Title : Evans syndrome in the background of 22q11.2 deletion syndrome

Background: Children treated for cancer are at risk of developing iron toxicity due to receiving red cell transfusions and myelosuppressive chemotherapy. Transfusions administered during prolonged episodes of marrow suppression may increase exposure to toxic, reactive forms of iron and thereby increase risk of extrahepatic iron accumulation and long-term organ damage. Objective: This study aimed to evaluate the severity and organ distribution of clinically significant iron overload through measurement of hepatic, cardiac, pancreatic, and pituitary iron deposition in an at-risk cohort of children and young adults treated for cancer. Methods: This retrospective study evaluated patients treated for any type of cancer who underwent an MRI due to clinical concern for evaluation of iron overload (n=103, 73 post-treatment). Data regarding cancer type and treatment, MRI and laboratory results, and treatment for iron overload were analyzed. Results: Over half (53%) of this sample had moderate or greater hepatic siderosis, 80% had pancreatic siderosis, and nearly half (45%) had pituitary siderosis and/or volume loss. Pancreatic iron was associated with both cardiac (p=0.0043) and pituitary iron (p=0.0101). Patients treated for acute myeloid leukemia or high-risk acute lymphoblastic leukemia had higher liver iron concentration (LIC) compared to other cancer types (median LIC 8.5 vs. 2.9 mg/g DLW, p=0.0011). Conclusion: Pediatric cancer patients are at risk for transfusional iron overload, with significant exposure to toxic forms of iron indicated by extrahepatic iron deposition (pancreas, heart and pituitary). Further studies should examine the effect of exposure to reactive iron on long-term outcomes and develop management recommendations.

Do we need more studies?Max M. van Noesel, MD, PhD, MSc1,2*Department of Solid Tumors, Princess Máxima Center for Pediatric Oncology, Utrecht, the NetherlandsDivision Imaging & Oncology, University Medical Center Utrecht, Utrecht, the Netherlands*Correspondance to: M.M van Noesel, MD, PhD, MSc, Department of Solid Tumors, Princess Máxima Center, Heidelberglaan 25, 3584 CS Utrechtc, Telephone: +31-6 5000 6581, Email: [email protected] Text word count: 968 Abstract: - Short running title: Highlight PBC-22-1061 Tables: - Figures: - Abbreviations: -

Comment on: Viral infections in pediatric brain tumor patients treated with targeted therapiesAimen Waqar KhanDepartment of Medicine, Jinnah Sindh Medical University, Karachi, PakistanDear Dr. Newburger,We have read with great enthusiasm the article titled Viral infections in pediatric brain tumor patients treated with targeted therapies by Lisa Mayr et al [1]. We commend the authors’ efforts in collating epidemiologic data and investigating infectious outcomes between pediatric patients being treated with targeted therapy versus conventional therapies. It was a pleasure to read such a well-written paper. We concur with the conclusion that patients receiving targeted therapies are made more susceptible to developing viral infections than those receiving conventional treatment. However, we would like to draw attention to some key points regarding the study following a thorough appraisal.To begin with, the retrospective nature of the study adds several unavoidable biases such as recollection bias and incorrect data retrieval, which may have been mitigated had the investigators included current cases at the time. The study is also limited in its single-centered scope making it difficult to generalize the findings to this particular pediatric demographic. Moreover, the comparison between the two subsets of brain tumor patients is also subject to several partialities. For instance, it is noted that those receiving targeted therapies were managed in an outpatient setting and by extension, exposed to greater environmental stressors than those being managed on conventional chemotherapy. As a result, a greater proportion of virological infections were reported in children receiving targeted therapy than those being managed conventionally. Further, due to the lack of available data correlating disease severity with treatment option, the possibility that patients receiving conventional chemotherapy simply had a lower disease grade than those on targeted therapies and vice versa exists. Knowing this is pertinent as the body’s ability to fight off infections is greatly influenced by the grade of cancer and hence degree of inflammation [2]. Next, it remains to be seen what the baseline nutritional status of the participants was as nutrition and metabolism are known to have a bearing on immune status and hence infectious susceptibility [3]. Finally, the deduction that patients treated with bevacizumab or mTOR (mechanistic target of rapamycin) inhibitors suffered more infections than those treated with other targeted therapeutic drugs cannot be made with certainty as not enough patients were treated with drugs other than bevacizumab or mTOR inhibitors for a fair and accurate comparison.In conclusion, multi-centered prospective studies are required to better lay claims regarding infectious outcomes and attention to potential influencers of immunity must be given to minimize bias in future studies.

Post-transplant lymphoproliferative disorder (PTLD) is a significant complication of solid organ transplantation due to the lifelong immunosuppression (IS), ranging from non-malignant lymphoproliferations to lymphomas. Plasmablastic lymphoma (PBL), a rare and aggressive lymphoma, usually presenting in immunocompromised individuals has been rarely reported in the post-transplant setting. Here we summarize the clinical and pathological features of two children with PBL and history of solid organ transplant.

The low incidence of vincristine-induced peripheral neuropathy (VIPN) in Kenyan children may result from low vincristine exposure. We performed a pharmacokinetically (PK) guided dose-escalation feasibility study of vincristine in Kenyan children (NCT05844670). Vincristine PK exposure was assessed with a previously developed nomogram. A 20% dose increase was recommended for participants with low exposure and no VIPN, hyperbilirubinemia or malnutrition. None of the fifteen participants developed VIPN. Low vincristine exposure was seen in only one participant: a dose increase was implemented without side-effects. Average vincristine exposure was high. In conclusion, the participants did not develop VIPN despite having high vincristine exposure.

The AYA gap for rhabdomyosarcomaSimone Hettmer1 and Lars H. Lindner2Division of Pediatric Hematology and Oncology, Department of Pediatric and Adolescent Medicine, University Medical Center Freiburg, University of Freiburg, Freiburg, Germany.Department of Medicine III, LMU University Hospital, LMU Munich, Marchioninistr. 15, 81377, Munich, Germany.To whom correspondence should be addressed. Email: [email protected]. Phone: +49 761 270-45140; Fax: +49 761 270-4518Cancer is the leading cause of death among adolescents and young adults (AYAs). Cancers diagnosed during the AYA period - defined by the National Cancer Institute as the age from 15 to 39 years - account for approximately 5% of all cancers [1]. As per the national report on the status of cancer (study period 2015-2019, [1]), 5-year relative survival rates for both children and AYAs suffering from cancer are high (85.1% for children and 85.8% for AYAs), and improvements in survival over time appear to be similar for both age groups [1]. Yet, the spectrum of cancer types diagnosed in AYAs varies widely. The most common malignancies are female breast cancer (15%), thyroid cancer (15%), testicular cancer (8%) and melanomas (7%) [1], but AYAs may also suffer from so-called pediatric cancers with peak incidence during childhood. When compared to their childhood counterparts, worse outcomes were reported for AYAs diagnosed with pediatric cancers, including but not limited to leukemias [2] and sarcomas [3]. This „AYA gap“ is of concern to both pediatric and adult oncologists.The accompanying paper by Harrison et al examines a cohort of 2151 patients with rhabdomyosarcomas (RMS) enrolled in consecutive Children’s Oncology Group (COG) trials, including 19% AYAs aged 15-39 years and 81% children aged 0-14 years [4]. Compared to children with RMS, AYAs experienced significantly lower 5-year event-free survival (EFS; 44% vs. 67%) and 5-year overall survival (OS; 52% vs. 78%). These observations are in line with a recent retrospective analysis of nearly 2000 patients treated on European paediatric Soft Tissue Sarcoma Group (EpSSG) protocols [3]. Importantly, relative survival of AYAs with RMS treated on EpSSG and COG protocols appears to be better [3, 4] than the survival observed in epidemiological studies such as EUROCARE-5 (39,6% 5-year relative survival among RMS patients aged 15–19 years, and 36·4% for those aged 20–39 years; study period 2000-2007 [5]). Survival benefits for AYA patients treated on pediatric RMS protocols are consistent with previous observations in AYAs receiving treatment according to pediatric acute lymphoblastic leukemia (ALL) protocols [2] or at pediatric cancer centers/ sites with pediatric oncology expertise [6]. AYA cancer patients appear to benefit from chemotherapy dose intensities higher than what is generally prescribed to older patients. They may also draw advantages from pediatric standards with respect to planning of multimodal treatment and cancer staging. For example, the bone marrow (rarely ever involved in adult-type soft tissue sarcomas (STS)) is the most frequent site of metastases in AYAs with RMS treated within the COG cohort reported by Harrison et al [4] and should always be considered when planning pre-treatment examinations of AYAs with RMS. All taken together, adult oncology providers of AYA patients with RMS are well advised to consult their pediatric oncology colleagues and/ or consider referral to an institution with pediatric oncology expertise.AYA cancer patients treated on pediatric protocols – including those suffering from RMS - still experience worse outcomes than their pediatric counterparts [2]. There is ample evidence to support higher risk biology, more aggressive clinical phenotypes and higher rates of early treatment failures in AYAs diagnosed with pediatric cancers – including leukemias andsarcomas- compared to children diagnosed with the same malignancies [2-4]. For RMS tumors, higher rates of alveolar histology tumors and metastatic disease in AYAs were observed in the COG cohort reported here [4], as well as in the EpSSG and other retrospective studies [3, 7]. In addition to higher-risk disease manifestation, more frequent treatment-related toxicities and higher rates of withdrawal from treatment contribute to worse outcomes of AYAs compared to children with cancer [2]. There is a direct association between age and treatment-related deaths for patients undergoing ALL treatment on pediatric protocols [2]. Harrison et al do not comment on differences in treatment-related toxicities between children and AYAs with RMS, but higher rates of vincristine neurotoxicity, nausea and pain were previously reported in older adolescents undergoing RMS treatment on pediatric protocols. Even in the absence of higher-grade toxicities, a high burden of low-grade adverse events can have a major impact on the ability to function in daily life, continue education, maintain employment or participate in social activities. Many AYAs with cancer need to rely more on their parents/ support persons, which threatens their age-appropriate strive for autonomy and may result in them rebelling against treatment recommendations or failing to self- manage complex medication plans [8]. Active involvement of AYAs in the development of a care plan, which considers dignity, normalcy and family/ social relationships may improve compliance and, ultimately, treatment success.RMS is the most common STS in children and adolescents and often referred to as a pediatric cancer. Nevertheless, it occurs at any age, and up to 40% of all cases are diagnosed in adults (including seniors) [9]. The molecular and histological heterogeneity of pediatric RMS was studied intensively in recent years [10]. However, the insights provided by Harrison et al [4] and Ferrrai et al [3] emphasize that the remarkable diversity apparent across the RMS spectrum is multidimensional. Distinct clinical and biological characteristics of RMS diagnosed in different age groups deserve further attention. The two main pediatric RMS subtypes are embryonal and alveolar RMS, whereas pleomorphic RMS and RMS not otherwise specified are predominant in older adults and considered fundamentally different cancers [9]. To obtain a better understanding of RMS diagnosed in AYAs, future study efforts should aim at investigating the full spectrum of the disease and differentially consider the molecular underpinnings and therapeutic requirements of RMS diagnosed at opposite ends of the AYA age range.

Abstract: Introduction: Germ cell tumors (GCT) encompass a wide variety of neoplasms with varying clinical behavior dependent on histology, staging, and site. GCT remain relatively uncommon in the pediatric population and most patients have a favorable prognosis. However, the well-established co-occurrence of primary mediastinal GCT (PMGCT) and acute myeloid leukemia (AML) has a dismal prognosis with few reported patients achieving sustained remission. Case presentation: An 18 y.o. male was concurrently diagnosed with PMGCT and AML, type M7. Cytogenetic analysis revealed a complex set of chromosomal alterations along with homozygous deletion of TP53. His concurrent oncologic processes were managed with a variety of chemotherapy regimens, complete surgical resection of the mediastinal mass, and hematopoietic stem cell transplant (HSCT). He is one of few patients with concurrent PMGCT and AML able to achieve remission with no evidence of disease nearly 5 years after completion of treatment. Conclusion: The rare, but well-identified, association between PMGCT and concurrent or subsequent AML has a dismal prognosis. Modern genetics sequencing has identified common aberrations, including i(12p), trisomy/tetrasomy 8, TP53, and PTEN mutations. With this knowledge, it may allow for future tailoring of therapy to improve the predicted outcome of patients with PMGCT and AML.

Pure red cell aplasia (PRCA) is characterized by isolated anemia and a marked reduction or absence of erythroid precursors in the bone marrow. Depending on the underlying etiology, treatment may include immunomodulation or cytotoxic agents, chronic red blood cell transfusions, or hematopoietic stem cell transplantation. Parvovirus B19 infection is a well-recognized cause of transient PRCA, typically resolving with viral clearance. We report an unusual late relapse of PRCA occurring years after parvovirus B19 eradication, unresponsive to steroids and mycophenolate mofetil. Remarkably, prolonged treatment with intravenous immune globulin (IVIG) resulted in complete remission, highlighting its therapeutic utility for idiopathic PRCA.

Background: The outcome of extramedullary infiltration (EMI) in pediatric acute myeloid leukemia (AML) is controversial, and little is known about the implications of stem cell transplantation (SCT) and gemtuzumab ozogamicin (GO) treatment on AML patients with EMI. Methods: We retrieved the clinical data of 713 pediatric AML patients from the TARGET dataset and analyzed the clinical and prognostic characteristics of patients with EMI at initial diagnosis and relapse. Results: A total of 123 patients were identified to have EMI at initial diagnosis and 64 presented with EMI at relapse. We discovered that the presence of EMI was associated with age ≤2 years, M5 morphology, abnormal karyotype, and KMT2A rearrangements. Hyperleukocytosis and complex karyotype were more prevalent in EMI relapse patients. Additionally, patients with EMI at diagnosis showed a reduced incidence of FLT3 ITD-/NPM1+, whereas EMI relapse patients displayed a lower frequency of FLT3 ITD+. Patients with EMI at diagnosis exhibited a lower rate of CR1 and higher incidence of relapse. Importantly, EMI at diagnosis independently predicted both shorter EFS and OS. Regarding relapse patients, the occurrence of EMI at relapse showed no impact on OS. However, relapse patients with myeloid sarcoma exhibited a poorer OS compared to those with exclusive CNS involvement. Furthermore, in reference to patients with EMI at initial diagnosis, SCT failed to improve the survival, whereas GO treatment may potentially enhance OS. Conclusion: EMI at initial diagnosis is an independent prognostic risk factor, GO treatment has the potential to improve survival for patients with EMI at diagnosis.

Venetoclax use in Patient with Ataxia Telangiectasia and Early-T-Cell Precursor Acute Lymphoblastic LeukemiaShaikha Alqahtani1, Ramya Ramakrishnan1, Shuyu E2 , Sa A. Wang2, Cesar Nunez1, David McCall1, Miriam B., Garcia1, Michael E. Roth1, Branko Cuglievan1, Amber Gibson1Department of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USADepartment of Hematopathology, Division of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA

Background: Concomitant Wilms tumor (WT) and autosomal dominant polycystic kidney disease (ADPKD) is exceedingly rare, presenting a diagnostic and technical challenge to pediatric surgical oncologists. The simultaneous workup and management of these disease processes is incompletely described. Procedure: We performed a retrospective analysis of patients treated at our institution with concomitant diagnoses of WT and ADPKD. We also review the literature on the underlying biology and management principles of these conditions. Results: We present three diverse cases of concomitant unilateral WT and ADPKD who underwent nephrectomy. One patient had preoperative imaging consistent with ADPKD with confirmatory testing postoperatively, one was found to have contralateral renal cysts intraoperatively with confirmatory imaging post-nephrectomy, and one was diagnosed in childhood post-nephrectomy. All patients are alive at last follow-up, and the patient with longest follow-up has progressed to end-stage kidney failure requiring transplantation and dialysis in adulthood. All patients underwent germline testing and were found to have no cancer predisposition syndrome or pathogenic or likely-pathogenic variants for WT. Conclusion: Concomitant inheritance of ADPKD and development of WT is extremely rare, and manifestations of ADPKD may not present until late childhood or adulthood. ADPKD is not a known predisposing condition for WT. When ADPKD diagnosis is made by family history, imaging, and/or genetic testing before WT diagnosis and treatment, the need for extensive preoperative characterization of cystic kidney lesions in children and increased risk of post-nephrectomy kidney failure warrant further discussion of surgical approach and peri-operative management strategies.

Rhabdomyosarcoma (RMS) is a highly aggressive pediatric cancer known for its therapeutic challenges, particularly when it becomes metastatic or recurrent. Traditional treatment approaches have shown limited success, prompting a growing interest in targeted therapies. The emergence of next-generation sequencing (NGS) has revolutionized our ability to identify actionable mutations in RMS, offering the promise of personalized treatments and improved patient outcomes. A recent case involving a 3-year-old child diagnosed with embryonal RMS highlighted the potential of next-generation sequencing (NGS) in clinical practice. Despite receiving initial chemotherapy, the patient’s tumor showed progressive growth. What made this case particularly intriguing was the discovery of co-occurring somatic mutations in the RAS/MAPK pathway, specifically in BRAF and HRAS genes, which are traditionally believed to be mutually exclusive. Notably, the BRAF mutation identified in this case, N581I, is a non-classical (Class III) hotspot mutation that had not been previously reported in embryonal RMS. This novel finding underscores the critical importance of comprehensive genetic profiling in pediatric cancers and suggests the existence of potential therapeutic avenues that target BRAF alterations. In conclusion, the integration of NGS technologies in clinical practice holds great promise for identifying previously unrecognized mutations in pediatric cancers like RMS. These findings have the potential to open up new treatment options and improve outcomes for young patients facing this aggressive disease.

Hemangioblastomas are the most common tumor associated with Von Hippel-Lindau (VHL) and a leading cause of mortality. We present five pediatric patients with VHL-associated hemangioblastomas treated with belzutifan, a HIF2a inhibitor. Three patients were started on belzutifan due to vision loss from progressive retinal hemangioblastomas. Within 1 year of treatment, all three patients had improvement in hemangioblastoma size and visual acuity. For patients with intracranial lesions, belzutifan resulted in an improvement in neurologic symptoms and hemangioblastoma size. Four patients experienced grade 1-2 anemia and two patients required a dose reduction. Our report suggests that belzutifan can be an effective therapy for pediatric patients with VHL-associated hemangioblastomas.

Here, we describe two patients with juvenile xanthogranuloma (JXG) manifesting with Langerhans cell histiocytosis-associated neurodegenerative disease (ND)-like radiological findings. One patient showed typical radiological abnormalities at onset, which worsened with progressing central nervous system symptoms 7 years after LCH-oriented chemotherapy. Another showed spontaneous regression of clinical symptoms, with a transient radiological change 1 year after salvage chemotherapy for recurrence of JXG. These data regarding JXG-associated ND will facilitate future investigation of the disease, as well as development of therapeutic interventions.

Background: Hydroxyurea remains underutilized in the pediatric sickle cell population despite its well-known efficacy in decreasing sickle cell complications and hospitalizations. Access to refills and liquid formulation remains a critical barrier to adherence to hydroxyurea regimens. This study was undertaken to determine the clinical impact of home-delivering compounded liquid hydroxyurea (LHU) to pediatric patients with sickle cell disease. Procedure/Methods: A retrospective cohort study was conducted using electronic health records and pharmacy databases. Pediatric patients younger than 21 years of hydroxyurea initiation from March 2016 to July 2020 who received compounded LHU from Boston Medical Center Pharmacy were included. The primary outcomes of the study were drug adherence (assessed by evaluating the proportion of days covered), rates of acute care utilization, laboratory values, and growth metrics before and after enrolling in the LHU delivery program. Results: The final cohort included 41 patients. Significant increases in hemoglobin 0.34 g/dl (95% CI: 0.04-0.63, p=0.02) and mean corpuscular volume 3.2 FI (95% CI: 0.92-5.4, p=0.007) occurred. Hospitalizations decreased by 51.3% (p=0.01), and acute chest syndrome episodes decreased by 86.4% (p=0.02) post-initiation of the LHU delivery program. Drug adherence had a median value of 0.95 one-year post-initiation of LHU. Conclusions: Home delivery of compounded LHU improved drug adherence, decreased hospitalizations, and improved laboratory outcomes in pediatric patients with sickle cell disease by overcoming barriers to access. Nationwide implementation of similar home delivery programs can significantly improve outcomes among pediatric patients with sickle cell disease.

Background The last major North American cooperative group clinical trial for relapsed favorable histology Wilms tumor (FHWT) was completed in 2002. The outcomes of patients with relapsed Wilms tumor subsequently treated outside of clinical trials is unknown. The aim of this study was to assess the efficacy and toxicity of salvage therapies used for patients with FHWT suffering first relapse. Methods We conducted a retrospective chart review of patients treated for first relapse of FHWT at six large North American institutions from January 2002 through August 2018. Results Ninety-four patients were identified. Thirty-six patients were classified as standard-risk relapse (SRR), 49 patients as high-risk relapse (HRR) and seven patients as very high-risk relapse (VHRR). Twenty-one patients with SRR were treated with Regimen I. The 4-year EFS and OS for SRR was 82.4% and 93.3%, respectively, with median follow up of 72 months. Twenty-eight HRR/VHRR patients were treated with ICE therapy while 13 received NWTS5 Stratum C. No patient completed protocol therapy per stratum C; median maintenance cycles administered was 2. The 4-year EFS and OS for HRR/VHRR was 32.6% and 58.3%, respectively, with median follow up of 33 months. Conclusions Outcomes for all strata of relapsed WT patients treated in a non-clinical setting appear to have similar outcomes as historical cohorts treated on NWTS5. Improved strategies are urgently needed for HRR and VHRR relapses.

An 11-year-old boy with Lowe syndrome developed secondary sexual characteristics within a few weeks, suggestive of precocious puberty. His blood tests were positive for serum-human chorionic gonadotropin, and imaging revealed a right thymic lobe mass containing small cystic lesions. A germ cell tumor with malignant potential was suspected. Thus, we performed an extended thymectomy with mediastinal lymph node dissection and confirmed germinoma of the right thymic lobe without lymph node metastasis; the patient underwent four courses of chemotherapy. Follow-up evaluations indicated no recurrence. Thus, we present a highly rare case report of thymic germinoma complicated by Lowe syndrome.