Characteristics and outcome of children with renal tumors in the Netherlands: The first five-year’s experience of national centralization

Around 6% of all childhood malignancies represent renal tumors, of which a majority includes Wilms tumor (WT). Although survival rates have improved over the last decades, specific patients are still at risk for adverse outcome. In the Netherlands, since 2015, pediatric oncology care for renal tumors has been centralized in the Princess Máxima Center for Pediatric Oncology. Here, we describe experiences of the first 5 years of centralized care and explore whether this influences the epidemiological landscape by comparing data with the Netherlands Cancer Registry (NCR). We identified all patients <19 years with a renal mass diagnosed between 01-01-2015 and 31-12-2019 in the Princess Máxima Center. Epidemiology, characteristics and management were analyzed. We identified 164 patients (including 1 patient who refused consent for registration), in our center with a suspicion of a renal tumor. The remaining 163 cases included WT (n = 118)/cystic partially differentiated nephroblastoma (n = 2)/nephrogenic rests only (n = 6) and non-WT (n = 37). In this period, the NCR included 138 children, 1 17-year-old patient was not referred to the Princess Máxima Center. Central radiology review (before starting treatment) was performed in 121/163 patients, and central pathology review in 148/152 patients that underwent surgery. Treatment stratification, according to SIOP/EpSSG protocols was pursued based on multidisciplinary consensus. Preoperative chemotherapy was administered in 133 patients, whereas 19 patients underwent upfront surgery. Surgery was performed in 152 patients, and from 133 biomaterial was stored. Centralization of care for children with renal tumors led to referral of all but 1 new renal tumor cases in the Netherlands, and leads to referral of very rare subtypes not registered in the NCR, that benefit from high quality diagnostics and multidisciplinary decision making. National centralization of care led to enhanced development of molecular diagnostics and other innovation-based treatments for the future.

Sensitive-stage embryo irradiation affects embryonic neuroblasts and adult motor function

Background Cranial radiation therapy for treating childhood malignancies in the central nervous system or accidental radiation exposure may result in neurological side effects in surviving adults. As tissue homeostasis is maintained by stem cells, understanding the effect of radiation on neural stem cells will provide clues for managing the neurological effects. Drosophila embryos were used as a model system whose sensitivity to irradiation-induced cell death changes from the sensitive to resistant stage during development. Objective Drosophila embryos at the radiation-sensitive stage were irradiated at various doses and the radiation sensitivity was tested regarding the appearance of apoptotic cells in the embryos and the embryonic lethality. Cell fates of the neural stem cells called neuroblasts (NBs) and adult motor function after irradiation were also investigated. Result Irradiation of Drosophila embryos at the radiation-sensitive stage resulted in a dose-dependent increase in the number of embryos containing apoptotic cells 75 min after treatment starting at 3 Gy. Embryonic lethality assayed by hatch rate was induced by 1 Gy irradiation, which did not induce cell death. Notably, no apoptosis was detected in NBs up to 2 h after irradiation at doses as high as 40 Gy. At 3 h after irradiation, as low as 3 Gy, the number of NBs marked by Dpn and Klu was decreased by an unidentified mechanism regardless of the cell death status of the embryo. Furthermore, embryonic irradiation at 3 Gy, but not 1 Gy, resulted in locomotor defects in surviving adults. Conclusion Embryonic NBs survived irradiation at doses as high as 40 Gy, while cells in other parts of the embryos underwent apoptosis at doses higher than 3 Gy within 2 h after treatment. Three hours after exposure to a minimum dose of 3 Gy, the number of NBs marked by Dpn and Klu decreased, and the surviving adults exhibited defects in locomotor ability.

Unilateral proptosis in a child-need for prompt diagnosis

Proptosis in a child often presents as a diagnostic dilemma. Proptosis can be secondary to infection or childhood malignancies. It warrants urgent and relevant investigations to facilitate correct diagnosis and treatment. The common causes of proptosis include infection and malignant lesions. Any delay in intervention in either of the causes can lead to significant morbidity or can impair the vision of the child. An orbital neoplasm in the pediatric age group is an uncommon clinical finding which can initially manifest as proptosis. Here, we report a case of a 2-year-old girl, presenting with progressive swelling of the right eye. An incisional biopsy confirmed the diagnosis of embryonal rhabdomyosarcoma (RMS). RMS is an aggressive tumor; hence, early diagnosis and prompt treatment are highly essential to prevent significant morbidity and can save the vision of the child.

miR-6315 Attenuates Methotrexate Treatment-Induced Decreased Osteogenesis and Increased Adipogenesis Potentially through Modulating TGF-β/Smad2 Signalling

Methotrexate (MTX) treatment for childhood malignancies has shown decreased osteogenesis and increased adipogenesis in bone marrow stromal cells (BMSCs), leading to bone loss and bone marrow adiposity, for which the molecular mechanisms are not fully understood. Currently, microRNAs (miRNAs) are emerging as vital mediators involved in bone/bone marrow fat homeostasis and our previous studies have demonstrated that miR-6315 was upregulated in bones of MTX-treated rats, which might be associated with bone/fat imbalance by directly targeting Smad2. However, the underlying mechanisms by which miR-6315 regulates osteogenic and adipogenic differentiation require more investigations. Herein, we further explored and elucidated the regulatory roles of miR-6315 in osteogenesis and adipogenesis using in vitro cell models. We found that miR-6315 promotes osteogenic differentiation and it alleviates MTX-induced increased adipogenesis. Furthermore, our results suggest that the involvement of miR-6315 in osteogenesis/adipogenesis regulation might be partially through modulating the TGF-β/Smad2 signalling pathway. Our findings indicated that miR-6315 may be important in regulating osteogenesis and adipogenesis and might be a therapeutic target for preventing/attenuating MTX treatment-associated bone loss and marrow adiposity.

IMMUNOHISTOCHEMICAL FEATURES IN SOFT TISSUE SARCOMAS

Sarcomas are relatively rare, accounting for only 1% of all adult malignancies and 15% of childhood malignancies [2]. According to the World Health Organization (WHO), the group of soft tissue sarcomas includes more than 100 different histological subtypes [3]. According to the recommmendations of the WHO to improve the accuracy of diagnosis in soft tissue sarcoma, the traditional histopathological examination should be supplemented with immunohistochemical and molecular methods [1]. It was carried out immunohistochemical research of CD31 receptor of Vascular Endothelial Growth Factor (VEGF) in 129 patients with STS. The age range of patients is on average 14-77 years with a peak in the age of 50-59 years. The most common reason for initial visit to a medical institution was palpable tumor (100%). It was studied the following correlative interdependences: It was determined that histodifferentiation of tumour is in inverse correlation with expression CD31 receptor. Distinctions of expression level of CD31 are shown, depending on the degree of tumor differentiation, presence or absence of its spontaneous necrotization, limphoid infiltration of pathological nidus and amount of vessels in tumor tissue. That is as high the degree of histological differentiation of tumour as low the level of expression CD31 receptor (χ2=35,4; p<0,001; р=-0,322). In FHTof ST is exposed inverse dependence between expression CD31 endotelial cells with spontaneous necrosis and lymphoid infiltration. As more the size and foci of spontaneous necrosis (χ2=67,1; p<0,001; р=-0,473) and lymphoid infiltration (χ2=46,1; p<0,001; р=-0,346), as low the level of expression CD31 receptor. It was found that the high level of espression CD31 receptor is in direct correlation with metastasis (χ2=18,6; р=0,42; p<0,001) and recurrence (χ2=9,43; р=0,30; p<0,01) of the process. Studied modern approaches to the diaqnostics and treatment of malignancies. One such approach is ”Oncology Control”, which means minimizing the risk of recurrence at the local and systemic level. Following treatment, follow-up should include history and physical examination accompanied by imaging (Ultrasound or MRI) every 3 to 6 month for 2 to 3 years, and then every 6 to 12 months thereafter to asses for recurrence. So in high positivity of CD31 receptor is exposed unfavourable prognosis in patients with STS. Summarizing before said we have come to the conclusion that immune-histo-chemical investigation of CD31 receptor of VEGF has important prognostical meaning in patients STS.

The scope of childhood cancer in South Africa: A response to ‘Childhood cancers in a section of the South African private health sector – Analysis of medicines claims data’

Childhood cancer is an under resourced medical field that is emerging as a great healthcare concern in low- and middle-income countries such as South Africa. Therefore, reporting data in this field that may inform policymakers should be representative of the subject matter. This article aims to discuss why medicines claims as an indicator for incidence, as per an article published in 2020, is not representative of childhood malignancies in the South African setting. Literature to support the commentary were sourced using Pubmed, Google scholar, and data presented by members of the South African Children’s Cancer Study Group (SACCSG). Private medical aid coverage in South Africa between 2002 and 2018 varied between 15.5% and 18.2%. Of these, 9.5% were children under 18 years and 3.5% were under the age of six. Only 13.5% of children were treated in private paediatric oncology units during 2015. The limitations in the study were the variable medical aid coverage, the disproportionate age representation, and lack of reliable indicators for measurement and calculation of incidence. Utilising one medicines claims database to evaluate the incidence of childhood cancer in South Africa is not representative and cannot inform policy.Contribution: This article highlights the importance of accurate registration of childhood cancer diagnoses, especially when data and conclusions based on these results inform policy. The study highlights the limitations of extrapolating general conclusions based on data representing only a small sector of the childhood cancer landscape in South Africa.

miR-542-3p Attenuates Bone Loss and Marrow Adiposity Following Methotrexate Treatment by Targeting sFRP-1 and Smurf2

Intensive methotrexate (MTX) treatment for childhood malignancies decreases osteogenesis but increases adipogenesis from the bone marrow stromal cells (BMSCs), resulting in bone loss and bone marrow adiposity. However, the underlying mechanisms are unclear. While microRNAs (miRNAs) have emerged as bone homeostasis regulators and miR-542-3p was recently shown to regulate osteogenesis in a bone loss context, the role of miR-542-3p in regulating osteogenesis and adipogenesis balance is not clear. Herein, in a rat MTX treatment-induced bone loss model, miR-542-3p was found significantly downregulated during the period of bone loss and marrow adiposity. Following target prediction, network construction, and functional annotation/ enrichment analyses, luciferase assays confirmed sFRP-1 and Smurf2 as the direct targets of miR-542-3p. miRNA-542-3p overexpression suppressed sFRP-1 and Smurf2 expression post-transcriptionally. Using in vitro models, miR-542-3p treatment stimulated osteogenesis but attenuated adipogenesis following MTX treatment. Subsequent signalling analyses revealed that miR-542-3p influences Wnt/β-catenin and TGF-β signalling pathways in osteoblastic cells. Our findings suggest that MTX treatment-induced bone loss and marrow adiposity could be molecularly linked to miR-542-3p pathways. Our results also indicate that miR-542-3p might be a therapeutic target for preserving bone and attenuating marrow fat formation during/after MTX chemotherapy.

EPIDEMIOLOGICAL PATTERNS OF PAEDIATRIC BRAIN TUMORS IN COIMBATORE

Background: Tumors of the nervous system are the second most common childhood tumors after leukemia,constituting approximately 35% of all childhood malignancies and remain the leading cause of cancer related deaths in children. In India,in the absence of a comprehensive population based national cancer registry,we depend on local hospital based registries for assessing the incidence of pediatric brain tumor.Hence,more and more institutional data are required to assess the actual disease load in India. Objective: The main objective of the present study is to assess the epidemiological patterns of brain tumors in children presenting in CMCH. Materials and Methods: Data regarding age,gender,topography and histopathology of 22 pediatric patients (0-18years)with brain tumors operated inCMCH over a period of 5 years(January 2015 to December 2019)was collected retrospectively and analysed. The results obtained were compared with available Indiandata and western literature. Results: Of 22 cases, males(63.6%) outnumbered females. In the present study, the most common anatomical site for brain tumors was cerebellum(45.5%) followed by cerebral hemispheres(36.2%), ventricles(13.6%) and sellar region(4.5%). The present study showed that Infratentorial tumors were more common (54.5%) as compared to Supratentorial tumors (45.5%).Thepresent study revealed that astrocytoma(36.4%) is the most common brain tumor in childhood. other common tumors include medulloblastoma(27.2%), followed by ependymoma(13.6%), oligodendroglioma(9%),pineal gland tumor(4.5%),craniopharyngioma(4.5%) and meningeal tumor(4.5%). Conclusion: From the present series, we conclude that, the frequencies of major histologic types of brain tumors found in the study do not differ substantially from that found in other developed and developing countries. Medulloblastomas and astrocytomas, which form the major histologic types in pediatric patients need special attention.

Management of Advanced Heart Failure in Children with Cancer Therapy-Related Cardiac Dysfunction

The evolution of cancer therapies has led to marked improvement in survival of those affected by childhood malignancies, while also increasing the recognition of early and late toxicities associated with cancer therapies. Cardiotoxicity can include cardiomyopathy/heart failure, coronary artery disease, stroke, pericardial disease, arrhythmias, and valvular and vascular dysfunction as a result of exposure to chemotherapy and/or radiation. Anthracyclines remain the most common cause of chemotherapy-induced cardiomyopathy (CCM) with varying clinical presentations including: acute, early onset, and late-onset. Many individuals develop cardiac dysfunction over the long-term, ranging from subclinical cardiac dysfunction to end-stage symptomatic heart failure. The focus of this review is on characterization of symptomatic heart failure in children with cancer therapy-related cardiac dysfunction (CTRCD) primarily due to CCM and utilization of advanced heart failure therapies, including ventricular assist device (VAD) support and heart transplantation, with consideration of unique patient-related factors.