Adeeb Oweidat MD, DESAIC, EDRA

Treatment for childhood solid tumors may lead to an increased risk for gonadal dysfunction/infertility. Discussion of risk should occur at diagnosis, any changes in therapy, and during survivorship. Gonadotoxic therapies were abstracted from 32 Children’s Oncology Group (COG) phase III, frontline solid tumor protocols, in use from 2000-2022. Risk for gonadal dysfunction/infertility was assessed based on gonadotoxic therapies, sex, and pubertal status and assigned as minimal, significant, and high following the Oncofertility Consortium Pediatric Initiative Network (PIN) risk stratification. Most protocols (65.6%, 21/32) contained at least one therapeutic arm with a high level of increased risk. Solid tumor therapies present challenges in risk stratification due to response-adjusted therapy and the need to account for radiation field in the risk assessment. This guide hopes to serve as a tool to assist in standardizing gonadotoxic risk assessments across disciplines and improve referral for fertility services and reproductive health counseling for patients receiving COG based solid tumor therapy.

OBJECTIVES In the etiology of childhood cancers, many genetic and environmental factors play a role. One of these factors is cigarette smoking and the main source of tobacco smoke exposure of children is parental smoking. However, establishing a causal relationship between parental smoking and childhood cancers has proven challenging due to difficulties in accurately detecting tobacco smoke exposure METHODS To address this issue, we used hair cotinine analysis and a questionnaire to get information about tobacco smoke exposures of pediatric cancer patients and healthy children. 104 pediatric cancer patients and 99 healthy children participated in our study. Parental smoking behaviours (pre-conceptional, during pregnancy and current smoking) and environmental tobacco smoke (ETS) exposures of children are compared. RESULTS We have found no differences between two groups by means of maternal smoking behaviours. However, the rates of paternal pre-conceptional smoking and smoking during pregnancy were significantly low in cancer patients (p<0,05). These data suggests that social desirability bias among fathers of cancer patients may have contributed to this discrepancy. According to questionnaire cancer patients had significantly lower ETS exposures than healthy children (p<0,05). However, ETS exposure assessment through cotinine analysis demonstrated that cancer patients had higher exposure to ETS compared to healthy children (p<0.001). CONCLUSION Our findings provide evidence supporting the potential role of smoking as a risk factor for childhood cancers. This study also revealed that questionnaires could cause biases. We suggest that cotinine analysis along with validated questionnaires can be used to prevent biases in studies of tobacco smoke in the etiology of childhood cancers.

Background: Recent data found a correlation between lymphopenia occurring early during craniospinal irradiation (CSI) and risk of disease recurrence in newly-diagnosed childhood medulloblastoma. 1 However, the population included patients that received myelosuppressive chemotherapy prior to or during RT. Here we investigate the effect of lymphopenia during RT in patients with newly-diagnosed pediatric medulloblastoma who did not receive myelosuppressive chemotherapy with RT. Procedure: We analyzed 54 patients with newly-diagnosed medulloblastoma (ages 2-21 years) treated between 1997-2013 with CSI. Log-rank tests were used to determine survival differences, and Cox proportional hazards regression was used to assess associations between patient characteristics and lymphopenia with disease recurrence risk. Results: 78% of patients (40/51) had grade ≥3 lymphopenia by RT week 3; 49% (23/47) improved to grade ≤2 lymphopenia by week 5. Similarly, the lowest median absolute lymphocyte count (ALC) occurred during RT week 3. Sixteen of 54 (30%) patients recurred an average of 30.2 months post-diagnosis. There was higher risk of disease recurrence in patients with grade ≥3 lymphopenia during weeks 4 (log-rank p=0.015; Cox p=0.03) and 5 (log-rank p=0.0009; Cox p=0.004) of RT. Recurrence-free survival was lower in patients with ALC Conclusions: Lymphopenia during RT weeks 4 and 5 correlates with increased risk of tumor recurrence in pediatric patients with newly-diagnosed medulloblastoma. Future studies should correlate baseline numbers of tumor-infiltrating lymphocytes with risks of lymphopenia during RT and tumor recurrence.

Background: There remains limited knowledge about the immune response to severe acute respiratory syndrome coronavirus 2 (SARS-COV2) vaccination in pediatric oncology patients, which is essential to provide counseling and risk adaptation in this vulnerable population. The goal of this study was to understand immunogenicity after vaccination in pediatric oncology patients and determine if certain clinical factors impacted response. Methods: Patients 0-25 years of age with a diagnosis of cancer and actively receiving therapy were enrolled on study. We excluded patients who were completely vaccinated prior to their cancer diagnosis. Blood samples were collected pre-vaccination, as well as 2, 4-6, and 8-12 weeks after vaccination. Healthy children who were fully vaccinated enrolled as controls. Clinical data and complete blood counts around time of vaccination were collected. To study B and T cell immunity, we measured neutralizing antibodies by enzyme-linked immunoassay and interferon gamma secretion by enzyme-linked immunospot, respectively. Results: 26 patients enrolled on study, for which 11 were evaluable oncology patients and 7 were healthy controls. Adequate B cell response was seen in 36.4% of patients and adequate T cell response in 77.8% of patients. Numbers were too small to detect differences based on malignancy type. There was no differences in immunity based on absolute lymphocyte count (ALC) or intensity of therapy. Conclusion: Pediatric oncology patients have a suboptimal immune response to SARS-COV2 vaccination. Booster doses will be imperative to provide optimal protection against COVID-19, however blood counts may not be a useful guide to optimize the time of administration.

Background and Objectives: Initially developed as immunosuppressive agents, mTOR inhibitors are currently used widely in the management of vascular malformations and tumors. The incidence of infectious complications in the vascular anomalies (VA) population is not well defined. The goal of this systematic review was to better define the types and severity of reported infectious complications in patients with VAs treated with mTOR inhibition. Methods: This was a systematic review conducted following PRISMA guidelines evaluating all research articles focused on infectious complications in patients with VAs treated with sirolimus or everolimus. Thirty articles including 1181 total patients and 315 infections (in 290 unique patients) were ultimately included. Results: The majority of infections were viral upper respiratory (n=137, 54%), followed by pneumonia (n=52, 20%), and cutaneous infections (n=20, 8%). There were 6 total infection-related fatalities, which all occurred in patients younger than 2 years. Only 1 case of Pneumocystis jirovecii pneumonia (PJP) was reported. This was in an infant with KHE who was also treated with steroids and did not receive PJP prophylaxis. Almost 1/3 (n=95, 32%) of infectious complications were graded 3 to 4 according to CTCAE criteria. Details of patient age, subtype of VA, and timing of infection were lacking from many reports. Conclusions: Most infectious complications reported in patients with VA on mTOR inhibitors were viral respiratory infections and non-severe. Bacteremia, infectious fatalities, and PJP are exceedingly rare. Future studies are needed to clarify the spectrum of infectious risks in VA patients and to provide guidance for infection prevention.

While the survival of children with cancer has improved over time, infection remains a major morbidity and mortality risk. We conducted a systematic literature review to determine the unmet needs in diagnosing infection in immunocompromised children with cancer. The comprehensive search strategy followed the guidelines established by the Cochrane Handbook for Systematic Reviews of Interventions and the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) 2020 statement and spanned multiple bibliographic databases and other public sources from January 1, 2012–June 23, 2022. From 5,188 records, 34 unique pediatric-focused studies met inclusion criteria. This review highlights the lack of published data on infectious disease testing in pediatric oncology patients and the need for well-designed clinical impact and cost-effectiveness studies of both existing and novel diagnostic platforms. Such studies are necessary to optimize diagnostic and antimicrobial stewardship, leading to improvement in patient outcomes.

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.

Monolobated Megakaryocytes in Diamond Blackfan Anemia withRPL5 Mutation at Disease Presentation Mimicking Myelodysplastic Syndrome

In March 2023, over 800 researchers, clinicians, patients, survivors, and advocates from the pediatric oncology community met to discuss the progress, plans, and future priorities of the National Cancer Institute’s Childhood Cancer Data Initiative. We present here the status of the initiative’s efforts in building its data ecosystem to provide access to childhood cancer data; updates on the Molecular Characterization Initiative; plans for implementing a Coordinated National Initiative for Rare Cancers in Children and Young Adults; and efforts to establish a framework for computable consent.

Background and Objectives: Kaposiform hemangioendothelioma (KHE) and tufted angioma (TA) are rare vascular tumors in children historically associated with significant morbidity and mortality. This study was conducted to determine first line therapy in the absence of available prospective clinical trials. Methods: Patients from 17 institutions diagnosed with KHE/TA between 2005-2020 with > 6 months follow-up were included. Response rates to sirolimus and vincristine were compared at 3 and 6 months. Durability of response and response to other treatment modalities were also evaluated. Results: Of 159 unique KHE/TA subjects, Kasabach-Merritt phenomenon (KMP) was present in 64 (40.3%) and only 2 patients were deceased (1.3%). Over 60% (n=96) demonstrated treatment response at 3 months and >70% (n=114) by 6 months (no significant difference across groups). The vincristine group had higher radiologic response at 3 months compared to sirolimus (72.7% vs 20%, p=0.03) but there was no differences between these groups at 6 months. There were no differences in rates of recurrent or progressive disease between vincristine and sirolimus. Conclusions: In this large, multicenter cohort of 159 patients with KHE/TA, rates of KMP were consistent with historical literature but the mortality rate (1.3%) was much lower. Overall treatment response rates were high (>70%) and there were no significant difference in treatment response or durability of disease comparing sirolimus to vincristine. Our results support individualized treatment decision plans depending on clinical scenario and patient/physician preferences. Response criteria and response rates reported here will be useful for guiding future treatment protocols for vascular tumors.

Rearrangements of the KMT2A gene are characteristic of infantile acute lymphoblastic leukemia (ALL) and are associated with increased lineage plasticity and resistance to therapy. Here, we describe the case of a 9-month-old infant with infantile ALL who experienced multiple immunophenotypic switches in her leukemia throughout therapy and ultimately achieved remission with the combination of CPX-351 and Inotuzumab. This case highlights the unique clinical challenges infantile ALL poses on monitoring therapeutic response with current methods of measuring minimal residual disease as well as the challenges in treating infantile B-ALL.

Background: While most research has largely focused on medical risks associated with reduced quality of life (QOL) in survivors, sociodemographic and family factors may also play a role. Thus, we examined sociodemographic factors and family factors associated with survivor QOL, including adolescent’s cancer-specific stress, mother’s general stress, and mother–adolescent communication. Methods: Mothers ( N=80) and survivors (ages 10-23, N=50) were assessed 5 years following initial diagnosis. Mothers completed measures regarding sociodemographic background adolescent’s cancer-specific stress, mother’s general stress, mother–adolescent communication, and adolescent QOL. Survivors also reported on their own QOL. Two hierarchical multiple regressions examined predictors of: (a) mother’s report of adolescent QOL and (b) survivor’s self-report of QOL. Results: The final model predicting mother-reported adolescent QOL was significant, F(5,74)=21.18, p<.001, and explained 59% of the variance in QOL. Significant predictors included adolescent stress ( β=-0.37, p<.001), mothers’ stress ( β=-0.42, p<.001), and communication ( β=0.19, p=.03). The final model predicting survivor-reported QOL was also significant, F(5,44)=5.16, p<.01 and explained 24% of the variance in QOL. Significant predictors included adolescent stress ( β=-.37, p=.01) and communication ( β=-.31, p=.04). Sociodemographic factors were not a significant predictor of QOL in any model. Conclusion: Family stress and communication offer potential points of intervention to improve QOL of pediatric cancer survivors from mother and survivor perspectives. While additional research is needed, healthcare professionals should encourage stress management and strong mother–child communication to enhance survivors’ long-term QOL. Such interventions may be helpful, irrespective of known sociodemographic factors that often affect health.

A document by Paul Meyers. Click on the document to view its contents.

Introduction: The risk of relapse in retinoblastoma is currently determined by the presence of high-risk histopathologic factors in the enucleated eye. However, the probability of developing metastatic disease is heterogeneous among these patients. Evaluating a biological marker to identify high-risk patients could be useful in clinical setting. This study aims to evaluate whether the expression of TFF1, a surrogate for subtype 2 retinoblastoma, is a prognostic marker for relapse and death. Methods: This multicenter cohort study included 273 patients, 48 of whom had extraocular disease. Immunohistochemical staining were performed for CRX, ARR3, TFF1 and Ki67. Tumors were classified as histological subtype 1 (HS1) if they had low or no expression of TFF1 (quick score (QS) ≤ 50) and as histological subtype 2 (HS2) if they expressed TFF1 diffusely (QS > 50). We studied the association between HS classification and outcome. Results: Of 273 patients, 35.9% were classified as HS1, 59.3% as HS2 and 4.8% were not evaluable. In multivariate analysis, patients with HS2 tumors had a higher probability of relapse and death than those with HS1 ( P < 0.0001 and P = 0.00020, respectively). We identified a higher-risk subgroup among HS2 tumors, presenting non-mutually exclusive expression of ARR3 and TFF1 and had an increased risk of relapse and death compared to tumors that displayed mutually exclusive expression ( P = 0.012 and P = 0.027, respectively). Conclusions: Expression of TFF1, especially when it is not-mutually exclusive with ARR3, is an independent prognostic marker of poor outcome in retinoblastoma.

Standard management of pediatric Non-Hodgkin’s Lymphoma (NHL) patients have included an initial assessment of the disease at presentation to establish it’s extent. This “staging” process has historically assigned patients using traditional classifications which were established decades ago when, like other pediatric malignancies, the more extensive involvement of the cancer for a patient directly correlated with the patient’s long term survival[[1]](#ref-0001). Advances in radiologic technology have evolved in the way the disease extent was evaluated, moving from conventional radiographs, to computerized tomography (CT) to magnetic resonance imaging (MRI) to most recently positron emission tomography (PET)[[2]](#ref-0002). Despite the development and use of PET scans for decades for various cancer diagnoses, the role of PET scans for NHL remains unclear[[3]](#ref-0003). Indeed, its value for many conditions is its ability to assess the response to initial therapy and establish the patient’s risk stratification guiding the remaining treatment plan[[4]](#ref-0004). Such efforts have not occurred in clinical trials of NHL and thus we are left to examine case series and try to discern its value for this disease.

Purpose Phase 1 study assessing the safety and toxicity of cabozantinib in combination with topotecan and cyclophosphamide for relapsed osteosarcoma and Ewing sarcoma. Methods Oral cabozantinib (25mg/m 2) was administered daily for 21 (dose level 1) or 14 (dose level -1B) days. Topotecan (0.75mg/m 2) and cyclophosphamide (250mg/m 2) were administered IV on days 1-5. A modified 3+3 design based upon first cycle dose-limiting toxicities (DLT) was used for dose escalation. Results Twelve patients with a median age of 15 (12.9-33.2) years were enrolled (7 with Ewing sarcoma; 5 with osteosarcoma); all were evaluable for toxicity. At dose level 1, three of six patients developed first cycle DLT: grade 3 epistaxis; grade 3 transaminitis; prolonged grade 2 thrombocytopenia. Six patients were enrolled on dose level -1B (interrupted cabozantinib, given days 8-21), with one first cycle DLT (grade 3 pneumothorax) observed. Of the 10 response evaluable patients, one had partial response (Ewing sarcoma), seven had stable disease, and two had progressive disease. Conclusions The recommended phase 2 doses and schedules for this combination are topotecan 0.75mg/m 2 IV days 1-5, cyclophosphamide 250mg/m 2 IV days 1-5, and cabozantinib 25mg/m 2 days 8-21. Non-concomitant administration of cabozantinib with cytotoxic therapy in this population has acceptable toxicity while allowing for potential disease control.

PARANEOPLASTIC JUVENILE IDIOPATHIC ARTHRITIS AS A MANIFESTATION OF A BENIGN TERATOMA IN A FIVE-YEAR-OLD GIRL