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In Figure S2 iron oxide nanoparticle distribution corresponds with TAM distribution on histopathology. (A) Prussian blue stain (blue) of a bone sarcoma shows similar iron distribution and co-localization with (B) CD68 and (C) CD163 macrophage stains (brown), indicating intracytoplasmatic iron within macrophages. Scale bars, 100µm.

Purpose: Tumor-associated macrophages (TAMs) in malignant tumors have been linked to tumor aggressiveness and represent a new target for cancer immunotherapy. As new TAM-targeted immunotherapies are entering clinical trials, it is important to detect and quantify TAM with noninvasive imaging techniques. The purpose of this study was to determine if ferumoxytol-enhanced MRI can detect TAM in lymphomas and bone sarcomas of pediatric patients and young adults.Experimental Design: In a first-in-patient, Institutional Review Board–approved prospective clinical trial, 25 pediatric and young adult patients with lymphoma or bone sarcoma underwent ferumoxytol-enhanced MRI. To confirm ferumoxytol enhancement, five pilot patients (two lymphoma and three bone sarcoma) underwent pre- and postcontrast MRI. Subsequently, 20 patients (10 lymphoma and 10 bone sarcoma) underwent ferumoxytol-enhanced MRI 24 to 48 hours after i.v. injection, followed by tumor biopsy/resection and macrophage staining. To determine if ferumoxytol-MRI can differentiate tumors with different TAM content, we compared T2* relaxation times of lymphomas and bone sarcomas. Tumor T2* values of 20 patients were correlated with CD68+ and CD163+ TAM quantities on histopathology.Results: Significant ferumoxytol tumor enhancement was noted on postcontrast scans compared with precontrast scans (P = 0.036). Bone sarcomas and lymphomas demonstrated significantly different MRI enhancement and TAM density (P < 0.05). Within each tumor group, T2* signal enhancement on MR images correlated significantly with the density of CD68+ and CD163+ TAM (P < 0.05).Conclusions: Ferumoxytol-enhanced MRI is immediately clinically applicable and could be used to stratify patients with TAM-rich tumors to immune-targeted therapies and to monitor tumor response to these therapies. Clin Cancer Res; 24(17); 4110–8. ©2018 AACR.

Objective To investigate in a large global sample of patients with retinoblastoma whether sex predilection exists for this childhood eye cancer. Methods A cross-sectional analysis including 4351 treatment-naive retinoblastoma patients from 153 countries who presented to 278 treatment centers across the world in 2017. The sex ratio (male/female) in the sample was compared to the sex ratio at birth by means of a two-sided proportions test at global level, country economic grouping, continent, and for selected countries. Results For the entire sample, the mean retinoblastoma sex ratio, 1.20, was higher than the weighted global sex ratio at birth, 1.07 (p n = 1940), 1.23 vs. 1.07 (p = 0.019); Asia (n = 2276), 1.28 vs. 1.06 (p n = 558), 1.52 vs. 1.11 (p = 0.008). Sensitivity analysis, excluding data from India, showed that differences remained significant for the remaining sample (χ2 = 6.925, corrected p = 0.025) and for Asia (χ2 = 5.084, corrected p = 0.036). Excluding data from Asia, differences for the remaining sample were nonsignificant (χ2 = 2.205, p = 0.14). Conclusions No proof of sex predilection in retinoblastoma was found in the present study, which is estimated to include over half of new retinoblastoma patients worldwide in 2017. A high male to female ratio in Asian countries, India in specific, which may have had an impact on global-level analysis, is likely due to gender discrimination in access to care in these countries, rather than a biological difference between sexes.

PURPOSE Brentuximab vedotin, an effective anti-CD30 antibody-drug conjugate approved for use in adults with classical Hodgkin lymphoma (HL), was introduced in this frontline trial to reduce prescribed radiation in children and adolescents with classical HL. METHODS Open-label, single-arm, multicenter trial for patients (age ≤ 18 years) with stage IIB, IIIB, or IV classical HL was conducted. Brentuximab vedotin replaced each vincristine in the OEPA/COPDac (vincristine, etoposide, prednisone, and doxorubicin/cyclophosphamide, vincristine, prednisone, and dacarbazine) regimen according to GPOH-HD2002 treatment group 3 (TG3); two cycles of AEPA and four cycles of CAPDac. Residual node radiotherapy (25.5 Gy) was given at the end of all chemotherapy only to nodal sites that did not achieve a complete response (CR) at the early response assessment (ERA) after two cycles of therapy. Primary objectives were to evaluate the safety and efficacy (complete remission at ERA) of this combination and the 3-year event-free (EFS) and overall survival (OS). The trials are registered at ClinicalTrials.gov (identifier: NCT01920932 ). RESULTS Of the 77 patients enrolled in the study, 27 (35%) achieved complete remission at ERA and were spared radiation. Patients who were irradiated received radiation to individual residual nodal tissue. At a median follow-up of 3.4 years, the 3-year EFS was 97.4% (SE 2.3%) and the OS was 98.7% (SE 1.6%). One irradiated patient experienced disease progression at the end of therapy and now remains disease free more than 6 years following salvage therapy, and one unexpected death occurred. Only 4% of patients experienced grade 3 neuropathy. CONCLUSION The integration of brentuximab vedotin in the frontline treatment of pediatric high-risk HL is highly tolerable, facilitated significant reduction in radiation exposure, and yielded excellent outcomes.

The detection of tumor-specific nucleic acids from blood increasingly is being used as a method of liquid biopsy and minimal residual disease detection. However, achieving high sensitivity and high specificity remains a challenge. Here, we perform a direct comparison of two droplet digital PCR (ddPCR)-based detection methods, circulating plasma tumor RNA and circulating plasma tumor DNA (ptDNA), in blood samples from newly diagnosed Ewing sarcoma patients. First, we developed three specific ddPCR-based assays to detect EWS-FLI1 or EWS-ERG fusion transcripts, which naturally showed superior sensitivity to DNA detection on in vitro control samples. Next, we identified the patient-specific EWS-FLI1 or EWS-ERG breakpoint from five patient tumor samples and designed ddPCR-based, patient-specific ptDNA assays for each patient. These patient-specific assays show that although plasma tumor RNA can be detected in select newly diagnosed patients, positive results are low and statistically unreliable compared with ptDNA assays, which reproducibly detect robust positive results across most patients. Furthermore, the unique disease biology of Ewing sarcoma enabled us to show that most cell-free RNA is not tumor-derived, although cell-free-DNA burden is affected strongly by tumor-derived DNA burden. Here, we conclude that, even with optimized highly sensitive and specific assays, tumor DNA detection is superior to RNA detection in Ewing sarcoma patients.

Previous studies have shown that children and adolescents with COVID-19 generally have mild disease. Children and adolescents with cancer, however, can have severe disease when infected with respiratory viruses. In this study, we aimed to understand the clinical course and outcomes of SARS-CoV-2 infection in children and adolescents with cancer.We did a cohort study with data from 131 institutions in 45 countries. We created the Global Registry of COVID-19 in Childhood Cancer to capture de-identified data pertaining to laboratory-confirmed SARS-CoV-2 infections in children and adolescents (19 years) with cancer or having received a haematopoietic stem-cell transplantation. There were no centre-specific exclusion criteria. The registry was disseminated through professional networks through email and conferences and health-care providers were invited to submit all qualifying cases. Data for demographics, oncological diagnosis, clinical course, and cancer therapy details were collected. Primary outcomes were disease severity and modification to cancer-directed therapy. The registry remains open to data collection.Of 1520 submitted episodes, 1500 patients were included in the study between April 15, 2020, and Feb 1, 2021. 1319 patients had complete 30-day follow-up. 259 (19·9%) of 1301 patients had a severe or critical infection, and 50 (3·8%) of 1319 died with the cause attributed to COVID-19 infection. Modifications to cancer-directed therapy occurred in 609 (55·8%) of 1092 patients receiving active oncological treatment. Multivariable analysis revealed several factors associated with severe or critical illness, including World Bank low-income or lower-middle-income (odds ratio [OR] 5·8 [95% CI 3·8-8·8]; p0·0001) and upper-middle-income (1·6 [1·2-2·2]; p=0·0024) country status; age 15-18 years (1·6 [1·1-2·2]; p=0·013); absolute lymphocyte count of 300 or less cells per mmIn this global cohort of children and adolescents with cancer and COVID-19, severe and critical illness occurred in one fifth of patients and deaths occurred in a higher proportion than is reported in the literature in the general paediatric population. Additionally, we found that variables associated with treatment modification were not the same as those associated with greater disease severity. These data could inform clinical practice guidelines and raise awareness globally that children and adolescents with cancer are at high-risk of developing severe COVID-19 illness.American Lebanese Syrian Associated Charities and the National Cancer Institute.

The ongoing coronavirus 2019 disease (COVID-19) pandemic strained medical systems worldwide. We report on the impact on pediatric oncology care in Latin American (LATAM) during its first year.Four cross-sectional surveys were electronically distributed among pediatric onco-hematologists in April/June/October 2020, and April/2021 through the Latin American Society of Pediatric Oncology (SLAOP) email list and St Jude Global regional partners.Four hundred fifty-three pediatric onco-hematologists from 20 countries responded to the first survey, with subsequent surveys response rates above 85%. More than 95% of participants reported that treatment continued without interruption for new and active ongoing patients, though with disruptions in treatment availability. During the first three surveys, respondents reported suspensions of outpatient procedures (54.2%), a decrease in oncologic surgeries (43.6%), radiotherapy (28.4%), stem cell transplants (SCT) (69.3%), and surveillance consultations (81.2%). Logistic regression analysis showed that at the beginning of the first wave, participants from countries with healthcare expenditure below 7% were more likely to report a decrease in outpatient procedures (odds ratio [OR]: 1.84, 95% CI: 1.19-2.8), surgeries (OR: 3, 95% CI: 1.9-4.6) and radiotherapy (OR: 6, 95% CI: 3.5-10.4). Suspension of surveillance consultations was higher in countries with COVID-19 case fatality rates above 2% (OR: 3, 95% CI: 1.4-6.2) and SCT suspensions in countries with COVID-19 incidence rate above 100 cases per 100,000 (OR: 3.48, 95% CI: 1.6-7.45). Paradoxically, at the beginning of the second wave with COVID-19 cases rising exponentially, most participants reported improvements in cancer services availability.Our data show the medium-term collateral effects of the pandemic on pediatric oncology care in LATAM, which might help delineate oncology care delivery amid current and future challenges posed by the pandemic.

Wilms tumour (WT) is a childhood embryonal tumour that is paradigmatic of the intersection between disrupted organogenesis and tumorigenesis. Many WT genes play a critical (non-redundant) role in early nephrogenesis. Improving patient outcomes requires advances in understanding and targeting of the multiple genes and cellular control pathways now identified as active in WT development. Decades of clinical and basic research have helped to gradually optimize clinical care. Curative therapy is achievable in 90% of affected children, even those with disseminated disease, yet survival disparities within and between countries exist and deserve commitment to change. Updated epidemiological studies have also provided novel insights into global incidence variations. Introduction of biology-driven approaches to risk stratification and new drug development has been slower in WT than in other childhood tumours. Current prognostic classification for children with WT is grounded in clinical and pathological findings and in dedicated protocols on molecular alterations. Treatment includes conventional cytotoxic chemotherapy and surgery, and radiation therapy in some cases. Advanced imaging to capture tumour composition, optimizing irradiation techniques to reduce target volumes, and evaluation of newer surgical procedures are key areas for future research.

PURPOSE Treatment abandonment because of enucleation refusal is a limitation of improving outcomes for children with retinoblastoma in countries with limited resources. Furthermore, many children present with buphthalmos and a high risk of globe rupture during enucleation. To address these unique circumstances, the AHOPCA II protocol introduced neoadjuvant chemotherapy with delayed enucleation. PATIENTS AND METHODS Patients with advanced unilateral intraocular disease (International Retinoblastoma Staging System [IRSS] stage I) were considered for upfront enucleation. Those with diffuse invasion of the choroid, postlaminar optic nerve, and/or anterior chamber invasion received six cycles of adjuvant chemotherapy (vincristine, carboplatin, and etoposide). Patients with buphthalmos and those with a perceived risk for enucleation refusal and/or abandonment were given two to three cycles of chemotherapy before scheduled enucleation followed by adjuvant chemotherapy to complete six cycles, regardless of pathology. RESULTS A total of 161 patients had unilateral IRSS stage I disease; 102 underwent upfront enucleation, and 59 had delayed enucleation. The estimated 5-year abandonment-sensitive event-free and overall survival rates for the group were 0.81 ± 0.03 and 0.86 ± 0.03, respectively. The 5-year estimated abandonment-sensitive event-free survival rates for patients undergoing upfront and delayed enucleation were 0.89 ± 0.03 and 0.68 ± 0.06, respectively ( P = .001). Compared with AHOPCA I, abandonment for patients with IRSS stage I retinoblastoma decreased from 16% to 4%. CONCLUSION AHOPCA describes the results of advanced intraocular retinoblastoma treated with neoadjuvant chemotherapy. In eyes with buphthalmos and patients with risk of abandonment, neoadjuvant chemotherapy can be effective when followed by enucleation and adjuvant chemotherapy. Our study suggests that this approach can save patients with buphthalmos from ocular rupture and might reduce refusal of enucleation and abandonment.

Ewing sarcoma (ES) is the second most common bone cancer in children, accounting for 2% of pediatric cancer diagnoses. Patients who present with metastatic disease at the time of diagnosis have a dismal prognosis, compared to the >70% 5-year survival of those with localized disease. Here, we utilized single-cell RNA sequencing (scRNA-seq) to characterize the transcriptional landscape of primary ES tumors, and to identify circulating tumor cells (CTCs) in peripheral blood at the time of diagnosis in order to further understand ES transcriptional heterogeneity and factors that drive metastasis. Methods: Viably frozen primary tumor and peripheral blood samples were obtained from 7 ES patients at the time of diagnosis and prior to the initiation of treatment. Tumors were dissociated into a single cell suspension and sorted for viability using FACS (fluorescence activated cell sorting) whereas peripheral blood samples were subjected to a size-based selection with the CellSieve microfiltration system. ScRNA-seq was performed using the 10xChromium platform and count matrices were generated using 10x Genomics Cell Ranger software. Quality control, integration, and cluster analysis was performed with Seurat. Results: Cluster analysis of integrated, primary tumor samples demonstrated that candidate ES cell clusters express FLI1 and ES marker NKX2-2 and cluster separately from immune cell populations. Additionally, using inferCNV, ES clusters were demonstrated to harbor chromosomal copy number alterations known to be associated with ES and that were previously identified clinically on preliminary pathology reports for each patient; further GSEA analysis showed significant overlap between published ES gene sets and genes upregulated in ES clusters. Further analysis of ES cells demonstrated that cell-cycle phase determined a cluster enriched in pro-proliferation gene signatures, and overall heterogeneity of expression of previously known therapeutic targets. Candidate ES CTCs were identified among the peripheral blood samples among clusters which corresponded with distinct immune cell populations. The candidate ES CTCs expressed NKX2-2 and demonstrated enrichment in oncogenic gene signatures. Conclusion: ScRNA-seq of primary ES tumors is feasible and demonstrates that ES tumor cells are largely homogeneous in nature; and candidate ES CTCs can be identified in peripheral blood at the time of diagnosis in ES patient and warrant further investigation as to their utility as a biomarker of metastatic disease. Citation Format: Sarah K. Nelson-Taylor, Avery Bodlack, Andrew Goodspeed, Amy Treece, Nathan Donaldson, Carrye Cost, Tim Garrington, Brian Greffe, Sandra Luna-Fineman, Jenna Sopfe, Masanori Hayashi. Single cell RNA sequencing of primary Ewing sarcoma tumors and identification of circulating tumor cells in patient-matched peripheral blood samples [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1681.

10046 Background: Retinoblastoma (RB) is the most common tumor of the eye in childhood. Intraocular RB cure rates approach 100%. Therefore, treatment now focuses on globe salvage preserving functional vision. The Research Into Visual Endpoints and RB Health Outcomes After Treatment (RIVERBOAT) consortium was established to examine patient health outcomes, including vision, in the contemporary therapy era. Methods: Patients with RB treated at consortium centers from 2007 to present were identified. Medical record abstraction was performed for disease presentation, treatment, and outcomes. A subset of the patients returned to centers and completed functional vision questionnaires (Child Vision Function Questionnaire - ages 0 – 7 and Cardiff Visual Ability Questionnaire for Children - ages > 8) and had visual acuity assessed. For participants who could not yet return for a study evaluation, medical record abstraction alone was performed. Results: Among 463 participants enrolled to date, 270 (58%) had unilateral disease. One patient with metastatic RB did not survive, resulting in overall survival of 99.6. There was one case of secondary leukemia. The eye group distribution (International Intraocular Retinoblastoma Classification) was 0.4% A, 5.6% B, 7.0% C, 36.0% D, 49.0% E and 2.0% not classified. 131 (49%) patients underwent primary enucleation and are not included in further analyses. Among the remaining 139 patients, 3% were treated with local ophthalmic therapy only, 22% with intravenous chemotherapy (IV) only, 53% with intra-arterial chemotherapy (IAC) only, 22% with IV and IAC, and 35% required secondary enucleation. Globe salvage after chemotherapy was successful in 100% A, 93% B, 82% C, 72% D, and 48% E eyes. This salvage was achieved with IV only, IAC only, or both in 22%, 58% and 20% respectively. The mean percentage of patients receiving IAC per year increased from 13% (2008 – 2013) to 21% (2014 – 2017) to 28% (2018 – 2022). In 29 patients without enucleation who reported functional vision to date, the mean scores (survey theoretical ranges) were 0.72 for < 3 years (0.57 to 0.87), 0.82 for 3 -7 years (0.56 to 0.94) and -2.72 for > 8 years (-2.53 to -0.51), all considered good functional vision. In 20 of these 29 patients, 4 eyes had normal vision (20/20-20/40) across A to D groups. Moderate vision loss (> 20/40 – 20/70) was noted in 3 D eyes and low vision (> 20/70 - < 20/200) in 1 D eye. Twelve B through E eyes met criteria for a legally blind eye (>20/200). Conclusions: In this cohort of RB patients with unilateral disease treated from 2007 - 2022, 66% required primary or secondary enucleation. Among 29 patients with globe salvage, self-reported functional vision was good, but 12 eyes in 20 of the patients were legally blind. IAC only or IV plus IAC was most used in those who avoided secondary enucleation. With ongoing cohort accrual and increased IAC use, it will remain to be determined if globe salvage with functional vision will improve.

10045 Background: Retinoblastoma (RB) is the most common tumor of the eye in childhood. Intraocular RB cure rates approach 100%. Therefore, treatment advances have focused on globe salvage preserving functional vision. The Research Into Visual Endpoints and RB Health Outcomes After Treatment (RIVERBOAT) consortium was established to examine patient health outcomes, including vision, in the contemporary therapy era. Methods: Patients with RB treated at consortium centers from 2007 to the present were identified. Medical record abstraction was performed for disease presentation, treatment, and outcomes. A subset of the patients returned to centers and completed functional vision questionnaires (Child Vision Function Questionnaire for ages 0 – 7 and Cardiff Visual Ability Questionnaire for Children for ages >8) and had visual acuity assessed. For participants who could not yet return for a study evaluation, medical record abstraction alone was performed. Results: Among 463 participants enrolled to date, 193 (42%) had bilateral disease. Two each had metastatic RB, trilateral RB, and secondary osteosarcoma. One patient each with metastatic RB and trilateral RB is deceased, with overall survival for the cohort of 99%. The eye group distribution (International Intraocular Retinoblastoma Classification) was 14% A, 22% B, 14% C, 28% D, 19% E and 3% not classified. Primary enucleation was performed in 43 (22%), secondary enucleation in 48 (25%) and bilateral enucleation in 1(0.5%). Intravenous chemotherapy (IV) alone was administered in 58%, intra-arterial chemotherapy (IAC) alone in 4%, with 31% receiving both. Among 145 patients who did not require secondary or bilateral enucleation, the distribution was 16% A, 21% B, 16% C, 28% D, 15% E, and 4% non-classified eyes. This salvage was achieved with IV alone, IAC alone, or both in 55%, 5% and 30% respectively and with ophthalmic therapy only in 10%. The mean percentage of patients receiving IAC per year increased from 6% in 2008 – 2013 to 11% in 2014 – 2022 and was stable at 11% in 2018 – 2022. Among 53 patients who have reported functional vision to date, the mean scores were 0.81 for < 3 years 0.80 for 3-7 years and -1.31 for those >8 years, all considered to be good functional vision. Among 50 eyes in 37 of these 53 patients, 33 had normal vision (20/20-20/40) across A to E groups. Moderate vision loss (> 20/40 – 20/70) was noted in 1 C and 1 B eye and low vision (> 20/70 - < 20/200) in 6 group B, C or D eyes. Nine B or D eyes were legally blind (>20/200). No patients had two legally blind eyes. Conclusions: In this cohort of RB patients with bilateral disease treated between 2007 and 2022, 52% have been successfully treated without enucleation. Self-reported functional vision in 53 of these patients with all group eyes was good. Only 6 of 50 eyes in 37 patients met criteria for legal blindness and 66% of eyes had normal vision. With cohort accrual ongoing, we will determine if these promising outcomes continue.

To investigate in a large global sample of patients with retinoblastoma whether sex predilection exists for this childhood eye cancer.A cross-sectional analysis including 4351 treatment-naive retinoblastoma patients from 153 countries who presented to 278 treatment centers across the world in 2017. The sex ratio (male/female) in the sample was compared to the sex ratio at birth by means of a two-sided proportions test at global level, country economic grouping, continent, and for selected countries.For the entire sample, the mean retinoblastoma sex ratio, 1.20, was higher than the weighted global sex ratio at birth, 1.07 (p 0.001). Analysis at economic grouping, continent, and country-level demonstrated differences in the sex ratio in the sample compared to the ratio at birth in lower-middle-income countries (n = 1940), 1.23 vs. 1.07 (p = 0.019); Asia (n = 2276), 1.28 vs. 1.06 (p 0.001); and India (n = 558), 1.52 vs. 1.11 (p = 0.008). Sensitivity analysis, excluding data from India, showed that differences remained significant for the remaining sample (χNo proof of sex predilection in retinoblastoma was found in the present study, which is estimated to include over half of new retinoblastoma patients worldwide in 2017. A high male to female ratio in Asian countries, India in specific, which may have had an impact on global-level analysis, is likely due to gender discrimination in access to care in these countries, rather than a biological difference between sexes.

Classic Hodgkin lymphoma (cHL) in young children (ages 0-6) is rare in high income countries (HICs) but is more prevalent in low- and middle-income countries (LMICs) like Guatemala. Given that the majority of cHL studies have evaluated adolescent/adults, and the immune system changes with age, we sought to characterize Epstein-Barr virus (EBV) expression, immune regulatory pathway markers and the tumor microenvironment in 42 children ages 0-6 with cHL from Guatemala. We found a very high frequency of EBV expression (97.5%). Hodgkin cells showed increased expression of PD1 ligands and CD137, indicative of shared immune regulatory mechanisms with adult cHL. Pediatric cHL also showed an increase in CD8+ tumor infiltrating lymphocytes and tumor associated macrophages within the tumor microenvironment. Despite 25 having high risk disease, only 4 patients died from progressive disease, relapse or infection.

Cancers arising from germline DNA mismatch-repair or polymerase-proofreading deficiencies (MMRD and PPD) in children harbour the highest mutational and microsatellite insertion/deletion (MS-indel) burden in humans and are lethal due to inherent resistance to chemo-irradiation. Although immune checkpoint inhibitors (ICI) have failed to benefit children in previous studies, we hypothesized that hypermutation caused by MMRD and PPD will improve outcomes following ICI in these patients. ICI treatment of 45 progressive/recurrent tumours from 38 patients revealed durable objective responses in the majority, culminating in 3-year survival of 41.4%. High mutation burden predicted response for ultra-hypermutant cancers (>100 mutations/Mb) enriched for combined MMRD+PPD, while MS-indels predicted response in MMRD tumours with lower mutation burden (10-100 mutations/Mb). Further, both mechanisms were associated with increased immune infiltration even in “immunologically-cold” tumours such as gliomas, contributing to the favorable response. Pseudo-progression (flare) was common and associated with immune activation in both the tumour microenvironment and systemically. Further, patients with flare continuing ICI treatment achieved durable responses. Our study demonstrates improved survival for patients with tumours not previously known to respond to ICI, including CNS and synchronous cancers, and identifies the dual roles of mutation burden and MS-indels in predicting sustained responses to immunotherapy.

Cancers arising from germline DNA mismatch repair deficiency or polymerase proofreading deficiency (MMRD and PPD) in children harbour the highest mutational and microsatellite insertion–deletion (MS-indel) burden in humans. MMRD and PPD cancers are commonly lethal due to the inherent resistance to chemo-irradiation. Although immune checkpoint inhibitors (ICIs) have failed to benefit children in previous studies, we hypothesized that hypermutation caused by MMRD and PPD will improve outcomes following ICI treatment in these patients. Using an international consortium registry study, we report on the ICI treatment of 45 progressive or recurrent tumors from 38 patients. Durable objective responses were observed in most patients, culminating in a 3 year survival of 41.4%. High mutation burden predicted response for ultra-hypermutant cancers (>100 mutations per Mb) enriched for combined MMRD + PPD, while MS-indels predicted response in MMRD tumors with lower mutation burden (10–100 mutations per Mb). Furthermore, both mechanisms were associated with increased immune infiltration even in ‘immunologically cold’ tumors such as gliomas, contributing to the favorable response. Pseudo-progression (flare) was common and was associated with immune activation in the tumor microenvironment and systemically. Furthermore, patients with flare who continued ICI treatment achieved durable responses. This study demonstrates improved survival for patients with tumors not previously known to respond to ICI treatment, including central nervous system and synchronous cancers, and identifies the dual roles of mutation burden and MS-indels in predicting sustained response to immunotherapy., Hypermutation and microsatellite burden determine responses and long-term survival following PD-1 blockade in children and young adults with refractory cancers resulting from germline DNA replication repair deficiency.

The COVID-19 pandemic quickly led to an abundance of publications and recommendations, despite a paucity of information on how COVID-19 affects children with cancer. This created a dire need for a trusted resource with curated information and a space for the pediatric oncology community to share experiences. The Global COVID-19 Observatory and Resource Center for Childhood Cancer was developed, launched, and maintained by the International Society of Pediatric Oncology and St. Jude Children's Research Hospital. The three components (Resource Library, Global Registry, and Collaboration Space) complement each other, establishing a mechanism to generate and transfer knowledge rapidly throughout the community. Fil: Moreira, Daniel C.. St. Jude Children's Research Hospital; Estados Unidos Fil: Sniderman, Elizabeth. St. Jude Children's Research Hospital; Estados Unidos Fil: Mukkada, Sheena. St. Jude Children's Research Hospital; Estados Unidos Fil: Chantada, Guillermo Luis. Universidad Austral. Facultad de Ciencias Biomédicas. Instituto de Investigaciones en Medicina Traslacional. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones en Medicina Traslacional; Argentina Fil: Bhakta, Nickhill. St. Jude Children's Research Hospital; Estados Unidos Fil: Foster, Whitney. St. Jude Children's Research Hospital; Estados Unidos Fil: Avula, Meghana. St. Jude Children's Research Hospital; Estados Unidos Fil: Homsi, Maysam R.. St. Jude Children's Research Hospital; Estados Unidos Fil: Faughnan, Lane. St. Jude Children's Research Hospital; Estados Unidos Fil: Happ, Brooke. St. Jude Children's Research Hospital; Estados Unidos Fil: Andujar, Allyson. St. Jude Children's Research Hospital; Estados Unidos Fil: Sonnenfelt, Jason. St. Jude Children's Research Hospital; Estados Unidos Fil: Dalvi, Rashmi. Bombay Hospital And Medical Research Centre; India Fil: Frazier, A. Lindsay. No especifíca; Fil: Hessissen, Laila. Universite Mohammed V. Rabat; Otros paises de África Fil: Kearns, Pamela R.. No especifíca; Fil: Luna Fineman, Sandra. No especifíca; Fil: Moreno, Arturo. Hospital Universitario de Puebla; México Fil: Saghir Khan, Muhammad. No especifíca; Fil: Sullivan, Michael. Royal Children's Hospital, Melbourne; Australia Fil: Devidas, Meenakshi. St. Jude Children's Research Hospital; Estados Unidos Fil: Santana, Victor. St. Jude Children's Research Hospital; Estados Unidos Fil: Caniza, Miguela. St. Jude Children's Research Hospital; Estados Unidos Fil: Pritchard Jones, Kathy. University College London; Estados Unidos Fil: Rodriguez Galindo, Carlos. St. Jude Children's Research Hospital; Estados Unidos

The COVID-19 pandemic poses an unprecedented health crisis in all socio-economic regions across the globe. While the pandemic has had a profound impact on access to and delivery of health care by all services, it has been particularly disruptive for the care of patients with life-threatening noncommunicable diseases (NCDs) such as the treatment of children and young people with cancer. The reduction in child mortality from preventable causes over the last 50 years has seen childhood cancer emerge as a major unmet health care need. Whilst survival rates of 85% have been achieved in high income countries, this has not yet been translated into similar outcomes for children with cancer in resource-limited settings where survival averages 30%. Launched in 2018, by the World Health Organization (WHO), the Global Initiative for Childhood Cancer (GICC) is a pivotal effort by the international community to achieve at least 60% survival for children with cancer by 2030. The WHO GICC is already making an impact in many countries but the disruption of cancer care during the COVID-19 pandemic threatens to set back this global effort to improve the outcome for children with cancer, wherever they may live. As representatives of the global community committed to fostering the goals of the GICC, we applaud the WHO response to the COVID-19 pandemic, in particular we support the WHO's call to ensure the needs of patients with life threatening NCDs including cancer are not compromised during the pandemic. Here, as collaborative partners in the GICC, we highlight specific areas of focus that need to be addressed to ensure the immediate care of children and adolescents with cancer is not disrupted during the pandemic; and measures to sustain the development of cancer care so the long-term goals of the GICC are not lost during this global health crisis. Fil: Pritchard Jones, Kathy. University College London; Estados Unidos Fil: de Abib, Simone C.V.. International Society Of Paediatric Surgical Oncology; Surinam. Universidade Federal de Sao Paulo; Brasil Fil: Esiashvili, Natia. University of Emory; Estados Unidos Fil: Kaspers, Gertjan J.L.. Princess Máxima Center for Pediatric Oncology; Países Bajos Fil: Rosser, Jon. No especifíca; Fil: van Doorninck, John A.. Rocky Mountain Hospital for Children; Estados Unidos Fil: Braganca, João M.L.. No especifíca; Fil: Hoffman, Ruth I.. No especifíca; Fil: Rodriguez Galindo, Carlos. St Jude Children’s Research Hospital; Estados Unidos Fil: Adams, Cary. Union for International Cancer Control; Suiza Fil: Connor, Stephen R.. Worldwide Hospice Palliative Care Alliance; Estados Unidos Fil: Abdelhafeez, Abdelhafeez H.. International Society of Paediatric Surgical Oncology; Suiza. St. Jude Children’s Research Hospital; Estados Unidos Fil: Bouffet, Eric. University Of Toronto. Hospital For Sick Children; Canadá. International Society of Paediatric Surgical Oncology; Suiza Fil: Howard, Scott C.. International Society of Paediatric Surgical Oncology; Suiza. University of Tennessee; Estados Unidos Fil: Challinor, Julia M.. International Society of Paediatric Surgical Oncology; Suiza. University of California; Estados Unidos Fil: Hessissen, Laila. Children Hospital of Rabat; Marruecos. International Society of Paediatric Surgical Oncology; Suiza Fil: Dalvi, Rashmi B.. Bombay Hospital Institute of Medical Sciences; India. International Society of Paediatric Surgical Oncology; Suiza Fil: Kearns, Pamela. International Society of Paediatric Surgical Oncology; Suiza Fil: Chantada, Guillermo Luis. International Society of Paediatric Surgical Oncology; Suiza. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Frazier, Lindsay A.. International Society of Paediatric Surgical Oncology; Suiza. Dana-Farber Cancer Institute; Estados Unidos Fil: Sullivan, Michael J.. University of Melbourne; Australia. International Society of Paediatric Surgical Oncology; Suiza Fil: Schulte, Fiona S.M.. University of Calgary; Canadá. International Society of Paediatric Surgical Oncology; Suiza Fil: Morrissey, Lisa K.. Boston Children’s Hospital; Estados Unidos. International Society of Paediatric Surgical Oncology; Suiza Fil: Kozhaeva, Olga. European Society for Paediatric Oncology; Bélgica Fil: Luna Fineman, Sandra. Children’s Hospital Colorado; Estados Unidos. International Society of Paediatric Oncology; Suiza Fil: Khan, Muhammad S.. Tawam Hospital; Emiratos Arabes Unidos

Although previous studies have suggested that the complications and mortality rate related to COVID-19 are substantially lower in the paediatric population,1 it is reasonable to consider that children with underlying conditions such as cancer will be at increased risk of severe disease... Fil: Vasquez, Liliana. Universidad de San Martín de Porres; Perú. Organización Panamericana de la Salud; Perú Fil: Sampor, Claudia. Fundacion Hospital de Pediatria Professor Dr. Juan P. Garrahan; Argentina Fil: Villanueva, Gabriela. Fundacion Hospital de Pediatria Professor Dr. Juan P. Garrahan; Argentina Fil: Maradiegue, Essy. Instituto Nacional de Enfermedades Neoplasicas; Perú Fil: Garcia Lombardi, Mercedes. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez"; Argentina Fil: Gomez García, Wendy. Hospital Infantil Dr. Robert Reid Cabral; República Dominicana Fil: Moreno, Florencia. Ministerio de Salud. Instituto Nacional del Cáncer; Argentina Fil: Diaz, Rosdali. Instituto Nacional de Enfermedades Neoplasicas; Perú Fil: Cappellano, Andrea M.. Universidade Federal de Sao Paulo; Brasil Fil: Portilla, Carlos Andres. Universidad del Valle; Colombia Fil: Salas, Beatriz. Hospital del Niño Manuel Ascencio Villarroel; Bolivia Fil: Nava, Evelinda. Hospital de Niños Jesus Garcia Coello; Venezuela Fil: Brizuela, Silvia. Instituto de Previsión Social ; Paraguay Fil: Jimenez, Soledad. Hospital Solca Núcleo de Loja; Ecuador Fil: Espinoza, Ximena. Hospital de Niños Dr. Roberto del Río; Chile Fil: Gassant, Pascale Yola. Hôpital Saint-Damien; Haití Fil: Quintero, Karina. Children's Hospital Dr Jose Renan Esquivel; Panamá Fil: Fuentes Alabi, Soad. Hospital Nacional de Niños Benjamin Bloom; El Salvador Fil: Velasquez, Thelma. No especifíca; Fil: Fu, Ligia. Hospital Escuela de Tegucigalpa; Honduras Fil: Gamboa, Yessika. National Children's Hospital; Costa Rica Fil: Quintana, Juan. Clinica Las Condes; Chile Fil: Castiglioni, Mariela. Hospital Pereira Rossell; Uruguay Fil: Nuñez, Cesar. Children's Cancer Hospital; Estados Unidos Fil: Moreno, Arturo. Hospital Universitario de Puebla; México Fil: Luna Fineman, Sandra. State University of Colorado at Boulder; Estados Unidos Fil: Luciani, Silvana. Pan American Health Organization; Estados Unidos Fil: Chantada, Guillermo Luis. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina. Hospital Sant Joan de Deu Barcelona; España

Background: Brentuximab vedotin is an anti-CD30 antibody-drug conjugate approved for use in adults with newly diagnosed and relapsed/refractory high-risk classical Hodgkin lymphoma (HL). Methods: Open label, single-arm, multicenter trial for patients (age < 18 years) with stage IIB, IIIB or IV classical HL. One dose of brentuximab vedotin (AdcetrisO) replaced each vincristine in the OEPA [vincristine, etoposide, prednisone, and doxorubicin]/COPDac [cyclophosphamide, vincristine, prednisone, and dacarbazine] regimen (2 cycles of AEPA and 4 cycles of CAPDac) according to GPOH-HD2002 treatment group 3 [TG3]. 1 Residual node radiotherapy (25·5 Gy) was given at the end of all chemotherapy only to nodal sites that did not achieve a complete response (CR) at the early response assessment (ERA) after 2 cycles of therapy. Primary objectives were to evaluate the safety and efficacy (complete remission at ERA) of this combination and the 3-year event-free and overall survival. Findings: Of the 77 patients enrolled in the study, 27 (35%) achieved complete remission at ERA and were spared radiation. Patients who were irradiated received radiation to individual residual nodal tissue. At a median follow-up of 3·4 years, the 3 year event-free survival was 97·4% (SE 2·3%) and overall survival 98·7% (SE 1·6%). One irradiated patient experienced disease progression at the end of therapy and now remains disease free more than 6 years following salvage therapy, and one unexpected death occurred. Only 4% patients experienced Grade 3 neuropathy. Interpretation: The integration of brentuximab vedotin in the frontline treatment of pediatric high-risk HL is highly tolerable, facilitated reduction in radiation exposure, and yielded excellent outcomes. Trial Registration: IND (#118603), The trial is registered with www.clinicaltrials.gov, NCT01920932. Funding Statement: Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under Award Number P30CA021765. Declaration of Interests: None to declare. Ethics Approval Statement: The trial was approved by the institutional review board of each participating center and monitored by the SJCRH Data, Safety, and Monitoring Board. Informed consent was obtained as per institutional guidelines.

PURPOSE: To provide clinically useful gadolinium-free whole-body cancer staging of children and young adults with integrated positron emission tomography / magnetic resonance (PET/MR) imaging in less than 1 h. PROCEDURES: In this prospective clinical trial, 20 children and young adults (11–30 years old, 6 male, 14 female) with solid tumors underwent 2-deoxy-2-[(18)F]fluoro-D-glucose ([(18)F]FDG) PET/MR on a 3T PET/MR scanner after intravenous injection of ferumoxytol (5mg Fe/kg) and [(18)F]FDG (2–3 MBq/kg). Time needed for patient preparation, PET/MR image acquisition and data processing was compared before (n = 5) and after (n = 15) time-saving interventions, using a Wilcoxon test. The ferumoxytol-enhanced PET/MR images were compared with clinical standard staging tests regarding radiation exposure and tumor staging results, using Fisher's exact tests. RESULTS: Tailored workflows significantly reduced scan times from 36 to 24 min for head to mid thigh scans (p < 0.001). These streamlined PET/MR scans were obtained with significantly reduced radiation exposure (mean 3.4 mSv) compared to PET/CT with diagnostic CT (mean 13.1 mSv; p = 0.003). Using the iron supplement ferumoxytol “off label” as an MR contrast agent avoided gadolinium chelate administration. The ferumoxytol-enhanced PET/MR scans provided equal or superior tumor staging results compared to clinical standard tests in 17 out of 20 patients. PET/MR had comparable detection rates for pulmonary nodules equal or greater 5 mm (94% vs. 100%), yet detected significantly fewer lung nodules compared to PET/CT for smaller nodules (20% vs 100%) (p = 0.03). [(18)F]FDG-avid nodules were detected with slightly higher sensitivity on the PET of the PET/MR compared to the PET of the PET/CT (59% vs 49%). CONCLUSION: Our streamlined ferumoxytol-enhanced PET/MR protocol provided cancer staging of children and young adults in less than 1 h with equivalent or superior clinical information compared to clinical standard staging tests. The detection of small pulmonary nodules with PET/MR needs to be improved.

Pediatric brain tumors with replication repair deficiency (RRD) are hypermutant and may respond favorably to immune checkpoint inhibition (ICI). We are collecting ongoing clinical and molecular data from patients with RRD hypermutant cancers treated with ICI as a part of our consortium registry study. Companion biomarkers include tumor mutational burden (TMB), neoantigens and genetic signatures obtained from whole genome and exome sequencing. Immune inference is obtained from RNAseq. Additionally, T-cell receptor rearrangement data are collected from the tumor and blood throughout treatment. From 2015–2018, 53 patients were treated with ICI and combination therapies. Of these 39 had brain tumors, with 93% having high grade gliomas. Two-year overall survival for the entire cohort is 47+/-8%, which compares favorably with historical controls. Tumor location had major impact on outcome. Non-CNS solid tumor patients have 2-year OS of 78+/-11%, all failures occurring within the first 2 months, and sustained responses are observed for 3 years. In contrast, OS for brain tumors is 39+/-10% with late recurrences observed even after 2 years of therapy (p=0.02). Large tumor size and total tumor burden are associated with higher rates of “flare” and poor outcome throughout all cancers. While all tumors are hypermutant, TMB and predicted neoantigens do not correlate with response. However, specific signatures extracted from SNVs and indels are significantly associated with response to ICI and favorable outcome (p=0.005). Notably, RRD IDH1 mutant glioblastomas have particularly poor response to ICI. Interestingly, glioblastomas (n=8) which failed single agent ICI had favorable responses to combination immunotherapies with prolonged survival of 65%+/-8% one year after failure vs 0 for untreated patients (p=0.01). The favorable outcome and responses to ICI are encouraging. Since brain tumors respond less favorably to ICI than other solid tumors, combination therapies based on tumor and immune signatures of these cancers may be beneficial.

Pediatric brain tumors with replication repair deficiency (RRD) are hypermutant and may respond to immune checkpoint inhibition (ICI). We performed a consortium registry study of ICI in recurrent RRD cancers. Clinical and companion biomarkers were collected longitudinally on all patients. Biomarkers included tumor mutational burden (TMB), neoantigens and genetic signatures obtained from whole genome and exome sequencing. Immune inference was obtained by RNAseq and T cell rearrangement was collected in the tumor and in blood throughout treatment. Of the 46 tumors on the study, 32 were brain tumors with glioblastoma in 96%. Rapid, objective responses (>50%) were observed in 50% of glioblastomas. Three year overall survival for the whole cohort was 48+/-8% which compares favorably with historical controls. Brain tumors fared worse with OS of 39+/-10% and late recurrences observed even after 2 years of therapy (p=0.02). Tumor size and acute “flare” constitute poor outcome throughout all cancers. While all tumors are hypermutant, TMB and predicted neoantigens correlated with response to ICI (p=0.02). Specific signatures extracted from SNVs and total mutations predicted response to ICI and favorable outcome (p=0.005). RNA inference and TCR reveal that the FLARE phenotype is mostly acute nonspecific immune response and not true progression. Finally, glioblastomas (n=8) which failed single agent ICI had favorable responses to combinational immunotherapies with prolonged survival of 65%+/-8% at one year after failure vs 0 for other patients (p=0.01). RRD glioblastomas exhibit favorable outcome and responses to ICI. Combinational therapies based on tumor and immune signatures of these cancers are necessary.

Purpose The global burden of cancer is slated to reach 21.4 million new cases in 2030 alone, and the majority of those cases occur in under-resourced settings. Formidable changes to health care delivery systems must occur to meet this demand. Although significant policy advances have been made and documented at the international level, less is known about the efforts to create national systems to combat cancer in such settings. Methods With case reports and data from authors who are clinicians and policymakers in three financially constrained countries in different regions of the world—Guatemala, Rwanda, and Vietnam, we examined cancer care programs to identify principles that lead to robust care delivery platforms as well as challenges faced in each setting. Results The findings demonstrate that successful programs derive from equitably constructed and durable interventions focused on advancement of local clinical capacity and the prioritization of geographic and financial accessibility. In addition, a committed local response to the increasing cancer burden facilitates engagement of partners who become vital catalysts for launching treatment cascades. Also, clinical education in each setting was buttressed by international expertise, which aided both professional development and retention of staff. Conclusion All three countries demonstrate that excellent cancer care can and should be provided to all, including those who are impoverished or marginalized, without acceptance of a double standard. In this article, we call on governments and program leaders to report on successes and challenges in their own settings to allow for informed progression toward the 2025 global policy goals.

Purpose: Tumor-associated macrophages (TAMs) in malignant tumors have been linked to tumor aggressiveness and represent a new target for cancer immunotherapy. As new TAM-targeted immunotherapies are entering clinical trials, it is important to detect and quantify TAM with noninvasive imaging techniques. The purpose of this study was to determine if ferumoxytol-enhanced MRI can detect TAM in lymphomas and bone sarcomas of pediatric patients and young adults. Experimental Design: In a first-in-patient, Institutional Review Board–approved prospective clinical trial, 25 pediatric and young adult patients with lymphoma or bone sarcoma underwent ferumoxytol-enhanced MRI. To confirm ferumoxytol enhancement, five pilot patients (two lymphoma and three bone sarcoma) underwent pre- and postcontrast MRI. Subsequently, 20 patients (10 lymphoma and 10 bone sarcoma) underwent ferumoxytol-enhanced MRI 24 to 48 hours after i.v. injection, followed by tumor biopsy/resection and macrophage staining. To determine if ferumoxytol-MRI can differentiate tumors with different TAM content, we compared T2* relaxation times of lymphomas and bone sarcomas. Tumor T2* values of 20 patients were correlated with CD68+ and CD163+ TAM quantities on histopathology. Results: Significant ferumoxytol tumor enhancement was noted on postcontrast scans compared with precontrast scans (P = 0.036). Bone sarcomas and lymphomas demonstrated significantly different MRI enhancement and TAM density (P < 0.05). Within each tumor group, T2* signal enhancement on MR images correlated significantly with the density of CD68+ and CD163+ TAM (P < 0.05). Conclusions: Ferumoxytol-enhanced MRI is immediately clinically applicable and could be used to stratify patients with TAM-rich tumors to immune-targeted therapies and to monitor tumor response to these therapies. Clin Cancer Res; 24(17); 4110–8. ©2018 AACR.

Many children with cancer in low- and middle-income countries are treated in hospitals lacking key infrastructure, including diagnostic capabilities, imaging modalities, treatment components, supportive care, and personnel. Childhood cancer treatment regimens adapted to local conditions provide an opportunity to cure as many children as possible with the available resources, while working to improve services and supportive care. This paper from the Adapted Treatment Regimens Working Group of the Pediatric Oncology in Developing Countries committee of the International Society of Pediatric Oncology outlines the design, development, implementation, and evaluation of adapted regimens and specifies levels of services needed to deliver them. Fil: Howard, Scott C.. University of Tennessee; Estados Unidos Fil: Davidson, Alan. University of Cape Town; Sudáfrica Fil: Luna Fineman, Sandra. University of Colorado; Estados Unidos Fil: Israels, Trijn. Vrije Unviversiteit Brussel; Bélgica Fil: Chantada, Guillermo Luis. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina. Universidad de Barcelona; España. Hospital Sant Joan de Deu Barcelona; España Fil: Lam, Catherine G.. St. Jude Children's Research Hospital; Estados Unidos Fil: Hunger, Stephen P.. University of Pennsylvania; Estados Unidos Fil: Bailey, Simon. Royal Victoria Infirmary Paediatric Neuro‐Oncology and Paediatric Oncology; Reino Unido Fil: Ribeiro, Raul C.. St. Jude Children's Research Hospital; Estados Unidos Fil: Arora, Ramandeep S.. Max Super‐Specialty Hospital. Department of Medical Oncology; India Fil: Pedrosa, Francisco. Real Hospital Português Real Oncopediatría; Brasil Fil: Harif, Mhamed. Hôpital 20. Department of Hematology ; Marruecos Fil: Metzger, Monika L.. St. Jude Children's Research Hospital; Estados Unidos

Corticosteroid treatment of paediatric leukaemia patients can lead to osteonecrosis (ON). We determined whether bone marrow oedema (BME) is an early sign of progressive ON and eventual bone collapse. In a retrospective study, two radiologists reviewed MR imaging characteristics of 47 early stage epiphyseal ON in 15 paediatric and adolescent leukaemia patients. Associations between BME on initial imaging studies and subchondral fracture, disease progression and bone collapse were assessed by Cochran-Mantel-Haenszel tests. Differences in time to progression and bone collapse between lesions with and without oedema were assessed by log rank tests. Forty-seven occurrences of ON were located in weight bearing joints, with 77% occurring in the femur. Seventeen lesions progressed to collapse, two lesions worsened without collapse, and 28 remained stable or improved. BME was significantly associated with subchondral fracture (p = 0.0014), disease progression (p = 0.0015), and bone collapse (p

Effective treatment of children with medulloblastoma requires a functioning multi-disciplinary team with adequate neurosurgical, neuroradiological, pathological, radiotherapy and chemotherapy facilities and personnel. In addition the treating centre should have the capacity to effectively screen and manage any tumour and treatment-associated complications. These requirements have made it difficult for many low and middle-income countries (LMIC) centres to offer curative treatment. This article provides management recommendations for children with standard-risk medulloblastoma (localised tumours in children over the age of 3-5 years) according to the level of facilities available.

Retinoblastoma remains incurable in many regions of the world. The major obstacles to cure are delayed diagnosis, poor treatment compliance, and lack of evidence-based recommendations for clinical management. Although enucleation is curative for intraocular disease, in developing countries retinoblastoma is often diagnosed after the disease has disseminated beyond the eye. A SIOP-PODC committee generated guidelines for the clinical management of retinoblastoma in developing countries and developed a classification system based on the resources available in those settings. Recommendations are provided for staging and treatment of unilateral and bilateral retinoblastoma and counseling of families for whom compliance is an issue.

Pediatric-type follicular lymphoma and pediatric marginal zone lymphoma are two of the rarest B-cell lymphomas. These lymphomas occur predominantly in the pediatric population and show features distinct from their more common counterparts in adults: adult-type follicular lymphoma and adult-type nodal marginal zone lymphoma. Here we report a detailed whole-exome deep sequencing analysis of a cohort of pediatric-type follicular lymphomas and pediatric marginal zone lymphomas. This analysis revealed a recurrent somatic variant encoding p.Lys66Arg in the transcription factor interferon regulatory factor 8 (IRF8) in 3 of 6 cases (50%) of pediatric-type follicular lymphoma. This specific point mutation was not detected in pediatric marginal zone lymphoma or in adult-type follicular lymphoma. Additional somatic point mutations in pediatric-type follicular lymphoma were observed in genes involved in transcription, intracellular signaling, and cell proliferation. In pediatric marginal zone lymphoma, no recurrent mutation was identified; however, somatic point mutations were observed in genes involved in cellular adhesion, cytokine regulatory elements, and cellular proliferation. A somatic variant in AMOTL1, a recurrently mutated gene in splenic marginal zone lymphoma, was also identified in a case of pediatric marginal zone lymphoma. The overall non-synonymous mutational burden was low in both pediatric-type follicular lymphoma and pediatric marginal zone lymphoma (4.6 mutations per exome). Altogether, these findings support a distinctive genetic basis for pediatric-type follicular lymphoma and pediatric marginal zone lymphoma when compared with adult subtypes and to one another. Moreover, identification of a recurrent point mutation in IRF8 provides insight into a potential driver mutation in the pathogenesis of pediatric-type follicular lymphoma with implications for novel diagnostic or therapeutic strategies.

Background Treatment refusal and abandonment are major causes of treatment failure for children with cancer in low- and middle-income countries (LMICs), like Guatemala. This study identified risk factors for and described the intervention that decreased abandonment. Methods This was a retrospective study of Guatemalan children (0–18 years) with cancer treated at the Unidad Nacional de Oncologia Pediatrica (UNOP), 2001–2008, using the Pediatric Oncology Network Database. Treatment refusal was a failure to begin treatment and treatment abandonment was a lapse of 4 weeks or longer in treatment. The impact of medicina integral, a multidisciplinary psychosocial intervention team at UNOP was evaluated. Cox proportional hazards analysis identified the effect of demographic and clinical factors on abandonment. Kaplan–Meier analysis estimated the survival. Results Of 1,789 patients, 21% refused or abandoned treatment. Abandonment decreased from 27% in 2001 to 7% in 2008 following the implementation of medicina integral. Factors associated with increased risk of refusal and abandonment: greater distance to the centre (P < 0.001), younger age (P = 0.017) and earlier year of diagnosis (P < 0.001). Indigenous race/ethnicity (P = 0.002) was associated with increased risk of abandonment alone. Abandonment correlated with decreased overall survival: 0.57 ± 0.02 (survival ± standard error) for those who completed therapy versus 0.06 ± 0.02 for those who abandoned treatment (P < 0.001) at 8.3 years. Conclusion This study identified distance, age, year of diagnosis and indigenous race/ethnicity as risk factors for abandonment. A multidisciplinary intervention reduced abandonment and can be replicated in other LMICs.

The aim of this study was to assess the safety profile of ferumoxytol as an intravenous magnetic resonance imaging contrast agent in children.We prospectively evaluated the safety of ferumoxytol administrations as an "off-label" contrast agent for magnetic resonance imaging in nonrandomized phase 4 clinical trials at 2 centers. From September 2009 to February 2015, 49 pediatric patients (21 female and 28 male, 5-18 years) and 19 young adults (8 female and 11 male, 18-25 years) were reported under an investigator-initiated investigational new drug investigation with institutional review board approval, in health insurance portability and accountability act compliance, and after written informed consent of the child's legal representative or the competent adult patient was obtained. Patients received either a single dose (5 mg Fe/kg) or up to 4 doses of ferumoxytol (0.7-4 mg Fe/kg) intravenously, which were approximately equivalent to one third of the dose for anemia treatment. We monitored vital signs and adverse events directly for up to 1 hour after injection. In addition, we examined weekly vitals, hematologic, renal, and liver serum panels for 1 month after injection in over 20 pediatric patients. At fixed time points before and after ferumoxytol injection, data were evaluated for significant differences by a repeated measures linear mixed model.Four mild adverse events, thought to be related to ferumoxytol, were observed within 1 hour of 85 ferumoxytol injections: 2 episodes of mild hypotension and 1 case of nausea in 65 injections in pediatric patients without related clinical symptoms. One young adult patient developed warmness and erythema at the injection site. All adverse events were self-resolving. No spontaneous serious adverse events were reported. At a dose of 5 mg Fe/kg or lower, intravenous ferumoxytol injection had no clinical relevance or statistically significant effect (P0.05) on vital signs, hematological parameters, kidney function, or liver enzymes within 1 month of the injection.Ferumoxytol was overall well tolerated among 49 pediatric and 19 young adult patients experiencing various tumors or kidney transplants without major adverse events or signs of hematologic and kidney impairment or liver toxicity. Larger studies are needed to determine the incidence of anaphylactic reactions.

Background Retinoblastoma is highly curable in high income countries. Low income countries have poor results due to advanced disease and lack of resources. Central American Association of Pediatric Hematology Oncology (AHOPCA) aimed to standardize the approach and to improve outcomes of patients with retinoblastoma. Procedure One hundred seventy-one patients, age

CCG-2961 incorporated 3 new agents, idarubicin, fludarabine and interleukin-2, into a phase 3 AML trial using intensive-timing remission induction/consolidation and related donor marrow transplantation or high-dose cytarabine intensifi-cation. Among 901 patients under age 21 years, 5-year survival was 52%, and event-free survival was 42%. Survival improved from 44% between 1996 and 1998 to 58% between 2000 and 2002 (P = .005), and treatment-related mortality declined from 19% to 12% (P = .025). Partial replacement of daunomycin with idarubicin in the 5-drug induction combination achieved a remission rate of 88%, similar to historical controls. Postremission survival was 56% in patients randomized to either 5-drug reinduction or fludarabine/cytarabine/idarubicin. For patients with or without a related donor, respective 5-year disease-free survival was 61% and 50% (P = .021); respective survival was 68% and 62% (P = .425). Donor availability conferred no benefit on those with inv(16) or t(8;21) cytogenetics. After cytarabine intensification, patients randomized to interleukin-2 or none experienced similar outcomes. Factors predictive of inferior survival were age more than 16 years, non-white ethnicity, absence of related donor, obesity, white blood cell count more than 100 000 × 109/L, −7/7q−, −5/5q−, and/or complex karyotype. No new agent improved outcomes; experience may have contributed to better results time.

70 Objectives Clinical measures of Parkinson’s disease progression suggest a slow process with significant variability both between patients and also within the individual over the course of disease. A number of “objective” imaging and non-imaging measures have been proposed as putative progression biomarkers although there is limited validation data available. The Parkinson9s (PD) progression marker initiative (PPMI) is an international, multicenter, longitudinal study assessing biochemical, clinical, and imaging biomarkers of disease progression. Scintigraphic biomarkers are being evaluated as indicators of progression include dopamine transporter (DAT) imaging with 123-I ioflupane SPECT. This study evaluates subregion-dependent striatal changes in dopamine transporter (DAT) binding using 123-I Ioflupane SPECT in PD participants in the PPMI study. Methods Baseline (n= 241), 1 year, and 2 year 123-I Ioflupane SPECT scans were acquired from 22 centers. Data were reconstructed, attenuation corrected, and analyzed by the core lab using a volume of interest template for extraction of counts and calculation of specific binding ratios (SBRs) and percent SBRs changes over time in six striatal subregions. Results Ongoing serial evaluation shows SBR reduction at 1 yr in 80% of 241 PD subjects. Specific binding ratios demonstrate 11.6% and 7.4% reductions over one year in the ipsilateral and contralateral striatum, respectively. Differences in the rates of DAT signal change are evident in subregions of the striatum. The fastest rates of change annualized over two years were noted, in order, for ipsilateral striatum; posterior putamen (-9.2% +/-11.4), anterior putamen(-8.7% +/- 8.8), and caudate( -6.9% +/-8.9). In contrast, contralaterally, posterior putamen (-6.4% +/-15.4), demonstrated the slowest rate of change with the anterior putamen (-8.0% +/-10.3), and the caudate ( -7.5%+/-9.4). Conclusions These data have implications for the potential use of dopamine transporter imaging as a serial marker of change in longitudinal Parkinson9s studies. Specifically, areas with greatest signal change and lowest variability might be more sensitive for detecting slowing rates of change with a disease modifying therapy. In summary, this study shows consistently increasing signal loss over one and two years with regional differences demonstrated for DAT imaging and confirmation of previously noted between subject variability.

Combining 18F-FDG PET with whole-body MR for paediatric cancer staging is practically feasible if imaging protocols can be streamlined. We compared 18F-FDG PET/STIR with accelerated 18F-FDG PET/FSPGR for whole-body tumour imaging in children and young adults. Thirty-three children and young adults (17.5 ± 5.5 years, range 10–30) with malignant lymphoma or sarcoma underwent a 18F-FDG PET staging examination, followed by ferumoxytol-enhanced STIR and FSPGR whole-body MR. 18F-FDG PET scans were fused with MR data and the number and location of tumours on each integrated examination were determined. Histopathology and follow-up imaging served as standard of reference. The agreement of each MR sequence with the reference and whole-body imaging times were compared using Cohen’s kappa coefficient and Student’s t-test, respectively. Comparing 18F-FDG PET/FSPGR to 18F-FDG PET/STIR, sensitivities were 99.3 % for both, specificities were statistically equivalent, 99.8 versus 99.9 %, and the agreement with the reference based on Cohen’s kappa coefficient was also statistically equivalent, 0.989 versus 0.992. However, the total scan-time for accelerated FSPGR of 19.8 ± 5.3 minutes was significantly shorter compared to 29.0 ± 7.6 minutes for STIR (p = 0.001). F-FDG PET/FSPGR demonstrated equivalent sensitivities and specificities for cancer staging compared to 18F-FDG PET/STIR, but could be acquired with shorter acquisition time. • Breath-hold FSPGR sequences shorten the data acquisition time for whole-body MR and PET/MR. • Ferumoxytol provides long-lasting vascular contrast for whole-body MR and PET/MR. • 18 F-FDG PET/FSPGR data provided equal sensitivity and specificity for cancer staging compared to 18 F-FDG PET/STIR.

Subacute methotrexate (MTX) encephalopathy is poorly understood. We performed a historical cohort study of all cases of subacute MTX encephalopathy at Lucile Packard Children’s Hospital from January 1, 2005, to December 31, 2011. Of 272 patients receiving MTX, 21 patients were diagnosed with subacute MTX encephalopathy. Nine patients (42.9%) in this study were Hispanic females, whereas Hispanic females represented 56 of 272 (20.6%) total patients (p=0.0084). Further comparison with the 2010 California census confirms a Hispanic female predominance (p=0.032). We report a predominance of Hispanic females with subacute MTX encephalopathy, which suggests a genetic polymorphism that increases disease risk.

More than 20 patients with persistent poliovirus infections have been identified and reported to WHO. To date, almost all of these patients have had B-cell immune deficiency disorders. Since there are limited data on patients with HIV infection who have received oral poliovirus vaccine (OPV), we studied adults and children to determine if persons with acquired immunodeficiency due to HIV infection or cancer chemotherapy in a developing country setting had prolonged excretion of polioviruses. Stool samples from 94 HIV-infected children and 101 adults and 50 children surviving cancer in Guatemala City were cultured for polioviruses. No polioviruses were detected in any of the 195 persons with HIV infection or the 50 with cancer. The evidence from this and other studies indicates that the persistent poliovirus excretion in HIV-infected individuals is an unlikely event.

Background Most children with cancer live in resource-limited countries where malnutrition is often prevalent. We identified the relationship between malnutrition and treatment-related morbidity (TRM), abandonment of therapy, and survival of children with cancer in Nicaragua to better inform targeted nutritional interventions. Procedure We conducted a retrospective review of patients aged 6 months to 18 years with newly diagnosed acute lymphoblastic leukemia, acute myeloid leukemia (AML), Wilms tumor, Hodgkin lymphoma, or Burkitt lymphoma (BL) who were treated between January 1, 2004, and December 31, 2007 at Children's Hospital Manuel de Jesus Rivera in Managua, Nicaragua. Statistical analysis examined the relations among nutritional status and cancer type, risk category, TRM, and event-free survival (EFS). Results Sixty-seven percent of patients (189/282) were malnourished at diagnosis. Malnutrition was highest among patients with Wilms tumor (85.7%), BL (75%), and AML (74.3%). A total of 92.2% of patients (225/244) experienced morbidity during the first 90 days. Malnutrition was associated with severe infection (P = 0.033). Severely malnourished patients had ≥grade 3 TRM on more days (P = 0.023) and were more likely to experience severe TRM on >50% of days (P = 0.032; OR, 3.27 [95% CI, 1.05–10.16]). Malnourished patients had inferior median EFS (2.25 vs. 5.58 years; P = 0.049), and abandoned therapy more frequently (P = 0.015). Conclusions In Nicaragua, pediatric oncology patients with malnutrition at diagnosis experienced increased TRM, abandoned therapy more frequently, and had inferior EFS. Standardized nutritional evaluation of patients with newly diagnosed cancer and targeted provision of nutritional support are essential to decrease TRM and improve outcomes.

Pediatric follicular lymphoma (pFL) is a rare neoplasm with features differing from follicular lymphoma arising in adults. Here, we describe a rare case of pFL that showed morphologic features partially overlapping with progressive transformation of germinal centers and reactive follicular hyperplasia. As typical of pFL, neoplastic B cells within follicles did not express B-cell leukemia/lymphoma 2 (BCL2). However, this case showed additional distinctive abnormal findings, which contributed to the diagnosis: (1) diffuse and uniform staining of immunoglobulin M (IgM) on cells within and outside of follicles, (2) abnormally dim expression of CD21 on follicular dendritic cells, and (3) expression of human germinal center-associated lymphoma (HGAL) and LIM domain only 2 (LMO2) on B cells in interfollicular and follicular areas. This case demonstrates the utility of these abnormal features, which can be seen in adult- or usual-type follicular lymphoma, in the diagnosis of pFL. Further studies are necessary to evaluate the significance of these findings in other cases of pFL.

Analysis of 327 consecutive cases at a pediatric referral hospital of Guatemala reveals that retinoblastoma accounts for 9.4% of all cancers and the estimated incidence is 7.0 cases/million children, higher than the United States or Europe. The number of familial cases is low, and there is a striking disparity in indigenous children due to late diagnosis, advanced disease, rapid progression and elevated mortality. Nine germline mutations in 18 patients were found; two known and five new mutations. Hypermethylation of RB1 was identified in 13% of the tumors. An early diagnosis program could identify cases at an earlier age and improve outcome of retinoblastoma in this diverse population.

Effective treatment of children with medulloblastoma requires a functioning multi-disciplinary team with adequate neurosurgical, neuroradiological, pathological, radiotherapy and chemotherapy facilities and personnel. In addition the treating centre should have the capacity to effectively screen and manage any tumour and treatment-associated complications. These requirements have made it difficult for many low and middle-income countries (LMIC) centres to offer curative treatment. This article provides management recommendations for children with standard-risk medulloblastoma (localised tumours in children over the age of 3-5 years) according to the level of facilities available.