Innovative advances in pediatric radiology: computed tomography reconstruction techniques, photon-counting detector computed tomography, and beyond.

In pediatric radiology, balancing diagnostic accuracy with reduced radiation exposure is paramount due to the heightened vulnerability of younger patients to radiation. Technological advancements in computed tomography (CT) reconstruction techniques, especially model-based iterative reconstruction and deep learning image reconstruction, have enabled significant reductions in radiation doses without compromising image quality. Deep learning image reconstruction, powered by deep learning algorithms, has demonstrated superiority over traditional techniques like filtered back projection, providing enhanced image quality, especially in pediatric head and cardiac CT scans. Photon-counting detector CT has emerged as another groundbreaking technology, allowing for high-resolution images while substantially reducing radiation doses, proving highly beneficial for pediatric patients requiring frequent imaging. Furthermore, cloud-based dose tracking software focuses on monitoring radiation exposure, ensuring adherence to safety standards. However, the deployment of these technologies presents challenges, including the need for large datasets, computational demands, and potential data privacy issues. This article provides a comprehensive exploration of these technological advancements, their clinical implications, and the ongoing efforts to enhance pediatric radiology's safety and effectiveness.

Mediastinal Radiotherapy-induced Early-onset Valvulopathy in a 6-Year-old Boy With Hodgkin Lymphoma.

Mediastinal radiotherapy for childhood cancers, particularly Hodgkin disease, has numerous potential adverse effects, including coronary artery disease, pericarditis, cardiomyopathy, valvular disease, and conduction abnormalities. The prevalence of valvular stenosis is relatively low, and regurgitation is more common. Mediastinal radiotherapy-induced valvular disease develops more than 10 years after radiotherapy. Here, we present a case of a 6-year-old boy with moderate to significant mitral stenosis + moderate mitral regurgitation and mild aortic regurgitation that appeared 1.5 months after radiotherapy and showed a progressive course.

Constitutional Microsatellite Instability, Genotype, and Phenotype Correlations in Constitutional Mismatch Repair Deficiency.

BACKGROUND & AIMS: Constitutional mismatch repair deficiency (CMMRD) is a rare recessive childhood cancer predisposition syndrome caused by germline mismatch repair variants. Constitutional microsatellite instability (cMSI) is a CMMRD diagnostic hallmark and may associate with cancer risk. We quantified cMSI in a large CMMRD patient cohort to explore genotype-phenotype correlations using novel MSI markers selected for instability in blood. METHODS: Three CMMRD, 1 Lynch syndrome, and 2 control blood samples were genome sequenced to >120× depth. A pilot cohort of 8 CMMRD and 38 control blood samples and a blinded cohort of 56 CMMRD, 8 suspected CMMRD, 40 Lynch syndrome, and 43 control blood samples were amplicon sequenced to 5000× depth. Sample cMSI score was calculated using a published method comparing microsatellite reference allele frequencies with 80 controls. RESULTS: Thirty-two mononucleotide repeats were selected from blood genome and pilot amplicon sequencing data. cMSI scoring using these MSI markers achieved 100% sensitivity (95% CI, 93.6%-100.0%) and specificity (95% CI 97.9%-100.0%), was reproducible, and was superior to an established tumor MSI marker panel. Lower cMSI scores were found in patients with CMMRD with MSH6 deficiency and patients with at least 1 mismatch repair missense variant, and patients with biallelic truncating/copy number variants had higher scores. cMSI score did not correlate with age at first tumor. CONCLUSIONS: We present an inexpensive and scalable cMSI assay that enhances CMMRD detection relative to existing methods. cMSI score is associated with mismatch repair genotype but not phenotype, suggesting it is not a useful predictor of cancer risk.

Ectopic parathyroid hormone as a rare aetiology of hypercalcemia with rhabdomyosarcoma: a new treatment strategy with zoledronic acid and Denosumab.

OBJECTIVES: Ectopic parathyroid hormone (PTH) secretion is rare in children with rhabdomyosarcoma, and only a few pediatric cases have been reported to date. Reports of the use of zoledronic acid (ZA) and Denosumab are limited for the treatment of hypercalcemia of malignancy (HCM) in the pediatric population. The aim of presenting this pediatric case of rhabdomyosarcoma accompanied by HCM, secondary to ectopic PTH secretion, was to highlight the benefits of ZA as a first-choice bisphosphonate in this situation with Denosumab as an alternative therapy. CASE PRESENTATION: The patient was diagnosed at 13 years with alveolar rhabdomyosarcoma. Multiple bone metastases first appeared at 15 years, but he remained normocalcemic until 17 years old when serum calcium was 15.1 mg/dL and PTH 249 pg/mL. While serum calcium responded well after ZA and Denosumab cycles, PTH remained elevated, reaching a peak value of 1851 pg/mL during treatment cycles. CONCLUSIONS: We report a patient with rhabdomyosarcoma accompanied by HCM, secondary to ectopic PTH, in whom the HCM was successfully managed with ZA and Denosumab. We believe that ZA should be the bisphosphonate of choice in pediatric HCM with rhabdomyosarcoma, while Denosumab may be another option in ZA-refractory cases.

Clinical practice of a genetics referral selection tool in pediatric cancer patients.

There are few guidelines for genetic counseling and management of pediatric cancer patients with probable cancer predisposition. In this study, we used a previously proposed patient selection tool by Jongmans and discussed the findings in regard to pediatric cancer patients we treated. Pediatric solid tumor patients who were treated in Kocaeli University Department of Pediatric Oncology were evaluated with the five main questions in Jongmans' referral tool. All of the patients and records of diagnostic imaging were examined and analyzed. One-hundred-twenty-three patients participated in the study. The most common indication for genetic counseling was 'consanguinity of the parents' with '≥2 malignancies at childhood age' following it. Fifty-two (42.28%) patients had indication for genetic counseling. We recommend developing and using genetics counseling selection tools such as Jongmans' which helps clinicians differentiate patients with probable cancer predisposition.

EWSR1(22q12) Translocation Positive Pediatric Adrenal Tumor with Loss of 1p, 11q, and Unbalanced Gain of 17q: Neuroblastoma or Ewing Sarcoma?

Background Although neuroblastoma and Ewing sarcoma/Primitive neuroectodermal tumor are different clinical entities, they are both a member of small round blue cell tumors and can mimic each other's behavior in clinical and molecular aspects. Case report: A 3 year-old girl with an abdominal mass was found to have a small round blue cell tumor originating from the right adrenal gland. High level of neuron specific enolase, initial genetic test results (N-Myc amplification: negative, loss of 1p, 11q, and unbalanced gain of 17q) and characteristic radiological appearance of the tumor suggested a preliminary diagnosis of neuroblastoma but further analysis showed CD99 expression and presence of EWSR1 rearrangement, which are mostly observed in Ewing sarcoma. Conclusion: Adrenal gland tumors of childhood with complex immunophenotypic features requires distinguishing two discrete tumors in the small round blue cell tumor group, neuroblastoma and Ewing sarcoma. Although no exact diagnosis of the tumor was made, we reached a good response with neuroblastoma treatment protocol.

Evaluation of Clinical Properties and Treatment Responses of Infantile Hemangioma.

BACKGROUND: Infantile hemangiomas are the most common vascular tumors in childhood. Although spontaneous regression is common; several infantile hemangioma patients need treatment due to possible morbidities. The aim of this study was to investigate the medical methods used in the treatment of infantile hemangiomas and to evaluate the factors affecting treatment response. METHODS: Clinical and demographic characteristics, risk factors, treatment indications, modalities, duration, and responses of 100 patients between January 2007 and January 2017 were evaluated. RESULTS: The most common form of hemangiomas was superficial lesions. Sixty three per cent of the patients were female. Ulceration and hemorrhage were found in 26% of the cases and ocular problems were detected in 3% of the cases. Among the indications for treatment were cosmetic reasons with 56%, ulcer and bleeding with 25% and risk of vision problems with 13%. Propranolol with/without steroid was used as first line treatment and response rates were: 84 patients with more than 50% response, 9 patients with less than 50% response and 7 patients with treatment refractory. The most important factor affecting the treatment response was age at the beginning of the treatment. Duration of treatment, presence of ulceration, location, and size of hemangioma were also found to have significant effects on responses. CONCLUSIONS: This study demonstrated the importance of the kind and initiation time of infantile hemangioma treatment. A strong positive effect can be reached by starting treatment before the end of the proliferation phase. J Drugs Dermatol. 2020;19(12): doi:10.36849/JDD.2020.5009.

Nuclear protein in testis midline carcinoma in a Turkish boy: a case report.

Background: Nuclear protein in testis (NUT) midline carcinoma (NMC) is an undifferentiated carcinoma, usually localized to the midline and presenting a translocation in the gene for bromodomain containing protein 4. Here, we report a rare case of NMC in an 8-year-old Turkish boy. Case report: There were masses in the lung, liver, and iliac wing representing metastases. Abdominal lymph node sampling revealed epithelial tumor infiltration with cellular pleomorphism. Immunohistochemistry was strongly positive for cytokeratin and epithelial membrane antigen protein. Because of undifferentiated carcinoma morphology, the tumor was considered to be a NMC. Immunoreactivity with antibodies to NUT and the presence of NUT clarified by fluorescence in situ hybridization (FISH) supported the diagnosis. Despite initial response to chemotherapy, the patient died 7 months after the diagnosis. Conclusions: Immunoreactivity for NUT antibodies along with a dual-color FISH and karyotype analysis was suggestive for diagnosis of NMC. In differential diagnosis of undifferentiated carcinomas that occur particularly at midline localization, NMC should be considered.

High-sensitivity microsatellite instability assessment for the detection of mismatch repair defects in normal tissue of biallelic germline mismatch repair mutation carriers.

INTRODUCTION: Lynch syndrome (LS) and constitutional mismatch repair deficiency (CMMRD) are hereditary cancer syndromes associated with mismatch repair (MMR) deficiency. Tumours show microsatellite instability (MSI), also reported at low levels in non-neoplastic tissues. Our aim was to evaluate the performance of high-sensitivity MSI (hs-MSI) assessment for the identification of LS and CMMRD in non-neoplastic tissues. MATERIALS AND METHODS: Blood DNA samples from 131 individuals were grouped into three cohorts: baseline (22 controls), training (11 CMMRD, 48 LS and 15 controls) and validation (18 CMMRD and 18 controls). Custom next generation sequencing panel and bioinformatics pipeline were used to detect insertions and deletions in microsatellite markers. An hs-MSI score was calculated representing the percentage of unstable markers. RESULTS: The hs-MSI score was significantly higher in CMMRD blood samples when compared with controls in the training cohort (p<0.001). This finding was confirmed in the validation set, reaching 100% specificity and sensitivity. Higher hs-MSI scores were detected in biallelic MSH2 carriers (n=5) compared with MSH6 carriers (n=15). The hs-MSI analysis did not detect a difference between LS and control blood samples (p=0.564). CONCLUSIONS: The hs-MSI approach is a valuable tool for CMMRD diagnosis, especially in suspected patients harbouring MMR variants of unknown significance or non-detected biallelic germline mutations.

More than Ophelia syndrome: Multiple paraneoplastic syndromes in pediatric Hodgkin lymphoma.

Demirsoy U, Alparslan B, Sen MC, Anik Y, Akansel G, Görür G, Gürel B, Aksu G, Çorapçioglu F. More than Ophelia syndrome: Multiple paraneoplastic syndromes in pediatric Hodgkin lymphoma. Turk J Pediatr 2019; 61: 139-141. Paraneoplastic syndromes in Hodgkin lymphoma (HL) can be seen with different symptoms and organ findings within a significant time before definite diagnosis of the primary disease. Achalasia, Holmes-Adie pupil, and limbic encephalitis are rarely reported paraneoplastic components in pediatric HL. In this report, we present an 11-year-old girl who had all these three paraneoplastic components synchronously before HL was identified.

Eosinophilic pustular folliculitis of infancy suppressed with cetirizine.

Eosinophilic pustular folliculitis of infancy is a rare inflammatory disease characterized by recurrent, itchy sterile pustules mainly located on the scalp. Topical agents are mostly effective to suppress the symptoms in the majority of cases. However, systemic agents that are safe for long-term use are required for patients with widespread or resistant lesions. We present a case with eosinophilic pustular folliculitis of infancy whose disease was suppressed with cetirizine but recurred after ceasing the drug.

A sensitive and scalable microsatellite instability assay to diagnose constitutional mismatch repair deficiency by sequencing of peripheral blood leukocytes.

Constitutional mismatch repair deficiency (CMMRD) is caused by germline pathogenic variants in both alleles of a mismatch repair gene. Patients have an exceptionally high risk of numerous pediatric malignancies and benefit from surveillance and adjusted treatment. The diversity of its manifestation, and ambiguous genotyping results, particularly from PMS2, can complicate diagnosis and preclude timely patient management. Assessment of low-level microsatellite instability in nonneoplastic tissues can detect CMMRD, but current techniques are laborious or of limited sensitivity. Here, we present a simple, scalable CMMRD diagnostic assay. It uses sequencing and molecular barcodes to detect low-frequency microsatellite variants in peripheral blood leukocytes and classifies samples using variant frequencies. We tested 30 samples from 26 genetically-confirmed CMMRD patients, and samples from 94 controls and 40 Lynch syndrome patients. All samples were correctly classified, except one from a CMMRD patient recovering from aplasia. However, additional samples from this same patient tested positive for CMMRD. The assay also confirmed CMMRD in six suspected patients. The assay is suitable for both rapid CMMRD diagnosis within clinical decision windows and scalable screening of at-risk populations. Its deployment will improve patient care, and better define the prevalence and phenotype of this likely underreported cancer syndrome.

High Infection-Related Mortality in Pediatric Acute Myeloid Leukemia without Preventive Antibiotics and Antifungals: Retrospective Cohort Study of a Single Center from a Middle-Income Country.

OBJECTIVE: This study aimed to evaluate infection-related mortality in patients with acute myeloid leukemia (AML) treated without preventive antibiotics and antifungals in a middle-income country. MATERIALS AND METHODS: Infection-related mortality was evaluated retrospectively in 49 pediatric patients. RESULTS: A total of 173 chemotherapy courses were administered as first-line chemotherapy. Four patients died during induction: one patient due to intracranial bleeding, two patients due to typhlitis, and one patient due to invasive fungal infection with pulmonary vascular invasion and massive bleeding. Another two patients died with resistant disease. During consolidation there were four infection-related deaths and one death due to cardiotoxicity. In first-line chemotherapy mortality was 22% (11/49); infection-related mortality was 14% (7/49). Event-free survival and overall survival at 6 years were 42.9% and 61.2% (95% CI: 44-76 and 66-99 months), respectively. CONCLUSION: Due to considerable infection-related deaths, antibacterial and mold-active antifungal prophylaxis may be tried during neutropenic periods in pediatric AML.

The Association of Oral Vitamin D and Calcium Supplementation With Bone Mineral Density in Pediatric Acute Lymphoblastic Leukemia Patients.

AIM: To investigate the association of calcium (Ca) and vitamin D (vit D) supplementation with bone mineral density (BMD) in pediatric acute lymphoblastic leukemia (ALL). MATERIALS AND METHODS: Group I (n=11): de novo ALL patients aged 1 to 18 years. Group II (n=46): pediatric ALL survivors in first complete remission and ALL patients on maintenance chemotherapy. We stratified group II into 3 subgroups according to the postdiagnosis period (group IIa: 8 to 24 mo, group IIb: 24 to 48 mo, group IIc: >48 mo). Group III (n=22): healthy siblings of group II. Daily oral vit D3 and Ca carbonate was given only to group I. In group I, BMD was measured at diagnosis and after completion of intensive chemotherapy (TP1 and TP2). RESULTS: A significant increase in Ca (P=0.024) and 25-OH vit D (P=0.01), and a decrease in magnesium (P=0.023) were detected at TP2 compared with TP1 in group I. Mean plasma levels of 25-OH vit D were <20 ng/mL in all the groups. Total body (P=0.005), total body less head (P=0.005), and L1 to L4 BMD Z scores (P=0.025) decreased significantly at TP2 compared with TP1. The lowest BMD scores were found at 8 to 24 months after diagnosis in unsupplemented patients. A gradual increase in BMD Z scores was shown, with the highest scores in group IIc. CONCLUSION: Vit D and Ca supplementation in pediatric ALL patients during intensive chemotherapy may not prevent bone mineral loss. BMD scores of pediatric ALL patients described by other studies, as a major decrease in the first 2 years and gradual increase afterward, was also observed in our patients.

Nonsyndromic Juvenile Myelomonocytic Leukemia With PTPN11 Mutation in a 9-Year-old Girl.

A 9.5-year-old girl with malaise, fever, massive hepatosplenomegaly, anemia, leukocytosis (37.9 × 10(9)/L), monocytosis (1.48 × 10(9)/L), and thrombocytopenia is presented. Hemoglobin F was increased (18%). Bone marrow erythroid/myeloid ratio was 40/1 with 7% myeloblast and 5% monocyte suggesting erythroleukemia or juvenile myelomonocytic leukemia (JMML). The patient had a fulminant course with respiratory compromise and died in 2 weeks before heterozygous somatic mutation in the PTPN11 gene was shown. JMML must be considered also in the patients older than 6 years. A cytopenic phase may precede JMML. Leucocytosis may be transient and there may be predominance of erythroid precursors in the bone marrow.

The Efficacy and Safety of Procedural Sedoanalgesia with Midazolam and Ketamine in Pediatric Hematology.

OBJECTIVE: The aim of this study is to investigate the efficacy and safety of sedoanalgesia performed outside the operating room by pediatricians trained in advanced airway management and life support. MATERIALS AND METHODS: Midazolam and ketamine were administered consecutively by intravenous route under cardiorespiratory monitoring for painful procedures of pediatric hematology. RESULTS: A total of 115 patients had 237 sedoanalgesia sessions. Sedation time was 24.02±23.37 s and sedation success was 92.5% (Ramsay scores of ≥5). Patient satisfaction was high. The recovery time was 28.81±14.4 min. Although statistically significant (p<0.01) increases in systolic and diastolic blood pressure, heart rate, and respiratory rate were observed without clinical importance, they improved without any intervention. No severe adverse events were observed. CONCLUSION: Sedoanalgesia with intravenous midazolam and ketamine for pediatric hematology and oncology patients' painful minor invasive procedures performed in an optimally equipped setting outside the operating room by pediatricians trained and certificated in advanced airway management and life support is effective and safe.

Do proinflammatory cytokine levels predict serious complication risk of infection in pediatric cancer patients?

Determination of risk of severe bacterial infection complication in children with cancer is important to diminish the cost of hospitalization and therapy. In this study, children with cancer (leukemia excluded) were evaluated for risk of severe infection complication, success of therapy and the relation between clinical and inflammatory parameters during neutropenic fever attacks. Children who fulfilled the criteria of neutropenic fever with cancer were enrolled in the study. During admission, together with clinical and laboratory parameters; interleukin-6, interleukin-8, soluble tumor necrosis factor receptor II, and soluble interleukin 2 reseptor ve procalcitonin levels were detected. Empirical therapy was started with piperacillin/tazobactam and relation between the inflammatory cytokine levels and therapy response parameters were evaluated. The study population included 31 children and 50 neutropenic attacks were studied. In 48% of the attacks, absolute neutrophile count was >100/mm(3) and infectious agents were shown microbiologically in 12% of the attacks. In the study group with piperacillin/tazobactam monotherapy, the success rate without modification was 58%. In the therapy modified group mean duration of fever, antibiotherapy and hospitalization were significantly longer than the group without modification. Inflammatory cytokines' levels during admission (interleukin-6, interleukin-8, soluble tumor necrosis factor reseptor II) were higher in patients with fever >3 days and in multiple regression analysis, it has been shown that they have a determinative role on fever control time. Other cytokines did not show any significant relationship with risk of severe bacterial infection complication and success of therapy.