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Background: Disease-modifying therapies (DMTs) are used to treat people with relapsing-onset multiple sclerosis (ROMS), but our knowledge is largely limited to their short-term effects. Objective: To determine (1) the impact of national-level DMT subsidy policy on DMT use and health outcomes in people with MS (PwMS) and (2) the long-term effects of DMT on disability and quality of life (QoL; 5-level EQ-5D version (EQ-5D-5L) utility value). Methods: This observational cohort study compared Australian and New Zealand populations with different levels of DMT availability 10–20 years post-ROMS diagnosis. Between-country differences were assessed using standardised differences. Associations were assessed with multivariable linear regression models. Results: We recruited 328 Australians and 256 New Zealanders. The Australian cohort had longer DMT treatment duration, greater proportion of disease course treated and shorter duration between diagnosis and starting DMT. The Australian cohort had lower median Expanded Disability Status Scale (EDSS) (3.5 vs 4.0) and Multiple Sclerosis Severity Score (MSSS) (3.05 vs 3.71) and higher QoL (0.71 vs 0.65). In multivariable models, between-country differences in disability and QoL were largely attributed to differential use of DMT. Conclusions: This study provides evidence for the impact of national-level DMT policy on disability outcomes in PwMS. Where DMTs are more accessible, PwMS experienced less disability progression and improved QoL 10–20 years post-diagnosis.

Background Tobacco cessation among patients with head/neck cancer continues to be challenging despite evidence that cessation improves treatment outcomes. The purpose of this study was to understand barriers/facilitators to tobacco cessation among patients with head/neck cancer and health care providers and to obtain perspectives toward the development of a patient-centered tobacco cessation intervention. Materials and Methods In-depth qualitative interviews with 10 health care providers and 21 patients with head/neck cancer (12 inpatients and 9 outpatients) who were current or former smokers. Results Health was a common motivator to quit among patients. Although most patients indicated that their health care provider asked and advised them to quit, they were unaware of cessation resources. Suggestions for a tobacco cessation program included involvement of former smokers, health care provider involvement/counseling, supporting written materials, and incorporating follow-up and family support. Health care providers identified patients’ anger/frustration associated with the disease, social/demographic issues, and poor quality of life as the three most frequent challenges in treating patients. Although all providers reported asking about tobacco use, 70% emphasized a lack of formal training in tobacco cessation and lack of time. Their suggestions for a cessation program included having a “quarterback” responsible for this component with support from the entire health care team and continuity between outpatient and inpatient services to promote cessation, prevent relapse, and highlight the importance of follow-up and social support. Conclusion There is great interest and need, both from patients and providers, for tobacco cessation services in the oncology setting tailored for patients with head/neck cancer in the context of cancer care. Implications for Practice Although the combination of pharmacotherapy and cognitive-behavioral intervention is the standard evidence-based treatment for tobacco dependence, it must be adapted to meet the needs and wants of patients and providers to be effective. This study provides an in-depth examination of such needs among patients with head and neck cancer and providers in the context of cancer care. Providers and patients emphasized the need of having a trained health care provider dedicated to providing tobacco cessation through seamless integration between outpatient and inpatient services as well as follow-up with an emphasis on family involvement throughout the process.

PURPOSE Children's Oncology Group (COG) AALL0331 tested whether pegaspargase intensification on a low-intensity chemotherapy backbone would improve the continuous complete remission (CCR) rate in a low-risk subset of children with standard-risk B-acute lymphoblastic leukemia (ALL). METHODS AALL0331 enrolled 5,377 patients with National Cancer Institute standard-risk B-ALL (age 1-9 years, WBC < 50,000/μL) between 2005 and 2010. Following a common three-drug induction, a cohort of 1,857 eligible patients participated in the low-risk ALL random assignment. Low-risk criteria included no extramedullary disease, < 5% marrow blasts by day 15, end-induction marrow minimal residual disease < 0.1%, and favorable cytogenetics ( ETV6-RUNX1 fusion or simultaneous trisomies of chromosomes 4, 10, and 17). Random assignment was to standard COG low-intensity therapy (including two pegaspargase doses, one each during induction and delayed intensification) with or without four additional pegaspargase doses at 3-week intervals during consolidation and interim maintenance. The study was powered to detect a 4% improvement in 6-year CCR rate from 92% to 96%. RESULTS The 6-year CCR and overall survival (OS) rates for the entire low-risk cohort were 94.7% ± 0.6% and 98.7% ± 0.3%, respectively. The CCR rates were similar between arms (intensified pegaspargase 95.3% ± 0.8% v standard 94.0% ± 0.8%; P = .13) with no difference in OS (98.1% ± 0.5% v 99.2% ± 0.3%; P = .99). Compared to a subset of standard-risk study patients given identical therapy who had the same early response characteristics but did not have favorable or unfavorable cytogenetics, outcomes were significantly superior for low-risk patients (CCR hazard ratio 1.95; P = .0004; OS hazard ratio 5.42; P < .0001). CONCLUSION Standard COG therapy without intensified pegaspargase, which can easily be given as an outpatient with limited toxicity, cures nearly all children with B-ALL identified as low-risk by clinical, early response, and favorable cytogenetic criteria.

We conducted the first human leukocyte antigen (HLA) allele and genome-wide association study to identify loci associated with hypersensitivity reactions exclusively to the PEGylated preparation of asparaginase (pegaspargase) in racially diverse cohorts of pediatric leukemia patients: St Jude Children's Research Hospital's Total XVI (TXVI, n = 598) and Children's Oncology Group AALL0232 (n = 2,472) and AALL0434 (n = 1,189). Germline DNA was genotyped using arrays. Genetic variants not genotyped directly were imputed. HLA alleles were imputed using SNP2HLA or inferred using BWAkit. Analyses between genetic variants and hypersensitivity were performed in each cohort first using cohort-specific covariates and then combined using meta-analyses. Nongenetic risk factors included fewer intrathecal injections (P = 2.7 × 10-5 in TXVI) and male sex (P = 0.025 in AALL0232). HLA alleles DQB1*02:02, DRB1*07:01, and DQA1*02:01 had the strongest associations with pegaspargase hypersensitivity (P

Adolescents and young adults (AYAs) with acute lymphoblastic leukemia have improved outcomes when treated with pediatric-inspired regimens. CALGB 10403 was the largest prospective study to evaluate the feasibility of using a pediatric regimen in AYAs with acute lymphoblastic leukemia up to 40 years of age. This article presents the toxicity events observed in the CALGB 10403 study and compares these toxicities vs those observed among AYAs treated on the same arm of the companion Children’s Oncology Group (COG) AALL0232 study. Toxicities in CALGB 10403 were similar to those observed in COG AALL0232. Some grade 3 to 4 adverse events were more often reported in CALGB 10403 compared with COG AALL0232 (hyperglycemia, hyperbilirubinemia, transaminase elevation, and febrile neutropenia). Adverse events correlated with body mass index ≥30 kg/m2 and some with increasing age. The mortality rate in CALGB 10403 was low (4%) and similar to that in the COG AALL0232 trial. A caveat to this analysis is that only 39% of CALGB 10403 patients completed all planned protocol treatment. In COG AALL0232, although 74% of patients aged

Drug resistance may pre-exist or arise during therapy, but how precisely cancer treatment itself influences these processes is a major gap in the understanding of therapy resistance in cancer. A study of acute lymphocytic leukemia now provides direct evidence of thiopurine-induced mutations in the gene encoding the tumor suppressor p53 that result in multi-drug-resistant relapse.

PURPOSE Nelarabine is effective in inducing remission in patients with relapsed and refractory T-cell acute lymphoblastic leukemia (T-ALL) but has not been fully evaluated in those with newly diagnosed disease. PATIENTS AND METHODS From 2007 to 2014, Children’s Oncology Group trial AALL0434 (ClinicalTrials.gov identifier: NCT00408005 ) enrolled 1,562 evaluable patients with T-ALL age 1-31 years who received the augmented Berlin-Frankfurt-Muenster (ABFM) regimen with a 2 × 2 pseudo-factorial randomization to receive escalating-dose methotrexate (MTX) without leucovorin rescue plus pegaspargase (C-MTX) or high-dose MTX (HDMTX) with leucovorin rescue. Intermediate- and high-risk patients were also randomly assigned after induction to receive or not receive six 5-day courses of nelarabine that was incorporated into ABFM. Patients who experienced induction failure were nonrandomly assigned to HDMTX plus nelarabine. Patients with overt CNS disease (CNS3; ≥ 5 WBCs/μL with blasts) received HDMTX and were randomly assigned to receive or not receive nelarabine. All patients, except those with low-risk disease, received cranial irradiation. RESULTS The 5-year event-free and overall survival rates were 83.7% ± 1.1% and 89.5% ± 0.9%, respectively. The 5-year disease-free survival (DFS) rates for patients with T-ALL randomly assigned to nelarabine (n = 323) and no nelarabine (n = 336) were 88.2% ± 2.4% and 82.1% ± 2.7%, respectively ( P = .029). Differences between DFS in a four-arm comparison were significant ( P = .01), with no interactions between the MTX and nelarabine randomizations ( P = .41). Patients treated with the best-performing arm, C-MTX plus nelarabine, had a 5-year DFS of 91% (n = 147). Patients who received nelarabine had significantly fewer isolated and combined CNS relapses compared with patients who did not receive nelarabine (1.3% ± 0.63% v 6.9% ± 1.4%, respectively; P = .0001). Toxicities, including neurotoxicity, were acceptable and similar between all four arms. CONCLUSION The addition of nelarabine to ABFM therapy improved DFS for children and young adults with newly diagnosed T-ALL without increased toxicity.

PURPOSE The Children’s Oncology Group (COG) protocol AALL0434 evaluated the safety and efficacy of multi-agent chemotherapy with Capizzi-based methotrexate/pegaspargase (C-MTX) in patients with newly diagnosed pediatric T-cell lymphoblastic lymphoma (T-LL) and gained preliminary data using nelarabine in high-risk patients. PATIENTS AND METHODS The trial enrolled 299 patients, age 1-31 years. High-risk (HR) patients had ≥ 1% minimal detectable disease (MDD) in the bone marrow at diagnosis or received prior steroid treatment. Induction failure was defined as failure to achieve a partial response (PR) by the end of the 4-week induction. All patients received the augmented Berlin-Frankfurt-Muenster (ABFM) C-MTX regimen. HR patients were randomly assigned to receive or not receive 6 5-day courses of nelarabine incorporated into ABFM. Patients with induction failure were nonrandomly assigned to ABFM C-MTX plus nelarabine. No patients received prophylactic cranial radiation; however, patients with CNS3 disease (CSF WBC ≥ 5/μL with blasts or cranial nerve palsies, brain/eye involvement, or hypothalamic syndrome) were ineligible. RESULTS At end-induction, 98.8% of evaluable participants had at least a PR. The 4-year event-free survival (EFS) and overall survival (OS) were 84.7% ± 2.3% and 89.0% ± 2.0%. The 4-year disease-free survival (DFS) from end-induction was 85.9% ± 2.6%. There was no difference in DFS observed between the HR and standard-risk groups ( P = .29) or by treatment regimen ( P = .55). Disease stage, tumor response, and MDD at diagnosis did not demonstrate thresholds that resulted in differences in EFS. Nelarabine did not show an advantage for HR patients. CNS relapse occurred in only 4 patients. CONCLUSION COG AALL0434 produced excellent outcomes in one of the largest trials ever conducted for patients with newly diagnosed T-LL. The COG ABFM regimen with C-MTX provided excellent EFS and OS without cranial radiation.

Leukemia, most commonly B-cell acute lymphoblastic leukemia (B-ALL), accounts for about 30% of childhood cancer diagnoses. While there have been dramatic improvements in childhood ALL outcomes, certain subgroups-particularly those who relapse-fare poorly. In addition, cure is associated with significant short- and long-term side effects. Given these challenges, there is great interest in novel, targeted approaches to therapy. A number of new immunotherapeutic agents have proven to be efficacious in relapsed or refractory disease and are now being investigated in frontline treatment regimens. Blinatumomab (a bispecific T-cell engager that targets cluster of differentiation [CD]-19) and inotuzumab ozogamicin (a humanized antibody-drug conjugate to CD22) have shown the most promise. Chimeric antigen receptor T (CAR-T) cells, a form of adoptive immunotherapy, rely on the transfer of genetically modified effector T cells that have the potential to persist in vivo for years, providing ongoing long-term disease control. In this article, we discuss the clinical biology and treatment of B-ALL with an emphasis on the role of immunotherapy in overcoming the challenges of conventional cytotoxic therapy. As immunotherapy continues to move into the frontline of pediatric B-ALL therapy, we also discuss strategies to address unique side effects associated with these agents and efforts to overcome mechanisms of resistance to immunotherapy.

In this study, we report the initial evaluation of choroidal neovascularization (CNV) secondary to choroidal osteoma and subsequent response to anti-vascular endothelial growth factor (anti-VEGF) treatment monitored with optical coherence tomography angiography (OCT-A). A 38-year-old female presented with an initial visual acuity of 20/150 in the left eye. Clinical examination revealed a choroidal osteoma. OCT demonstrated both subretinal and intraretinal fluid. OCT-A was performed and showed CNV. A course of ten treatments with ranibizumab showed an improvement of visual acuity to 20/30–3, improvement of subretinal and intraretinal fluid, as well as attenuation of CNV. Our report demonstrates OCT-A as a useful tool for both initial evaluation of CNV and following treatment response to anti-VEGF therapy.

Purpose In 2012, four patients with multiple asymptomatic, indolent, unilateral, choroidal lesions were described. We suspected benign-behaving lymphocytes infiltrating the choroid. This article expands the number of patients and duration of follow-up and speculates further on the etiology. Although histopathologic confirmation of these lesions is still unknown, the natural course of these patients is excellent and should be distinguished from aggressive choroidal lymphoma. Methods To qualify for the study, the patients had to meet the following criteria: 1) Patients collected had asymptomatic choroidal infiltrates as demonstrated in the figures; 2) absence of vitreous cells; 3) no evidence of concomitant systemic malignancy; 4) no systemic inflammatory diseases, including sarcoidosis; 5) no birdshot chorioretinopathy; 6) no conjunctival or orbital lesions; and 7) advanced multimodal imaging and clinical follow-up were performed. Results There were 11 eyes of 11 patients seen. Follow-up ranged from 4 months to 12 years and 1 month (mean 50.2 months; median 24 months). Systemic workup was unrevealing. No patients in this cohort developed systemic, conjunctival, orbital, or vitreoretinal lymphoma or inflammatory disease. No patients developed symptoms or vision loss. Conclusion This entity is an indolent choroidal infiltrative disease. It resembles some cases of choroidal lymphoma and may represent an indolent lymphocytic infiltrate.

Wax microsphere bound oxycodone was developed as an abuse-deterrent opioid and maintains a similar pharmacokinetic profile whether administered with or without an intact capsule. We hypothesized that microsphere oxycodone could be utilized for extended release analgesia in patients undergoing radiation (RT) for head-and-neck cancer (HNC) and would not need to be discontinued due to dysphagia or gastrostomy tube dependence. We performed a prospective trial that enrolled participants > 18 years with histologically confirmed HNC who were scheduled to receive RT. Analgesia was prescribed in accordance with the WHO pain ladder. Microsphere oxycodone was initiated when total daily opioid dose exceeded 30 mg of morphine sulfate equivalent and was titrated weekly during RT. Pain level and effect on quality of life were assessed using the Brief Pain Inventory. The primary feasibility endpoint was frequency of microsphere oxycodone discontinuation within 3 months of RT for reasons other than pain resolution. Twenty-six eligible patients were enrolled. Microsphere oxycodone was initiated in 16 (61.5%) patients. Six (23.1%) patients utilized a gastrostomy tube to administer microsphere oxycodone during all or part of RT. Microsphere oxycodone was discontinued in 1 (7.6%) patient due to perceived inefficacy. No patients were discontinued due to toxicity or difficulty with administration. Ratings for average pain was 3.1 (± 3.4) at enrollment, 4.0 (± 2.4) at week 6 of RT, and 1.8 (± 2.2) at 3-month follow-up. These results support the feasibility and safety of microsphere oxycodone for extended release analgesia among patients with HNC undergoing RT.

Neurological disorders are the leading cause of disability and the second leading cause of death worldwide. In the past 30 years, the absolute numbers of deaths and people with disabilities owing to neurological diseases have risen substantially, particularly in low-income and middle-income countries, and further increases are expected globally as a result of population growth and ageing. This rise in absolute numbers of people affected suggests that advances in prevention and management of major neurological disorders are not sufficiently effective to counter global demographic changes. Urgent measures to reduce this burden are therefore needed. Because resources for health care and research are already overstretched, priorities need to be set to guide policy makers, governments, and funding organisations to develop and implement action plans for prevention, health care, and research to tackle the growing challenge of neurological disorders.

PURPOSE Children’s Oncology Group (COG) AALL0331 tested whether intensified postinduction therapy that improves survival in children with high-risk B-cell acute lymphoblastic leukemia (ALL) would also improve outcomes for those with standard-risk (SR) ALL. PATIENTS AND METHODS AALL0331 enrolled 5,377 patients between 2005 and 2010. All patients received a 3-drug induction with dexamethasone, vincristine, and pegaspargase (PEG) and were then classified as SR low, SR average, or SR high. Patients with SR-average disease were randomly assigned to receive either standard 4-week consolidation (SC) or 8-week intensified augmented Berlin-Frankfurt-Münster (BFM) consolidation (IC). Those with SR-high disease were nonrandomly assigned to the full COG-augmented BFM regimen, including 2 interim maintenance and delayed intensification phases. RESULTS The 6-year event-free survival (EFS) rate for all patients enrolled in AALL0331 was 88.96% ± 0.46%, and overall survival (OS) was 95.54% ± 0.31%. For patients with SR-average disease, the 6-year continuous complete remission (CCR) and OS rates for SC versus IC were 87.8% ± 1.3% versus 89.1% ± 1.2% ( P = .52) and 95.8% ± 0.8% versus 95.2% ± 0.8% ( P = 1.0), respectively. Those with SR-average disease with end-induction minimal residual disease (MRD) of 0.01% to < 0.1% had an inferior outcome compared with those with lower MRD and no improvement with IC (6-year CCR: SC, 77.5% ± 4.8%; IC, 77.1% ± 4.8%; P = .71). At 6 years, the CCR and OS rates among 635 nonrandomly treated patients with SR-high disease were 85.55% ± 1.49% and 92.97% ± 1.08%, respectively. CONCLUSION The 6-year OS rate for > 5,000 children with SR ALL enrolled in AALL0331 exceeded 95%. The addition of IC to treatment for patients with SR-average disease did not improve CCR or OS, even in patients with higher MRD, in whom it might have been predicted to provide more value. The EFS and OS rates are excellent for this group of patients with SR ALL, with particularly good outcomes for those with SR-high disease.

Purpose: Treatment outcomes for childhood acute lymphoblastic leukemia (ALL) have improved steadily, but a significant proportion of patients still experience relapse due to drug resistance, which is partly explained by inherited and/or somatic genetic alternations. Recently, we and others have identified genetic variants in the ARID5B gene associated with susceptibility to ALL and also with relapse. In this study, we sought to characterize the molecular pathway by which ARID5B affects antileukemic drug response in patients with ALL. Experimental Design: We analyzed association of ARID5B expression in primary human ALL blasts with molecular subtypes and treatment outcome. Subsequent mechanistic studies were performed in ALL cell lines by manipulating ARID5B expression isogenically, in which we evaluated drug sensitivity, metabolism, and molecular signaling events. Results: ARID5B expression varied substantially by ALL subtype, with the highest level being observed in hyperdiploid ALL. Lower ARID5B expression at diagnosis was associated with the risk of ALL relapse, and further reduction was noted at ALL relapse. In isogenic ALL cell models in vitro, ARID5B knockdown led to resistance specific to antimetabolite drugs (i.e., 6-mercaptopurine and methotrexate), without significantly affecting sensitivity to other antileukemic agents. ARID5B downregulation significantly inhibited ALL cell proliferation and caused partial cell-cycle arrest. At the molecular level, the cell-cycle checkpoint regulator p21 (encoded by CDKN1A) was most consistently modulated by ARID5B, plausibly as its direct transcription regulation target. Conclusions: Our data indicate that ARID5B is an important molecular determinant of antimetabolite drug sensitivity in ALL, in part, through p21-mediated effects on cell-cycle progression.

The delayed intensification (DI) enhanced outcome for patients with acute lymphoblastic leukemia (ALL) treated on BFM 76/79 and CCG 105 after a prednisone-based induction. Childrens Oncology Group protocols P9904/9905 evaluated DI via a post-induction randomization for eligible National Cancer Institute (NCI) standard (SR) and high-risk (HR) patients. A second randomization compared intravenous methotrexate (IV MTX) as a 24- (1 g/m(2)) vs. 4-h (2 g/m(2)) infusion. NCI SR patients received a dexamethasone-based three-drug and NCI HR/CNS 3 SR patients a prednisone-based four-drug induction. End induction MRD (minimal residual disease) was obtained but did not impact treatment. DI improved the 10-year continuous complete remission (CCR) rate; 75.5 ± 2.5% vs. 81.8 ± 2.2% p = 0.002, whereas MTX administration did not; 4-h 80.8 ± 1.9%; 24-h 81.4 ± 1.9% (p = 0.7780). Overall survival (OS) at 10 years did not differ with DI: 91.4 ± 1.6% vs. 90.9 ± 1.7% (p = 0.25) without but was higher with the 24-h MTX infusion; 4-h 91.1 ± 1.4%; 24-h 93.9 ± 1.2% (p = 0.0209). MRD predicted outcome; 10-year CCR 87.7 ± 2.2 and 82.1 ± 2.5% when MRD was

Background Dysphagia is one of the most common complications of anterior cervical spine surgery, and there is a need to establish that the means of testing for it are reliable and valid. The objective of this study was to measure observer variability of the fiberoptic endoscopic evaluation of swallowing (FEES) test, specifically when used for evaluation of dysphagia in patients undergoing revisionary anterior cervical decompression and fusion (ACDF). Methods Images from patients undergoing revision ACDF at a single institution were collected from May 1, 2010, through July 1, 2014. Two senior certified speech pathologists independently evaluated the swallowing function of patients preoperatively and at 2 weeks postoperatively. Their numeric evaluations of the Rosenbeck Penetration-Aspiration Scale and the Swallowing Performance Scale during the FEES were then compared for interrater reliability. Results Positive agreement between raters was 94% for the preoperative Penetration-Aspiration Scale (prevalence-adjusted bias-adjusted κ, 0.77). The postoperative Penetration-Aspiration Scale showed reliability coefficients for κ, Kendall's W, and intraclass correlation coefficient (ICC) of 0.34 (fair agreement), 0.70 (extremely strong agreement), and 0.35 (poor agreement), respectively. The preoperative Swallowing Performance Scale showed strong agreement, with a Kendall's W coefficient of 0.68, and fair reliability, with an ICC of 0.40. The postoperative Swallowing Performance Scale indicated extremely strong agreement between raters, with a Kendall's W of 0.82, and good agreement, with an ICC of 0.53. Conclusions The FEES test appears to be a reliable assessor of dysphagia in patients undergoing ACDF and may be a useful measure for exploring outcomes in this population.

Adolescent and young adult (AYA) patients 16–30 years old with high-risk acute lymphoblastic leukemia (HR-ALL) have inferior outcomes compared to younger HR-ALL patients. AALL0232 was a Phase 3 randomized Children’s Oncology Group trial for newly diagnosed HR B-ALL (1–30 years). Between 2004 and 2011, 3154 patients enrolled with 3040 eligible and evaluable for induction. AYA patients comprised 20% of patients (16–21 years, n = 551; 22–30 years, n = 46). 5-year event-free survival and overall survival was 65.4 ± 2.2% and 77.4 ± 2.0% for AYA patients compared to 78.1 ± 0.9% and 87.3 ± 0.7% for younger patients (p

Genetic alterations in the RUNX1 gene are associated with benign and malignant blood disorders, particularly of megakaryocyte and myeloid lineages. The role of RUNX1 in acute lymphoblastic leukemia (ALL) is less clear, particularly in terms of how germline genetic variation influences the predisposition to this type of leukemia. Sequencing DNA of 4836 children with B cell ALL (B-ALL) and 1354 with T cell ALL (T-ALL), we identified 31 and 18 germline RUNX1 variants, respectively. RUNX1 variants in B-ALL consistently showed minimal damaging effects. In contrast, 6 T-ALL–related variants resulted in drastic loss of RUNX1 activity as a transcription activator in vitro. Ectopic expression of dominant-negative RUNX1 variants in human CD34(+) cells repressed differentiation into erythroid cells, megakaryocytes, and T cells, while promoting myeloid cell development. Chromatin immunoprecipitation sequencing of T-ALL models showed distinctive patterns of RUNX1 binding by variant proteins. Further whole-genome sequencing identified the JAK3 mutation as the most frequent somatic genomic abnormality in T-ALL with germline RUNX1 variants. Cointroduction of RUNX1 variant and JAK3 mutation in hematopoietic stem and progenitor cells in mice gave rise to T-ALL with the early T cell precursor phenotype. Taken together, these results indicate that RUNX1 is an important predisposition gene for T-ALL and point to biology of RUNX1-mediated leukemogenesis in the lymphoid lineages.

Background: Patients with late, occurring ≥18 months post-diagnosis, isolated central nervous relapse (iCNS-R) of B-acute lymphoblastic leukemia (ALL) have excellent outcomes with chemotherapy plus cranial radiotherapy, with 5-yr overall survival (OS) approaching 80% in POG 9412. Subsequent relapse and radiation-related morbidity remain the causes of treatment failure and long-term sequelae. COG AALL02P2 aimed to maintain outcomes in patients with late iCNS-R using intensified chemotherapy and a decrease in cranial irradiation from 1800 to 1200 cGy. Procedures: COG AALL02P2 enrolled 118 eligible patients with B-ALL and early iCNS-R who received intensified systemic therapy, triple intrathecal chemotherapy and 1200 cGy cranial irradiation delivered at 12 months, with maintenance chemotherapy continuing until104 weeks post-diagnosis. Results: The 3-yr event-free and overall survival (EFS) and OS were 64.3±4.5% and 79.6±3.8%, with 46.1% (18/39) of relapses including the CNS. Of the 112 patients who completed therapy, 78 received protocol-specified radiation. Study enrollment was closed after interim monitoring analysis showed inferior EFS compared to POG 9412. Patients with initial NCI standard risk classification fared better than high risk patients. Conclusions: COG AALL02P2 showed inferior EFS but similar OS compared to POG 9412. Limitations included a small sample size, more intensive prior therapies, and a significant number of patients (34/118, 29%) who did not receive protocol-directed radiation due to early relapse prior to 1 year or did not otherwise follow the treatment plan. New approaches are needed to improve outcome for these patients and determine the optimal timing and dose of cranial radiation in the treatment of iCNS-R.

RUNX1 is a transcription factor critical for definitive hematopoiesis and genetic alterations in RUNX1 have been implicated in both benign and malignant blood disorders, particularly of the megakaryocyte and myeloid lineages. Somatic RUNX1 mutations are reported in B- and T-cell acute lymphoblastic leukemia (B-ALL and T-ALL), but germline genetic variation of RUNX1 in these lymphoid malignancies have not been comprehensively investigated. Sequencing 4,836 children with B-ALL and 1,354 cases of T-ALL, we identified 31 and 18 unique germline RUNX1 variants in these two ALL subtypes, respectively. RUNX1 variants in B-ALL were predicted to have minimal impact. By contrast, 54.5% of variants in T-ALL result in complete or partial loss of RUNX1 activity as a transcription activator in vitro, with dominant negative effects for 4 variants. Ectopic expression of dominant negative deleterious RUNX1 variants in human CD34+ cells repressed differentiation into erythroid, megakaryocytes, and T cells, while promoting differentiation towards myeloid cells. We then performed chromatin immunoprecipitation profiling in isogenic T-ALL models with variants introduced by genome editing of endogenous RUNX1. We observed highly distinctive patterns of DNA binding and target genomic loci by RUNX1 proteins encoded by the truncating vs missense variants. The p.G365R RUNX1 variant resulted in a novel methylation site in RUNX1 and alteration in its interaction with CBFβ. Further whole genome sequencing showed that JAK3 mutation was the most frequent somatic genomic abnormality in T-ALL with germline RUNX1 variants. Consistently, co-introduction of RUNX1 variant and JAK3 mutation in hematopoietic stem and progenitor cells in mouse gave rise to T-ALL with early T-cell precursor phenotype in vivo, compared to thymic T-ALL seen in mice with JAK3 mutation alone. Taken together, these results indicated that RUNX1 is an important predisposition gene for ALL, especially in T-ALL and also pointed to novel biology of RUNX1-mediated leukemogenesis in the lymphoid lineages.

Simple Summary Acute lymphoblastic leukemia minimal residual disease (MRD) refers to the presence of residual leukemia cells following the achievement of complete remission, but below the limit of detection using conventional morphologic assessment. Up to two thirds of children may have MRD detectable after induction therapy depending on the biological subtype and method of detection. Patients with detectable MRD have an increased likelihood of relapse. A rapid reduction of MRD reveals leukemia sensitivity to therapy and under this premise, MRD has emerged as the strongest independent predictor of individual patient outcome and is crucial for risk stratification. However, it is a poor surrogate for treatment effect on long term outcome at the trial level, with impending need of randomized trials to prove efficacy of MRD-adapted interventions. Abstract Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer and advances in its clinical and laboratory biology have grown exponentially over the last few decades. Treatment outcome has improved steadily with over 90% of patients surviving 5 years from initial diagnosis. This success can be attributed in part to the development of a risk stratification approach to identify those subsets of patients with an outstanding outcome that might qualify for a reduction in therapy associated with fewer short and long term side effects. Likewise, recognition of patients with an inferior prognosis allows for augmentation of therapy, which has been shown to improve outcome. Among the clinical and biological variables known to impact prognosis, the kinetics of the reduction in tumor burden during initial therapy has emerged as the most important prognostic variable. Specifically, various methods have been used to detect minimal residual disease (MRD) with flow cytometric and molecular detection of antigen receptor gene rearrangements being the most common. However, many questions remain as to the optimal timing of these assays, their sensitivity, integration with other variables and role in treatment allocation of various ALL subgroups. Importantly, the emergence of next generation sequencing assays is likely to broaden the use of these assays to track disease evolution. This review will discuss the biological basis for utilizing MRD in risk assessment, the technical approaches and limitations of MRD detection and its emerging applications.

Favorable histology (FH) Wilms tumor (WT) is one of the most curable of all human cancers, yet a small minority of patients fail treatment. The underlying biological pathways that lead to therapy resistance are unknown. We report a case of initially unresectable, FH WT which revealed limited necrosis and persistent blastemal predominant histology following neoadjuvant chemotherapy. Despite intensification of therapy and whole abdominal radiation, the patient relapsed and succumbed to her disease. In an effort to discover candidate drivers of drug resistance, whole exome sequencing and copy number analysis were performed on samples from all 3 tumor specimens. Sequencing results revealed outgrowth of clones with a dramatically different genetic landscape including dominant mutations that could explain therapy evasion, some of which have not been previously reported in WT. Our results implicate PPM1D, previously shown to be associated with drug resistance in other tumors, as the major driver of treatment failure.

The Children’s Cancer Group 1991 study was a clinical trial for children with National Cancer Institute standard-risk acute lymphoblastic leukemia (ALL). This trial demonstrated that 5 doses of vincristine and escalating IV methotrexate (MTX) without leucovorin rescue in the interim maintenance (IM) phases resulted in superior event-free survival (EFS) when compared with 2 doses of vincristine, oral (PO) MTX, PO mercaptopurine, and dexamethasone. This report describes a favorable outcome of this regimen in patients with Down syndrome (DS). Forty-four patients with DS were randomized to the arms containing PO MTX during IM, and 31 to those containing IV MTX. Ten-year EFS rates for patients with DS randomized to IV MTX vs PO MTX were 94.4% ± 5.4% vs 81.5% ± 6.6%, respectively. IV methotrexate with strict escalation parameters, as given in this study, was well tolerated, although the mean total tolerated dose received was lower in patients with DS than in those without DS. There was no increase in hepatic toxicity, systemic infections, or treatment-related deaths in patients with DS during IM on either the IV or PO MTX arms, as compared with those without DS. The incidence of mucositis was increased in patients with DS as compared with patients without DS, particularly among patients who received IV MTX. This trial was registered at www.clinicaltrials.gov as #NCT00005945.

Background Higher intakes of cruciferous vegetables (CVs) and green leafy vegetables (GLVs) in observational studies are associated with improvements in survival and cancer-related biomarkers in patients diagnosed with head and neck cancer (HNC). These results have yet to be corroborated in a randomized clinical trial (RCT). Objective Determine the feasibility of implementing a 12-week RCT to increase CV and GLV intake in posttreatment HNC survivors. Design and participants This was a two-arm RCT conducted among 24 posttreatment HNC survivors. Survivors were recruited from a southeastern, National Cancer Institute–designated Comprehensive Cancer Center between January 2015 and September 2016. Intervention There were two groups: (1) an experimental group (n=12) receiving weekly 15- to 30-minute telephone dietary counseling from a registered dietitian nutritionist stressing 2.5 cups per week CVs and 3.5 cups per week GLVs, and (2) an attention control group (n=12) receiving weekly 15- to 30-minute telephone dietary counseling from a registered dietitian nutritionist focusing on general healthy eating for cancer survivors. Participants completed a baseline survey, three 24-hour dietary recalls, phlebotomy, and anthropometric measures prior to randomization and at the end of the 12-week study period. The experimental group also completed weekly vegetable record recalls. Main outcome measures Primary outcomes included feasibility, recruitment, retention, adherence, and safety. Secondary outcomes included inflammatory markers and carotenoids. Statistical analyses performed Descriptive statistics were generated for demographic, epidemiological, and clinical variables as well as the primary feasibility outcomes. Between- and within-group comparisons of mean serum cytokine and carotenoid levels were performed using appropriate statistical tests depending on their respective distributions for the purpose of generating preliminary effect sizes. Results Overall, 350 incident HNC cases were screened for eligibility, and 98 were eligible for study participation. Reasons for ineligibility and exclusion included deceased (n=93); wrong or inactive telephone numbers, or unable to be reached, or lost to follow-up (n=93); not meeting inclusion criteria (n=39); and too ill to participate (n=27). Of the 98 eligible HNC cases, 24 agreed to participate, for an enrollment rate of 25%. The most common reason for nonparticipation was distance (n=48), as participants were asked to report for two on-site assignments. The retention rate was 96%. Mean intervention adherence rates for weekly goals were 67% CV, 74% GLV, and 71% overall. Completion rate of weekly counseling calls was 90%. The experimental group reported an overall mean increase of 5.5 cups GLV and 3.5 cups CV per week from baseline intake, respectively. No significant between- or within-arm differences were observed for inflammatory markers or carotenoids. Conclusion A posttreatment intervention aimed at increasing CV and GLV intake in HNC survivors is feasible. A larger RCT is needed to assess the efficacy of this intervention on disease outcomes.

With modern chemotherapy, approximately 90% of patients with pediatric acute lymphoblastic leukemia are now cured. However, subsets of patients can be identified who remain at very high risk of relapse with expected 4-year disease-free survival rates

Background: Oral and pharyngeal cancers (OPC) represent the seventh most common type of cancer and the seventh leading cause of deaths by cancer worldwide. Few studies have assessed the occupational exposure risks associated with OPC and in many cases the results are conflicting. The aim of this study was to determine, through a systematic review, the association of OPC and exposure to different occupational carcinogenic substances. Methods: The addressed focused question was "Is there an association of occupational carcinogenic substances with OPC?" PubMed, MEDLINE, EMBASE, and ISI Web of Science databases were searched between January 1995 up to and including July 2016 using the keywords "oral cancer," "pharyngeal cancer," "pharyngeal neoplasms," "oral neoplasms," "occupational disease," "occupational exposure," and "occupational risk factor" in various combinations. Letters to the Editor, review articles, case reports, and unpublished articles were excluded. Results: Fourteen original articles were included. Majority of the studies were conducted in European countries and used a case-control design. The results showed a significant association between formaldehyde, wood dust, coal dust, asbestos, welding fumes, and risk of developing OPC, while marginal association was observed with metal and leather dust. No associated risk was observed for textile fibers. Conclusion: There is some evidence to suggest associations of occupational substances with OPC, particularly in the pharynx. Future well-designed studies are required to confirm or rule out with confidence the associated exposure risk of these substances.

Introduction: Although overall survival rates for children with acute lymphoblastic leukemia (ALL) are excellent, the prognosis for certain patients remains suboptimal. Risk-stratification has impr...

Human immunodeficiency virus has plagued mankind since the 1980’s when the first case was documented. Human immunodeficiency virus-induced immunocompromised state can lead to several systemic and local manifestations, which often culminates in mortality. Oral candidiasis was one of the most prevalent opportunistic infections noted in human immunodeficiency virus-infected patients. The advent of highly active antiretroviral therapy has led to a significant reduction in both the mortality and the morbidity of infected patients. The combined antiretroviral therapy has also led to a decrease in the incidence of opportunistic infections including oral candidiasis. Thus, the presence of well-established oral candidiasis in human immunodeficiency virus-infected patients under highly active antiretroviral therapy could be considered as an indicator of potential treatment failure. The present manuscript aims to review the published literature assessing the effect of highly active antiretroviral therapy on the incidence of oral candidiasis in human immunodeficiency virus-infected patients.

Infants with KMT2A‐rearranged acute lymphoblastic leukemia (KMT2A-r ALL) have a poor prognosis. KMT2A-r ALL overexpresses FLT3, and the FLT3 inhibitor (FLT3i) lestaurtinib potentiates chemotherapy‐induced cytotoxicity in preclinical models. Children’s Oncology Group (COG) AALL0631 tested whether adding lestaurtinib to post‐induction chemotherapy improved event-free survival (EFS). After chemotherapy induction, KMT2A-r infants received either chemotherapy only or chemotherapy plus lestaurtinib. Correlative assays included FLT3i plasma pharmacodynamics (PD), which categorized patients as inhibited or uninhibited, and FLT3i ex vivo sensitivity (EVS), which categorized leukemic blasts as sensitive or resistant. There was no difference in 3-year EFS between patients treated with chemotherapy plus lestaurtinib (n = 67, 36 ± 6%) vs. chemotherapy only (n = 54, 39 ± 7%, p = 0.67). However, for the lestaurtinib-treated patients, FLT3i PD and FLT3i EVS significantly correlated with EFS. For FLT3i PD, EFS for inhibited/uninhibited was 59 ± 10%/28 ± 7% (p = 0.009) and for FLTi EVS, EFS for sensitive/resistant was 52 ± 8%/5 ± 5% (p

Reverse phase protein arrays (RPPA) can assess protein expression and activation states in large numbers of samples (n>1000) and evidence suggests feasibility in the setting of multi-institution clinical trials. Despite evidence in solid tumors, little is known about protein stability in leukemia. Proteins collected from leukemia cells in blood and bone marrow biopsies must be sufficiently stable for analysis. Using 58 leukemia samples, we initially assessed protein/phospho-protein integrity for the following preanalytical variables: 1) shipping vs local processing, 2) temperature (4°C vs ambient temperature), 3) collection tube type (heparin vs Cell Save (CS) preservation tubes), 4) treatment effect (pre- vs post-chemotherapy) and 5) transit time. Next, we assessed 1515 samples from the Children's Oncology Group Phase 3 AML clinical trial (AAML1031, NCT01371981) for the effects of transit time and tube type. Protein expression from shipped blood samples was stable if processed in ≤72h. While protein expression in pre-chemotherapy samples was stable in both heparin and CS tubes, post-chemotherapy samples were stable in only CS tubes. RPPA protein extremes is a successful quality control measure to identify and exclude poor quality samples. These data demonstrate that a majority of shipped proteins can be accurately assessed using RPPA. SIGNIFICANCE: RPPA can assess protein abundance and activation states in large numbers of samples using small amounts of material, making this method ideal for use in multi-institution clinical trials. However, there is little known about the effect of preanalytical handling variables on protein stability and the integrity of protein concentrations after sample collection and shipping. In this study, we used RPPA to assess preanalytical variables that could potentially affect protein concentrations. We found that the preanalytical variables of shipping, transit time, and temperature had minimal effects on RPPA protein concentration distributions in peripheral blood and bone marrow, demonstrating that these preanalytical variables could be successfully managed in a multi-site clinical trial setting.

Early T-cell precursor phenotype acute lymphoblastic leukemia (ETP-ALL) is a subtype of T-ALL with a unique immunophenotype and genetic abnormalities distinct from conventional T-ALL. A subset of T lymphoblastic lymphoma (T-LLy) also demonstrates the early T-cell precursor immunophenotype and may be a counterpart of ETP-ALL. Unlike ETP-ALL, the incidence, clinical features, and genomic features of ETP-LLy are unknown. We reviewed the immunophenotyping data of 218 T-LLy patients who enrolled in the Children’s Oncology Group AALL0434 clinical trial and identified 9 cases (4%) exhibiting a definitive ETP immunophenotype. We performed single-nucleotide polymorphism array profiling on 9 ETP-LLy and 15 non-ETP T-LLy cases. Compared with non-ETP T-LLy, ETP-LLy showed less frequent deletion of 9p (CKDN2A/B), more frequent deletion of 12p (ETV6) and 1p (RPL22), and more frequent absence of biallelic T-cell receptor γ deletions. Recurrent abnormalities previously described in ETP-ALL such as deletions of 5q and 13q and gain of 6q were not observed in ETP-LLy cases. There were no failures of therapy among the ETP-LLy subtype with a 4-year event-free survival of 100%. Overall, ETP-LLy does not exhibit unifying genetic alterations but shows some distinct genomic features from non-ETP T-LLy suggesting that ETP-LLy may be a distinct entity from non-ETP T-LLy.

To appraise the utility of a novel EMR-based checklist for complex head and neck microvascular free-tissue reconstruction.A prospectively collected retrospective matched cohort study from a single tertiary care academic institution.A retrospective matched cohort study from an academic tertiary care center with 76 total patients analyzed for disease-specific and quality outcomes before and after implementation of an EMR-based checklist tailored to complex head and neck care. The intervention group consisted of 38 consecutive patients undergoing microvascular free tissue reconstruction after implementation of the EMR-based checklist strategy. A historic cohort of 38 patients was derived by matching patients meticulously for disease-specific and surgical characteristics. Primary outcomes included post-operative medical and surgical complications, intensive care requirements, 30-day reoperation rates, hospital length of stay, and completion of preoperative metastatic evaluations. Secondary outcomes included patterns of antibiotic administration, ultimate discharge dispositions, flap survival, and recognition of preoperative hypothyroidism in previously radiated patients.Implementation of the perioperative checklist yielded an overall reduction in major medical complications (10.5% vs. 29.0%, P .05*), post-operative antibiotic administration (17.4% vs. 44.7%, P .05*), hospital length of stay (median (IQR) days 6 (1) versus 7 (3.25), P .05*), and improved metastatic evaluation completion (92.1% vs. 63.2%, P .05*). There was an improved discharge disposition (92.1% vs. 73.7%, P .05*). No difference was observed in major wound complications (50.0% vs. 57.9%, P = .49), 30-day re-operation rates (31.5% vs. 34.2%, P = .81), 30-day readmission rates (21.1% vs. 21.1%, P .99), escalations to intensive-care (13.2% vs. 21.1%, P = .36), or flap survival (97.4% vs. 89.5%, P = .17).Use of our EMR-based perioperative checklist reduced major medical complications, post-operative antibiotic administration, hospital length of stay, and improved discharge outcomes for patients undergoing microvascular free-tissue reconstruction.3 Laryngoscope, 131:E2251-E2256, 2021.

Purpose: AALL0932 evaluated two randomized maintenance interventions to optimize disease-free survival (DFS) while reducing the burden of therapy in children with newly diagnosed NCI standard-risk (SR) B-acute lymphoblastic leukemia (B-ALL). Methods: AALL0932 enrolled 9,229 patients with B-ALL; 2,364 average-risk (AR) patients were randomly assigned (2 × 2 factorial design) at the start of maintenance therapy to vincristine/dexamethasone pulses every 4 (VCR/DEX4) or every 12 (VCR/DEX12) weeks, and a starting dose of weekly oral methotrexate of 20 mg/m2 (MTX20) or 40 mg/m2 (MTX40). Results: Five-year event-free survival and overall survival (OS) from enrollment (with 95% CIs), for all eligible and evaluable SR B-ALL patients (n = 9,226), were 92.0% (91.1% and 92.8%) and 96.8% (96.2% and 97.3%), respectively. The 5-year DFS and OS from the start of maintenance for randomly assigned AR patients were 94.6% (93.3% and 95.9%) and 98.5% (97.7% and 99.2%), respectively. The 5-year DFS and OS for patients randomly assigned to receive VCR/DEX4 (n = 1,186) versus VCR/DEX12 (n = 1,178) were 94.1% (92.2% and 96.0%) and 98.3% (97.2% and 99.4%) v 95.1% (93.3% and 96.9%) and 98.6% (97.7% and 99.6%), respectively ( P = .86 and .69). The 5-year DFS and OS for AR patients randomly assigned to receive MTX20 versus MTX40 were 95.1% (93.3% and 96.8%) and 98.8% (97.9% and 99.7%) v 94.2% (92.2% and 96.1%) and 98.1% (97.0% and 99.2%), respectively ( P = .92 and .89). Conclusions: The 0NCI-SR AR B-ALL who received VCR/DEX12 had outstanding outcomes despite receiving one third of the vincristine/dexamethasone pulses previously used as standard of care on Children's Oncology Group (COG) trials. The higher starting dose of MTX of 40 mg/m2/week did not improve outcomes when compared with 20 mg/m2/week. The decreased frequency of vincristine/dexamethasone pulses has been incorporated into frontline COG B-ALL trials to decrease the burden of therapy for patients and their families.

Purpose Pediatric oncology patients undergoing active chemotherapy are suspected to be at a high risk for severe disease secondary to severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2) infection; however, data to support this are lacking. We aim to describe the characteristics of coronavirus disease 2019 (COVID‐19) in this population and also its impact on pediatric cancer care in the New York region during the peak of the pandemic. Patients and Methods This multicenter, retrospective study included 13 institutions. Clinical and laboratory information on 98 patients ≤21 years of age receiving active anticancer therapy, who tested positive for SARS‐CoV‐2 by nasopharyngeal swab polymerase chain reaction (PCR), was collected. Results Of the 578 pediatric oncology patients tested for COVID‐19, 98 were positive, of whom 73 were symptomatic. Most experienced mild disease, 28 required inpatient management, 25 needed oxygen support, and seven required mechanical ventilation. There is a slightly higher risk of severe disease in males and obese patients, though not statistically significant. Persistent lymphopenia was noted in severe cases. Delays in cancer therapy occurred in 67% of SARS‐CoV‐2‐positive patients. Of four deaths, none were solely attributable to COVID‐19. The impact of the pandemic on pediatric oncology care was significant, with 54% of institutions reporting delays in chemotherapy, 46% delays in surgery, and 30% delays in transplant. Conclusion In this large multi‐institutional cohort, we observed that mortality and morbidity from COVID‐19 amongst pediatric oncology patients were low overall, but higher than reported in general pediatrics. Certain subgroups might be at higher risk of severe disease. Delays in cancer care due to SARS‐CoV‐2 remain a concern.

As a pathogen spread primarily by the respiratory route COVID-19 infection not only poses significant risks to health care workers, but to dentists and dental health care workers, owing to the potential prolonged exposure and proximity to patients. This holds true for non-dentist health care workers who often in the setting of emergency departments and urgent care centers are tasked with addressing oral symptoms including abscesses, damaged teeth, jaw injuries and other dental urgencies. Infection control practice guidelines were evaluated for COVID-19 infection prevention in a dental setting. In this brief review, protective measures to reduce the risk of COVID-19 infection for dentists and non-dentist health care providers will be introduced. This includes patient eval uation, personal and patient protective equipment use, sterilization and disinfection protocols. (c) 2020 Elsevier Inc. All rights reserved.

Background Neuromyelitis optica spectrum disorder (NMOSD) is associated with significant morbidity and mortality. Several therapies have been recommended for NMOSD and more recently clinical trials have demonstrated efficacy for three monoclonal antibody therapies. We present a retrospective observational study of treatment response in NMOSD. Methods This was a retrospective, unblinded, observational study of treatment efficacy for rituximab and traditional immunosuppressive therapy in patients with AQP4 antibody positive NMOSD. Treatment efficacy was assessed using annualised relapse rates (ARR), time to first relapse and expanded disability status scale (EDSS) scores. Results Complete relapse and treatment data were available for 43/68 (63%) of AQP4 antibody positive NMOSD cases covering 74 episodes of treatment. In a time to first relapse analysis rituximab showed a risk ratio of 0.23 (95% CI 0.08 – 0.65) when compared with no treatment and there was a non-significant reduction in ARR of 35% compared to pre-treatment. β-interferon (p = 0.0002) and cyclophosphamide (p = 0.0034) were associated with an increased ARR compared to pre-treatment. Rituximab (median 4.0 [range 0.0 – 7.0]; p = 0.042) and traditional immunosuppressive therapy (median 4.0 [range 0.0 – 8.0]; p = 0.016) were associated with a lower final EDSS compared to β-interferon (median 6.0 [range 4.0 – 7.5]). Conclusions These data provide additional support for the use of rituximab in preference to traditional immunosuppressive agents and MS disease modifying therapies as first line treatment of NMOSD.