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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.

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.

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.

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

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.

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.

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.

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.

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.

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.

Objective To evaluate the practice of empiric antibiotics for febrile, nonneutropenic pediatric oncology patients with a central venous catheter (CVC) in place. Study design Episodes of fever without neutropenia (absolute neutrophil count [ANC] ≥500 cells/mm 3 ) were reviewed retrospectively in pediatric oncology patients with a CVC undergoing chemotherapy. Characteristics and symptoms were compared between patients with bacteremia and patients without bacteremia. Results A total of 392 episodes of nonneutropenic fever in 138 subjects (52 females; 38%) were reviewed. In this cohort, the median age at an episode was 7 years, and the majority of patients had a diagnosis of acute leukemia (54%). Median ANC was 3100 cells/mm 3 (IQR, 1570-5980 cells/mm 3 ). Median temperature was 38.7°C (IQR, 38.3-39.2°C). Twenty-four infectious episodes (6%) occurred in 18 subjects, and 5 CVCs required removal; all patients requiring removal admitted and received antibiotics owing to chills. There were no significant difference in age, sex, or ANC between patients with bacteremia and those without bacteremia; however, mean temperature was higher in the patients with bacteremia (39.4°C vs 38.7°C; P = .003). No deaths due to sepsis occurred, and no CVCs were removed because antibiotics were not administered empirically. Conclusion Our practice of observing pediatric oncology patients undergoing chemotherapy with CVCs who are not neutropenic does not appear to lead to increased serious adverse outcomes and avoids antibiotic exposure for >90% of patients without a bacterial infection.

Involvement of the falx cerebri in infants with stage 4 neuroblastoma is thought to be rare. The falx is derived from the neural crest and thus may be a location for primary neuroblastoma. Its propensity for metastasis is unknown. Management of neuroblastoma in this location is potentially challenging. We describe two children less than 18 months of age who were successfully managed with chemotherapy alone (without radiation or surgery) for falx involvement with neuroblastoma.

Myelodysplastic syndromes (MDS) and myeloproliferative syndromes (MPS) of childhood are a heterogeneous group of clonal disorders of hematopoiesis with overlapping clinical features and inconsistent nomenclature. Although a number of genetic conditions have been associated with MDS and MPS, the overall contribution of inherited predispositions is uncertain. We report a retrospective study examining clinical features, genetic associations, and outcomes in 167 children with MDS and MPS. Of these patients, 48 had an associated constitutional disorder. One hundred one patients had adult-type myelodysplastic syndrome (A-MDS), 60 had juvenile myelomonocytic leukemia (JMML), and 6 infants with Down syndrome had a transient myeloproliferative syndrome (TMS). JMML was characterized by young age at onset and prominent hepatosplenomegaly, whereas patients with A-MDS were older and had little or no organomegaly. The most common cytogenetic abnormalities were monosomy 7 or del(7q) (53 cases); this was common both in patients with JMML and those with A-MDS. Leukemic transformation was observed in 32% of patients, usually within 2 years of diagnosis. Survival was 25% at 16 years. Favorable prognostic features at diagnosis included age less than 2 years and a hemoglobin F level of less than 10%. Older patients tended to present with an adult-type MDS that is accommodated within the French-American-British system. In contrast, infants and young children typically developed unique disorders with overlapping features of MDS and MPS. Although the type and intensity of therapy varied markedly in this study, the overall outcome was poor except in patients with TMS.

Summary Background Imaging tests are essential for staging of children with cancer. However, CT and radiotracer-based imaging procedures are associated with substantial exposure to ionising radiation and risk of secondary cancer development later in life. Our aim was to create a highly effective, clinically feasible, ionising radiation-free staging method based on whole-body diffusion-weighted MRI and the iron supplement ferumoxytol, used off-label as a contrast agent. Methods We compared whole-body diffusion-weighted MRI with standard clinical 18 F-fluorodeoxyglucose ( 18 F-FDG) PET/CT scans in children and young adults with malignant lymphomas and sarcomas. Whole-body diffusion-weighted magnetic resonance images were generated by coregistration of colour-encoded ferumoxytol-enhanced whole-body diffusion-weighted MRI scans for tumour detection with ferumoxytol-enhanced T1-weighted MRI scans for anatomical orientation, similar to the concept of integrated 18 F-FDG PET/CT scans. Tumour staging results were compared using Cohen's κ statistics. Histopathology and follow-up imaging served as the standard of reference. Data was assessed in the per-protocol population. This study is registered with ClinicalTrials.gov, number NCT01542879. Findings 22 of 23 recruited patients were analysed because one patient discontinued before completion of the whole-body scan. Mean exposure to ionising radiation was 12·5 mSv (SD 4·1) for 18 F-FDG PET/CT compared with zero for whole-body diffusion-weighted MRI. 18 F-FDG PET/CT detected 163 of 174 malignant lesions at 1325 anatomical regions and whole-body diffusion-weighted MRI detected 158. Comparing 18 F-FDG PET/CT to whole-body diffusion-weighted MRI, sensitivities were 93·7% (95% CI 89·0–96·8) versus 90·8% (85·5–94·7); specificities 97·7% (95% CI 96·7–98·5) versus 99·5% (98·9–99·8); and diagnostic accuracies 97·2% (93·6–99·4) versus 98·3% (97·4–99·2). Tumour staging results showed very good agreement between both imaging modalities with a κ of 0·93 (0·81–1·00). No adverse events after administration of ferumoxytol were recorded. Interpretation Ferumoxytol-enhanced whole-body diffusion-weighted MRI could be an alternative to 18 F-FDG PET/CT for staging of children and young adults with cancer that is free of ionising radiation. This new imaging test might help to prevent long-term side-effects from radiographic staging procedures. Funding Thrasher Research Fund and Clinical Health Research Institute at Stanford University.

Abstract 57a Purpose: A significant percentage of patients in Central America present with buphthalmos, carrying a high risk of globe rupture and orbital contamination. In 2007, AHOPCA introduced chemotherapy before enucleation in children with buphthalmos. Methods: Patients with advanced intraocular disease were considered standard-risk and underwent enucleation. Those with diffuse invasion of choroid, postlaminar optic nerve, or anterior chamber invasion received 4-6 cycles of adjuvant chemotherapy (vincristine, carboplatin, etoposide). Patients with buphthalmos or perceived to be at risk for abandonment were considered high-risk, given 2-3 cycles of chemotherapy before enucleation to compete 6 cycles regardless of pathology. All cases were discussed via online meetings. Results: From 2007 to 2014, 396 patients were enrolled; 240 had IRSS stage I (174 unilateral). 143 had upfront enucleation, 95 had pre-enucleation chemotherapy, 1 is pending enucleation and 1 abandoned before enucleation. The standard-risk group 69 had risk pathology and 76 had no risk factors; 125 had no events, 5 abandoned 11 relapsed/progressed and 2 died of toxicity. Of 95 high-risk group, 8 abandoned, 20 relapse/progressive, 6 had toxic deaths and 61 are alive at last follow-up (median time of 4 years). Of high risk group, 55 were unilateral, 82% are alive. At 7 years OS (abandonment-censored) was 95±0.02 and 79±0.04 for standard-risk and high-risk (p=0.008). Conclusion: AHOPCA addressed advanced intraocular disease with an innovative approach. In eyes with buphthalmos and patients with risk of abandonment, neo-adjuvant chemotherapy is effective, when followed by post-enucleation chemotherapy. This approach avoids ocular rupture and intensified therapy, and reduces refusal/abandonment rate. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST: No COIs from the authors.

Abstract 59 Background: Abandonment of therapy is a major cause of therapeutic failure in the treatment of childhood cancer in Low and Middle Income Countries (LMIC). This study examines factors associated with increased risk of therapy abandonment in Guatemalan children with cancer and the rates of therapy abandonment before and after implementation of a multidisciplinary psychosocial intervention program. Methods: A retrospective population-based study was performed to identify risk factors for abandonment of therapy in Guatemalan children, ages 0-18, with cancer who were seen at UNOP from 2001-2008. Patient data was collected from the Pediatric Oncology Networked Database (POND4Kids). Abandonment was defined as a lapse of 4 weeks in planned treatment or failure to begin treatment for a potentially curable cancer. Cox proportional hazards analysis identified the effect of age, sex, year of diagnosis, distance travelled to UNOP, ethnicity, and principal diagnosis on abandonment of therapy. Kaplan Meier analysis was used to evaluate survival. Results: A retrospective analysis of 1,789 charts was performed and 367 patients abandoned therapy. The rate of abandonment decreased from 27% in 2001 to 7% in 2008 following a multidisciplinary psychosocial intervention program. Greater distance to UNOP (p = 0.00), younger age (p = 0.02) and earlier year of diagnosis (p = 0.00) were associated with increased risk of abandonment. Abandonment of therapy correlated with decreased survival. The cumulative survival at 8.3 years was 0.57 ± 0.02 (survival±SE) for those who completed therapy vs 0.06 ± 0.02 for those who abandoned and refused therapy (p=0.000) in an abandonment sensitive analysis. Conclusion: This study identified distance, age, and year of diagnosis as risk factors for abandonment of therapy for pediatric cancer in Guatemala. This study highlights risk factors for abandonment of therapy and the role of targeted interventions in altering rates of abandonment that could be replicated in other LMIC countries. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST: No COIs from the authors.

More than one-half of adults with non-Hodgkin's B cell lymphomas present with low-grade follicular lymphomas. These tumor cells are found in close association with follicular T lymphocytes and dendritic cells, suggesting that the surrounding cells may play a role in the support of follicular tumors. Supernatants from activated human peripheral blood lymphocytes were found to promote the in vitro proliferation of follicular tumor cells. This effect was entirely due to interleukin 3 (IL-3), a factor generally thought to cause the growth and differentiation of immature hematopoietic cells. IL-3 receptors were detected on fresh isolates of all primary follicular cell tumors examined. These findings suggest that follicular cell tumors may be dependent in vivo on IL-3 and that therapies directed against IL-3, its receptor, or the T cells that produce it may be effective treatment for follicular lymphoma.

Retinoblastoma, a curable eye tumor, is associated with poor survival in Central America (CA). To develop a retinoblastoma program in El Salvador, Guatemala, and Honduras, twinning initiatives were undertaken between local pediatric oncology centers, nonprofit foundations, St. Jude Children's Research Hospital, and the University of Tennessee Hamilton Eye Institute.The retinoblastoma program focused on developing early diagnosis programs in Honduras with national vaccination campaigns, developing treatment protocols suited to local conditions, building local networks of oncologists and ophthalmologists, training local healthcare providers, using modern donated equipment for diagnosis and treatment, and the ORBIS Cybersight consultation program and Internet meetings to further education and share expertise. Pediatric ophthalmologists and oncologists worked with foundations to treat patients locally with donated equipment and Internet consultations, or at the center in Guatemala.Number of patients successfully treated increased after the program was introduced. For 2000-2003 and 2004-2007, patients abandoning/refusing treatment decreased in Guatemala from 20 of 95 (21%) to 14 of 123 (11%) and in Honduras from 13 of 37 (35%) to 7 of 37 (19%). Survival in El Salvador was good and abandonment/refusal low for both periods. Of 18 patients receiving focal therapy for advanced disease, 14 have single remaining eyes.Development of the program in CA has decreased abandonment/refusal and enabled ophthalmologists at local centers to use modern equipment to provide better treatment. This approach might serve as a guide for developing other multispecialty programs.

Background About 250–300 children with newly diagnosed cancer are treated each year at the Unidad Nacional de Oncologia Pediatrica in Guatemala City; less than 5% of them have soft tissue sarcomas (STS). The aim of the article was to evaluate whether the therapeutic standards achieved in STS in developed countries could be reproduced in a low-income country. Patients and Methods We reviewed the clinical data, treatment and outcome of 80 patients, 47 cases of rhabdomyosarcoma (RMS) and 33 of non-rhabdomyosarcoma soft tissue sarcoma (NRSTS), treated between January 2000 and October 2007. Results Most of the RMS patients had advanced disease at diagnosis (87% groups III–IV). Their 3-year event-free survival rate (EFS) was 26.4% if abandoning the treatment was considered as an event, or 32.4% if it was censored (14 patients abandoned the treatment), and the 3-year overall survival rate (OS) was 43.5%. Local progression/relapse was the main cause of treatment failure. Among the patients with NRSTS, the EFS at 3 years was 36.4% (when abandoning the treatment was considered as an event) or 43.3% (when it was censored), and the OS was 44.2%. Outcome was satisfactory for synovial sarcoma patients, those with tumors ≤5 cm, and those with localized disease. Conclusions Overall results were unsatisfactory compared to results reported from developed countries. Late diagnosis and the consequently high proportion of cases of advanced disease at diagnosis, the large number of patients failing to complete the treatment, and the poor quality of local control (in RMS) adversely influence outcome. Pediatr Blood Cancer 2008;51:760–764. © 2008 Wiley-Liss, Inc.

Pediatric cancer programs in low-income countries (LIC) can improve outcomes. However, treatment must be tailored to the patient's living conditions and the availability of supportive care. In some cases, a more intense regimen will decrease survival since the increase in death from toxicity may exceed any decrease in relapse. Attempts to practice evidence-based pediatric oncology are thwarted by the lack of evidence derived from local experience in LIC to determine optimal therapy. This report summarizes treatment regimens used by pediatric oncologists from 15 countries of the Caribbean, Central and South America who participate in the Monza International School of Pediatric Hematology/Oncology (MISPHO). Patients with hepatoblastoma, Wilms tumor, and histiocytosis treated on unmodified published protocols had outcomes comparable to those in high-income countries (HIC). Those with rhabdomyosarcoma, osteosarcoma, Hodgkin lymphoma, and acute myeloid leukemia treated with unmodified regimens had event-free survival estimates 10%-20% lower than those reported in HIC due to higher rates of toxic death, abandonment of therapy, and relapse. Treatment of retinoblastoma is complicated by advanced stages and extraocular disease at diagnosis; improved outcomes depend on education of pediatricians and the public to recognize early signs of this disease. Use of unmodified protocols for Burkitt lymphoma and acute lymphoblastic leukemia have been associated with unacceptable toxicity in LIC, so MISPHO centers have modified published regimens by giving lower doses of methotrexate and reducing use of anthracyclines. Despite the use of all-trans-retinoic acid during induction for acute promyelocytic leukemia, the incidence of fatal hemorrhage remains unacceptably high.

Abstract 718 Hodgkin Lymphoma (HL) is highly curable with reported event-free survival (EFS) estimates of greater than 80% even in high-risk patients. Unfortunately, EFS of HL in low-income countries is much lower, about 50%. The Asociación de Hemato-Oncología Pediátrica de Centro América (AHOPCA) is a collaborative group that designs therapeutic guidelines (protocols) for the treatment of selected malignant disorders in Central America and the Dominican Republic. In 2004 AHOPCA designed a new protocol for the treatment of high-risk HL (stage IIB, IIIB and IV). The purpose of the protocol (AHOPCA LH 2004) was to provide proven effective therapy that would improve survival, decrease toxicity and decrease abandonment of therapy in this group of patients. Because of its short duration (12 weeks of chemotherapy) and reported efficacy, Stanford V was selected but modified to adapt to the local circumstances. We hereby report the preliminary results of AHOPCA LH 2004 which closed to accrual in April 2009. Methods: All newly diagnosed biopsy proven HL patients Ann Arbor stages IIB, IIIB and IV, that presented within the seven AHOPCA centers between April 2004 and April 2009 were eligible. Treatment consisted of a modified Stanford V regimen with dose-equivalent cyclophosphamide substituting for nitrogen mustard since the latter was unavailable in Central America. Involved field radiation therapy (IFRT) was reduced from the original 35 Gy. Chemotherapy was given for 12 weeks without the use of growth factor support as follows: doxorubicin 25 mg/m2 and vinblastin 6 mg/m2 intravenous (IV) weeks 1,3,5,7,9 and 11; vincristine 1.4 mg/m2 (maximum 2 mg) and bleomycin 6 units/m2 IV weeks 2,4,6,8,10 and 12; cyclophosphamide 600 mg/m2 IV weeks 1,5 and 9; etoposide 60 mg/m2 IV daily for 2 days weeks 3,7 and 11; prednisone 40 mg/m2 (maximum 60 mg/day) orally given every other day weeks 1 through 10 with tapering of dose over weeks 11 and 12; Response evaluation with diagnostic imaging studies of the initially involved sites of disease was performed at the end of all prescribed chemotherapy. Patients that had achieved a complete response at that point received 20 Gy IFRT, patients with less than a complete response received 25 Gy. Trimethoprim and acyclovir prophylaxis was given to all patients. Patient data was collected and entered prospectively in POND, a web-based electronic data base, provided by St Jude Children's Research Hospital. Toxicities were recorded according to CTCAE 3.0. Results: 221 patients were enrolled of which 206 were evaluable. Fifteen patients were excluded from the analysis for major protocol deviations. Male subjects predominated (79%) with a median age of 10 years (2-19). The risk distribution consisted of 49 (23%) stage IIB, 100 (48%) stage IIIB, 4 (2%) stage IVA and 50 (24%) stage IVB. Histological classification of HL was: nodular sclerosis 45%, mixed cellularity 42%, lymphocyte predominant 5%, lymphocyte depleted 2% and classical not otherwise specified 6%. The most important grade 3 and 4 toxicities were hematological (75%) and there were two grade 5 toxicities, one infectious and one pulmonary. EFS (±SE) at 3 years was 55.4 % (± 4.4), considering abandonment of therapy as an event, and the overall survival (±SE) was 75.1% (±4.2). Abandonment of therapy was 14.6% for the whole cohort, however it was worse for the largest cohort of patients, stage IIIB, 20%. EFS by stage was: stage IIB 79% (± 6%), IIIB 56% (± 7%) and IVB 29% (± 8%). Stage IVB patients clearly had the worse prognosis, however children < 5 years old had an excellent EFS of 90% regardless of stage or histology but a larger proportion had mixed cellularity HL (60%). Conclusions: Our modified Stanford V is a well tolerated regimen with minimal toxicities that does not require growth factor support and can be delivered in an outpatient setting. However, the EFS of patients was less than expected for the group as a whole, (55.4%), and the abandonment rate still unacceptable despite the ease of administration. We have no clear explanation for the excellent survival of children Disclosures: No relevant conflicts of interest to declare.