[This corrects the article DOI: 10.3389/fonc.2024.1323176.].

Neurofibromatosis type 1 (NF1) is a complex multisystem genetic disorder that requires long-term, age-specific monitoring and multidisciplinary care. NF1 symptom burden can significantly affect the quality of life and impose a substantial economic burden on patients and their families. The approval and widespread availability of mitogen-activated protein kinase (MEK) inhibitors such as selumetinib for NF1-related plexiform neurofibromas have revolutionized the standard of care for patients with NF1, however their effective utilization hinges on early recognition of NF1. We present a consensus manuscript describing the challenges observed in the Arabian Gulf Cooperation Council (GCC) for diagnosing and managing NF1. Experts from the GCC also present recommendations for the early recognition and management of NF1 and its complications. A referral pathway that can play a crucial role in helping primary healthcare providers refer their patients to experts is also proposed. Increasing the availability and accessibility of genetic testing at an affordable cost and optimizing personalized NF1 care are essential for NF1 management. Developing regional guidelines for NF1 management and establishing NF1 centers of excellence may facilitate better care and outcomes for patients with NF1 in the GCC region.

Abstract Introduction: At present, there is no supporting evidence-based therapy of proven efficacy to treat posterior fossa syndrome (PFS) after surgical resection of posterior fossa tumors in children where only 22% of patients may experience a full recovery. However, zolpidem, a nonbenzodiazepine hypnotics drug, seems to be a possible treatment option for PFS symptoms. Methods and Materials: This was a retrospective chart review for all children with brain tumors younger than 15 years diagnosed with confirmed PFS after surgical resection at King Abdulaziz Medical City, Jeddah, and received zolpidem to alleviate the PFS symptoms between May 2016 and April 2019. Results: A total of 6 pediatric patients who experienced PFS symptoms (median of 4 days, range 1–7 days) were included. The most commonly observed symptoms were irritability, hypotonia, swallowing deficit, unsteady walking, and delayed speech. To alleviate the PFS symptoms, zolpidem was commenced 2–5 days postoperatively. The median duration of use was 13.5 days. During the hospital course, recovery of speech was observed after 2 weeks in most patients (50%) while 83.3% of patients recovered their normal speech in 4 months although not fully ambulated. No discontinuation of zolpidem use was reported because of adverse events. Conclusion: Most of our children (83.3%) who experienced PFS postresection responded to zolpidem trials which may represent a promising research field.

Introduction Tumor lysis syndrome (TLS) is a life-threatening metabolic abnormality. The incidence of TLS depends on the underlying malignancy. In a recent analysis of hematological malignancy, the incidence of clinical TLS in children was 3.8%, laboratory TLS 46.2%, and hyperphosphatemia 32.7%. Sevelamer is effective for the treatment of hyperphosphatemia associated with renal failure; however, there is no clear data that it has the same effect in treating hyperphosphatemia with TLS. Methods This was a retrospective study among children aged ≤14 years with hematological malignancy who developed TLS and received sevelamer to treat hyperphosphatemia at Princess Norah Oncology Center, King Abdulaziz Medical City (KAMC) in Jeddah from January 2012 to December 2016. Results A total of 34 patients received sevelamer. The majority was male (64%), with a median age of six years. The median sevelamer dose per day was 1600 mg, while the median duration of use was two days. Phosphate level was significantly decreased at different times (24 hours, 48 hours, and 72 hours) during sevelamer usage, p-value <0.001. Conclusion In our study, the use of sevelamer resulted in a significant decrease in phosphate levels. This finding further consolidates the efficacy of sevelamer in treating hyperphosphatemia with TLS. However, further research into the drug's kinetics is recommended.

Background The frequency of pathogenic/likely pathogenic (P/LP) germline mutations in cancer-related genes among children with cancer in highly consanguineous populations is not well studied. Methods Whole-exome sequencing of germline DNA was performed in 60 children with acute leukemia. We used the St. Jude Pediatric Cancer Variant Pathogenicity Information Exchange (PeCanPIE) data portal for the classification of germline variants by the St. Jude Medal Ceremony pipeline. Results Fifty-seven patients had acute lymphoblastic leukemia (ALL) and three patients had acute myeloid leukemia. Parental consanguinity was present in 27 (45%) patients. All patients were of Arab ancestry. Three patients (5%) had a history of cancer in their siblings. Five patients (8.3%) had P/LP germline mutations in cancer-related genes. Three patients with B-ALL had heterozygous pathogenic mutations in TP53, BRCA1, and BRCA2; one patient with B-ALL had homozygous pathogenic mutation in PMS2; and one patient with T-ALL had LP homozygous mutation in AK2 that was associated with reticular dysgenesis. Among patients who had history of parental consanguinity, three (11%) had P/LP germline mutations compared with two (8%) in the absence of parental consanguinity. Fourteen (23%) patients had gold medal variants in cancer-related genes, 13 were heterozygous, and one was homozygous. Silver medal variants were present in 35 (58%) patients; all were heterozygous except one homozygous. Conclusions Children with acute leukemia in Saudi Arabia had low frequency of P/LP mutations in cancer-related genes despite the high rate of consanguinity. Larger studies using whole-genome sequencing are needed to further explore the heritability of childhood leukemia.

PURPOSE Cancer treatment shortages are complex and a persistent problem worldwide. Patients with cancer are most vulnerable to drug shortages, which provides opportunities to examine the extent of the challenge(s) facing Saudi Arabia and to provide recommendations toward mitigating the impact of cancer treatment shortages on patient outcomes. MATERIALS AND METHODS A qualitative methodologic approach was conducted in April 2019 using a validated questionnaire and structured panel discussion for data generation. RESULTS Overall, 55 responses were received from practicing oncology health care professionals (26 pharmacists and 29 physicians). The annual average number of treated patients with cancer per institution was 640 (adults [n = 400] and pediatric [n = 240]). All respondents (100%) reported that cancer treatment shortages constitute a current problem in their center, with an average of 5 (range, 1-9) per month. The panelists recognized 2 fundamental points. First, the definition of cancer drug shortages should be standardized and recognized at the national level. Second, the current system must be improved to ensure proper and efficient use of the current resources. On that basis, the panelists developed 9 recommendations for action. CONCLUSION Cancer drug shortage is a significant problem in all health centers in Saudi Arabia. This study presents challenges that should be addressed at the national level and essential consensus recommendations for a coordinated action developed by a panel of experts to tackle the current national problem of cancer treatment shortages. Implementing these recommendations will provide a blueprint for management of national drug shortages in general and cancer treatment shortages in particular.

BackgroundTravel burden has a substantial psychosocial impact and financial strain on childhood cancer patients and their families.AimsTo study the geographic distribution of childhood cancer and assess the travel burden for care in Saudi Arabia.MethodsThis was a cross-sectional multi-institutional study that enrolled 1657 children with cancer who were diagnosed between 2011 and 2014. Cancer type/stage, city/region of residence, and city/region of treating centre were recorded. Travel burden was measured based on a 1-way distance in kilometres from the city centre to the treatment institution. This study was supported by Sanad Children's Cancer Support Association.ResultsDiagnosis was leukaemia (45.2%), non-CNS solid tumours (30.2%), lymphoma (12.3%), CNS tumours (11.8%) and histiocytosis (0.5%). Childhood cancer centres were in the same city as where the patients lived in 652 (39.3%) cases, same region but different city in 308 (18.6%), different regions in 613 (37%), and not known in 84 (5.1%). The mean 1-way travel distance for patients who lived in different regions was 790 (range, 116-1542) km. A total of 536 (32%) patients lived ≥ 400 km and 216 (13%) > 1000 km from the treatment centre. Among 642 patients with acute lymphoblastic leukaemia who required 2-3 years of therapy, 197 (31%) lived ≥ 400 km and 94 (15%) >1000 km from the treatment centre.ConclusionsNearly two thirds of patients with childhood cancer lived in different cities than the treatment centres, including one third of patients who lived ≥ 400 km away. There is a need to develop strategies to improve access to childhood cancer care.

BACKGROUND:During the coronavirus disease (COVID-19) pandemic, patients with cancer in rural settings and distant geographical areas will be affected the most by curfews. Virtual management (telemedicine) has been shown to reduce health costs and improve access to care.OBJECTIVE:The aim of this survey is to understand oncologists' awareness of and views on virtual management, challenges, and preferences, as well as their priorities regarding the prescribing of anticancer treatments during the COVID-19 pandemic.METHODS:We created a self-administrated electronic survey about the virtual management of patients with cancer during the COVID-19 pandemic. We evaluated its clinical sensibility and pilot tested the instrument. We surveyed practicing oncologists in Gulf and Arab countries using snowball sampling via emails and social media networks. Reminders were sent 1 and 2 weeks later using SurveyMonkey.RESULTS:We received 222 responses from validated oncologists from April 2-22, 2020. An awareness of virtual clinics, virtual multidisciplinary teams, and virtual prescriptions was reported by 182 (82%), 175 (79%), and 166 (75%) respondents, respectively. Reported challenges associated with virtual management were the lack of physical exam (n=134, 60%), patients' awareness and access (n=131, 59%), the lack of physical attendance of patients (n=93, 42%), information technology (IT) support (n=82, 37%), and the safety of virtual management (n=78, 35%). Overall, 111 (50%) and 107 (48%) oncologists did not prefer the virtual prescription of chemotherapy and novel immunotherapy, respectively. However, 188 (85%), 165 (74%), and 127 (57%) oncologists preferred the virtual prescription of hormonal therapy, bone modifying agents, and targeted therapy, respectively. In total, 184 (83%), 183 (83%), and 176 (80%) oncologists preferred to continue neoadjuvant, adjuvant, and perioperative treatments, respectively. Overall, 118 (53%) respondents preferred to continue first-line palliative treatment, in contrast to 68 (30%) and 47 (21%) respondents indicating a preference to interrupt second- and third-line palliative treatment, respectively. For administration of virtual prescriptions, all respondents preferred the oral route and 118 (53%) preferred the subcutaneous route. In contrast, 193 (87%) did not prefer the intravenous route for virtual prescriptions. Overall, 102 (46%) oncologists responded that they would "definitely" prefer to manage patients with cancer virtually.CONCLUSIONS:Oncologists have a high level of awareness of virtual management. Although their survey responses indicated that second- and third-line palliative treatments should be interrupted, they stated that neoadjuvant, adjuvant, perioperative, and first-line palliative treatments should continue. Our results confirm that oncologists' views on the priority of anticancer treatments are consistent with the evolving literature during the COVID-19 pandemic. Challenges to virtual management should be addressed to improve the care of patients with cancer.

Background & aim: Hereditary cancer susceptibility syndromes (HCSS) are reported in up to one-third of children with cancer. Diagnosis of HCSS is crucial for implementation of surveillance protocols. We identified children who fulfilled criteria for HCSS in Saudi Arabia using the American College of Medical Genetics and Genomics (ACMG) guidelines, addressing the utility of these guidelines in a highly consanguineous population. Methods: This multi-center cross-sectional study recruited 1858 children with cancer between January 2011 and December 2014. HCSS criteria were based on the ACMG guidelines. Results: Seven hundred and four (40.4%) out of 1742 eligible patients fulfilled criteria for HCSS. Consanguinity was reported in 629 (38%) patients, with 50 (2.9%) first-degree, 535 (30.7%) second-degree, and 272 (15.6%) third-degree relatives affected with cancer. Two hundred and eighty eight (17.4%) leukemia and 87 (5.3%) brain tumour patients fulfilled HCSS criteria, with parental consanguinity being the most frequent criterion in both (leukemia 85.4%, brain tumors 83.9%). However, leukemia was less frequent in patients of consanguineous parents (p = 0.023). Conclusion: Four out of 10 children with cancer fulfilled criteria for HCSS, most often due to consanguinity. This higher than expected prevalence suggests the need to validate consanguinity as a criterion for HCSS in highly consanguineous populations.

Treatment modality impacts outcome of childhood low-grade glioma (LGG). Optimizing management in developing countries can be challenging. This study evaluates the clinical characteristics, treatment, and factors influencing outcome of childhood LGG in Saudi Arabia.

Introduction: Atypical teratoid/rhabdoid tumor (AT/RT) of the central nervous system is characterized by SMARCB1/INI deletion or mutation in the long arm of chromosome 22 11( 22q11.2), also resulting in loss of nuclear expression of INI1 protein immunohistochemically. AT/RT tumors usually occur in children below 3 years. The tumor is usually seen in the cerebellum or the cerebrum, with an extremely rare incidence in the spinal cord. Materials and Methods: We report a rare case of AT/RT in a 6-year-old boy who had a primary spinal cord lesion in the thoracolumbar junction. Pathology revealed loss of nuclear staining of INI1 immunohistochemically. This is the first case reported with mixed intraspinal lesion (intra- and extramedullary). The patient underwent two surgeries and received radiotherapy and chemotherapy; however, he died 16 months after the initial presentation. Results and Discussion: We reviewed the literature on all children with spinal cord AT/RT. The review showed that the cervical region is the most common location of origin, especially in younger children. Reported cases were treated with a combination of surgery, systemic and intrathecal chemotherapy, and radiation therapy, and a survival time of 18 months represented the best outcome. Overall mean survival time was 10 months. (c) 2018 S. Karger AG, Basel

e13086 Background: Hereditary cancer susceptibility syndromes (HCSS) contribute to the cause of up to 29% of childhood cancer. The Saudi population has high rate of consanguineous marriages and this might increase the prevalence of HCSS. Methods: Our study is a cross sectional multi-center study of children less than age 14 years who were diagnosed with cancer between January 2011 and December 2014. Data collected were: demographics, number of primary cancers, and cancer details. Parents were interviewed about consanguinity and the occurrence of cancer in 1st, 2nd, and 3rddegree relatives. HCSS risk assessment was based on the ACMG 2015 practice guidelines. The study was funded by Sanad children's cancer support association. Results: A total of 1291 patients (leukemia 49%, lymphoma 11%, brain tumors 10%, non-Ewings sarcoma 7.3%, Wilms tumor 6.1%, and others 16.6%) were enrolled as of December 2015. The median age at diagnosis was 5.1 years, male:female ratio was 1.3:1, and median sibship size was 4 (range, 0-12). Parental consanguinity was reported in 38%, mostly first degree. The number of patients with criteria that warrants HCSS work up is shown in the Table. A total of 486 (37.6%) met those criteria (leukemia 58%, non-Ewings sarcoma 19.4%, brain 12.8%, retinoblastoma 4.9%, hepatoblastoma 4.5%, and adrenocortical carcinoma 0.4%). Conclusions: Nearly 4 out of 10 children with cancer in Saudi Arabia met criteria for HCSS, most often due to parental consanguinity. The use of consanguinity solely as a risk factor for HCSS in our population needs to be determined. Genetic testing of at risk patients is on-going. Criteria Number of patients 1. Leukemia 282 A. Parental consanguinity 176 B. 2nd primary in the patient 4 C. Sibling with childhood cancer 0 D. Relative with LFS associated tumor ≤ 45 years 55 E. > 1 criteria 47 2. Non-Ewing Sarcoma 94 3. Brain tumor 62 A. Parental consanguinity 43 B. 2nd primary in the patient 0 C. Sibling with childhood cancer 1 D. Relative with Lynch syndrome associated cancer 1 E. Relative with LFS associated tumor ≤ 45 years 6 F. > 1 criteria 11 4. Retinoblastoma 24 5. Hepatoblastoma < 5 years 22 6. Adrenocortical carcinoma 2 Total 486 LFS, Li-Fraumeni syndrome.

Central nervous system tumors are the most common pediatric solid tumors and a leading cause of cancer‐related mortality and morbidity in this age group. Survival rates have improved significantly over the last decades for most of the tumor types, as a consequence of improvements in neuroimaging, neurosurgery and neuroanesthesia, radiation oncology, and medical oncology. The complexity of the management of these patients requires a multidisciplinary approach and has led to the emergence of a new subspecialty of pediatric neuro‐oncologists who are dedicated to the management and follow‐up of this population. This review highlights the most critical advances in the diagnostic and treatment modalities of pediatric brain tumors. A specific review of the most common tumor types discusses treatment options, controversies, and ongoing developments, with an emphasis on cooperative trials.

Background. Sevelamer is a phosphate-binder used effectively for the treatment of hyperphosphatemia in patients treated with dialysis. Objectives. To describe the safety of sevelamer in children with hyperphosphatemia secondary to tumor lysis syndrome and the serum phosphate concentrations observed following its administration. Procedure. A retrospective chart review of all children with leukemia/lymphoma diagnosed between November 2002 and April 2004 who received sevelamer during their initial admission was conducted. We monitored the effects of sevelamer on serum phosphate concentration, calcium/phosphate product and renal function at hours 24, 48, and 72 from sevelamer initiation. Results. Thirteen patients received sevelamer during the Study period. Their median age was 13 years (range 2.7-17.9) and eight were boys. Nine children had acute lymphoblastic leukemia, one had acute myeloid leukemia and 3 had non-Hodgkin's lymphoma. The most frequently used dose of sevelamer was 400 mg orally twice daily. The median duration of sevelamer therapy was 2 days (range 1 -7). Two children were excluded from the efficacy analysis due to concurrent use of dialysis. Mean serum phosphate levels decreased after sevelamer administration, in eleven patients, from a baseline 2.2 mmol/L +/- 0.4 (95% Cl, 1.7-3.1) to 1.1 mmol/L +/- 0.2 at hour 72 (95%Cl, 0.6-1.5). The only toxicity attributed to sevelamer was mild vomiting in three patients. Conclusions. Sevelamer appears to be effective and tolerable for the treatment of hyperphosphatemia associated with tumor lysis syndrome.

Synovial sarcoma accounts for between 6 and 10% of childhood sarcomas and histological diagnosis can be challenging, even for experienced pathologists. Several other tumors enter the differential diagnosis, including malignant peripheral nerve sheath tumor, Ewing sarcoma/primitive neuroectodermal tumor and undifferentiated sarcoma. Several recent reports utilizing expression array techniques have documented expression of the MYCN oncogene in synovial sarcoma. In order to more fully investigate this finding, a series of 12 synovial sarcomas and 29 other sarcomas (four malignant peripheral nerve sheath tumors, 15 Ewing sarcoma/ primitive neuroectodermal tumors, 10 undifferentiated sarcomas) were examined for MYCN expression and gene amplification. By RT-PCR, nine of 12 synovial sarcomas (75%) expressed MYCN. Five synovial sarcomas (42%) expressed MYCN at high levels. Of the other sarcomas, one malignant peripheral nerve sheath tumor (25%) and five Ewing sarcoma/ primitive neuroectodermal tumors (33%) expressed MYCN at low levels, and all other cases were negative for MYCN. None of the synovial sarcomas had genomic amplification, suggesting that high MYCN expression levels resulted from epigenetic phenomena. Examination of selected downstream targets of MYCN in synovial sarcoma revealed expression of MCM7 (minichromosome maintenance protein 7) in all synovial sarcomas, and expression of nestin (n = 10; 83%), ID2 (inhibitor of DNA binding protein 2) (n 6; 50%) and MRP1 (multidrug resistance protein 1) (n 1; 8%) in a subset of synovial sarcomas. Expression of downstream targets did not correlate with expression of MYCN. Neither MYCN nor expression of downstream targets significantly correlated with metastases at presentation, progression-free survival or overall survival in this small series. In summary, high levels of MYCN expression was useful for distinguishing synovial sarcoma from other childhood-spindled cell sarcomas with specificity and sensitivity of 100 and 42%, respectively, in this series. The clinical and biological significance of this finding deserves further study.