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Peutz-Jeghers syndrome (PJS) is a rare hereditary disease characterised by hyperpigmentation of the oral mucosa and gastrointestinal hamartomatous polyps. We report a case of a 27-year-old man who presented with a 5-day history of epigastric pain and rectal bleeding. Computed tomography suggested small bowel obstruction secondary to ileocolic intussusception and an incidental polyp in the mid jejunum. The patient underwent exploratory laparotomy during which right hemicolectomy and small bowel resection were performed. Histology from surgical specimens revealed Peutz-Jeghers polyps, one of which had low-grade dysplasia. This case emphasises that although rare, adults with PJS can present with intussusception. Also illustrated is the extremely rare possibility of concurrent polyps occurring in different parts of the bowel with neoplastic transformation. Intussusception is a challenge to diagnose because the presentation is often non-specific. Clinical history-taking and physical examination along with prompt axial imaging is important for the diagnosis. Careful examination of the bowel and polypectomy during laparotomy may prevent neoplastic transformation and short bowel syndrome.

Pediatric acute myeloid leukemia (AML) is genetically heterogenous (Olsson et al., 2016). t(X;6)(p11;q23) is a rare but recurrent chromosomal translocation in infant AML thought to be associated with male sex and basophilic differentiation (Dastugue et al., 1997). Here we report molecular characterization of AML with t(X;6)(p11;q23);MYB-GATA1 in two female infants and demonstrate preserved GATA1 expression in the sample tested. These findings further debunk a concept that this fusion was restricted to males, in whom it disrupts the only copy of the X-linked GATA1 gene, causing presumable complete loss of GATA1 function. Our data also demonstrate the power and efficiency of RNA sequencing for subclassification of leukemia on a clinically relevant timeline., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Treatment of resistant or recurrent acute lymphoblastic leukemia (ALL) remains a challenge. It was previously demonstrated that the adhesion molecule integrin α4, referred to hereafter as α4, mediates the cell adhesion-mediated drug resistance (CAM-DR) of B-cell ALL by binding to vascular cell adhesion molecule-1 (VCAM-1) on bone marrow stroma. In addition, it was previously observed that the blockade of α4 with natalizumab or inhibition using the small molecule antagonist TBC3486 sensitized relapsed ALL cells to chemotherapy. However, α4-targeted therapy is not clinically available for the treatment of leukemia to date. In the present study, the use of a novel non-peptidic small molecule integrin α4 antagonist, AVA4746, as a potential new approach to combat drug-resistant B-ALL was explored. An in vitro co-culture = model of primary B-ALL cells and an in vivo xenograft model of patient-derived B-ALL cells were utilized for evaluation of AVA4746. VLA-4 conformation activation, cell adhesion/de-adhesion, endothelial tube formation, in vivo leukemia cell mobilization and survival assays were performed. AVA4746 exhibited high affinity for binding to B-ALL cells, where it also efficiently blocked ligand-binding to VCAM-1. In addition, AVA4746 caused the functional de-adhesion of primary B-ALL cells from VCAM-1. Inhibition of α4 using AVA4746 also prevented angiogenesis in vitro and when applied in combination with chemotherapy consisting of Vincristine, Dexamethasone and L-asparaginase, it prolonged the survival of ~33% of the mice in an in vivo xenograft model of B-ALL. These data implicate the potential of targeting the α4-VCAM-1 interaction using AVA4746 for the treatment of drug-resistant B-lineage ALL., Competing Interests: The authors declare that they have no competing interests., (Copyright: © Ruan et al.)

Several chemotherapeutic agents and novel immunotherapies provide excellent control of systemic and central nervous system (CNS) leukemia but can be highly neurotoxic. The manifestations of subacute methotrexate neurotoxicity are diverse and require vigilant management; nonetheless, symptoms are transient in almost all patients. As methotrexate is a crucial drug to prevent CNS relapse, it is important to aim to resume it after full neurologic recovery. Most children tolerate methotrexate rechallenge without significant delays or prophylactic medications. Neurotoxicity is more frequent with newer immunotherapies such as CD19- chimeric antigen receptor T (CAR T) cells and blinatumomab. A uniform grading system for immune effector cell-associated neurotoxicity syndrome (ICANS) and algorithms for management based on severity have been developed. Low-grade ICANS usually resolves within a few days with supportive measures, but severe ICANS requires multispecialty care in the intensive care unit for life-threatening seizures and cerebral edema. Pharmacologic interventions include anticonvulsants for seizure control and glucocorticoids to reduce neuroinflammation. Anticytokine therapies targeted to the pathophysiology of ICANS are in development. By using illustrative patient cases, we discuss the management of neurotoxicity from methotrexate, CAR T cells, and blinatumomab in this review., (Copyright © 2021 by The American Society of Hematology.)

The PI3K/Akt pathway-and in particular PI3Kδ-is known for its role in drug resistant B-cell acute lymphoblastic leukemia (B-ALL) and it is often upregulated in refractory or relapsed B-ALL. Myc proteins are transcription factors responsible for transcribing pro-proliferative genes and c-Myc is often overexpressed in cancers. The chromatin regulator BRD4 is required for expression of c-Myc in hematologic malignancies including B-ALL. Previously, combination of BRD4 and PI3K inhibition with SF2523 was shown to successfully decrease Myc expression. However, the underlying mechanism and effect of dual inhibition of PI3Kδ/BRD4 in B-ALL remains unknown. To study this, we utilized SF2535, a novel small molecule dual inhibitor which can specifically target the PI3Kδ isoform and BRD4. We treated primary B-ALL cells with various concentrations of SF2535 and studied its effect on specific pharmacological on-target mechanisms such as apoptosis, cell cycle, cell proliferation, and adhesion molecules expression using in vitro and in vivo models. SF2535 significantly downregulates both c-Myc mRNA and protein expression through inhibition of BRD4 at the c-Myc promoter site and decreases p-AKT expression through inhibition of the PI3Kδ/AKT pathway. SF2535 induced apoptosis in B-ALL by downregulation of BCL-2 and increased cleavage of caspase-3, caspase-7, and PARP. Moreover, SF2535 induced cell cycle arrest and decreased cell counts in B-ALL. Interestingly, SF2535 decreased the mean fluorescence intensity (MFI) of integrin α4, α5, α6, and β1 while increasing MFI of CXCR4, indicating that SF2535 may work through inside-out signaling of integrins. Taken together, our data provide a rationale for the clinical evaluation of targeting PI3Kδ/BRD4 in refractory or relapsed B-ALL using SF2535., Competing Interests: DD has ownership interest (including stock, patents, etc.) in and is a consultant/advisory board member of SignalRx Pharmaceuticals Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Ruan, Kim, Ogana, Wan, Hurwitz, Nichols, Abdel-Azim, Coba, Seo, Loh, Gang, Abdel-Azim, Hsieh, Lieber, Parekh, Pal, Bhojwani, Durden and Kim.)

Purpose: To compare real-time intraocular pressure (IOP) response to occlusion break event in 2 phacoemulsification systems., Setting: Iladevi Cataract and IOL Research Center, India., Design: Randomized, experimental study., Methods: Rabbits were randomized to:Group I (n = 10 eyes), Centurion Vision system with active fluidics, or, Group II (n = 10 eyes), Centurion with Active Sentry. Within each group, parameter set 1 (IOP 30 mm Hg, aspiration flow rate [AFR] 20 mL/min, and vacuum 600 mm Hg) and parameter set 2 (IOP 50 mm Hg, AFR 25 mL/min, and vacuum 600 mm Hg) were tested. Real-time rate of drop and rise of IOP after occlusion break event (mm Hg per second) and percentage reduction of IOP from maximum during nuclear fragment removal were compared., Results: 10 rabbits (20 eyes) were included. Rate of drop of IOP after occlusion break was not significantly different between groups. Rate of rise of IOP was statistically significantly higher in Group II with both parameter sets (199.09 ± 69.28 vs 94.33 ± 45.66 in parameter set 1, P = .006; and 256 ± 45.05 vs 165.25 ± 51.80 in parameter set 2, P = .005), suggesting faster recovery to baseline IOP after occlusion break. The mean percentage reduction of IOP from maximum was significantly higher in Group I (P = .003)., Conclusions: Rise of IOP to baseline after occlusion break event was faster and mean percentage reduction of IOP from maximum during nuclear fragment removal was lower when using the Centurion Vision system with the Active Sentry upgrade compared with the traditional handpiece. The ability to sense IOP at the level of the handpiece with the Active Sentry upgrade allows faster mitigation of surge response., (Copyright © 2021 Published by Wolters Kluwer on behalf of ASCRS and ESCRS.)

The clinical development of antibody-drug conjugates (ADCs) has gained momentum in recent years and these agents are gradually moving into frontline regimens for pediatric acute leukemias. ADCs consist of a monoclonal antibody attached to a cytotoxic payload by a cleavable linker. This structure allows for highly cytotoxic agents to be directly delivered to leukemia cells leading to cell death and avoids excessive off-tumor toxicity. Near universal expression on B-cell acute lymphoblastic leukemia (ALL) blasts and the ability of rapid internalization has rendered CD22 an ideal target for ADC in B-ALL. Inotuzumab ozogamicin, the anti-CD22 antibody linked to calicheamicin led to complete remission rates of 60-80% in patients with relapsed/refractory B-ALL. In acute myeloid leukemia (AML), the CD33 targeting gemtuzumab ozogamicin has demonstrated modest improvements in survival and is the only ADC currently licensed in the United States for pediatric patients with de novo AML. Several other ADCs have been developed and tested clinically for leukemia but have achieved limited success to date. The search for additional leukemia-specific targets and optimization of ADC structure and specificity are ongoing efforts to improve their therapeutic window. This review provides a comprehensive overview of ADCs in acute leukemias, with a focus on pediatric ALL and AML.

Introduction: A major goal of the current personalized medicine era is to utilize pharmacogenetics (PGx) in order to influence how medications and therapies are prescribed by providers. However, disparities for prescribing medications between adults and children exist. Research has shown that children are not just small adults and there are different challenges for pediatric providers in regards to ordering and interpreting PGx tests. The goal of this study was to obtain an initial understanding of current pharmacogenetic testing by pediatric providers, as well as determine perceived barriers., Methods: We distributed an online survey to pediatric providers at six different institutions across the U.S., Results: Of the 252 respondents who completed the survey, 24 percent reported previously ordering PGx tests, however, over 90 percent of respondents reported they would feel more comfortable ordering and interpreting results with the assistance of a pharmacist, geneticist, genetic counselor or PGx expert. Additionally, participants identified specific barriers towards the utilization of PGx testing, as well as suggested solutions to overcome these barriers, including increasing provider education regarding testing, collaboration through a multidisciplinary team approach and established PGx programs., Conclusion: As the pharmacogenetic field continues to demonstrate clinical utility in the pediatric population, it will be important to continuously identify and address barriers that exist for providers to allow for more successful implementation of PGx in the pediatric setting, as well as enhance patient care., (Copyright© South Dakota State Medical Association.)

5-year overall survival rates have surpassed 90% for childhood acute lymphocytic leukaemia, but survivors are at risk for permanent health sequelae. Although event-free survival appropriately represents the outcome for cancers with poor overall survival, this metric is inadequate when cure rates are high but challenged by serious, persistent complications. Accordingly, a group of experts in paediatric haematology-oncology, representative of 17 international acute lymphocytic leukaemia study groups, launched an initiative to construct a measure, designated severe toxicity-free survival (STFS), to quantify the occurrence of physician-prioritised toxicities to be integrated with standard cancer outcome reporting. Five generic inclusion criteria (not present before cancer diagnosis, symptomatic, objectifiable, of unacceptable severity, permanent, or requiring unacceptable treatments) were used to assess 855 health conditions, which resulted in inclusion of 21 severe toxicities. Consensus definitions were reached through a modified Delphi process supplemented by two additional plenary meetings. The 21 severe toxicities include severe adverse health conditions that substantially affect activities of daily living and are refractory to therapy (eg, refractory seizures), are without therapeutic options (eg, blindness), or require substantially invasive treatment (eg, cardiac transplantation). Incorporation of STFS assessment into clinical trials has the potential to improve and diversify treatment strategies, focusing not only on traditional outcome events and overall survival but also the frequencies of the most severe toxicities. The two major aims of this Review were to: prioritise and define unacceptable long-term toxicity for patients with childhood acute lymphocytic leukaemia, and define how these toxicities should be combined into a composite quantity to be integrated with other reported outcomes. Although STFS quantifies the clinically unacceptable health tradeoff for cure using childhood acute lymphocytic leukaemia as a model disease, the prioritised severe toxicities are based on generic considerations of relevance to any other cancer diagnosis and age group., Competing Interests: Declaration of interests ER reports grants from Pfizer and has been on a data and safety monitoring board for Celgene, outside the submitted work. KS reports personal fees from Jazz Pharmaceuticals, Servier, Amgen, and Medscape, and personal fees and grants from Servier, outside the submitted work. All other authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

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/m 2 /d) in combination with clofarabine (40 mg/m 2 ), etoposide (100 mg/m 2 ), and dexamethasone (8 mg/m 2 ) 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/m 2 /d, 6 were treated at the dose level of 40 mg/m 2 /d, and 4 were treated at the dose level of 60 mg/m 2 /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/m 2 /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., (© 2021 American Cancer Society.)

Detection of somatic genetic drivers is important for risk stratification and treatment selection in pediatric leukemias; however, newly recognized genetic markers may not be detected by routine karyotyping and fluorescence in situ hybridization (FISH). To identify the combination of assays that provides the highest detection rate for clinically significant molecular abnormalities, we tested 160 B- lymphoblastic leukemia (B-ALL) by karyotyping, FISH, chromosomal microarray analysis (CMA) and the custom next-generation sequencing (NGS) panel, OncoKids Ⓡ . In addition, we tested 40 myeloid malignancies with karyotyping, chromosomal microarray analysis (CMA), and OncoKids Ⓡ ; 36/40 myeloid malignancies were also tested with FISH. In B-ALL, individual testing methods had the following diagnostic yields for the key genetic drivers: karyotype 34%; basic FISH panel 45%; FISH panel with IGH and CRLF2 probes 65%; CMA 48%; OncoKids Ⓡ 39%. CMA and OncoKids Ⓡ testing allowed detection of key genetic drivers in 42% of the samples that remained unknown upon testing by conventional methods. In myeloid malignancies, OncoKids Ⓡ had the highest yield for detection of both primary and secondary DNA mutations and RNA fusions. Our data highlights the complementarity between CMA and NGS and conventional cytogenetics/FISH in pediatric leukemia diagnostics. Due to rapid turn-around-time, FISH may be useful as an initial screening method in B-ALL. Our data also suggests NGS testing with a comprehensive panel, despite a longer turnaround time, is a good alternative to karyotyping and FISH in pediatric AML due to its superior detection rate., Competing Interests: Declaration of Competing Interest Matthew C. Hiemenz is an employee of Foundation Medicine, Inc., a wholly owned subsidiary of Roche Holdings Inc. and Roche Finance Ltd., and has an equity interest in an affiliate of these Roche entities., (Copyright © 2021. Published by Elsevier Inc.)

Background: There is increasing concern that persistent infection of SARS-CoV-2 within immunocompromised hosts could serve as a reservoir for mutation accumulation and subsequent emergence of novel strains with the potential to evade immune responses., Methods: We describe three patients with acute lymphoblastic leukemia who were persistently positive for SARS-CoV-2 by real-time polymerase chain reaction. Viral viability from longitudinally-collected specimens was assessed. Whole-genome sequencing and serological studies were performed to measure viral evolution and evidence of immune escape., Findings: We found compelling evidence of ongoing replication and infectivity for up to 162 days from initial positive by subgenomic RNA, single-stranded RNA, and viral culture analysis. Our results reveal a broad spectrum of infectivity, host immune responses, and accumulation of mutations, some with the potential for immune escape., Interpretation: Our results highlight the potential need to reassess infection control precautions in the management and care of immunocompromised patients. Routine surveillance of mutations and evaluation of their potential impact on viral transmission and immune escape should be considered., Competing Interests: Declaration of Competing Interests S.D.B. has consulted for Regeneron, Sanofi, and Novartis on topics unrelated to this study. S.D.B., and K.R. have filed provisional patent applications related to serological tests for SARS-CoV-2 antibodies. All other authors have no competing interests., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: There is increasing concern that persistent infection of SARS-CoV-2 within immunocompromised hosts could serve as a reservoir for mutation accumulation and subsequent emergence of novel strains with the potential to evade immune responses., Methods: We describe three patients with acute lymphoblastic leukemia who were persistently positive for SARS-CoV-2 by real-time polymerase chain reaction. Viral viability from longitudinally-collected specimens was assessed. Whole-genome sequencing and serological studies were performed to measure viral evolution and evidence of immune escape., Findings: We found compelling evidence of ongoing replication and infectivity for up to 162 days from initial positive by subgenomic RNA, single-stranded RNA, and viral culture analysis. Our results reveal a broad spectrum of infectivity, host immune responses, and accumulation of mutations, some with the potential for immune escape., Interpretation: Our results highlight the need to reassess infection control precautions in the management and care of immunocompromised patients. Routine surveillance of mutations and evaluation of their potential impact on viral transmission and immune escape should be considered., Funding: The work was partially funded by The Saban Research Institute at Children's Hospital Los Angeles intramural support for COVID-19 Directed Research (X.G. and J.D.B.), the Johns Hopkins Center of Excellence in Influenza Research and Surveillance HHSN272201400007C (A.P.), NIH/NIAID R01AI127877 (S.D.B.), NIH/NIAID R01AI130398 (S.D.B.), NIH 1U54CA260517 (S.D.B.), an endowment to S.D.B. from the Crown Family Foundation, an Early Postdoc.Mobility Fellowship Stipend to O.F.W. from the Swiss National Science Foundation (SNSF), and a Coulter COVID-19 Rapid Response Award to S.D.B. L.G. is a SHARE Research Fellow in Pediatric Hematology-Oncology., Competing Interests: Conflict of Interest S.D.B. has consulted for Regeneron, Sanofi, and Novartis on topics unrelated to this study. S.D.B., and K.R. have filed provisional patent applications related to serological tests for SARS-CoV-2 antibodies. All other authors have no competing interests.

To determine the effect of commonly used intravitreal agents on immediate and long-term IOP elevations and their association, if any, with glaucoma. Literature searches in PubMed and the Cochrane databased in January 2020 yielded 407 individual articles. Of these, 87 were selected for review based on our inclusion criteria. Based on the evidence provided, 20 were assigned level I, 27 level II, and 22 level III. Eight articles were rejected because of poor quality, insufficient clarity, or irrelevance based on standardized protocols set out by the American Academy of Ophthalmology. The studies that reported on short-term IOP elevation (i.e., between 0 and 60 min) showed that an immediate increase in IOP is seen in all patients who receive anti-VEGF agents or triamcinolone acetonide when measured between 0 and 30 min of intravitreal injection and that the IOP elevation decreases over time. The data on long-term IOP elevation were mixed; Pretreatment with glaucoma medications, anterior chamber tap, vitreous reflux, longer intervals between injections, and longer axial lengths were associated with lower IOP elevations after injection of anti-VEGF agents, while the position of the implant vis-à-vis, the anterior chamber was important for steroid therapy. Data were mixed on the relationship between IOP increase and the type of intravitreal injection, number of intravitreal injections, preexisting glaucoma, and globe decompression before injection. There were no data on the onset or progression of glaucoma in the studies reviewed in this assessment. However, some studies demonstrated RNFL thinning in patients receiving chronic anti-VEGF therapy. Most, if not all, intravitreal agents cause ocular hypertension, both in the short term and long term. The functional consequences of these observations are not very clear., Competing Interests: None

Competing Interests: None

Background: Novel therapies are urgently needed for pediatric patients with relapsed acute myeloid leukemia (AML)., Methods: To determine whether the histone deacetylase inhibitor panobinostat could be safely given in combination with intensive chemotherapy, a phase 1 trial was performed in which 17 pediatric patients with relapsed or refractory AML received panobinostat (10, 15, or 20 mg/m 2 ) before and in combination with fludarabine and cytarabine., Results: All dose levels were tolerated, with no dose-limiting toxicities observed at any dose level. Pharmacokinetic studies demonstrated that exposure to panobinostat was proportional to the dose given, with no associations between pharmacokinetic parameters and age, weight, or body surface area. Among the 9 patients who had sufficient (>2%) circulating blasts on which histone acetylation studies could be performed, 7 demonstrated at least 1.5-fold increases in acetylation. Although no patients had a decrease in circulating blasts after single-agent panobinostat, 8 of the 17 patients (47%), including 5 of the 6 patients treated at dose level 3, achieved complete remission. Among the 8 complete responders, 6 (75%) attained negative minimal residual disease status., Conclusions: Panobinostat can be safely administered with chemotherapy and results in increased blast histone acetylation. This suggests that it should be further studied in AML., (© 2020 American Cancer Society.)

Purpose: To report intraoperative performance and long-term postoperative outcomes after scleral fixation of intraocular lenses (IOLs) with polytetrafluoroethylene suture (PTFE)., Setting: Raghudeep Eye Hospital, Ahmedabad, India., Design: Prospective, interventional case series., Methods: One hundred eyes undergoing scleral fixation of IOLs using PTFE suture (Gore-Tex) with 12 months or more postoperative follow-up were included. The primary outcome measures were occurrence of intraoperative and postoperative complications such as glaucoma, suture-related complications, and inflammation within the follow-up period. The secondary outcome measure was improvement in visual acuity (VA)., Results: Of the 100 eyes, posteriorly dislocated IOLs (53 eyes) followed by dropped nuclei (33 eyes) were the most common surgical indications. Mean follow-up was 23 months (range 12 months to 5 years). Seventy-one patients (77.17%) had 18 months or more follow-up; 21 eyes had a rise in intraocular pressure in the early postoperative period; 12 of them required glaucoma surgery. Early complications were vitreous hemorrhage in 13 eyes, retinal detachment in 6 eyes, and transient hyphema in 1 eye. Late postoperative complications were cystoid macular edema (9 eyes), epiretinal membrane (3 eyes), and bullous keratopathy (3 eyes). Mean VA improved from 0.92 ± 0.16 (SD) logarithm of the minimum angle of resolution (logMAR) preoperatively to 0.41 ± 0.27 logMAR. LogMAR at final follow-up was 0.41 ± 0.28 (P < .01). There were no cases of suture-related complications (erosion/breakage/granuloma) or IOL decentration throughout the follow-up period., Conclusions: Scleral fixation of IOLs with PTFE suture was found to be safe and well tolerated. All eyes had well-centered IOLs, with no suture-related complications during long-term follow-up. VA improved significantly with acceptable postoperative complications.

Neurotoxicity is a well-documented adverse effect of methotrexate in the treatment of pediatric cancers. The spectrum of symptoms is broad, can include stroke-like episodes and seizures, and classically resolves within days. The majority of patients tolerate subsequent doses without recurrence of symptoms. The population of patients who experience persistent and irreversible neurologic symptoms is poorly described, with the existing literature suggestive of a relationship with radiation therapy. The authors present a case series of 2 patients with pre-B-cell acute lymphoblastic leukemia who developed severe and ultimately fatal methotrexate-related neurotoxicity in the absence of radiation.

Resistance to multimodal chemotherapy continues to limit the prognosis of acute lymphoblastic leukemia (ALL). This occurs in part through a process called adhesion-mediated drug resistance, which depends on ALL cell adhesion to the stroma through adhesion molecules, including integrins. Integrin α6 has been implicated in minimal residual disease in ALL and in the migration of ALL cells to the central nervous system. However, it has not been evaluated in the context of chemotherapeutic resistance. Here, we show that the anti-human α6-blocking Ab P5G10 induces apoptosis in primary ALL cells in vitro and sensitizes primary ALL cells to chemotherapy or tyrosine kinase inhibition in vitro and in vivo. We further analyzed the underlying mechanism of α6-associated apoptosis using a conditional knockout model of α6 in murine BCR-ABL1+ B-cell ALL cells and showed that α6-deficient ALL cells underwent apoptosis. In vivo deletion of α6 in combination with tyrosine kinase inhibitor (TKI) treatment was more effective in eradicating ALL than treatment with a TKI (nilotinib) alone. Proteomic analysis revealed that α6 deletion in murine ALL was associated with changes in Src signaling, including the upregulation of phosphorylated Lyn (pTyr507) and Fyn (pTyr530). Thus, our data support α6 as a novel therapeutic target for ALL., (© 2020 by The American Society of Hematology.)

Purpose: Treatment failure from drug resistance is the primary reason for relapse in acute lymphoblastic leukemia (ALL). Improving outcomes by targeting mechanisms of drug resistance is a potential solution., Patients and Methods: We report results investigating the epigenetic modulators decitabine and vorinostat with vincristine, dexamethasone, mitoxantrone, and PEG-asparaginase for pediatric patients with relapsed or refractory B-cell ALL (B-ALL). Twenty-three patients, median age 12 years (range, 1-21) were treated in this trial., Results: The most common grade 3-4 toxicities included hypokalemia (65%), anemia (78%), febrile neutropenia (57%), hypophosphatemia (43%), leukopenia (61%), hyperbilirubinemia (39%), thrombocytopenia (87%), neutropenia (91%), and hypocalcemia (39%). Three subjects experienced dose-limiting toxicities, which included cholestasis, steatosis, and hyperbilirubinemia ( n = 1); seizure, somnolence, and delirium ( n = 1); and pneumonitis, hypoxia, and hyperbilirubinemia ( n = 1). Infectious complications were common with 17 of 23 (74%) subjects experiencing grade ≥3 infections including invasive fungal infections in 35% (8/23). Nine subjects (39%) achieved a complete response (CR + CR without platelet recovery + CR without neutrophil recovery) and five had stable disease (22%). Nine (39%) subjects were not evaluable for response, primarily due to treatment-related toxicities. Correlative pharmacodynamics demonstrated potent in vivo modulation of epigenetic marks, and modulation of biologic pathways associated with functional antileukemic effects., Conclusions: Despite encouraging response rates and pharmacodynamics, the combination of decitabine and vorinostat on this intensive chemotherapy backbone was determined not feasible in B-ALL due to the high incidence of significant infectious toxicities. This study is registered at http://www.clinicaltrials.gov as NCT01483690., (©2020 American Association for Cancer Research.)

Background: In a multicenter phase 1 study of children with relapsed/refractory acute lymphoblastic leukemia (ALL), moxetumomab pasudotox, an anti-CD22 immunotoxin, demonstrated a manageable safety profile and preliminary evidence of clinical activity. A phase 2 study further evaluated efficacy., Procedure: This international, multicenter, phase 2 study enrolled children with relapsed/refractory B-cell precursor ALL who received moxetumomab pasudotox 40 µg/kg intravenously every other day, for six doses per 21-day cycle. The primary objective was to evaluate the complete response (CR) rate. Secondary objectives included safety, pharmacokinetics, and immunogenicity evaluations., Results: Thirty-two patients (median age, 10 years) were enrolled at 16 sites; 30 received study drug and were evaluable for safety; 28 were evaluable for response. The objective response rate was 28.6%, with three patients (10.7%) achieving morphologic CR, and five patients (17.9%) achieving partial response. Disease progression occurred in 11 patients (39.3%). Ten patients (33.3%) experienced at least one treatment-related serious adverse event, including capillary leak syndrome (CLS; n = 6), hemolytic uremic syndrome (HUS; n = 4), and treatment-related death (n = 1) from pulmonary edema. No differences were observed in inflammatory markers in patients who did or did not develop CLS or HUS., Conclusions: Despite a signal for clinical activity, this phase 2 study was terminated at interim analysis for a CR rate that did not reach the stage 1 target. Preclinical data suggest enhanced efficacy of moxetumomab pasudotox via continuous infusion or in combination regimens; thus, further studies designed to optimize the efficacy and safety of moxetumomab pasudotox in pediatric ALL may be warranted., (© 2020 Wiley Periodicals, Inc.)

As a prototype of genomics-guided precision medicine, individualized thiopurine dosing based on pharmacogenetics is a highly effective way to mitigate hematopoietic toxicity of this class of drugs. Recently, NUDT15 deficiency was identified as a genetic cause of thiopurine toxicity, and NUDT15 -informed preemptive dose reduction was quickly adopted in clinical settings. To exhaustively identify pharmacogenetic variants in this gene, we developed massively parallel NUDT15 function assays to determine the variants' effect on protein abundance and thiopurine cytotoxicity. Of the 3,097 possible missense variants, we characterized the abundance of 2,922 variants and found 54 hotspot residues at which variants resulted in complete loss of protein stability. Analyzing 2,935 variants in the thiopurine cytotoxicity-based assay, we identified 17 additional residues where variants altered NUDT15 activity without affecting protein stability. We identified structural elements key to NUDT15 stability and/or catalytical activity with single amino acid resolution. Functional effects for NUDT15 variants accurately predicted toxicity risk alleles in patients treated with thiopurines with far superior sensitivity and specificity compared to bioinformatic prediction algorithms. In conclusion, our massively parallel variant function assays identified 1,152 deleterious NUDT15 variants, providing a comprehensive reference of variant function and vastly improving the ability to implement pharmacogenetics-guided thiopurine treatment individualization., Competing Interests: The authors declare no competing interest.

Purpose: To determine the utility of the dexamethasone implant (IVD) as an alternative to systemic steroids as prophylaxis against cystoid macular edema (CMO) in patients with chronic, recurrent CMO associated intermediate or posterior uveitis (IU/PU), and cataract undergoing cataract surgery., Methods: This was a randomized, parallel design, and clinical trial. Patients with IU/PU and cataract scheduled for cataract surgery were randomly assigned to receive the IVD concurrently with cataract surgery (Group 1: 20 patients) or systemic steroids (Group 2: 23 patients) tapered over 4-6 weeks along with uneventful cataract surgery and routine postoperative care. Patients with glaucoma/contraindications to steroids were excluded. All patients were followed up for 6 months., Outcome Measure: Primary-incidence of postoperative CMO. Secondary-the change in BCVA (corrected distance visual acuity) and Central Subfield thickness (CST) and complications. Appropriate statistical analysis was done., Results: The median age was 47.3 ± 4.23 years (group 1) and 49.12 ± 5.32 years (Group 2). One patient (Group 1) and two (Group 2) developed CMO. The BCVA improved significantly in both groups (p = 0.013). The CST change was insignificant. Four patients (Group 1) required intraocular pressure (IOP) lowering medications. Three patients (Group 2) required early steroid taper., Conclusions: IVD is a good alternative as prophylaxis in IU/PU and cataract in preventing postoperative CMO.

Purpose: To determine the risk factors associated with sustained intraocular pressure (IOP) rise in patients enrolled in the treat and extend (T&E) protocol receiving aflibercept/ranibizumab therapy for 3 years., Design: Retrospective, observational chart review. Setting . Multicentric. Patients . 789 patients (1021 eyes; 602 males) enrolled in T&E using aflibercept/ranibizumab for diabetic macular edema (DME), wet age-related macular degeneration (AMD), or macular edema in retinal vein occlusion (RVO). Intervention . The history, examination (clinical and special investigations), and treatment records were thoroughly scrutinized. Sustained IOP rise was defined as a rise in IOP above baseline by ≥6 mmHg and/or >24 mmHg on 2 or more consecutive visits. The Wilk-Shapiro test was used for confirming normality of data. The Mantel-Haenszel test and generalized estimating equations were used to analyse multicentric data as well as to analyse data from both eyes of the same patients in the event that both eyes were under therapy. The relative risk, chi-square test (with and without Yates' correction), and univariate and multivariate analysis were used wherever appropriate. Statistical significance was set at P < 0.05. The primary outcome measure was the determination of risk factors for sustained IOP rise with ranibizumab/aflibercept therapy. Secondary outcome measures included determining the incidence of IOP rise (short term and sustained), visual field, and retinal nerve fibre layer (RNFL) changes., Results: The mean follow-up was 42.4 months. Male gender, South Asian ethnicity, older age, presence of AMD and vein occlusion, use of ranibizumab, higher number of injections, narrow angles, switch to bevacizumab/ranibizumab, and preexisting glaucoma were associated with sustained IOP rise. No significant visual field and RNFL changes were seen. The overall incidence was 8.91%. No patient required filtering surgery. No patient with IOP rise returned to baseline., Conclusion: IOP rise is an important consideration as the chronicity of the condition can eventually lead to glaucomatous changes in eyes with already compromised vision. Follow-ups and use of appropriate therapy can be determined correspondingly., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2020 Alper Bilgic et al.)

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., (©2019 American Association for Cancer Research.)

Purpose: To determine the utility and safety of the intravitreal dexamethasone implant as primary therapy (pro re nata [PRN]) in phakic eyes with early treatment-naive diabetic macular edema (DME)., Design: Prospective, case series., Participants: Patients with diabetes mellitus whose eyes were phakic and had early treatment-naive clinically significant macular edema., Methods: Patients whose eyes were phakic with DME (<3 months) were included if the central subfield thickness (CST) was >300 μm and corrected distance visual acuity (CDVA) between 0.3 and 1.0 logarithm of minimum angle of resolution. A comprehensive ocular and systemic examination was performed and the implant injected PRN using a standardized technique. Patients had follow-up at least monthly for 2 years. Descriptive statistics were used to analyze categorical variables in terms of size and proportions. The repeated-measures analysis of variance test was used to determine the change in CDVA, CST, intraocular pressure, and hard exudate area over time., Main Outcome Measures: The primary outcome measure was the determination of the change in CDVA at month 24 from baseline. Secondary outcome measures included determining the change in CST, median number of injections, proportion gaining 15 letters, and complications, if any., Results: A total of 153 patients (85 males) were included. At 2 years, mean CDVA improved from 0.62 to 0.4 logarithm of minimum angle of resolution, and median CST improved from 397 to 236 μm. The median number of injections was 1.6. Cataract developed in 3 patients with a clear lens, and 31 patients required topical antiglaucoma therapy. Proliferative disease developed in 4 patients, which was managed with panretinal photocoagulation. None of the study patients required rescue therapy., Conclusions: In patients with treatment-naive phakic eyes who had DME, primary therapy with the intravitreal dexamethasone implant PRN (for 2 years) resulted in significantly improved mean CDVA. A fifth of the patients required control of intraocular pressure, and new-onset cataract developed in 3 of 153 patients., (Copyright © 2019 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Trabeculectomy is the commonest surgical intervention performed worldwide for the treatment of open-angle glaucoma. However, the use of antimetabolites during trabeculectomy has been associated with various bleb related complications. We report this interesting case to highlight unique clinical presentation and management of a leftover mitomycin-C sponge causing blebitis., Competing Interests: There are no conflicts of interest.

Although inotuzumab ozogamicin (InO) is recognized as an effective agent in relapsed acute lymphoblastic leukemia (ALL) in adults, data on safety and efficacy in pediatric patients are scarce. We report the use of InO in 51 children with relapsed/refractory ALL treated in the compassionate use program. In this heavily pretreated cohort, complete remission was achieved in 67% of patients with overt marrow disease. The majority (71%) of responders were negative for minimal residual disease. Responses were observed irrespective of cytogenetic subtype or number or type of prior treatment regimens. InO was well-tolerated; grade 3 hepatic transaminitis or hyperbilirubinemia were noted in 6 (12%) and grade 3/4 infections in 11 (22%) patients. No patient developed sinusoidal obstruction syndrome (SOS) during InO therapy; however, 11 of 21 (52%) patients who underwent hematopoietic stem cell transplantation (HSCT) following InO developed SOS. Downregulation of surface CD22 was detected as a possible escape mechanism in three patients who developed a subsequent relapse after InO. We conclude that InO is a well-tolerated, effective therapy for children with relapsed ALL and prospective studies are warranted. Identification of risk factors for developing post-HSCT SOS and strategies to mitigate this risk are ongoing.

Glucocorticoids (GCs) are used in combination chemotherapies as front-line treatment for B cell acute lymphoblastic leukemia (B-ALL). Although effective, many patients relapse and become resistant to chemotherapy and GCs in particular. Why these patients relapse is not clear. We took a comprehensive, functional genomics approach to identify sources of GC resistance. A genome-wide shRNA screen identified the transcriptional coactivators EHMT2, EHMT1, and CBX3 as important contributors to GC-induced cell death. This complex selectively supports GC-induced expression of genes contributing to cell death. A metaanalysis of gene expression data from B-ALL patient specimens revealed that Aurora kinase B (AURKB), which restrains GC signaling by phosphorylating EHMT1-2, is overexpressed in relapsed B-ALL, suggesting it as a potential contributor to relapse. Inhibition of AURKB enhanced GC-induced expression of cell death genes, resulting in potentiation of GC cytotoxicity in cell lines and relapsed B-ALL patient samples. This function for AURKB is distinct from its canonical role in the cell cycle. These results show the utility of functional genomics in understanding mechanisms of resistance and rapidly identifying combination chemotherapeutics., Competing Interests: The authors declare no conflict of interest.

Purpose: To determine the usefulness of preoperative optical coherence tomography (OCT) examination to detect asymptomatic macular abnormalities in patients scheduled for cataract surgery., Methods: Design: Prospective, interventional case series., Setting: Iladevi Cataract and Visakha Eye Center, Ahmedabad, India., Study Population: Patients undergoing cataract surgery and intraocular lens (IOL) implantation for senile cataracts. Preoperatively no retinal/macular pathology was identified on clinical evaluation., Intervention: All eyes underwent macular 5-line raster evaluation using spectral-domain OCT before and after cataract surgery (monthly for 3 months). Central subfield thickness (CST) analysis was done., Outcome Measures: The primary outcome measure was determining the incidence of asymptomatic retinal lesions on OCT examination in clinically "normal" maculas. Secondary outcome measures included documenting change in corrected distance visual acuity and OCT thickness postoperatively., Results: A total of 1444 eyes were evaluated. OCT revealed asymptomatic lesions in 133 (9.21%) patients. At 3 months, all eyes showed significant median visual improvement (from 0.45 ± 0.13 logMAR to 0.06 ± 0.08 logMAR; P = .015) and insignificant median CST change (from 223.34 ± 21.1 μm to 249.12 ± 19.24 μm; P = .19). One eye showed increased vitreomacular traction (3 months). Patients with asymptomatic lesions did not have significantly worse postoperative visual outcomes at 3 months (from 0.52 ± 0.16 logMAR to 0.14 ± 0.1 logMAR; P = .12)., Conclusion: A total of 9.21% patients with clinically normal maculas had subtle pathology detected on OCT, but this subset of patients did not have worse postoperative visual outcomes compared to eyes with normal OCT scans. Thus, a careful pre-cataract surgery fundus examination remains an essential part of the presurgical patient evaluation., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Purpose: To determine the association between the dexamethasone implant position in the vitreous cavity and ocular hypertension (OHT)., Methods: Retrospective review of patients with at least one intravitreal dexamethasone implant injection between 2012 and 2016. Patients who had a minimum follow-up for 6 months and documented evidence of the implant position were included in the study. Steroid responders, glaucoma patients, vitrectomized eyes, and eyes with liquefied vitreous were excluded. Relevant data were collected from patient charts. Three positions (P1, P2, and P3) were identified: P1 (in contact with the pars plana/ciliary body region), P2 (anterior to vortex veins), and P3 (posterior to vortex veins). Ocular hypertension was defined as absolute intraocular pressure > 25 mmHg and/or intraocular pressure rise > 10 mmHg. The relationship between implant position and intraocular pressure rise after factoring in other characteristics was the outcome measure. Appropriate statistical analysis was performed., Results: A total of 377 patients (432 eyes; 257 males; 677 injections) were eligible for analysis. The median age was 57.24 (±6.32) years. Eighty-eight eyes had OHT. Of these, 54 eyes had the implant in P1. P1 was associated with high intraocular pressure response (>15 mmHg; P = 0.004) and early (<15 days) onset OHT (r = 0.84, P < 0.001)., Conclusion: Anterior position of dexamethasone implant in situ increases the risk of OHT.

Background and Purpose: Survivors of acute lymphoblastic leukemia are at risk for neurocognitive deficits and leukoencephalopathy. We performed a longitudinal assessment of leukoencephalopathy and its associations with long-term brain microstructural white matter integrity and neurocognitive outcomes in survivors of childhood acute lymphoblastic leukemia treated on a modern chemotherapy-only protocol., Materials and Methods: One hundred seventy-three survivors of acute lymphoblastic leukemia (49% female), treated on a chemotherapy-only protocol, underwent brain MR imaging during active therapy and repeat imaging and neurocognitive testing at follow-up (median, 13.5 years of age; interquartile range, 10.7-17.6 years; median time since diagnosis, 7.5 years; interquartile range, 6.3-9.1 years). Persistence of leukoencephalopathy was examined in relation to demographic and treatment data and to brain DTI in major fiber tracts and neurocognitive testing at follow-up., Results: Leukoencephalopathy was found in 52 of 173 long-term survivors (30.0%) and persisted in 41 of 52 (78.8%) who developed it during therapy. DTI parameters were associated with leukoencephalopathy in multiple brain regions, including the corona radiata (fractional anisotropy, P = .001; mean diffusivity, P < .001), superior longitudinal fasciculi (fractional anisotropy, P = .02; mean diffusivity, P < .001), and superior fronto-occipital fasciculi (fractional anisotropy, P = .006; mean diffusivity, P < .001). Mean diffusivity was associated with neurocognitive impairment including in the genu of the corpus callosum ( P = .04), corona radiata ( P = .02), and superior fronto-occipital fasciculi ( P = .02)., Conclusions: Leukoencephalopathy during active therapy and neurocognitive impairment at long-term follow-up are associated with microstructural white matter integrity. DTI may be more sensitive than standard MR imaging for detection of clinically consequential white matter abnormalities in childhood acute lymphoblastic leukemia survivors treated with chemotherapy and in children undergoing treatment., (© 2018 by American Journal of Neuroradiology.)

A pediatric patient diagnosed initially with B-lymphoblastic leukemia (B-ALL) relapsed with lineage switch to acute myeloid leukemia (AML) after chimeric antigen receptor T-cell (CAR-T) therapy and hematopoietic stem cell transplant. A TCF3-ZNF384 fusion was identified at diagnosis, persisted through B-ALL relapse, and was also present in the AML relapse cell population. ZNF384-rearrangements define a molecular subtype of B-ALL characterized by a pro-B-cell immunophenotype; furthermore, ZNF384-rearrangements are prevalent in mixed-phenotype acute leukemias. Lineage switch following CAR-T therapy has been described in patients with KMT2A (mixed lineage leukemia) rearrangements, but not previously in any patient with ZNF384 fusion., (© 2018 Wiley Periodicals, Inc.)

Competing Interests: There are no conflicts of interest

Introduction: Acute lymphoblastic leukemia (ALL) therapy confers risk for venous thromboembolism (VTE) and associated acute and long-term morbidity. Obesity increases VTE risk in the general population but its impact on ALL therapy-associated VTE is unknown., Methods: In a retrospective cohort of children treated for ALL between 2008 and 2016 (n = 294), we analyzed obesity at diagnosis (body mass index [BMI] ≥95%) and subsequent development of VTE. A subset participated in two concurrent prospective ALL trials studying body composition via dual-energy X-ray absorptiometry (DXA) (n = 35) and hypercoagulability via thromboelastography (TEG) (n = 46). Secondary analyses explored whether precise measurement of body fat and/or global hemostasis ex vivo by TEG could further delineate VTE risk in the obese., Results: Overall, we found 27/294 (9.2%) patients developed symptomatic VTE during therapy, 19/27 (70%) occurred during Induction. Study-defined "serious" VTE developed in 4/294 (1.4%) of patients. Obesity but not overweight was strongly predictive of symptomatic VTE (obesity odds ratio = 3.8, 95% confidence interval 1.5-9.6, p = 0.008). In the DXA subset, only 2/35 patients developed symptomatic VTE. However, within those prospectively screened during Induction, 30% (14/46) developed VTE; eight (17%) of these were asymptomatic and found only via screening., Conclusions: In this pediatric ALL cohort, obesity conferred more than a three-fold increased risk for symptomatic VTE. In a subgroup of patients who underwent active screening, up to a third were noted to have VTE (symptomatic and asymptomatic). TEG did not predict VTE. Additional studies are necessary to validate these findings and to further refine a risk-stratified approach to thrombo-prevention during ALL therapy., (Copyright © 2018. Published by Elsevier Ltd.)

Objective: Tritan anomaly is a known acquired color defect seen in diabetic patients, with or without the evidence of clinical signs of diabetic retinopathy (DR). We report a case of a 45-year-old diabetic patient with tritan pattern color defect associated with obstructive sleep apnea and its partial reversal with continuous positive airway pressure (CPAP) ventilation. Methods: A 45-year-old male with diabetes, wildlife photographer by profession, presented with specific complaints of seeing all objects in the surrounding with a greenish tinge in both the eyes. He underwent a comprehensive eye examination including Farnsworth-Munsel 100 (FM 100) hue test, multifocal electroretinogram, microperimetry, spectral domain optical coherence tomography (SDOCT), and arterial oxygen saturation. Results: The subject was found to have a low arterial oxygen saturation (PaO2) of 86%. He was then advised inhalation of 100% oxygen for 15 min, following which he reported improvement in his visual symptoms. FM 100, OCT, and microperimetry were repeated after oxygenation. He was referred to a specialty hospital for further evaluation of the cause for reduced blood oxygen saturation and was further advised for sleep study, where he was diagnosed to have obstructive sleep apnea (OSA) with an apnea-hypopnea index of 20.9. Conclusion: The subject was advised weight loss measures and oral application of continuous positive airway pressure. Since then, he is under our regular follow-up and has never experienced or complained of any color vision problems. This case report highlights the presence of associated systemic disorders like obstructive sleep apnea in individuals with diabetes that can present with color vision problems., Competing Interests: The authors declare that they have no competing interests.

Background: Hepatotoxicity and pancreatitis are common treatment-related toxicities (TRTs) during contemporary treatment regimens for acute lymphoblastic leukemia (ALL). Limited detailed data from Children's Oncology Group (COG) regimens has been previously reported to enable identification of patient and treatment risk factors for these toxicities and their impact on outcomes., Procedure: We analyzed a retrospective pediatric ALL cohort treated at a single institution according to COG regimens from 2008 to 2015. The primary endpoint was cumulative incidence of study-defined "severe" hepatotoxicity (Common Terminology Criteria for Adverse Events [CTCAE] Grade ≥ 4 transaminitis or Grade ≥ 3 hyperbilirubinemia) and clinically significant pancreatitis (any grade). Pancreatitis was additionally classified using the Ponte di Legno (PdL) toxicity criteria. Secondary endpoints were chemotherapy interruptions, early disease response (end of induction [EOI] minimal residual disease [MRD]), and event-free survival (EFS)., Results: We identified 262 patients, of whom 71 (27%) and 28 (11%) developed hepatotoxicity and pancreatitis, respectively. Three cases of pancreatitis did not fulfill PdL criteria despite otherwise consistent presentations. Both TRTs occurred throughout therapy, but approximately 25% of hepatotoxicity (18/71) and pancreatitis (8/28) occurred during induction alone. Both obesity and age (≥10 years) were identified as predictors of hepatotoxicity (subdistribution hazard ratio [SHR] obesity = 1.75, 95% confidence interval [95% CI] 1.04-2.96; SHR age ≥10 = 1.9, 95% CI 1.19-3.10) and pancreatitis (SHR obesity = 2.18, 95% CI 1.01-4.67; SHR age ≥ 10 = 2.76, 95% CI 1.19-6.39, P = 0.018). Dose interruptions were common but neither toxicity influenced EOI MRD nor EFS., Conclusions: Obese and/or older children are particularly at risk for hepatotoxicity and pancreatitis, and may benefit from toxicity surveillance and chemoprotective strategies to prevent or mitigate associated morbidity., (© 2017 Wiley Periodicals, Inc.)

While early studies reported superior survival for cancer patients enrolled on clinical trials, recent findings are inconclusive. We investigated the association between enrollment on contemporary trials and event-free survival (EFS) in pediatric B-cell acute lymphoblastic leukemia (B-ALL). In a retrospective cohort of 274 children (1-21 years) treated for B-ALL from 2008 to 2015, 55.5% enrolled with no disparity in enrollment by age, sex, or ethnicity. Three-year EFS was similar for enrolled and not enrolled patients (90.1% [95% CI, 82.5-94.5] versus 86.5% [95% CI, 77.7-92.0]). Clinical trial enrollment did not affect pediatric B-ALL survival, albeit in a limited-size cohort treated at a single academic institution., (© 2017 Wiley Periodicals, Inc.)

Novel therapies are needed to overcome chemotherapy resistance for children with relapsed/refractory acute lymphoblastic leukemia (ALL). Moxetumomab pasudotox is a recombinant anti-CD22 immunotoxin. A multicenter phase 1 study was conducted to determine the maximum-tolerated cumulative dose (MTCD) and evaluate safety, activity, pharmacokinetics, and immunogenicity of moxetumomab pasudotox in children, adolescents, and young adults with ALL (N = 55). Moxetumomab pasudotox was administered as a 30-minute IV infusion at doses of 5 to 50 µg/kg every other day for 6 (cohorts A and B) or 10 (cohort C) doses in 21-day cycles. Cohorts B and C received dexamethasone prophylaxis against capillary leak syndrome (CLS). The most common treatment-related adverse events were reversible weight gain, hepatic transaminase elevation, and hypoalbuminemia. Dose-limiting CLS occurred in 2 of 4 patients receiving 30 µg/kg of moxetumomab pasudotox every other day for 6 doses. Incorporation of dexamethasone prevented further dose-limiting CLS. Six of 14 patients receiving 50 µg/kg of moxetumomab pasudotox for 10 doses developed hemolytic uremic syndrome (HUS), thrombotic microangiopathy (TMA), or HUS-like events, exceeding the MTCD. Treatment expansion at 40 µg/kg for 10 doses (n = 11) exceeded the MTCD because of 2 HUS/TMA/HUS-like events. Dose level 6B (ie, 50 µg/kg × 6 doses) was the MTCD, selected as the recommended phase 2 dose. Among 47 evaluable patients, an objective response rate of 32% was observed, including 11 (23%) composite complete responses, 5 of which were minimal residual disease negative by flow cytometry. Moxetumomab pasudotox showed a manageable safety profile and evidence of activity in relapsed or refractory childhood ALL. This trial was registered at www.clinicaltrials.gov as #NCT00659425.

The 2016 World Health Organization (2016 WHO) classification of hematopoietic malignancies classifies neoplasms with a fusion between the FIP1L1 and PDGFRA genes in 4q12 into a group called "myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB or FGFR1 or with PCM1-JAK2". Neoplasms characterized by this fusion are pluripotent stem cell disorders that can show both myeloid and lymphoid differentiation. They typically occur in adult patients and most are characterized by eosinophilia. We describe identification of a FIP1L1-PDGFRA fusion in a 13-year-old boy who presented with T-lymphoblastic leukemia/lymphoma without eosinophilia. Detection of FIP1L1-PDGFRA driven neoplasms at diagnosis is usually critical for proper treatment, since almost all reported cases responded to tyrosine kinase inhibitors. However, our patient's leukemia was refractory to standard chemotherapy, and did not show a meaningful response to tyrosine kinase inhibitor therapy. Testing for a FIP1L1-PDGFRA rearrangement is at present limited to patients with idiopathic hypereosinophilia, and we hypothesize that this abnormality may be under-diagnosed in children with acute leukemias., (Copyright © 2017 Elsevier Inc. All rights reserved.)

The quest continues for targeted therapies to reduce the morbidity of chemotherapy and to improve the response of resistant leukemia. Adhesion of acute lymphoblastic leukemia (ALL) cells to bone marrow stromal cells triggers intracellular signals that promote cell-adhesion-mediated drug resistance (CAM-DR). Idelalisib, an U.S. Food and Drug Administration (FDA)-approved PI3Kδ-specific inhibitor has been shown to be effective in CLL in down-regulating p-Akt and prolonging survival in combination with Rituximab; herein we explore the possibility of its use in B ALL and probe the mechanism of action. Primary B ALL in contact with OP9 stromal cells showed increased p-Akt ser473 . Idelalisib decreased p-Akt in patient samples of ALL with diverse genetic lesions. Addition of idelalisib to vincristine inhibited proliferation when compared to vincristine monotherapy in a subset of samples tested. Idelalisib inhibited ALL migration to SDF-1α in vitro and blocked homing of ALL cells to the bone marrow in vivo. This report tests PI3Kδ inhibitors in a more diverse group of ALL than has been previously reported and is the first published report of idelalisib inhibiting homing of ALL cells to bone marrow. Our data support further pre-clinical evaluation of idelalisib for the therapy of B ALL., Competing Interests: Gilead Sciences provided the drugs and some funding for this research; aside from that the authors declare no conflict of interest.

During the 2016 Therapeutic Advances for Childhood Leukemia & Lymphoma (TACL) Consortium investigators' meeting (Los Angeles, CA), a Biology Working Group was established to support the consortium's mission of developing innovative therapies for currently incurable childhood leukemias and lymphomas. The charge of the Biology Working Group was to address how TACL could advance biological investigations of pediatric relapsed/refractory hematologic malignancies while undertaking forward-looking therapeutic trials. To this end, the TACL Biology Committee was established to provide the scientific platform needed to further develop preclinical and translational studies that will advance the understanding and treatment of relapsed and refractory disease. The Biology Committee will focus on ensuring state-of-the-art studies that address biological components of early phase clinical trials, and developing a central biology bank of materials from these early phase trials for interrogations into the mechanisms of disease resistance.

A 4-year-old girl presented with decreased vision since 3 months. Visual acuity was 20/20 in right eye and counting fingers at 2 meters in the left. Left eye examination revealed exotropia, retinal telangiectasia, extensive subretinal exudation over the macula and exudative retinal detachment suggestive of Coats' disease. Fundus fluoroscein angiography highlighted the hallmark 'light bulb' retinal telangiectasias, macular retinochoroidal anstamosis and peripheral nonperfused retina. The patient was treated with focal laser photocoagulation to the retinal telangiectatic vessels and scatter laser photocoagulation of the non-perfused retina., Competing Interests: There are no conflicts of interest.