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Introduction: Collaborative studies have contributed to improved survival of pediatric Hodgkin lymphoma in well-resourced settings, but few are documented in resource-constrained countries. The South Africa Children’s Cancer Study Group initiated harmonization of management protocols in 2015. This article analyzes barriers and enablers of the process. Methods: Clinician-researchers at 11 state-funded pediatric oncology units completed preparatory questionnaires in June 2018. Parameters included infrastructure, access to therapeutic modalities and clinician numbers. A reassessment of 13 sites (two new pediatric oncology unit) in February 2021 ascertained changes in resources and identified challenges to full participation. Questions investigated the presence and quality of diagnostic radiology, availability of surgeons, cytology/pathology options and hematology laboratory facilities. Results: The response rate was 11/11 to survey 1 and 13/13 to survey 2. The anticipated pre-study barriers to participation of pediatric oncology units included time constraints and understaffing. PET-CT was unavailable to two centers. The majority of pediatric oncology units met the minimum criteria to participate. The interim survey confirmed chemotherapy and radiotherapy availability nearly 100% of the time. One site reported improved access to radiotherapy while another reported improved access to PET-CT. Barriers to participation included excessive times to obtain regulatory approvals, time constraints and lack of dedicated research staff. Enablers include the simple management algorithm and communication tools. Conclusion: This study demonstrates that multicenter collaboration and harmonization of management protocols are achievable in a middle-income setting. Minimal funding is required but full participation to run high-quality studies requires more financial investment. Focused funding and increased prioritization of research may address systemic barriers to full participation.

Purpose Primary mediastinal B cell lymphoma (PMBCL) is a highly curable subtype of non-Hodgkin lymphoma that is diagnosed predominantly in adolescents and young adults. Consequently, long-term treatment-related morbidity is critical to consider when devising treatment strategies that include different chemoimmunotherapy strategies with or without radiation therapy. Furthermore, adaptive approaches using the end-of-chemotherapy (EOC) positron emission tomography (PET)/computed tomography (CT) scanning may help to determine which patients may benefit from additional therapies. We aimed to develop evidence-based guidelines for treating these patients. Methods and Materials We conducted a systematic review in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guideline using the PubMed database. The ARS expert committee, composed of radiation oncologists, hematologists, and pediatric oncologists, developed consensus guidelines using the modified Delphi framework. Results Nine studies met the full criteria for inclusion based on reporting outcomes on patients with primary mediastinal B cell lymphoma with EOC PET/CT response scored with the 5-point Deauville scale. These studies formed the evidence for these guidelines in managing patients with PMBCL according to the EOC PET response, including after a 5-point Deauville scale of 1 to 3, 4, or 5, and for patients with relapsed and refractory disease. The expert group also developed guidance on radiation simulation, treatment planning, and plan evaluation based on expert opinion. Conclusions Various treatment approaches exist in the management of PMBCL, including different chemoimmunotherapy regimens, the use of consolidative radiation therapy, and adaptive approaches based on EOC PET/CT response. These guidelines can be used by practitioners to provide appropriate treatment according to different disease scenarios.

Radiotherapy (RT) technology and utilization has considerably evolved over the last 50 years in the management of pediatric Hodgkin lymphoma (HL). In response to significant late effects from RT in HL survivors, clinical trials in the United States and Europe have evaluated ways to maintain high cure rates while reducing late toxicities from treatment. While numerous differences exist with respect to the RT guidelines embedded within therapeutic protocols across the cooperative groups, greater agreement is observed in the indications for RT, doses, volumes, and the incorporation of modern treatment modalities. This report provides an overview of RT delivery in pediatric HL protocols in the United States and Europe and examines areas of consensus on the utilization and delivery of RT in pediatric HL.

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.

Chemotherapy dosages are often compromised, but most reports lack data on dosages that are actually delivered. In two consecutive acute lymphoblastic leukemia trials that differed in their asparaginase formulation, native E. coli L-asparaginase in St. Jude Total 15 (T15, n=365) and pegaspargase in Total 16 (T16, n=524), we tallied the dose intensities for all drugs on the low-risk or standard-risk arms, analyzing 504,039 dosing records. The median dose intensity for each drug ranged from 61-100%. Dose intensities for several drugs were more than 10% higher on T15 than on T16: cyclophosphamide (P

Pediatric early warning systems (PEWS) aid in the early identification of deterioration in hospitalized children with cancer; however, they are under-used in resource-limited settings. The authors use the knowledge-to-action framework to describe the implementation strategy for Proyecto Escala de Valoracion de Alerta Temprana (EVAT), a multicenter quality-improvement collaborative, to scale-up PEWS in pediatric oncology centers in Latin America.Proyecto EVAT mentored participating centers through an adaptable implementation strategy to: (1) monitor clinical deterioration in children with cancer, (2) contextually adapt PEWS, (3) assess barriers to using PEWS, (4) pilot and implement PEWS, (5) monitor the use of PEWS, (6) evaluate outcomes, and (7) sustain PEWS. The implementation outcomes assessed included the quality of PEWS use, the time required for implementation, and global program impact.From April 2017 to October 2021, 36 diverse Proyecto EVAT hospitals from 13 countries in Latin America collectively managing more than 4100 annual new pediatric cancer diagnoses successfully implemented PEWS. The time to complete all program phases varied among centers, averaging 7 months (range, 3-13 months) from PEWS pilot to implementation completion. All centers ultimately implemented PEWS and maintained high-quality PEWS use for up to 18 months after implementation. Across the 36 centers, more than 11,100 clinicians were trained in PEWS, and more than 41,000 pediatric hospital admissions had PEWS used in their care.Evidence-based interventions like PEWS can be successfully scaled-up regionally basis using a systematic approach that includes a collaborative network, an adaptable implementation strategy, and regional mentorship. Lessons learned can guide future programs to promote the widespread adoption of effective interventions and reduce global disparities in childhood cancer outcomes.Pediatric early warning systems (PEWS) are clinical tools used to identify deterioration in hospitalized children with cancer; however, implementation challenges limit their use in resource-limited settings. Proyecto EVAT is a multicenter quality-improvement collaborative to implement PEWS in 36 pediatric oncology centers in Latin America. This is the first multicenter, multinational study reporting a successful implementation strategy (Proyecto EVAT) to regionally scale-up PEWS. The lessons learned from Proyecto EVAT can inform future programs to promote the adoption of clinical interventions to globally improve childhood cancer outcomes.

BACKGROUND: Although mortality due to COVID-19 has been reportedly low among children with cancer, changes in health-care services due to the pandemic have affected cancer care delivery. This study aimed to assess the effect of the COVID-19 pandemic on childhood cancer care worldwide. METHODS: A cross-sectional survey was distributed to paediatric oncology providers worldwide from June 22 to Aug 21, 2020, through the St Jude Global Alliance and International Society for Paediatric Oncology listservs and regional networks. The survey included 60 questions to assess institution characteristics, the number of patients diagnosed with COVID-19, disruptions to cancer care (eg, service closures and treatment abandonment), adaptations to care, and resources (including availability of clinical staff and personal protective equipment). Surveys were included for analysis if respondents answered at least two thirds of the items, and the responses were analysed at the institutional level. FINDINGS: Responses from 311 health-care professionals at 213 institutions in 79 countries from all WHO regions were included in the analysis. 187 (88%) of 213 centres had the capacity to test for SARS-CoV-2 and a median of two (range 0-350) infections per institutution were reported in children with cancer. 15 (7%) centres reported complete closure of paediatric haematology-oncology services (median 10 days, range 1-75 days). Overall, 2% (5 of 213) of centres were no longer evaluating new cases of suspected cancer, while 43% (90 of 208) of the remaining centers described a decrease in newly diagnosed paediatric cancer cases. 73 (34%) centres reported increased treatment abandonment (ie, failure to initiate cancer therapy or a delay in care of 4 weeks or longer). Changes to cancer care delivery included: reduced surgical care (153 [72%]), blood product shortages (127 [60%]), chemotherapy modifications (121 [57%]), and interruptions to radiotherapy (43 [28%] of 155 institutions that provided radiotherapy before the pandemic). The decreased number of new cancer diagnoses did not vary based on country income status (p=0·14). However, unavailability of chemotherapy agents (p=0·022), treatment abandonment (p

Background A phase 1 study was conducted to determine the maximum tolerated dose of bendamustine when given in combination with clofarabine, etoposide, and dexamethasone daily for 5 days in children and adolescents with relapsed or refractory hematologic malignancies. Methods Patients younger than 22 years with second or greater relapsed or refractory acute leukemia or lymphoma after 2 or more prior regimens were eligible. With the rolling 6 design, participants received escalating doses of bendamustine (30, 40, or 60 mg/m2 /d) in combination with clofarabine (40 mg/m2 ), etoposide (100 mg/m2 ), and dexamethasone (8 mg/m2 ) daily for 5 days. Optional pharmacokinetic studies were performed in cycle 1 on day 1 and day 5. Results Sixteen patients were enrolled. Six patients were treated at the dose level of 30 mg/m2 /d, 6 were treated at the dose level of 40 mg/m2 /d, and 4 were treated at the dose level of 60 mg/m2 /d. The dose-limiting toxicity was prolonged myelosuppression. The combination was otherwise well tolerated. The recommended dose of bendamustine in this combination was 30 mg/m2 /d for 5 days. Ten responses were observed after 1 cycle: 6 complete remissions, 1 durable minimal residual disease-negative complete remission without platelet recovery in a patient with early T-cell precursor leukemia, and 3 partial remissions. Six patients proceeded to transplantation. The event-free survival rate was 40.6% (95% confidence interval [CI], 17.5%-63.7%) at 1 year and 33.9% (95% CI, 11.9%-55.9%) at 3 years. Conclusions Bendamustine is well tolerated in combination with clofarabine, etoposide, and dexamethasone. The combination administered over 5 days is effective for multiple relapsed and refractory hematologic malignancies. This trial is registered with ClinicalTrials.gov (NCT01900509). Lay summary Improvements to the existing chemotherapy regimen are still needed for patients who relapse after targeted therapies and immunotherapies and for those who are not eligible for or have no access to such therapies. A regimen combining cyclophosphamide, clofarabine, and etoposide has been used in relapsed and refractory pediatric patients with hematologic malignancies. This study shows that substituting bendamustine for cyclophosphamide in combination with clofarabine and etoposide is safe and effective.

There is growing evidence supporting an inherited basis for susceptibility to acute lymphoblastic leukemia (ALL) in children. In particular, we and others reported recurrent germline ETV6 variants linked to ALL risk, which collectively represent a novel leukemia predisposition syndrome. To understand the influence of ETV6 variation on ALL pathogenesis, we comprehensively characterized a cohort of 32 childhood leukemia cases arising from this rare syndrome. Of 34 nonsynonymous germline ETV6 variants in ALL, we identified 22 variants with impaired transcription repressor activity, loss of DNA binding, and altered nuclear localization. Missense variants retained dimerization with wild-type ETV6 with potentially dominant-negative effects. Whole-transcriptome and whole-genome sequencing of this cohort of leukemia cases revealed a profound influence of germline ETV6 variants on leukemia transcriptional landscape, with distinct ALL subsets invoking unique patterns of somatic cooperating mutations. 70% of ALL cases with damaging germline ETV6 variants exhibited hyperdiploid karyotype with characteristic recurrent mutations in NRAS, KRAS, and PTPN11. In contrast, the remaining 30% cases had a diploid leukemia genome and an exceedingly high frequency of somatic copy-number loss of PAX5 and ETV6, with a gene expression pattern that strikingly mirrored that of ALL with somatic ETV6-RUNX1 fusion. Two ETV6 germline variants gave rise to both acute myeloid leukemia and ALL, with lineage-specific genetic lesions in the leukemia genomes. ETV6 variants compromise its tumor suppressor activity in vitro with specific molecular targets identified by assay for transposase-accessible chromatin sequencing profiling. ETV6-mediated ALL predisposition exemplifies the intricate interactions between inherited and acquired genomic variations in leukemia pathogenesis.

The NCCN Clinical Practice Guidelines in Oncology for Hodgkin Lymphoma (HL) provide recommendations for the management of adult patients with HL. The NCCN panel meets at least annually to review comments from reviewers within their institutions, examine relevant data, and reevaluate and update their recommendations. Current management of classic HL involves initial treatment with chemotherapy alone or combined modality therapy followed by restaging with PET/CT to assess treatment response. Overall, the introduction of less toxic and more effective regimens has significantly advanced HL cure rates. This portion of the NCCN Guidelines focuses on the management of classic HL.

BACKGROUND Data on primary hypothyroidism and its long-term impact on the health, cognition, and quality of life (QOL) of childhood cancer survivors are limited. This study examined the prevalence of and risk factors for primary hypothyroidism and its associations with physical, neurocognitive, and psychosocial outcomes. METHODS This was a retrospective study with a cross-sectional health outcome analysis of an established cohort comprising 2965 survivors of childhood cancer (52.8% male; median current age, 30.9 years, median time since cancer diagnosis, 22.3 years). Multivariable logistic regression estimated odds ratios (ORs) and 95% confidence intervals (CIs) for associations between primary hypothyroidism and cancer-related risk factors, cardiovascular disease risk factors, frailty, neurocognitive and QOL outcomes, social attainment, and subsequent thyroid carcinoma. Associations between serum free thyroxine and thyrotropin levels at assessment and health outcomes were explored. RESULTS The prevalence of primary hypothyroidism was 14.7% (95% CI, 13.5%-16.0%). It was more likely in females (OR, 1.06; 95% CI, 1.03-1.08), was less likely in non-Whites (OR, 0.96; 95% CI, 0.93-0.99), was associated with thyroid radiotherapy (higher risk at higher doses), and was more common if cancer was diagnosed at an age ≥ 15.0 years versus an age

Made available in DSpace on 2022-04-29T08:46:15Z (GMT). No. of bitstreams: 0 Previous issue date: 2022-01-01 Introduction: Brazil has many inequities in the healthcare provided nationwide. Therefore, in order to access challenges in treatment, available resources and current practices, to identify barriers in delivering a good quality of care among Brazilian centers treating children and adolescents with Non-Hodgkin Lymphoma (NHL) and to generate a future prospective guideline, a customized online survey was distributed to pediatric hematologists and oncologists across the country. Results: A total of 97 surveys were completed (35% response rate), from 47 cities in all Brazilian regions and 79 units of care, with a median of 1 answer by the center (range 1 - 5). Most respondents work at an institution supported exclusively by public/philanthropic resources (58%), with an average of 5 to 9 new cases/year (49%), and 41% have 4 to 6 oncologists/centers. Additionally, 22% have no easy access to the intensive care unit, 26% have no access to Rasburicase, 28% have no access to Rituximabe as front-line therapy and 41% have unreliable methotrexate monitoring levels. Those differences cannot be explained thoroughly by regional wealth variances, nor by the financing model. Regarding the pathology service, 70% consider having reasonable quality assistance, but the timeframe to deliver diagnosis is satisfactory to 46%. There is no uniform management of care, with the current guideline from the Sociedade Brasileira de Oncologia Pediátrica being adopted by 54 to 59%, depending on the NHL subtype. Conclusion: This study provides insights into the heterogeneity of care among Brazilian centers. Recognizing those diversities will support the design of effective strategies and collaboration nationwide. Faculdade de Medicina de Botucatu Universidade Estadual Paulista (UNESP), Av. Prof. Mário Rubens Guimarães Montenegro, s/n, CEP 18618687 Hospital Martagão Gesteira Hospital Samaritano Higienópolis Instituto do Tratamento do Câncer Infantil (ITACI) Hospital das Clínicas Universidade de São Paulo Hospital da Criança José de Alencar Fundação Pio-XII Hospital de Amor da Amazônia St Jude Children's Research Hospital Faculdade de Medicina de Botucatu Universidade Estadual Paulista (UNESP), Av. Prof. Mário Rubens Guimarães Montenegro, s/n, CEP 18618687

PURPOSE The widely used, risk-based Lymphome Malin de Burkitt (LMB) chemotherapy regimen has improved survival rates for children with mature B-cell non-Hodgkin lymphoma (NHL); however, associated late effects remain understudied. We assessed late health outcomes after LMB treatment in the Childhood Cancer Survivor Study. PATIENTS AND METHODS Multivariable regression models compared chronic health conditions, health status, and socioeconomic and neurocognitive outcomes between survivors of NHL treated with the LMB regimen (n = 126), survivors of NHL treated with non-LMB regimens (n = 444), and siblings (n = 1,029). RESULTS LMB survivors were a median age of 10.2 years (range, 2.5 to 20.5 years) at diagnosis and 24.0 years (range, 10.3 to 35.3 years) at evaluation. Compared with siblings, LMB survivors were at increased risk for adverse health outcomes. However, survivors of NHL treated with LMB and non-LMB regimens did not differ with regard to risk of having any chronic health conditions, impaired health status, neurocognitive deficits, or poorer socioeconomic outcomes. Increased risk for the following specific neurologic conditions was observed in LMB survivors compared with non-LMB survivors: epilepsy (relative risk [RR], 15.2; 95% CI, 3.1 to 73.4); balance problems (RR, 8.9; 95% CI, 2.3 to 34.8); tremors (RR, 7.5; 95% CI, 1.9 to 29.9); weakness in legs (RR, 8.1; 95% CI, 2.5 to 26.4); severe headaches (RR, 3.2; 95% CI, 1.6 to 6.3); and prolonged arm, leg, or back pain (RR, 4.0; 95% CI, 2.2 to 7.1). The survivors from the group C LMB risk group (n = 50) were at the highest risk for these conditions; however, except for worse functional status (odds ratio, 2.7; 95% CI, 1.2 to 5.8), they were not at increased risk for other adverse health status or socioeconomic outcomes compared with non-LMB survivors. CONCLUSION Survivors treated with LMB and non-LMB regimens are largely comparable in late health outcomes except for excess neurotoxicity among LMB survivors. These data inform treatment efforts seeking to optimize disease control while minimizing toxicity.

Background and purpose The use of radiotherapy (RT) for pediatric patients with Hodgkin lymphoma (HL) experiencing disease progression or recurrence (15%) is controversial. We report treatment patterns and outcomes for pediatric patients with refractory/recurrent HL (rrHL) treated with curative-intent RT. Materials and methods Forty-six patients with rrHL treated with salvage RT at our institution were identified. All received risk-adapted, response-based frontline therapy and were retrieved with cytoreductive regimens followed by RT to failure sites, with or without autologous hematopoietic cell transplantation (AHCT). Cumulative incidence (CIN) of local failure (LF) and survival were estimated after salvage RT and regression models determined predictors of LF after salvage RT. Results RT was administered as part of frontline therapy in 70% of patients, omitted for early response assessment in 13%, or deferred for primary progression in 17%. AHCT was omitted in 20% of patients. Median initial and salvage dose/site were 25.5 Gy and 30.6 Gy, respectively. Eight patients experienced progression. Two died without progression (median follow-up from salvage RT = 3.8 years). The 5-year CIN of LF after salvage RT was 17.7% (95% confidence interval [CI], 8.2–30.2%). The 5-year freedom from subsequent treatment failure and overall survival (OS) was 80.1% (95% CI, 69.2–92.6%) and 88.5% (95% CI, 79.5–98.6%), respectively. Inadequate response to salvage systemic therapy (p = 0.048) and male sex (p = 0.049) were significantly associated with LF after salvage RT. Conclusion rrHL is responsive to salvage RT, with low LF rates after moderate doses. OS is excellent, despite refractory disease. Initial salvage therapy response predicts subsequent LF.

The epidemiology, outcome and targeted immunotherapy in adolescent and young adult non-Hodgkin and Hodgkin lymphoma were discussed during the 6th International Symposium on Childhood, Adolescent and Young Adult Non-Hodgkin Lymphoma September 26th-29th 2018 in Rotterdam, the Netherlands. This review summarizes some of those presentations, as well as other current and novel antibody therapy, immune check-point inhibitors, chimeric antigen receptor T cells, cancer vaccines and cytotoxic T lymphocyte therapy.

The World Health Organization (WHO) designates early integration of palliative care as an ethical responsibility in the treatment of children with serious illness. Although structural barriers may influence provision of pediatric palliative care (PPC) for children with cancer in resource-limited settings, underlying physician perceptions may also impede early integration of PPC in cancer care.To investigate perceptions among physicians in Latin America about the integration of palliative care for children with cancer.This survey study used the Assessing Doctors' Attitudes on Palliative Treatment (ADAPT) survey, which was developed for physicians who care for children with cancer and was initially distributed in Eurasia. The survey was modified for use in Latin America, including translation into Spanish and adaptation for cultural context. The survey was distributed between August 21, 2020, and January 31, 2021, to physicians treating children with cancer in 17 Latin American countries. Each country had a specific survey distribution method based on guidance of local experts.The ADAPT survey evaluated physicians' understanding of palliative care principles, comfort in addressing patient and family suffering, and identification of barriers to PPC integration for children with cancer. Univariate and multivariable linear regression analyses were used to assess factors associated with physicians' knowledge about and comfort with PPC practice and whether independent physician variables were associated with survey response alignment with WHO guidance on PPC. Open-ended questions were analyzed qualitatively to supplement the quantitative data.A total of 874 physicians from 17 countries participated, with an overall response rate of 39.9% (874 of 2193) and a median country response rate of 51.4% (range, 23.7%-100%). Most respondents were aged 35 years or older (577 [66.0%]), and 594 (68.0%) identified as female. Most physicians (486 [55.6%]) had no formal PPC training, and 303 (34.7%) had no access to PPC experts for consultation. Physician perspectives on PPC were generally aligned with WHO guidance (mean [SD] alignment, 83.0% [14.1%]; range among respondents, 24.0%-100%). However, only 438 respondents (50.1%) felt comfortable addressing physical symptoms of patients receiving PPC, 295 (33.8%) felt comfortable addressing emotional symptoms, and 216 (24.7%) felt comfortable addressing grief and bereavement needs of the patient's family. A total of 829 participants (94.8%) desired further education and training in PPC.Although physicians' perspectives aligned well with WHO guidance for PPC, this survey study identified opportunities for improving physician training in symptom management and emotional support for children with cancer and their families. These findings may inform the development of targeted interventions to improve the quality of PPC for children with cancer in Latin America.

Waldeyer's ring (WR) involvement in pediatric Hodgkin lymphoma (HL) is extremely rare and criteria for determining involvement and response to treatment are unclear. The international Staging, Evaluation, and Response Criteria Harmonization for Childhood, Adolescent and Young Adult Hodgkin Lymphoma (SEARCH for CAYAHL) Group performed a systematic review of the literature in search of involvement or response criteria, or evidence to support specific criteria. Only 166 cases of HL with WR involvement were reported in the literature, 7 of which were pediatric. To date no standardized diagnostic or response assessment criteria are available. Given the paucity of evidence, using a modified Delphi survey technique, expert consensus statements were developed by the SEARCH group to allow for a more consistent definition of disease and response evaluation related to this rare site of involvement among pediatric oncologists. The available evidence and expert consensus statements are summarized.

Background Osteonecrosis is a debilitating complication in children and adolescents with acute lymphoblastic leukemia or acute lymphoblastic lymphoma (LLy). An objective screening test to identify patients at risk for symptomatic, extensive joint involvement will help manage osteonecrosis. Methods We performed a prospective, longitudinal pilot study with whole-joint magnetic resonance imaging (MRI) of shoulders, elbows, hips, knees, ankles, and hindfeet to evaluate the incidence and timing of osteonecrosis involving multiple joints in 15 patients with LLy aged 9-21 years at diagnosis. Results Osteonecrosis affecting ≥30% of the epiphysis occurred in eight of 15 patients, with a high prevalence in hips (12 of 26 examined [46%]) and knees (10 of 26 [38%]) post reinduction I and in shoulders (seven of 20 [35%]) post reinduction II. Most osteonecrotic hips and knees with ≥30% epiphyseal involvement became symptomatic and/or underwent surgery (100% and 82%, respectively). All eight patients with ≥30% epiphyseal involvement had multijoint involvement. Seven of these patients had hip or knee osteonecrosis by the end of remission induction, and only these patients developed osteonecrosis that became symptomatic and/or underwent surgery in their hips, knees, shoulders, ankles, and/or feet; all of these joints were associated with epiphyseal abnormalities on post reinduction I imaging. Conclusions MRI screening in adolescent patients with LLy revealed osteonecrosis in multiple joints. Initial screening with hip and knee MRI at the end of induction may identify susceptible patients who could benefit from referrals to subspecialties, more extensive follow-up imaging of other joints, and early medical and surgical interventions.

Background and objectives: Children with Hodgkin lymphoma (HL) and Human Immunodeficiency Virus (HIV) have low 5 year overall survival rates in South Africa, home to the world’s largest HIV population. We aimed to explore factors impacting on survival in children with HIV and HL by comparing those with and without HIV, and to determine long term survival. Methods: A retrospective study was conducted to determine survival rates and prognostic factors in South African children and adolescents with HL. Univariate risk factor analysis was performed to analyse prognostic factors. Results: Between January 2000 and December 2010, 271 children and adolescents with HL were eligible for analysis. Compared to the 242 HIV-uninfected patients, the 29 HIV-infected patients were younger (median 7.2 vs 10.0 years, p=0.052) and more likely to present with Stage IV disease (p=0.000) The 5-year overall survival rate (OS) of HIV-infected patients of 49% versus 84% for HIV-uninfected patients (p=0.001) appeared to be associated with hypoalbuminaemia (

Context.—Several countries of the Central America and Caribbean region have been sharing regional neuroblastoma (NB) treatment guidelines. However, there is no standardization in the diagnosis, subclassification, or tumor biology to aid in the risk stratification of these patients.Objective.—To examine the histology and assess the accuracy of the local pathology reports; to evaluate the usefulness of manual MYCN immunohistochemistry (IHC); and to use NB as a model to identify the needs to establish a central pathology review (CPR) program in this region.Design.—A retrospective CPR of specimens derived from patients with a diagnosis of NB and treated under the regional NB guidelines between 2012 and 2017 was conducted, allowing for a comparison between local diagnoses and the CPR diagnoses. Manual MYCN IHC was performed in the confirmed NB specimens and the results compared with known fluorescence in situ hybridization or automated IHC results, when available.Results.—The 156 specimens reviewed included 460 blocks and 183 original slides. Neuroblastoma was confirmed in 138 samples (88.5%), but low concordance rates for Shimada classification (n = 39; 25.0%), mitotic-karyorrhectic index (n = 4; 2.5%), and International Neuroblastoma Pathology Classification (n = 18; 11.5%) were noted. Manual MYCN IHC performed on 120 specimens showed conclusive results in 89.2% (28 positive, 23.4%; 79 negative, 65.8%) and questionable results in 10.8% (n = 13).Conclusions.—This retrospective CPR highlights the need for a CPR program to serve this region, to ensure correct diagnosis and subclassification of NB, and to provide manual MYCN IHC—with reflexing to fluorescence in situ hybridization, if questionable. This approach can further regional collaboration, enhance test utilization, and ultimately improve patients' outcomes.

Adolescents and young adults (AYAs) comprise the largest age group affected by Hodgkin lymphoma (HL). Despite excellent overall survival of AYA patients with HL due to advances in treatment regimens, therapy-associated late effects continue to be a concern in HL survivors, especially for younger patients who have decades of life remaining. Since the first clinical trial for HL with chemotherapy in 1964, subsequent protocols have attempted to reduce chemotherapy-induced toxicities and yet maintain high overall survival rates. Today, new analytic methods applied to data from survivorship cohorts, such as the recently described cumulative burden of disease metric, can be used to inform changes for future protocols. Although pediatric and adult trial consortia have followed this process, the AYA population, an age cohort split between pediatric and adult health care services, faces many barriers to care and is the least likely to be enrolled in clinical trials. AYA patients with HL theoretically have a choice to be treated in pediatric or adult protocols when presented with these options. Recent efforts by the National Clinical Trials Network, the Children’s Oncology Group, and others have been made to ensure that the burden of choice for the AYA population is not greater than the burden of disease.

Background Pleural effusion at presentation in Hodgkin lymphoma has been associated with inferior outcome but has not been systematically evaluated. Objective To determine whether pleural effusion at presentation in children with Hodgkin lymphoma is a primary indicator of poor prognosis or secondary to associated factors. Materials and methods Children’s Oncology Group (COG) AHOD0031, a randomized, response-based, centrally reviewed protocol, enrolled 1,712 eligible patients

The NCCN Clinical Practice Guidelines in Oncology for Hodgkin Lymphoma (HL) provide recommendations for the management of adult patients with HL. The NCCN Guidelines Panel meets at least annually to review comments from reviewers within the NCCN Member Institutions, examine relevant data, and reevaluate and update the recommendations. These NCCN Guidelines Insights summarize recent updates centered on treatment considerations for relapsed/refractory classic HL.

BACKGROUND Children with acute lymphoblastic leukemia (ALL) can develop reduced bone mineral density (BMD). However, data from patients who received treatment on a frontline regimen without cranial irradiation are limited, and no genome-wide analysis has been reported. METHODS Lumbar BMD was evaluated by quantitative computed tomography at diagnosis, after 120 weeks of continuation therapy, and after 2 years off therapy in pediatric patients with ALL (ages 2-18 years at diagnosis) who were treated on the St. Jude Total XV Protocol. Clinical, pharmacokinetic, and genetic risk factors associated with decreased BMD Z-scores were evaluated. RESULTS The median BMD Z-score in 363 patients was 0.06 at diagnosis, declined to -1.08 at week 120, but partly recovered to -0.72 after 2 years off therapy; BMD in patients with low BMD Z-scores at diagnosis remained low after therapy. Older age (≥10 years vs 2-9.9 years at diagnosis; P

Rearrangements in KMT2A (KMT2Ar) are associated with pediatric, adult and therapy-induced acute leukemias. Infants with KMT2Ar acute lymphoblastic leukemia (ALL) have a poor prognosis, with an event-free-survival (EFS) of 33.6-36.9%. In the context of the remarkable improvements in the treatment of childhood ALL, the dismal outcome of infantile KMT2Ar ALL and the lack of any significant progress for more than two decades are striking . The St. Jude Total Therapy 16 study (the most recently reported study of a program for childhood ALL that begun in 1962) yielded a 5-year EFS of 88.2% overall. Total 16 enrolled all subtypes of newly diagnosed pediatric ALL patients including infants, with intensity of treatment adapted to presenting clinical and genomic features, and early treatment response as determined by minimal/measurable residual disease (MRD). KMT2Ar infants were treated on an intensified high-risk arm and received clofarabine in combination with cyclophosphamide and etoposide (CCE) at two points during treatment: Induction days 22-25 and Reinduction I. Infants who lacked KMT2Ar and KMT2Ar patients who were one year of age or older received the same risk-directed treatment plan given to all other patients enrolled on study. A total of 28 patients with KMT2Ar were enrolled on Total 16; the 19 patients > 1 year of age received standard-risk therapy, and the 9 patients < 1 year of age received high-risk therapy on the infant arm with CCE. The probabilities of 5-year EFS and overall survival in KMT2Ar patients > 1 year of age and those < 1 year of age were 73.3% vs. 44.4% (p=0.071) and 84.2% vs. 55.6% (p=0.060), respectively. Six of the nine infants were MRD-positive on Induction day 15 prior to CCE (MRD-positive range, 0.012% to 13.7%; median, 2.13%) with MRD negative status ( 1 year of age and 12.5% for those < 1 year of age (p=0.454). Five infants remain alive (four in CR1, one in CR2), while four expired in CR1. Three deaths were secondary to infection, including a multi-drug resistant soft tissue bacterial infection during Induction days 1-21, a respiratory syncytial virus pneumonia during Reinduction II, and a chronic parainfluenza 3 infection during Continuation weeks 70-101 that led to chronic pneumonitis and interstitial fibrosis. The fourth patient developed grade 5 pulmonary hypertension following induction, a complication potentially compounded by their presenting WBC count of 905 x 10 9/L and pulmonary leukostasis. A comparison of 3-year cumulative risk of selected major toxic effects of treatment revealed that high-risk infants had a lower incidence of asparaginase allergic reactions, osteonecrosis, hyperglycemia, and pancreatitis; in contrast, the incidence of fever and neutropenia, hepatic toxicity and seizures, was similar in high-risk patients regardless of age. Infants had a higher risk of thrombosis (46.7% vs. 23.1%, p 1 year of age that received one or more clofarabine-containing Reintensification chemotherapy cycles prior to hematopoietic stem cell transplant in first remission (CR1). This revealed a higher frequency of infections in infants, suggesting a greater susceptibility to this complication independent from clofarabine exposure (mean number of episodes, 2.39 vs. 1, p Disclosures Gruber: Kura Oncology: Consultancy. Coustan-Smith: Juno Therapeutics: Patents & Royalties; Nkarta Therapeutics: Current holder of individual stocks in a privately-held company; Medisix Therapeutics: Current holder of individual stocks in a privately-held company. Campana: Nkarta Therapeutics: Current holder of stock options in a privately-held company; Medisix Therapeutics: Current holder of stock options in a privately-held company; Juno: Other: patent licensing payments; Juno Therapeutics (a Bristol-Myers Squibb company),: Other: patents on methods for minimal residual disease detection.. Evans: St. Jude Children's Research Hospital, Emeritus Member (began Jan 2021): Ended employment in the past 24 months; BioSkryb, Inc.: Membership on an entity's Board of Directors or advisory committees; Princess Máxima Center for Pediatric Oncology, Scientific Advisory Board, Chair: Membership on an entity's Board of Directors or advisory committees. Pui: Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; Novartis: Other: Data Monitoring Committee.

Purpose: Ninety percent of children with cancer live in low- and middle-income countries, and fewer than 40% survive. In these countries, rates of treatment abandonment can be up to 50-60%, contributing to the mortality gap. Fatalistic cancer beliefs may lead to delayed diagnosis and poor outcomes, including treatment abandonment. This study explored the evolution of Guatemalan parents' cancer beliefs during initial pediatric cancer communication, and the sociocultural and contextual factors that influence these beliefs. Methods: Twenty families of children with cancer were included in this study. We audio-recorded initial psychosocial and diagnostic conversations between parents, psychologists, and oncologists, then conducted semi-structured interviews with parents. Audio-recordings were transcribed and translated from Spanish into English and thematically analyzed. Results: Guatemalan parents' beliefs evolve as they learn about cancer through various sources. Sources of information external to the cancer center, including prior experiences with cancer, media exposure, community discussion, and clinical encounters, contribute to pre-existing beliefs, many of which are fatalistic and influenced by Mayan spirituality. Sources internal to the cancer center include psychologists and oncologists, other providers, other patients and families. Psychologists acknowledge pre-existing beliefs and deliver cancer education using verbal explanations and hand-drawings. Oncologists provide diagnostic information and outline treatment plans. Both support hope by providing a path toward cure. Parents' lived experience is a culmination of sources and simultaneously independent. Ultimately most parents arrive at an understanding of cancer that is consistent with an allopathic medical model and offers optimism about outcomes. Conclusion: An interdisciplinary communication process that includes multimedia education, is attentive to pre-existing beliefs, and supports hope may encourage acceptance of the allopathic model and need for treatment. Providers in settings of all resource levels may be able to use these techniques to support cross-cultural cancer communication, reduce treatment abandonment, and improve therapy adherence. Citation Format: Dylan Graetz, Silvia Rivas, Lucia Fuentes, Annie Caceres-Serrano, Gia Ferrara, Antillon-Klussmann, Monika Metzger, Carlos Rodriguez-Galindo, Jennifer Mack. The Evolution of Parents' Beliefs about Childhood Cancer: A Qualitative Study in Guatemala [abstract]. In: Proceedings of the 9th Annual Symposium on Global Cancer Research; Global Cancer Research and Control: Looking Back and Charting a Path Forward; 2021 Mar 10-11. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2021;30(7 Suppl):Abstract nr 10.

OBJECTIVES Glucocorticoids such as dexamethasone have pleiotropic effects, including desired antileukemic, anti-inflammatory, or immunosuppressive effects, and undesired metabolic or toxic effects. The most serious adverse effects of dexamethasone among patients with acute lymphoblastic leukemia are osteonecrosis and thrombosis. To identify inherited genomic variation involved in these severe adverse effects, we carried out genome-wide association studies (GWAS) by analyzing 14 pleiotropic glucocorticoid phenotypes in 391 patients with acute lymphoblastic leukemia. PATIENTS AND METHODS We used the Projection Onto the Most Interesting Statistical Evidence integrative analysis technique to identify genetic variants associated with pleiotropic dexamethasone phenotypes, stratifying for age, sex, race, and treatment, and compared the results with conventional single-phenotype GWAS. The phenotypes were osteonecrosis, central nervous system toxicity, hyperglycemia, hypokalemia, thrombosis, dexamethasone exposure, BMI, growth trajectory, and levels of cortisol, albumin, and asparaginase antibodies, and changes in cholesterol, triglycerides, and low-density lipoproteins after dexamethasone. RESULTS The integrative analysis identified more pleiotropic single nucleotide polymorphism variants (P=1.46×10(-215), and these variants were more likely to be in gene-regulatory regions (P=1.22×10(-6)) than traditional single-phenotype GWAS. The integrative analysis yielded genomic variants (rs2243057 and rs6453253) in F2RL1, a receptor that functions in hemostasis, thrombosis, and inflammation, which were associated with pleiotropic effects, including osteonecrosis and thrombosis, and were in regulatory gene regions. CONCLUSION The integrative pleiotropic analysis identified risk variants for osteonecrosis and thrombosis not identified by single-phenotype analysis that may have importance for patients with underlying sensitivity to multiple dexamethasone adverse effects.

This portion of the NCCN Guidelines for Hodgkin lymphoma (HL) focuses on the management of classical HL. Current management of classical HL involves initial treatment with chemotherapy or combined modality therapy followed by restaging with PET/CT to assess treatment response using the Deauville criteria (5-point scale). The introduction of less toxic and more effective regimens has significantly advanced HL cure rates. However, long-term follow-up after completion of treatment is essential to determine potential long-term effects.

This topic addresses the treatment of newly diagnosed patients with favorable prognosis stage I and II Hodgkin lymphoma. In most cases, combined modality therapy (chemotherapy followed by involved site radiation therapy) constitutes the current standard of care. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer-reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment. By combining the most recent medical literature and expert opinion, this revised guideline can aid clinicians in the appropriate use of combined modality therapy for favorable prognosis stage I and II Hodgkin lymphoma. Increasing information about the late effects of treatment has led to attempts to decrease toxicity by using less chemotherapy (decreased duration and/or intensity or different agents) and less radiation therapy (reduced volume and/or dose) while maintaining excellent efficacy.

Background Children diagnosed with cancer are at a significantly higher risk of developing a thrombotic event (TE) compared with the general population. The rarity of these events makes it difficult to discern the specific risk factors; however, age, sex, presence of central venous lines, inherited thrombophilia, and mediastinal mass may play a role. The primary aim of this study is to identify prognostic characteristics of children diagnosed with non-lymphoblastic lymphomas associated with a greater risk of developing a TE early on in their disease, with an increased focus on mediastinal mass characteristics. Methods Retrospective chart review of pediatric patients diagnosed with non-lymphoblastic lymphoma between 2004 and 2014 at St. Jude Children's Research Hospital. Results TE occurred in 8.5% (n = 28/330) of individuals at a median of 21 days from the diagnosis of a non-lymphoblastic lymphoma, with 60% of TEs occurring within 30 days of diagnosis. Of the variables evaluated, only presence of a peripherally inserted central catheter (odds ratio [OR]: 3.14 [95% CI: 1.24-7.98; P = 0.02]) and degree of superior vena cava (SVC) compression of > 25% increased the odds of developing a TE (OR: 2.2 [95% CI: 1.01-4.93; P = 0.048]). Conclusion Pediatric patients with non-lymphoblastic lymphoma are at increased risk of developing TEs. In contrast to previous studies, the presence of a mediastinal mass alone was not associated with a higher risk of TE, but individuals with a mediastinal mass with 25% or greater degree of SVC compression were more likely to develop a TE. This finding highlights a high-risk group of children who may benefit from prophylactic anticoagulation.

PURPOSE Direct assessment of Leydig cell function in childhood cancer survivors has been limited. The objectives of this study were to describe the prevalence of and risk factors for Leydig cell failure (LCF), Leydig cell dysfunction (LCD), and associated adverse health outcomes. PATIENTS AND METHODS In this retrospective study with cross-sectional health outcomes analysis, we evaluated 1,516 participants (median age, 30.8 years) at a median of 22.0 years after cancer diagnosis. LCF was defined as serum total testosterone less than 250 ng/dL (or 8.67 nmol/L) and luteinizing hormone greater than 9.85 IU/L, and LCD by testosterone as 250 ng/dL or greater and luteinizing hormone greater than 9.85 IU/L. Polytomous logistic regression evaluated associations with demographic and treatment-related risk factors. Log-binomial regression evaluated associations with adverse physical and psychosocial outcomes. Piecewise exponential models assessed the association with all-cause mortality. RESULTS The prevalence of LCF and LCD was 6.9% and 14.7%, respectively. Independent risk factors for LCF included an age of 26 years or older at assessment, testicular radiotherapy at any dose, and alkylating agents at cyclophosphamide equivalent doses of 4,000 mg/m2 or greater. The risk increased with older age, higher doses of testicular radiotherapy, and cyclophosphamide equivalent doses. LCF was significantly associated with abdominal obesity, diabetes mellitus, erectile dysfunction, muscle weakness, and all-cause mortality. LCD was associated with unilateral orchiectomy and the same risk factors as LCF; no significant associations were found with adverse physical or psychosocial outcomes. CONCLUSION Older age, testicular radiotherapy, and exposure to alkylating agents were associated with LCF, which was associated with adverse physical and psychosexual outcomes. LCD, although having similar risk factors, was not associated with adverse health outcomes. Additional studies are needed to investigate the role of sex hormone replacement in mitigating the burden from adverse outcomes in survivors.