measurement of toxicity index. Citation Format: Reema N. Alsubaiee, Amani Alghamdi, Bahauddeen M. Alrfaei. Targeting PINK1 reduces medulloblastoma progression in animal models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6505.

A rare Encounter with Pediatric Malignant Peripheral Nerve Sheath Tumor in Nasal Sinuses and Orbit.

This case report explores a rare and aggressive Malignant Peripheral Nerve Sheath Tumor (MPNST) in a 7-year-old child affecting nasal sinuses, maxilla, and orbit, an exceptionally uncommon pediatric manifestation unrelated to Neurofibromatosis 1. The child presented with alarming symptoms-nasal obstruction, snoring, epistaxis, and difficulty swallowing-underscoring the case's urgency. Non-contrast computed tomography revealed an extensive mass infiltrating nasopharynx, nasal cavity, maxillary sinus, ethmoid sinuses, and orbit, causing destructive consequences. Histopathology confirmed a high-grade MPNST, marked by rapid growth and early metastasis, highlighting management challenges. The rarity of pediatric MPNST in the nasal cavity is discussed, emphasizing the need for a broad differential diagnosis. Treatment involves surgical resection and adjuvant chemoradiation with a grim prognosis due to diagnostic complexities and morphological mimicry in young patients.

Abstract B047: Inhibition of the polyamine pathway: a novel therapeutic approach to treat aggressive pediatric medulloblastoma

Abstract Medulloblastoma is the most common pediatric malignant brain tumor. Polyamines, critical intracellular polycations governing key cell processes such as DNA replication, translation, and cell proliferation, are frequently upregulated in cancer. We previously showed that the polyamine pathway is critical to the growth and survival of pediatric diffuse midline gliomas and MYC amplified neuroblastoma. Given the activity of polyamine inhibition in DMG, and given the critical role of MYC in medulloblastoma, we sought to investigate the potential of polyamine pathway inhibition as a therapeutic approach for medulloblastoma. We compared the expression of regulators of the polyamine pathway in a cohort of pediatric medulloblastoma tumors from patients enrolled in the Zero Childhood Cancer (ZERO) Personalized Medicine Program and found significant over-expression compared with normal fetal brain samples. Analysis of Cavalli dataset of 763 medulloblastoma samples, found that high expression of polyamine biosynthetic genes predicted poor overall survival, and low expression of catabolic flux genes significantly correlated with better outcomes. We next treated medulloblastoma cells treated with a polyamine synthesis inhibitor, DFMO, and found that led to a compensatory increase in polyamine transporter protein expression. Conversely, treatment with the polyamine transport inhibitor AMXT 1501 led to compensatory increase in ODC1, the key polyamine synthetic enzyme. Dual targeting of the polyamine pathway, (DFMO and AMXT 1501) showed a potent and synergistic inhibition of cell proliferation and reduced the clonogenic potential of medulloblastoma cells in soft agar clonogenic assays. Flow cytometric analysis of Annexin V-stained cells showed that treatment with DFMO and AMXT 1501 in combination led to induction of apoptosis. Furthermore, we found that dual polyamine inhibition potently sensitized medulloblastoma cells, particularly Group 3, to the chemotherapeutic agent SN-38, leading to complete eradication of medulloblastoma cells in both cytotoxicity assays and clonogenic assays at nanomolar chemotherapeutic concentrations. We are currently validating this treatment strategy in aggressive orthotopic medulloblastoma models. Our findings suggest that inhibiting both polyamine synthesis and uptake holds promise for sensitizing highly aggressive pediatric medulloblastoma tumors to chemotherapy. Currently, AMXT 1501 combined with DFMO is undergoing evaluation in a Phase I clinical trial for adults (NCT05500508). Building on these promising results, we are developing a Phase I/II clinical trial for children with aggressive brain tumors through the international CONNECT consortium. Citation Format: Aaminah Khan, Anjana Gopalakrishnan, Jie Liu, Mark R. Burns, Maria Tsoli, David S. Ziegler. Inhibition of the polyamine pathway: a novel therapeutic approach to treat aggressive pediatric medulloblastoma [abstract]. In: Proceedings of the AACR Special Conference on Brain Cancer; 2023 Oct 19-22; Minneapolis, Minnesota. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_1):Abstract nr B047.

Impact of the COVID-19 pandemic on the demographic and disease burden of pediatric malignant solid tumors in China: a single-center, cross-sectional study.

With the development of the novel coronavirus disease 2019 (COVID-19), China implemented measures in an attempt to control the infection rate. We conducted a single-center, cross-sectional study to ascertain the impact of the COVID-19 pandemic on the equitable availability of medical resources for children diagnosed with malignant solid tumors in China. Data on the demographics, clinical characteristics, and medical expenses of 876 patients diagnosed with neuroblastoma, rhabdomyosarcoma (RMS), Wilms tumor, hepatoblastoma (HB), Ewing sarcoma (ES), and central nervous system (CNS) tumors from 2019 to 2021, during the COVID-19 pandemic, were retrospectively collected from the National Center for Children's Health. The Pearson χ2 test and Mann-Whitney test were performed to analyze the differences among variables. Except for the regional origin of children with tumors during the epidemic, no significant differences were found in the demographic or clinical characteristics of patients at initial diagnosis. The number of patients from northern China and northeastern China who attended Beijing Children's Hospital (BCH) increased after the outbreak of COVID-19 (P=0.001). There was no significant alteration observed in the frequency of hospitalizations per individual per annum (P=0.641) or the mean expense incurred per individual per hospitalization (P=0.361). In addition, the medical insurance coverage rate of real-time settlement increased year by year. After the COVID-19 outbreak, the origin of patients with solid tumor who visited BCH was concentrated in the northern region of China. COVID-19 had no impact on the other demographic factors, clinical characteristics, or economic burden of patients with pediatric malignant solid tumors.

Factors influencing delayed high-dose methotrexate excretion and its correlation with adverse reactions after treatment in children with malignant hematological tumors.

High-dose methotrexate (HDMTX) is crucial in treating pediatric malignant hematological tumors. However, its use is often complicated by delayed excretion and associated adverse reactions, which can significantly affect treatment outcomes and patient safety. Identifying risk factors is essential for safer, more effective therapy. This study aimed to investigate the influencing factors for delayed excretion and their correlation with adverse reactions in children with malignant hematological tumors after receiving HDMTX chemotherapy. From April to October 2021, the clinical information of children who had undergone HDMTX chemotherapy and had their blood tested for drug concentration was gathered by the Department of Hematology and Oncology at Shanghai Children's Medical Center. Via univariate and multivariate logistic regression, the factors affecting the delayed excretion of HDMTX were examined, and the relationship between delayed excretion and unfavorable effects in children was determined. This study included 99 patients comprising 199 courses of HDMTX. The occurrence rate of HDMTX delayed excretion was 20.1%. Age ≥9 years and a 24-hour methotrexate (MTX) concentration of 64 µmol/L were independent risk factors for delayed MTX excretion according to multivariate logistic regression analysis (P<0.05). Negative side effects, such as fever, infection, mucositis, gastrointestinal response, and decreased platelet count in children with delayed excretion were statistically significant when compared to those of children with normal excretion. White blood cell reduction, hemoglobin levels below 65 g/L, MTX excretion delay, and concomitant etoposide treatment were all independent risk factors for infection in children. To estimate the risk of delayed MTX excretion during HDMTX therapy, patient laboratory data should be scrutinized, especially for patients ≥9 years or those with a 24-hour MTX concentration of greater than 64 µmol/L.

Histopathologic and immunophenotypic characterization of patient-derived pediatric malignant hepatocellular tumor xenografts (PDXs)

Advances in targeted therapies for pediatric hepatocellular tumors have been limited due to a paucity of clinically relevant models. Establishment and validation of intrahepatic patient-derived xenograft (PDX) models would help bridging this gap. The aim of this study is to compare the histomorphologic and immunophenotypic fidelity of patient tumors and their corresponding intrahepatic PDX models. Murine PDX models were established by intrahepatic implantation of patient tumors. Pathology slides from both patients and their corresponding PDX models were reviewed and quantitatively assessed for various histologic components and immunophenotypic markers. Ten PDX models were successfully established from nine patients with pre- (n=3) and post- (n=6) chemotherapy samples; diagnosed of hepatoblastoma (n=8) and hepatocellular neoplasm, not otherwise specified (n=1). Two of nine (22.2%) patients showed ≥75% fetal component; however, the corresponding PDX models did not maintain this fetal differentiation. High grade histology was seen in three patients (33.3%) and overrepresented in six PDX models (60%). Within the subset of three PDXs that were further characterized, significant IHC concordance was seen in all 3 models for CK7, CK19, Ki-67, and p53; and 2 of 3 models for Sox9 and Beta-catenin. GPC-3 and GS showed variable to moderate concordance, while Hepar was the least concordant. Our study shows that in general, the PDX models appear to represent the higher-grade component of the original tumor and show significant concordance for Ki-67, making them appropriate tools for testing new therapies for the most aggressive, therapy-resistant tumors.

Elucidating cellular response to treatment with viral immunotherapies in pediatric high-grade glioma and medulloblastoma

HSV G207, a double-stranded, DNA virus, and the polio:rhinovirus chimera, PVSRIPO, a single positive-strand RNA virus, are viral immunotherapies being used to treat pediatric malignant brain tumors in clinical trials. The purpose of this work is to elucidate general response patterns and putative biomarkers of response. Multiple pediatric high-grade glioma and medulloblastoma cell lines were treated with various multiplicities of infection of G207 or PVSRIPO. There was a significant inverse correlation between expression of one HSV cellular receptor, CD111, and the lethal dose of 50% of cells (LD50) of cells treated with G207 (r = -0.985, P<0.001) but no correlation between PVSRIPO cellular receptor expression (CD155) and LD50. RNA sequencing of control cells and cells treated for 8 and 24 h revealed that there were few shared differentially expressed (DE) genes between cells treated with PVSRIPO and G207: GCLM, LANCL2, and RBM3 were enriched whilst ADAMTS1 and VEGFA were depleted. Likewise, there were few shared DE genes enriched between medulloblastoma and high-grade glioma cell lines treated with G207: GPSM2, CHECK2, SEPTIN2, EIF4G2, GCLM, GDAP1, LANCL2, and PWP1. Treatment with G207 and PVSRIPO appear to cause disparate gene enrichment and depletion suggesting disparate molecular mechanisms in malignant pediatric brain tumors.

Dabrafenib and trametinib as a promising treatment option for pediatric population with low-grade gliomas that have BRAF V600E mutation; a breakthrough in the field of neuro-oncology

Two-thirds of all pediatric malignant central nervous tumors, including high-grade (glioblastoma, anaplastic astrocytoma) and low-grade (ganglioglioma, pilocytic astrocytoma) carcinomas, are gliomas. Low-grade glioma (LGG) exhibits genetic alterations caused by the BRAF kinase mutation, such as replacing glutamic acid (E) in place of valine (V) at the 600 positions, known as the V600E point mutation. Pediatric low-grade gliomas (PLGGs) also comprise around one-third of juvenile brain tumors and are the most frequent central nervous system tumors. Patients were randomized 2:1 to dabrafenib plus trametinib (D+T) or carboplatin plus vincristine (C+V). Where possible, complete surgical removal is the mainstay of treatment for progressing or symptomatic PLGG. Radiation therapy has historically been used to treat PLGG in both up-front and salvage scenarios. To delay or avoid the necessity for radiation therapy in young children with advancing or incompletely resected PLGG, chemotherapy was created in 1980. On 16 March 2023, the Food and Drug Administration approved the use of trametinib (Mekinist, Novartis) with dabrafenib (Tafinlar, Novartis) in pediatric patients suffering from LGG who require systemic therapy and are at least one year old. Nevertheless, early-stage clinical trials have produced encouraging results that may revolutionize the treatment of LGG in the near future.

Effect of Chemotherapy on hs- C Reactive Protein, Some Blood Picture and Kidney Function in Patients With Neuroblastoma

Background: Neuroblastoma, the most common extra-cranial malignant pediatric solid tumor and one with a high mortality rate. Children suffering from Neuroblastoma after chemotherapy suffer from anemia, severe infections, and effects on some organs of the body. Therefore, the current study aims to study the effect of chemotherapy on inflammatory factor (high-sensitivity C-reactive Protein), some hematological parameters such as white blood cells, platelets, and hemoglobin, and some kidney function such as urea and Creatinine in children with Neuroblastoma before and after three cycles of chemotherapy. Materials and methods: 70 cases were divided into three groups: Group A; 35 healthy children are included as a control group., and group B; consists of 35 newly diagnosed patients and group C; following three chemotherapy rounds (same patients newly diagnosed), with an age range from 2 months to 12 years. They had attended Basrah Specialist Hospital for Children from May 2022 to the end of March 2023. Results: When compared to the control group, the results of the current study showed a significant rise (p˂0.05) in the levels of high-sensitivity C-reactive protein, white blood cells, and platelets in the sera samples of patients with Neuroblastoma Conclusion: This study came to the conclusion that Neuroblastoma treatment considerably changed a number of hematological markers and hs-crp. Consequently, it is essential to monitor these signs.

Clinical spectrum and clinicopathological correlation of pediatric orbital tumors: 20 years' experience from a tertiary eye care center.

To study the epidemiological profile of various pediatric orbital tumors and determine their clinicopathological correlation over 20 years. A retrospective analysis of all pediatric patients with orbital tumors from the medical records between 1995 and 2015 was done. Tumors were categorized based on their cellular origin. Demographic details, clinical and histopathological diagnoses, frequency, and clinicopathological correlation were studied. A total of 265 pediatric patients with orbital tumors were analyzed, of which 145 (54.7%) patients were males and 120 (45.3%) were females. The mean age was 7 years (median: 6 years; range: 10 days-16 years). The distribution of lesions in each group was as follows: vasculogenic, 76 (28.7%); lipogenic and myxoid, 66 (25%); myogenic, 31 (11.7%); optic nerve and meningeal, 22 (8.3%); lymphoid and lymphoproliferative, 18 (6.8%); secondary orbital tumors, 14 (5.2%); histiocytic, 9 (3.4%); miscellaneous, 9 (3.4%), lacrimal gland, 8 (3%); mesenchymal with neural differentiation, 6 (2%); osseous, 4 (1.5%), and fibrocystic, 2 (0.8%). The most common benign and malignant pediatric orbital tumors were dermoid cysts (65, 24.5%) and rhabdomyosarcoma (31, 11.7%). A statistically significant ( P < 0.0001) clinicopathological correlation was observed in 208 (83.2%) out of 250 biopsy-proven cases. Pediatric orbital neoplasms include a broad spectrum of benign and malignant lesions. Vasculogenic tumors constitute the majority of them, followed by lipogenic and myxoid tumors. A thorough knowledge of the incidence, clinical profile, imaging features, and histopathology of specific orbital tumors aids in accurate diagnosis and their successful management.

Imaging features at the time of diagnosis of osteosarcoma and Ewing sarcoma in children

IntroductionOsteosarcoma and Ewing sarcoma are the most frequent malignant bone tumours in children. The aim of this study is to characterize clinical and radiological features at presentation of a large cohort of children with these diseases, radiological findings useful to differentiate them and the main prognostic factors. Material and methodsRetrospective analysis of clinical and imaging findings of 83 children diagnosed and treated of Ewing sarcoma and osteosarcoma in a paediatric hospital during a period of 10 years. ResultsBoth tumours showed aggressive radiological features such as permeative or moth-eaten margins, cortical disruption, discontinuous periosteal reaction, intense contrast uptake, tumoral necrosis and soft-tissue component. They differed in their location, osseous matrix and gender predilection. Osteosarcoma occurred more frequently in the metaphysis of long bones (62%) with a blastic appearance (53%). Ewing sarcoma showed a predilection for male patients (71%), occurred in flat bones (42%) and in the diaphysis of long bones (58%) with a lytic appearance (82%). 29% of children presented with primary metastasis, most frequently located in the lungs. Survival rates were 78% in OS and 76% in Ewing sarcoma. Metastatic disease, aggressive radiological features and low percentage of tumoral necrosis after neoadjuvant chemotherapy were associated with poor prognosis (p < 0.05). ConclusionsImaging can confidently diagnose malignant paediatric bone tumours in children and may differentiate Ewing sarcoma from osteosarcoma, based on gender, location and appearance of the neoplasm. Metastatic disease, presence of aggressive radiological features and low percentage of tumoral necrosis after neoadjuvant chemotherapy were associated with poor prognosis.

Computed tomography-based radiomics to assess risk stratification in pediatric malignant peripheral neuroblastic tumors.

This study aimed to develop and validate an analysis system based on preoperative computed tomography (CT) to predict the risk stratification in pediatric malignant peripheral neuroblastic tumors (PNTs). A total of 405 patients with malignant PNTs (184 girls and 221 boys; mean age, 33.8 ± 29.1 months) were retrospectively evaluated between January 2010 and June 2018. Radiomic features were extracted from manually segmented tumors on preoperative CT images. Spearman's rank correlation coefficient and the least absolute shrinkage and selection operator (LASSO) were used to eliminate redundancy and select features. A risk model was built to stratify low-, intermediate-, and high-risk groups. An image-defined risk factor (IDRFs) model was developed to classify 266 patients with malignant PNTs and one or more IDRFs into high-risk and non-high-risk groups. The performance of the predictive models was evaluated with respect to accuracy (Acc) and receiver operating characteristic (ROC) curve, including the area under the ROC curve (AUC). The risk model demonstrated good discrimination capability, with an area under the curve (AUC) of 0.903 to distinguish high-risk from non-high-risk groups, and 0.747 to classify intermediate- and low-risk groups. In the IDRF-based risk model with the number of IDRFs, the AUC was 0.876 for classifying the high-risk and non-high-risk groups. Radiomic analysis based on preoperative CT images has the potential to stratify the risk of pediatric malignant PNTs. It had outstanding efficiency in distinguishing patients in the high-risk group, and this predictive model of risk stratification could assist in selecting optimal aggressive treatment options.

DISP-12. BRAIN CANCER CANADA FUNDS CRITICALLY NEEDED RESEARCH AND ADVOCATES FOR PATIENTS, WITH THE AIM TO IMPROVE OUTCOMES FOR CANADIANS DIAGNOSED WITH PRIMARY MALIGNANT BRAIN TUMOURS

Abstract Brain Cancer Canada (BCC) is a national, volunteer-driven charity supporting paediatric and adult primary malignant brain tumour research and patient advocacy. To achieve these goals BCC 1) awards grants to Canadian doctors and scientists advancing brain cancer research, and 2) advocates for equitable pharmacare for brain cancer patients. BCC is committed to funding innovative research projects, with the aim to improve treatment options for patients. Led by its Scientific Advisory Committee, submissions are reviewed, screened, and undergo a systematic evaluation by the panel. Recommendations on successful proposals are provided to the board for approval. This May, the charity awarded 5 research grants, totaling $380,000 CAD. These projects include supporting the acquisition of a next-generation DNA Sequencer, advancing FET-PET/MRI imaging, pioneering a novel approach to combat Diffuse Intrinsic Pontine Glioma (DIPG), developing a novel dual-hit therapeutic approach for glioblastoma, and other projects focusing on precision medicine. BCC has taken a deliberate and firm stand in highlighting the drug coverage disparities that exist for patients afflicted with brain cancer BCC’s Pharmacare Advocacy Committee has found that disparities exist owing to the lack of a national drug program, and a patchwork of alternative schemes varying by province/territory. These findings are well documented by others. For example, our research shows that temozolomide (TMZ), the global standard of care for treating gliomas, is not covered in 4 provinces. Our pharmacare research on TMZ and 5 other drugs further confirm the disparity in coverage that hinders patient welfare and imposes a confusing and detrimental strain on the healthcare system. With, the dependence on take-home medication increasing, it is critical we take immediate action in supporting this marginalized group. With the support of The Society for Neuro-Oncology, Brain Cancer Canada will be better positioned to reach its goals and support people affected by primary malignant brain tumours.

TMIC-55. TURNING ENEMY INTO ALLY: HIJACK BRAIN TUMOR CELLS TO BREAK DOWN THE BLOOD-TUMOR BARRIER

Abstract A major obstacle in brain cancer treatment is the blood-tumor barrier (BTB), which limits the delivery of a vast majority of therapeutic agents. Medulloblastoma (MB), the most common pediatric malignant brain tumor, consists of four subgroups (WNT, SHH, Group 3, Group 4). Increasing BTB permeability of non-WNT MB is essential for effectively treating patients by overcoming this drug delivery impediment. Since the BTB is exposed to biofluids such as blood and brain interstitial fluid, which present dynamic osmotic challenges, we hypothesized that cell volume regulation plays a crucial role in BTB integrity. Using a genetically engineered mouse model of SHH MB, we show that tumor-specific knockout of volume-regulated ion channel, Lrrc8a, significantly increases BTB permeability and enhances the therapeutic response of MB-bearing mice to vismodegib, an FDA-approved antagonist of the SHH pathway. Lrrc8a-deficient tumor cells develop ectopic contact with blood vessels, permitting tumor cell-derived Tgfβ2 to activate Tgfβ signaling in endothelial cells. Consequently, endothelial cells in Lrrc8a knockout MB lose endothelial characteristics and gain mesenchymal features, indicative of Tgfβ signaling-induced endothelial-mesenchymal transition (EndMT). Furthermore, tumor-specific LRRC8A knockdown enhances BTB permeability in a xenograft human Group 3 MB model. Collectively, our findings establish Lrrc8a/LRRC8A as a therapeutic target to increase the therapy response of MB and provide evidence that inducing EndMT could be a strategy for enhancing BTB permeability to treat brain cancer.

Infantile type I pleuropulmonary blastoma presenting with dyspnea due to compression by pneumothorax and an occupying tumor: a case report

BackgroundPleuropulmonary blastoma (PPB) is an extremely rare and malignant pediatric lung tumor. Purely cystic PPB has a more favorable prognosis than solid PPB, but may be difficult to distinguish from a certain type of “benign” congenital pulmonary airway malformation before and during surgery. The influence of tumor rupture on long life prognosis has not been clarified in detail.Case presentationA 5-month-old boy underwent emergency transfer from another hospital due to a left thoracic cystic lesion and left pneumothorax detected on chest radiography performed for persistent wheeze and cough. Contrast-enhanced computed tomography of the chest revealed marked deviation of the mediastinum to the right due to a giant cystic lesion and pneumothorax. Thoracotomy was performed on hospital day 2. A cystic lesion had developed from the distal alveolar region of lower lobe of the left lung and the tumor showed a tiny adhesion to the left diaphragm and a tiny rupture near the adhesion. Partial lung excision including the cyst and scraping of the adhesion were performed. Histopathological investigations revealed immature blast cell-like mesenchymal cells and differentiated striated muscle cells in a dense cambium layer were found under the epithelium of the cystic lesion. Type I PPB was diagnosed.ConclusionsSurgery should be performed with the possibility of type I PPB in mind when an extrapulmonary cystic lung lesion is found. Since issues such as the pathogenesis and long-term prognosis of ruptured cases remain unclear, continued careful follow-up of this case will be required.

Diagnostic MRI characteristics of pediatric clear cell sarcoma of the kidney and rhabdoid tumor of the kidney: A retrospective multi-center SIOP-RTSG Radiology panel study

IntroductionClear cell sarcoma of the kidney (CCSK) and rhabdoid tumor of the kidney (RTK) are rare malignant pediatric renal tumors, both accounting for 1–5% of diagnoses. Within the International Society of Pediatric Oncology-Renal Tumor Study Group (SIOP-RTSG) protocols diagnostic invasive procedures to determine histology are discouraged. MRI has become the preferred imaging modality, however, non-invasive discrimination of CCSK and RTK remains challenging. Therefore, this study aims to identify diagnostic MRI-characteristics of CCSK and RTK, in the largest series of patients to date. Material and methodsFive SIOP-RTSG national review radiologists identified national diagnostic MRIs of histologically proven CCSKs and RTKs. Scan-protocols were based on MRI-guidelines following SIOP-RTSG protocols. Radiologists assessed their national cases using a validated case report form (CRF). ResultsRetrospectively, 59 patients were identified (n = 38 CCSK, n = 21 RTK). CCSKs showed a high median volume (576 cm3, range 54–4414), which was lower for RTKs (290 cm3, range 20–761) (p = 0.006 *10-3). Fifty-two percent (11/21) of RTK-patients showed disease at other locations, predominantly the lungs and brain, compared to 8% of CCSK-patients (3/38). RTKs showed ill-defined margins (12/21, 57%) and infiltrative growth pattern (13/21, 62%). CCSKs appeared hyper-intense on T2-weighted imaging (27/38, 71%) with a characteristics band-like enhancement (13/38, 34%), whereas RTK cases often showed T2-weighted hypo-intensity (11/21, 52%). The overall mean ADC-value for CCSK was 1.11 * 10-3 mm2/s (range 0.57–2.07 *10-3 mm2/s), and 0.72 * 10-3 mm2/s (range 0.53–0.90 *10-3 mm2/s) for RTK. ConclusionsThis retrospective study suggests a small size, T2-weighted hypo-intensity and an aggressive growth pattern may be characteristic for RTK. CCSK often showed a typical band-like enhancement pattern with relatively high ADC-values. Identified MRI-characteristics may be used in future studies focusing on validation and discrimination from especially WT, aiming for an early non-invasive diagnosis.

6 Feasibility and Perceived Benefit of an Interdisciplinary Rehabilitation Approach within a Tertiary Pediatric Hematology/Oncology Setting

Objective:Medulloblastoma is the most common pediatric malignant brain tumor. Approximately 29% of medulloblastoma patients experience postoperative posterior fossa syndrome (PFS) characterized by impairments in speech, motor, and mood. An interdisciplinary rehabilitation approach is associated with greater rehabilitation gains than a single discipline approach for brain injury patients with significant rehabilitation needs. However, literature regarding the feasibility and utility of this approach within a tertiary care pediatric hematology/oncology setting is lacking. The Acute Neurological Injury (ANI) service was developed to coordinate care for neurologically complex hematology/oncology patients receiving active cancer treatment, including those with PFS. ANI care coordination includes bimonthly interdisciplinary team meetings, interdisciplinary goal implementation for each patient, parent psychoeducation about applicable brain-behavior relationships (including PFS) at treatment initiation, neuropsychological assessment at transition times throughout treatment, cognitive remediation, and coordinated end of treatment transition planning. We gathered caregiver perspective on this approach within a tertiary care pediatric hematology/oncology setting.Participants and Methods:Parents of children and young adults (ages 4-20) with PFS after medulloblastoma resection who received coordinated care as part of the ANI program (n=20) were interviewed at least 4 months following completion of cancer treatment. 75% experienced postoperative mutism while the remainder experienced significantly decreased speech without mutism. All received cranial-spinal irradiation and focal boosts to tumor sites followed by chemotherapy per multi-institutional treatment protocol. Caregivers were interviewed regarding perceived feasibility and utility of ANI program components including parent psychoeducation, neuropsychological assessment, cognitive remediation, and interdisciplinary team coordination/goal setting, as well as parental supports. Yes/no responses were gathered as well as responses regarding the perceived utility of aspects of the interdisciplinary ANI program approach via a five-point Likert scale.Results:Surveys were completed by 66% of families contacted. Mean age at first contact with neuropsychology as part of the ANI program was 9.45 years (SD=4.4 years). Mean time between end of treatment and parent interview was 3.20 years (SD=2.01 years). Most parents reported that initial psychoeducation about PFS helped to decrease their concerns (81%) and increased their understanding of their child’s functioning in the context of PFS (88%). They reported benefit from neuropsychological assessment reports prior to initiating adjuvant treatment (92%), at end of treatment (90%), and one year following initiation of cancer treatment (100%), though they perceived less benefit from assessments intended to inform provider interventions during treatment (81% and 66%). Reports were shared most often with schools (75%), behavioral therapists (50%), physicians (50%), and rehabilitation specialists (25%). Parents indicated that the interdisciplinary ANI program approach was helpful (94%) and the coordinated interdisciplinary goal was beneficial (92%). Most parents favored the weekly frequency of cognitive remediation sessions (83%). Much interest was voiced in establishing a formal mentoring program to offer peer support by parents whose children have previously experienced PFS to those acutely managing a new PFS diagnosis (95%). Of note, all participants indicated that they would be willing to serve in a peer mentor role (100%).Conclusions:The interdisciplinary ANI program approach is feasible with perceived benefits to families managing new PFS and medulloblastoma diagnoses and receiving active cancer treatment.

Diagnóstico inicial del osteosarcoma y sarcoma de Ewing en la edad pediátrica

IntroductionOsteosarcoma and Ewing sarcoma are the most frequent malignant bone tumours in children. The aim of this study is to characterize clinical and radiological features at presentation of a large cohort of children with these diseases, radiological findings useful to differentiate them and the main prognostic factors. Material and methodsRetrospective analysis of clinical and imaging findings of 83 children diagnosed and treated of Ewing sarcoma and osteosarcoma in a paediatric hospital during a period of 10years. ResultsBoth tumours showed aggressive radiological features such as permeative or moth-eaten margins, cortical disruption, discontinuous periosteal reaction, intense contrast uptake, tumoral necrosis and soft-tissue component. They differed in their location, osseous matrix and gender predilection. Osteosarcoma occurred more frequently in the metaphysis of long bones (62%) with a blastic appearance (53%). Ewing sarcoma showed a predilection for male patients (71%), occurred in flat bones (42%) and in the diaphysis of long bones (58%) with a lytic appearance (82%). 29% of children presented with metastases at diagnosis, most frequently located in the lungs. Survival rates were 78% in osteosarcoma and 76% in Ewing sarcoma. Metastatic disease, aggressive radiological features and low percentage of tumoral necrosis after neoadjuvant chemotherapy were associated with poor prognosis (P<.05). ConclusionsImaging can confidently diagnose malignant paediatric bone tumours in children and may differentiate Ewing sarcoma from osteosarcoma, based on gender, location and appearance of the neoplasm. Metastatic disease, presence of aggressive radiological features and low percentage of tumoral necrosis after neoadjuvant chemotherapy were associated with poor prognosis.

Critical elements in the operative management of pediatric malignant ovarian germ cell tumors

Performance of the appropriate operation is highly important to ensure that any patient with a suspected ovarian germ cell tumor receives optimal therapy that prioritizes cure while simultaneoulsy minimizing risk of short and long-term toxicities of treatment. The following critical elements of any operative procedure performed for a suspected pediatric or adolescent ovarian germ cell tumor are reviewed: 1. Complete resection of the tumor via ipsilateral oophorectomy while avoiding tumor rupture and spillage, and 2. Performance of complete intraperitoneal staging at the time of initial tumor resection.