Search

Background: Radiolabeled antibody 131 I-omburtamab was administered intraventricularly in patients with leptomeningeal disease under an institutionally approved study (#NCT03275402). Radiation safety precautions were tailored for individual patients, enabling outpatient treatment based on in-depth, evidence-based recommendations for such precautions. The imperative advancement of streamlined therapeutic administration procedures, eliminating the necessity for inpatient isolation and resource-intensive measures, holds pivotal significance. This development bears broader implications for analogous therapies within the pediatric patient demographic., Methods: Intraventricular radioimmunotherapy (RIT) with 925-1850 MBq (25-50 mCi) of 131 I-omburtamab was administered via the Ommaya reservoir, in designated rooms within the pediatric ambulatory care center. Dosimeters were provided to staff involved in patient care to evaluate exposure during injection and post-administration. Post-administration exposure rate readings from the patient on contact, at 0.3 m, and at 1 m were taken within the first 30 min, and the room was surveyed after patient discharge. Duration of radiation exposure was calculated using standard U.S. Nuclear Regulatory Commission (US NRC) regulatory guidance recommendations combined with mean exposure rates and whole-body clearance estimates. Exposure rate measurements and clearance data provided patient-specific precautions for four cohorts by age: < 3 y/o, 3-10 y/o, 10-18 y/o, and 18+., Results: Post-administration exposure rates for patients ranged from 0.16 to 0.46 µSv/hr/MBq at 0.3 m and 0.03-0.08 µSv/hr/MBq at 1 m. Radiation exposure precautions ranged from 1 to 10 days after release for the four evaluated cohorts. Based on the highest measured exposure rates and slowest whole-body clearance, the longest precautions were approximately 78% lower than the regulatory guidance recommendations. Radiation exposure to staff associated with 131 I-omburtamab per administration was substantially below the annual regulatory threshold for individual exposure monitoring., Conclusion: 131 I-omburtamab can be administered on an outpatient basis, using appropriate patient-based radiation safety precautions that employ patient-specific exposure rate and biological clearance parameters. This trial is registered with the National Library of Medicine's ClinicalTrials.gov. The registration number is NCT03275402, and it was registered on 7 September 2017. The web link is included here. https://clinicaltrials.gov/study/NCT03275402 ., (© 2024. The Author(s).)

Objective: To study the clinico- radiological profile and outcome of isolated paramedian hemipontine infarcts., Materials and Methods: This is a prospective cross- sectional study. 50 consecutive patients admitted between January 2019 and December 2020 with a diagnosis of isolated paramedian hemipontine stroke were included. The locations of the infarcts were classified as follows- caudal; middle; rostral; dorsomedian; caudal and middle; and middle and rostral pons. The clinico- radiological profiles were studied and the outcomes were assessed using NIHSS (National Institutes of Health Stroke Scale) and mRS (modified Rankin score). Data was analysed using SPSS 22 version software. Paired t-test was used as a test of significance to identify the mean differences between the two quantitative variables., Results: Majority of the subjects were 51- 60 years (34 percent). The most common risk factors were hypertension and type 2 diabetes mellitus. The most common clinical features were hemiparesis and speech disturbances. Pure motor hemiparesis (PMH) is the common syndrome seen in paramedian hemipontine strokes with infarcts located in caudal; middle; caudal and middle; and middle and rostral pons. In ataxic hemiparesis, infarcts were located in dorsomedian pons. In dysarthria clumsy hand syndrome, infarcts were located at rostral pons. 44 percent of the subjects had left vertebral artery abnormality. There was a statistically significant difference in the mean NIHSS and mRS when compared at admission/ discharge and at 3 months., Conclusion: Isolated paramedian hemipontine stroke syndromes have good topographical correlation with patients usually having a good functional outcome at the end of three months.

Two significant obstacles hinder the advancement of Radiology AI. The first is the challenge of overfitting, where small training data sets can result in unreliable outcomes. The second challenge is the need for more generalizability, the lack of which creates difficulties in implementing the technology across various institutions and practices. A recent innovation, deep neuroevolution (DNE), has been introduced to tackle the overfitting issue by training on small data sets and producing accurate predictions. However, the generalizability of DNE has yet to be proven. This paper strives to overcome this barrier by demonstrating that DNE can achieve satisfactory results in diverse external validation sets. The main innovation of the work is thus showing that DNE can generalize to varied outside data. Our example use case is predicting brain metastasis from neuroblastoma, emphasizing the importance of AI with limited data sets. Despite image collection and labeling advancements, rare diseases will always constrain data availability. We optimized a convolutional neural network (CNN) with DNE to demonstrate generalizability. We trained the CNN with 60 MRI images and tested it on a separate diverse collection of images from over 50 institutions. For comparison, we also trained with the more traditional stochastic gradient descent (SGD) method, with the two variants of (1) training from scratch and (2) transfer learning. Our results show that DNE demonstrates excellent generalizability with 97% accuracy on the heterogeneous testing set, while neither form of SGD could reach 60% accuracy. DNE's ability to generalize from small training sets to external and diverse testing sets suggests that it or similar approaches may play an integral role in improving the clinical performance of AI., (© 2024. The Author(s) under exclusive licence to Society for Imaging Informatics in Medicine.)

Clinical manifestations of liver inflammation in alcohol-associated liver disease (ALD) can range from asymptomatic to severe alcoholic hepatitis. While biopsy is the gold standard for identifying liver inflammation, it is an invasive procedure with risks of bleeding, visceral damage, and infection. We aim to establish the state of the current literature on non-invasive markers of inflammation in ALD. We searched Ovid MEDLINE, Embase, and the Cochrane Library for original studies on the association between one or more non-invasive biomarker(s) and histological inflammation or hepatitis in ALD patients. Exclusion criteria were lack of histological data, abstract only, non-English-language articles, and animal studies. Two independent reviewers screened abstracts, reviewed full texts, and extracted data from included papers. Our search identified 8051 unique studies. Title and abstract screening resulted in 563 studies, and full-text screening resulted in 31 studies for final inclusion. The majority were single-center observational cohorts with an average sample size of 124. Review of these studies identified 44 unique biomarkers and 8 calculated scores associated with histological inflammation and/or hepatitis, in addition to a metabolomic panel of 468 metabolites. Six studies examined diagnostic accuracy for histological inflammation and/or hepatitis. The highest area under the receiver operating characteristic curve was 0.932 using a model based on four metabolites. This review highlights the available literature on non-invasive markers of inflammation in ALD. There is a dearth of studies that evaluate the diagnostic accuracy of these biomarkers, and larger studies are needed to confirm findings identified in small cohorts., (© 2023 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Goals: To identify factors associated with transplantation and death in alcohol-associated liver disease (ALD) patients presenting with first evidence of ascites., Background: Ascites development is a poor prognostic sign for patients with cirrhosis. Among ALD patients, the baseline factors at time of ascites development that are associated with eventual transplantation or death are currently unknown., Study: Adult patients with ascites in the "Evaluating Alcohol Use in Alcohol-related Liver Disease Prospective Cohort Study" (NCT03267069 clinicaltrials.gov) were identified from 2016 to 2020. Demographic, clinical, and laboratory factors at initial ascites presentation were identified as potential predictors of transplant and death as competing risks., Results: A total of 96 patients were identified. Median (interquartile range) follow-up time was 2.00 years (0.87 to 3.85). By last follow-up, 34/96 patients had been transplanted (35.4%) and 11/96 had died (11.4%). Prognostic factors for transplant included age per decade [hazard ratio (HR): 0.52 (95% CI, 0.33 to 0.83)], employed status [HR: 0.35 (95% CI, 0.14 to 0.90)], and sodium [HR: 0.94 (95% CI, 0.90 to 0.99)], whereas prognostic factors for death were body mass index [HR: 1.11 (95% CI, 1.00 to 1.22)], Charlson index [HR: 2.14 [95% CI, 1.13 to 4.08]), Maddrey Discriminant Function >32 (HR: 5.88 (95% CI, 1.18, 29.39)], aspartate aminotransferase [HR: 0.99 (95% CI, 0.98 to 0.997)], and a prior 12-month abstinence period [HR: 5.53 (95% CI, 1.10 to 27.83)], adjusted for age, sex, and ALD subcategory., Conclusions: Several factors at initial ascites presentation are associated with increased risk of transplantation or death and validation in larger cohorts will allow for improved risk stratification for ALD patients., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Chronic liver disease (CLD) is a highly prevalent condition. There is burgeoning recognition that there are many people with subclinical liver disease that may nonetheless be clinically significant. CLD has a variety of systemic aberrations relevant to stroke, including thrombocytopenia, coagulopathy, elevated liver enzymes, and altered drug metabolism. There is a growing body of literature on the intersection of CLD and stroke. Despite this, there have been few efforts to synthesize these data, and stroke guidelines provide scant guidance on this topic. To fill this gap, this multidisciplinary review provides a contemporary overview of CLD for the vascular neurologist while appraising data regarding the impact of CLD on stroke risk, mechanisms, and outcomes. Finally, the review addresses acute and chronic treatment considerations for patients with stroke-ischemic and hemorrhagic-and CLD., Competing Interests: Disclosures Dr Parikh: personal compensation for medicolegal consulting. Dr Kamel: Principal Investigator (ARCADIA [Atrial Cardiopathy and Antithrombotic Drugs In Prevention After Cryptogenic Stroke], NINDS (National Institute of Neurological Disorders and Stroke) U01NS095869; in-kind study drug [BMS (Bristol Myers Squibb)-Pfizer Alliance for Eliquis]; ancillary study support [Roche Diagnostics]); Deputy Editor (JAMA Neurology); member, clinical trial steering/executive committees (Medtronic, Janssen, and Javelin Medical); member, End Point Adjudication Committees (AstraZeneca, Novo Nordisk, and Boehringer Ingelheim); and ownership interest (TETMedical, Inc). Dr VanWagner: research support (W.L. Gore & Associates; NHLBI (National Heart, Lung, and Blood Institute) R56 HL155093); consultant (Gerson Lehrman Group, Numares, Slingshot Insights, and Noble Consultants); medicolegal consulting; and associate editor (Liver Transplantation). The other authors report no conflicts.

Introduction: The prevalence of myocardial infarction (MI) among young Indian adults is on the rise with reports suggesting 32.7% of all deaths in men and 32.6% of all deaths in women between 2010-13 were due to cardiovascular diseases (CVDs). Though various long-term cohort studies have established risk assessment scores none of them are specific to the Indian population. In this study, we look to establish which scoring system among the American College of Cardiology (ACC), Joint British Society (JBS3) and Framingham Risk Scores (FRS) would be reliable for the Indian population. A timely intervention based on the most reliable score can help mitigate cardiovascular diseases., Materials and Methods: In this cross-sectional study, we included Indian adults, aged more than 40 years, with first MI. Patients previously on lipid lowering drugs were excluded. Demographic data, history, clinical information, laboratory data and other investigations were noted. Subsequently the predicted cardiovascular risk scores based on JBS3, ACC, and FRS were calculated and divided into low risk, intermediate and high risk based on the categorization of the risk scores individually., Results: There were 102 (79.1%) males and 23 (17.8%) females with a mean age of 51.01 years (standard deviation [SD]=12.82, p value <0.001). There was considerable prevalence of type 2 diabetes mellitus with 56 (47.1%) of the subjects being known diabetics. The mean 10-year risk of MI based on ACC was 12.42% (SD=10.45), mean JBS3 score was 14.45% (SD=12.67) and mean FRS score was 15.75% (SD=14.71). FRS scores when categorized, 48 (40.3%) patients had low risk, 30 (23.3%) had medium risk and 43 (33.3%) had high risk. As for ACC score, 39 (35.8%) patients were in low risk and 29 (26.6%) in intermediate risk, borderline in 18 (16.5%) and high risk in 23 (21.1%). In JBS3 scores, 53 (46.5%) patients were in low risk, 32 (28.1%) were in moderate risk and 29 (25.4%) in high risk., Conclusion:  The absolute value of 10-year risk scores was highest for FRS scores. The proportion of patients whose scores were under the category of high risk was highest for FRS., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Raj et al.)

Background and Purpose: We examined the association of chronic liver disease with cognition and brain imaging markers of cognitive impairment using data from two large randomized controlled trials that included participants based on diabetes and hypertension, two common systemic risk factors for cognitive impairment and dementia., Methods: We performed post hoc analyses using data from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) and Systolic Blood Pressure Intervention Trial (SPRINT) studies, which included participants with diabetes and hypertension, respectively. Data were from the NHLBI Biologic Specimen and Data Repository Information Coordinating Center. In ACCORD, our measure of chronic liver disease was the Dallas Steatosis Index (DSI). In SPRINT, we used self-reported chronic liver disease. We used linear regression to evaluate the association between the measure of chronic liver disease and both baseline and longitudinal cognitive test performance and brain magnetic resonance imaging volume measurements., Results: Among 2969 diabetic participants in ACCORD, the mean age of participants was 62 years, 47% were women. The median DSI was 1.0 (IQR, 0.2-1.8); a DSI of 1.0 corresponds to approximately a > 70% probability of having NAFLD. Among 2890 hypertensive participants in SPRINT, the mean age was 68 years, and 37% were women, and 60 (2.1%) had chronic liver disease. There were no consistent associations between liver disease and cognitive performance or brain volumes at baseline or longitudinally after adjustment., Conclusion: Markers of chronic liver disease were not associated with cognitive impairment or related brain imaging markers among individuals with diabetes and hypertension., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Sex differences in stroke outcomes have been noted, but whether this extends to stroke recurrence is unclear. We examined sex differences in recurrent stroke using data from the Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke (POINT) trial., Patients and Methods: We assessed the risk of recurrent stroke in women compared to men using data from the POINT trial. Adults >18 years old were randomized within 12 hours of onset of minor ischemic stroke or transient ischemic attack (TIA), and followed for up to 90 days for ischemic stroke, our primary outcome. We used Cox proportional hazards model adjusted for demographics and stroke risk factors to evaluate the association between sex and stroke recurrence. We used interaction term testing and prespecified subgroup analyses to determine if the association between sex and recurrent stroke differed by age (<60 versus >60 years old), locale (US versus non-US), and index event type (stroke versus TIA). Last, we evaluated whether sex modified the effect of common stroke risk factors on stroke recurrence., Results: Of 4,881 POINT trial participants with minor stroke or high-risk TIA, 2,195 (45%) were women. During the 90-day follow-up period, 267 ischemic strokes occurred; 121 were in women and 146 in men. The cumulative risk of recurrent ischemic stroke was not significantly different among women (5.76%; 95% CI, 4.84%-6.85%) compared to men (5.67%; 95% CI, 4.83%-6.63%). Women were not at a different risk of recurrent ischemic stroke compared to men (hazard ratio [HR], 1.02; 95% CI, 0.80-1.30) in unadjusted models or after adjusting for covariates. However, there was a significant interaction of age with sex (P=0.04). Among patients <60 years old, there was a non-significantly lower risk of recurrent stroke in women compared to men (HR 0.66; 95% CI 0.42-1.05). Last, sex did not modify the association between common stroke risk factors and recurrent stroke risk., Discussion and Conclusion: Among patients with minor stroke or TIA, the risk of recurrent ischemic stroke and the impact of common stroke risk factors did not differ between men and women., Competing Interests: Declaration of conflicting interests: EB and SSO declare that there is no conflict of interest. HK serves as a principal investigator for the NIH-funded ARCADIA trial (National Institute of Neurological Disorders and Stroke U01NS095869) which receives in-kind study drug from the BMS-Pfizer Alliance for Eliquis® and ancillary study support from Roche Diagnostics, serves as Deputy Editor for JAMA Neurology, serves as a steering committee member of Medtronic’s Stroke AF trial (uncompensated), and serves on an endpoint adjudication committee for a trial of empagliflozin for Boehringer-Ingelheim. NP has received grants from the Leon Levy Foundation and the New York State Empire Clinical Research Investigator Program unrelated to this work and personal compensation for medicolegal consulting., (© European Stroke Organisation 2021.)

Context: Tuberculosis (TB) is a common infectious disorder in developing countries. A significant load of patients with extrapulmonary TB are diagnosed in our institute, mostly involving the spine., Aim: We aimed to present our experience in the surgical management of spinal TB., Setting and Design: This was a retrospective observational study., Materials and Methods: Seventy patients (year 2016-2018) who underwent surgical management with minimum of 1-year follow-up (17 patients lost during follow-up) were graded as per the American Spinal Injury Association (ASIA) grading system for neurological deficits. All were surgically treated with laminectomy and epidural abscess drainage/transpedicular debridement of granulation with/without spinal stabilization. Thoracic and lumbar cases were managed by posterior approach; among them, 12 patients who had no significant cord compression and good ASIA grade with facet involvement (requiring fusion) underwent minimally invasive pedicle screw fixation. Cervical cases were managed mostly by anterior approach. All patients received Anti-tubercular treatment (ATT) post operatively as per protocol postoperatively, following which magnetic resonance imaging (MRI) spine was done., Statistical Analysis: Data were analyzed using SPSS software version 18.0 (SPSS Inc. Released in 2009. PASW Statistics for Windows, version 18.0. Chicago, IL, USA: SPSS Inc.). The continuous variables were analyzed using descriptive statistics using mean and standard deviation., Results: The average age was 42.5 years. The most common location was thoracic (28 patients), followed by lumbar (20 patients), cervical (16 patients), and thoracolumbar (6 patients). Twenty patients had epidural abscess with cord compression. All patients who presented within 4 weeks of onset of symptoms showed a statistically significant improvement postsurgery. Sixteen patients with epidural abscess had good neurological recovery immediately after surgery (ASIA B to ASIA D/E). Four patients with epidural abscess with late presentation remained ASIA A after surgery. All patients had good fusion rates (follow-up X-ray) at 1 year. After ATT course completion, all patients had complete eradication of disease (MRI spine)., Conclusion: Surgical treatment for spinal TB, if performed early (within 4 weeks) with good decompression, results in satisfactory clinical outcome with early improvement in the neurological deficits. Posterior approach to the spine with decompression and fixation gives good results, and minimally invasive procedures further help lessen muscle dissection, less pain, and early mobilization., Competing Interests: There are no conflicts of interest., (Copyright: © 2021 Asian Journal of Neurosurgery.)

Objective: Indirect bypass surgeries for moyamoya disease have included modifications of procedures involving placement of the superficial temporal artery on the brain pial surface. We evaluate the functional and angiographic outcomes of patients treated with encephaloduroarteriomyosynangiosis (indirect) revascularization and examine the outcome in relation to demographic and radiological factors., Materials and Methods: Patients treated surgically for moyamoya disease over a 14-year period were identified. Demographics, clinical presentation, and radiology were analyzed to assign a stage for the disease (Suzuki staging) and the extent of revascularization (Matsushima grade) at the last follow-up. A modified Rankin score was used to assess the clinical status at presentation and the functional outcome at follow-up., Results: There were 46 patients operated on by a single surgeon over a 14-year period. A higher incidence of motor deficits, seizures, and speech deficits was seen in the pediatric population. Age, sex, preoperative Suzuki disease stage, and hemispheric involvement had no bearing on angiographic outcome at last follow-up. Three of 46 patients (6.5%) developed immediate postoperative complications. Among 43 patients on follow-up, 39 had stable disease or showed improvement in clinical symptoms with 90% event-free status at last follow-up., Conclusions: Indirect revascularization procedures are an effective alternative to direct cerebral revascularizations in the early or advanced stages of moyamoya disease. This is effective in a predominant ischemic presentation as noted in our series., Competing Interests: None

Purpose: The tyrosine kinase receptor anaplastic lymphoma kinase (ALK) can be abnormally activated in neuroblastoma, and somatic ALK mutations occur in 6%-10% of patients. The differential clinical impact of these mutations has not been clearly elucidated., Methods: Data on patients with neuroblastoma harboring ALK mutations were retrospectively analyzed. ALK sequencing was performed by whole-genome sequencing, hybrid-based capture of targeted exomes, or hotspot ALK mutation profiling. The differential impact of ALK mutation site on clinical characteristics, response to treatment, and survival was analyzed. In a subgroup of patients with locoregional neuroblastoma diagnosed after 2014, the impact of all ALK mutations was compared with wild-type ALK., Results: Of 641 patients with neuroblastoma with ALK status analyzed on at least one tumor sample, 103 (16%) had tumors harboring ALK mutations. Mutations existed across all ages (birth to 67.8 years), stages (30% locoregional and 70% metastatic), and risk groups (20%, 11%, and 69% with low-, intermediate-, and high-risk disease, respectively). Mutation sites included F1174 (51%), R1275 (29%), R1245 (10%), and others (10%). Mutation site was not prognostic for progression-free survival or overall survival in the entire cohort, high-risk subgroup, or locoregional subgroup. Locoregional tumors with any ALK mutation were generally invasive: L2 by International Neuroblastoma Research Group staging in 30/31 patients with a 2-year progression-free survival (59%, 95% CI, 37.4 to 80.5) that was inferior to historical controls. This observation was corroborated in the post-2014 subgroup in which gross total resection was less likely for ALK -mutated tumors., Conclusion: Somatic ALK mutations are present across all stages and risk groups of neuroblastoma. No specific mutation carries differential prognostic significance. Locoregional neuroblastoma has an invasive phenotype when harboring somatic ALK mutations in this population., (© 2021 by American Society of Clinical Oncology.)

Abstinence in patients with alcohol-associated liver disease (ALD) reduces mortality. Most predictors of relapse are not quantifiable, preventing objective analysis of relapse risk and targeted intervention to improve clinical outcomes. We prospectively enrolled patients with ALD from November 2016 to December 2019 and administered a survey with two previously published scales to assess insight into alcohol-use disorder (Hanil Alcohol Insight Scale [HAIS]) and social support (Community Assessment Inventory Scale [CAIS]). Relapse was assessed using surveys and metabolite testing. Unadjusted and prespecified adjusted regression analyses identified predictors of relapse. We enrolled 81% of eligible patients (n = 136), of whom 58 had follow-up data available at the time of analysis. Over a median follow-up of 1 year (interquartile range: 0.5-1.4), 10 patients relapsed (17%). Patients who relapsed were more likely to continue drinking despite either a diagnosis of liver disease or a decompensating event, and were less likely to have been transplanted (all P < 0.05). In unadjusted regression, the HAIS and the "support inside the home" subcategory of the CAIS were predictive of relapse, with odds ratio (OR) = 0.84 (95% confidence interval 0.72-0.97) and 0.85 (0.74-0.97). In adjusted regression, the HAIS was no longer significant, with adjusted OR = 0.70 (0.49-1.00, P = 0.05), whereas the "support inside the home' subcategory of CAIS remained significant, with adjusted OR = 0.69 (0.51-0.92, P = 0.01). Conclusions : Risk factors for relapse in patients with ALD were identified and quantified prospectively, suggesting opportunities to objectively identify patients at risk for relapse as well as to intervene to prevent relapse., (© 2021 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of the American Association for the Study of Liver Diseases.)

The spectrum of germline predisposition in pediatric cancer continues to be realized. Here we report 751 solid tumor patients who underwent prospective matched tumor-normal DNA sequencing and downstream clinical use (clinicaltrials.gov NCT01775072). Germline pathogenic and likely pathogenic (P/LP) variants were reported. One or more P/LP variants were found in 18% (138/751) of individuals when including variants in low, moderate, and high penetrance dominant or recessive genes, or 13% (99/751) in moderate and high penetrance dominant genes. 34% of high or moderate penetrance variants were unexpected based on the patient's diagnosis and previous history. 76% of patients with positive results completed a clinical genetics visit, and 21% had at least one relative undergo cascade testing as a result of this testing. Clinical actionability additionally included screening, risk reduction in relatives, reproductive use, and use of targeted therapies. Germline testing should be considered for all children with cancer.

Purpose: Anti-GD2 monoclonal antibody (mAb) has proven efficacy in high-risk neuroblastoma (HR-NB). A small phase I GD2/GD3 vaccine trial (n = 15) described long-term survival and a favorable safety profile among patients with a history of disease progression (PD). The kinetics of mounting antibody response to vaccine and its prognostic impact on survival are now investigated in a phase II study (ClinicalTrials.gov identifier: NCT00911560)., Patients and Methods: One hundred two patients with HR-NB who achieved remission after salvage therapies were enrolled in this trial. They received seven subcutaneous injections of GD2/GD3 vaccine spanning 1 year plus oral β-glucan starting at week 6 after the third dose of vaccine. Serum anti-vaccine antibody titers were quantified by enzyme-linked immunosorbent assay. Single nucleotide polymorphisms (SNPs) were determined by quantitative polymerase chain reaction. Kaplan-Meier and landmark Cox Regression models were used for survival estimates., Results: Patients had a history of one (63%), two (21%), or three to six (16%) episodes of PD. 82% of them progressed following anti-GD2 mAb (m3F8/dinutuximab/naxitamab) therapy. Vaccine-related toxicities were self-limited injection-associated local reactions and fever without any > grade 3 toxicities. The progression-free survival (PFS) was 32% ± 6%, and the overall survival (OS) was 71% ± 7% at 5 years. Serum anti-GD2 (immunoglobulin G1 [IgG1] and IgM) and anti-GD3 (IgG1) titers showed notable increases following the initiation of β-glucan at week 6. There was an association between IgG1 titer and SNP rs3901533 of dectin-1, the β-glucan receptor. Multivariable analyses showed that anti-GD2-IgG1 titer ≥ 150 ng/mL by week 8 was associated with favorable PFS and OS, while having prior episodes of PD and the time from last PD to vaccine were associated with PFS., Conclusion: GD2/GD3 vaccine plus β-glucan elicited robust antibody responses in patients with HR-NB with prior PD. Higher anti-GD2-IgG1 titer was associated with improved survival.

Natural killer (NK) cell-mediated antibody-dependent toxicity is a potent mechanism of action of the anti-GD2 murine monoclonal antibody 3F8 (m3F8). Killer immunoglobulin-like receptor (KIR) and HLA genotypes modulate NK activity and are key prognostic markers in m3F8-treated patients with neuroblastoma. Endogenous NK-cells are suppressed in the setting of high tumor burden and chemotherapy. Allogeneic NK-cells however, demonstrate potent anti-neuroblastoma activity. We report on the results of a phase I clinical trial of haploidentical NK-cells plus m3F8 administered to patients with high-risk neuroblastoma after conditioning chemotherapy. The primary objective was to determine the maximum tolerated NK-cell dose (MTD). Secondary objectives included assessing anti-neuroblastoma activity and its relationship to donor-recipient KIR/HLA genotypes, NK function, and donor NK chimerism. Patients received a lymphodepleting regimen prior to infusion of haploidentical CD3-CD56+ NK-cells, followed by m3F8. Overall and progression free survival (PFS) were assessed from the time of first NK-cell dose. Univariate Cox regression assessed relationship between dose and outcomes. Thirty-five patients received NK-cells at one of five dose levels ranging from <1×10 6 to 50×10 6 CD3-CD56+cells/kg. One patient experienced grade 3 hypertension and grade 4 pneumonitis. MTD was not reached. Ten patients (29%) had complete or partial response; 17 (47%) had no response; and eight (23%) had progressive disease. No relationship was found between response and KIR/HLA genotype or between response and FcγRIII receptor polymorphisms. Patients receiving >10×10 6 CD56+cells/kg had improved PFS (HR: 0.36, 95%CI: 0.15-0.87, p = 0.022). Patient NK-cells displayed high NKG2A expression, leading to inhibition by HLA-E-expressing neuroblastoma cells. Adoptive NK-cell therapy in combination with m3F8 is safe and has anti-neuroblastoma activity at higher cell doses.

Background: The rationale for studying the combination of bevacizumab, irinotecan, and temozolomide (BIT) in neuroblastoma (NB) is based on the following: (i) vascular endothelial growth factor (VEGF) expression is associated with an aggressive phenotype, (ii) anti-VEGF antibody bevacizumab enhances irinotecan-mediated suppression of NB xenografts, (iii) bevacizumab safety has been established in pediatric phase I studies, and (iv) irinotecan + temozolomide (IT) is a standard salvage chemotherapy., Procedure: We conducted a phase II study of BIT in patients with measurable/evaluable refractory or relapsed high-risk NB (www.clinicaltrials.gov, NCT01114555). Each cycle consisted of bevacizumab (15 mg/kg intravenously [IV]) on days 1 and 15 plus irinotecan (50 mg/m 2 /day IV) and temozolomide (150 mg/m 2 /day orally) on days 4-8. Patients could have previously received, but not relapsed on, IT. An early stopping rule mandated continuing therapy only if more than five patients of 27 evaluable patients achieved partial response (PR) or complete response (CR) after four cycles., Results: Thirty-three heavily pretreated patients (nine primary refractory; 24 relapsed) received one to eight cycles of BIT. Toxicities were expected and transient. Grade 4 toxicities were neutropenia (30%) and thrombocytopenia (24%). Grade 3 toxicities included hepatic transaminitis (15%), proteinuria (9%), and diarrhea (3%). Overall responses were as follows: three CR (all in prior IT-treated patients), 18 no response, and 12 progressive disease. Only one of 23 patients assessable for the early stopping rule regarding efficacy achieved PR/CR, so patient accrual was discontinued. Median progression-free survival and overall survival was 7.7 ± 1.7 and 31.5 ± 5.6 months, respectively; all patients continued anti-NB therapy post-BIT., Conclusions: BIT was well tolerated, but the addition of bevacizumab did not improve response rates in resistant NB compared to historical data for IT., (© 2017 Wiley Periodicals, Inc.)

Background: Although nephrectomy rates are higher in children with neuroblastoma who have image-defined risk factors and/or high-risk disease who undergo resection prior to chemotherapy, no published data outline the key radiographic and clinical characteristics associated with nephrectomy., Methods: With IRB approval, imaging studies of children undergoing primary resection of intraabdominal neuroblastoma between 2000 and 2014 were retrospectively reviewed. Fisher's exact and Wilcoxon rank-sum tests were used to compare categorical and continuous variables, respectively, with p-values adjusted for multiple testing using the false discovery rate approach., Results: Twenty-seven of 380 consecutive patients with CT imaging obtained prior to primary neuroblastoma resection underwent partial or total nephrectomy. On preoperative imaging, renal vessel narrowing and encasement and tumor invasion of the renal hilum, pelvis, and/or parenchyma were present significantly more frequently among patients undergoing nephrectomy. Delayed renal excretion of contrast, hydronephrosis, and tumors with MYCN amplification were also more prevalent in the nephrectomy group., Conclusion: Encasement and narrowing of renal vessels, delayed excretion, and tumor invasion into the kidney, particularly pelvis and capsule invasion, are significantly associated with partial or total nephrectomy at initial neuroblastoma resection. These observations provide valuable information for surgical planning as well as presurgical discussions with families prior to neuroblastoma resection., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Although (131) I-metaiodobenzylguanidine ((131) I-MIBG) therapy is increasingly used for children with high-risk neuroblastoma, a paucity of lead-lined rooms limits its wider use. We implemented radiation safety procedures to comply with New York City Department of Health and Mental Hygiene regulations for therapeutic radioisotopes and administered (131) I-MIBG using rolling lead shields., Procedure: Patients received 0.67 GBq (18 mCi)/kg/dose (131) I-MIBG on an IRB-approved protocol (NCT00107289). Radiation safety procedures included private room with installation of rolling lead shields to maintain area dose rates ≤0.02 mSv/hr outside the room, patient isolation until dose rate <0.07 mSv/hr at 1 m, and retention of a urinary catheter with collection of urine in lead boxes. Parents were permitted in the patient's room behind lead shields, trained in radiation safety principles, and given real-time radiation monitors., Results: Records on 16 (131) I-MIBG infusions among 10 patients (age 2-11 years) were reviewed. Mean ± standard deviation (131) I-MIBG administered was 17.67 ± 11.14 (range: 6.11-40.59) GBq. Mean maximum dose rates outside treatment rooms were 0.013 ± 0.008 mSv/hr. Median time-to-discharge was 3 days post-(131) I-MIBG. Exposure of medical staff and parents was below regulatory limits. Cumulative whole-body dose received by the physician, nurse, and radiation safety officer during treatment was 0.098 ± 0.058, 0.056 ± 0.045, 0.055 ± 0.050 mSv, respectively. Cumulative exposure to parents was 0.978 ± 0.579 mSv. Estimated annual radiation exposure for inpatient nurses was 0.096 ± 0.034 mSv/nurse. Thyroid bioassay scans on all medical personnel showed less than detectable activity. Contamination surveys were <200 dpm/100 cm(2) ., Conclusions: The use of rolling lead shields and implementation of specific radiation safety procedures allows administration of high-dose (131) I-MIBG and may broaden its use without dedicated lead-lined rooms., (© 2016 Wiley Periodicals, Inc.)