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Background: Prognosis for patients with high-risk neuroblastoma (HR-NBL) is guarded despite aggressive therapy, and few studies have characterized outcomes after radiotherapy in relation to radiation treatment fields., Methods: Multi-institutional retrospective cohort of 293 patients with HR-NBL who received autologous stem cell transplant (ASCT) and EBRT between 1997-2021. LRR was defined as recurrence at the primary site or within one nodal echelon beyond disease present at diagnosis. Follow-up was defined from the end of EBRT. Event-free survival (EFS) and OS were analyzed by Kaplan-Meier method. Cumulative incidence of locoregional progression (CILP) was analyzed using competing risks of distant-only relapse and death with Gray's test., Results: Median follow-up was 7.0 years (range: 0.01-22.4). Five-year CILP, EFS, and OS were 11.9 %, 65.2 %, and 77.5 %, respectively. Of the 31 patients with LRR and imaging review, 15 (48.4 %) had in-field recurrences (>12 Gy), 6 (19.4 %) had marginal failures (≤12 Gy), and 10 (32.3 %) had both in-field and marginal recurrences. No patients receiving total body irradiation (12 Gy) experienced marginal-only failures (p = 0.069). On multivariable analyses, MYCN amplification had higher risk of LRR (HR: 2.42, 95 % CI: 1.06-5.50, p = 0.035) and post-consolidation isotretinoin and anti-GD2 antibody therapy (HR: 0.42, 95 % CI: 0.19-0.94, p = 0.035) had lower risk of LRR., Conclusions: Despite EBRT, LRR remains a contributor to treatment failure in HR-NBL with approximately half of LRRs including a component of marginal failure. Future prospective studies are needed to explore whether radiation fields and doses should be defined based on molecular features such as MYCN amplification, and/or response to chemotherapy., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: SGD has received travel expenses from Loxo, Roche, and Salarius and consulting fees from Amgen, Bayer, and Jazz. TIY receives in-kind software support from MIM software to support a multicenter pediatric registry. Prior Presentation: Presented in part at the 64th Annual Meeting of the American Society for Radiation Oncology, San Antonio, TX, October 23–26, 2022., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Purpose: The National Cancer Institute-Children's Oncology Group (NCI-COG) Pediatric MATCH trial assigns patients age 1-21 years with refractory malignancies to phase II treatment arms of molecularly targeted therapies on the basis of genetic alterations detected in their tumor. Patients with activating alterations in the mitogen-activated protein kinase pathway were treated with ulixertinib, an extracellular signal-regulated kinase (ERK)1/2 inhibitor., Methods: As there were no previous pediatric data, ulixertinib was initially tested in a dose escalation cohort to establish the recommended phase II dose (RP2D) before proceeding to the phase II cohort. Ulixertinib was administered at 260 mg/m 2 /dose orally twice a day (dose level 1 [DL1], n = 15) or 350 mg/m 2 /dose orally twice a day (DL2, n = 5). The primary end point was objective response rate; secondary end points included safety/tolerability and progression-free survival (PFS)., Results: Twenty patients (median 12 years; range, 5-20) were treated, all evaluable for response. CNS tumors comprised 55% (11/20) of diagnoses, with high-grade glioma and low-grade glioma most common (n = 5 each). All CNS tumors except one harbored BRAF fusions or V600E mutations. Rhabdomyosarcoma (n = 5) was the most frequent non-CNS diagnosis. DL1 was declared the RP2D in the dose escalation cohort after dose-limiting toxicities in Cycle 1 occurred in 1/6 patients at DL1 and 2/5 patients at DL2, including fatigue, anorexia, rash, nausea, vomiting, diarrhea, dehydration, hypoalbuminemia, and hypernatremia. No objective responses were observed. Six-month PFS was 37% (95% CI, 17 to 58). Three patients with BRAF -altered CNS tumors achieved stable disease >6 months., Conclusion: Ulixertinib, a novel targeted agent with no previous pediatric data, was successfully evaluated in a national precision medicine basket trial. The pediatric RP2D of ulixertinib is 260 mg/m 2 /dose orally twice a day. Limited single-agent efficacy was observed in a biomarker-selected cohort of refractory pediatric tumors.

Background: Prior studies suggest that norepinephrine transporter (NET) and vesicular monoamine transporter 2 (VMAT2) mediate meta-iodobenzylguanidine (MIBG) uptake and retention in neuroblastoma tumors. We evaluated the relationship between NET and VMAT2 tumor expression and clinical response to 131 I-MIBG therapy in patients with neuroblastoma., Methods: Immunohistochemistry (IHC) was used to evaluate NET and VMAT2 protein expression levels on archival tumor samples (obtained at diagnosis or relapse) from patients with relapsed or refractory neuroblastoma treated with 131 I-MIBG. A composite protein expression H-score was determined by multiplying a semi-quantitative intensity value (0-3+) by the percentage of tumor cells expressing the protein., Results: Tumor samples and clinical data were available for 106 patients, of whom 28.3% had partial response (PR) or higher. NET H-score was not significantly associated with response (≥PR), though the percentage of tumor cells expressing NET was lower among responders (median 80% for ≥PR vs. 90% for 131 I-MIBG therapy in patients with relapsed/refractory neuroblastoma. Increased VMAT2 protein expression is associated with a more differentiated disease phenotype., (© 2023 Wiley Periodicals LLC.)

Objective: Neuroblastoma with spinal involvement accounts for up to 30% of pediatric spinal tumors and can cause profound neurological deficits. Chemotherapy is the preferred treatment option, but in select patients resection may be indicated. The goal of this study was to identify preoperative factors that led to early surgical intervention, with a specific emphasis on identifying differences on long-term neurological function and spinal deformity in the recent treatment era., Methods: A retrospective chart review was performed on all children diagnosed with neuroblastoma at a single institution from 2007 to 2020. Patient demographics, symptoms (motor deficit and sphincter dysfunction), and tumor characteristics (e.g., 123I metaiodobenzylguanidine [MIBG] avidity, MYCN amplification, chromosomal abnormality, pathology, catecholamine secretion, and stage) were recorded. Spine involvement included neural or vertebral extension, spinal cord compression, and/or T2 signal change on MRI. Survival, neurological status (motor deficit, sphincter dysfunction), and spine deformity at last follow-up were compared using univariate and multivariate analyses. The variables that contributed to neurological and deformity outcome were assessed with binomial logistic and linear regression models using R software., Results: Seventy-seven of the 160 patients with neuroblastoma had spinal neuroblastoma, meaning either bone metastases alone (n = 43) or intraspinal extension with or without neurological deficit (n= 34). Most patients with spinal neuroblastoma were treated with chemotherapy and/or radiation therapy (97% and 57%, respectively). Resection of the spinal tumor was performed in 14 (18%) patients, all of whom also received chemotherapy. Between the surgical and nonsurgical patients, no baseline demographic differences were found. However, surgical patients were more likely to present with either motor deficits (50% vs 5%, p = 0.0011) or bladder/bowel dysfunction (14% vs 0%, p 0.035), and a shorter median time to onset of neurological symptoms (33 vs 80 days, p = 0.0096). Surgical patients also had a significantly shorter median overall survival (33.0 vs 54 months, p = 0.014). Of the 14 patients who underwent spine surgery, 2 patients underwent surgery at the time of diagnosis while the remaining 12 underwent initial chemotherapy followed later by resection. The 2 patients who underwent initial surgery had excellent outcomes, with neither long-term motor or bowel/bladder deficits nor spinal deformity., Conclusions: Surgical patients had shorter overall survival. However, the 2 patients with radiographic evidence of cord compression and acute neurological symptom onset who underwent initial, immediate surgery within 3 days of diagnosis had fewer long-term neurological deficits than surgical patients who underwent initial trials of chemotherapy. Thus, acute decompression may provide benefit in carefully selected patients with acute neurological deficits and cord compression on imaging.

Background: Venetoclax is frequently used as salvage treatment in pediatric, adolescent, and young adult (AYA) patients with advanced hematologic malignancies. However, more data are needed from real-world studies to guide the safe and appropriate use of venetoclax in this population., Procedure: We retrospectively reviewed the medical records of all patients diagnosed with hematologic malignancies less than 30 years of age treated with venetoclax outside of clinical trials at the University of California San Francisco Benioff Children's Hospitals from 2016 to 2022., Results: We identified 13 patients (acute myeloid leukemia, n = 8; B-acute lymphoblastic leukemia, n = 3; myelodysplastic syndrome, n = 2) aged 4 months to 27 years. A median of 3 prior lines of therapy weregiven (range 0-5). All patients received venetoclax in combination with either a hypomethylating agent or conventional chemotherapy. Three (23%) patients achieved complete remission (CR); two (15%) achieved partial remission (PR); 3 (23%) had stable disease (SD), and five (42%) had progressive disease. Median survival and time to progression from venetoclax initiation was 9 months (range 2.5-52 months) and 3 months (range 2 weeks to 7.5 months), respectively. Six patients (46%) developed grade 3 or higher infections while receiving venetoclax, including bacteremia due to atypical organisms, invasive pulmonary infections with Aspergillus, cytomegalovirus (CMV) viremia, skin infections, and encephalitis with bacterial brain abscesses., Conclusions: Venetoclax in combination with hypomethylating agents or cytotoxic chemotherapy was effective in a subset of pediatric/AYA patients with advanced hematologic malignancies, but multiple severe infections were observed, particularly among patients who received venetoclax in combination with chemotherapy. Prospective studies will be required to determine the optimal dose and duration of venetoclax in this population., (© 2023 Wiley Periodicals LLC.)

Objectives: There is no study on Helicobacter pylori ( H. pylori ) infection in pupils of Ho Chi Minh city (HCMC), the most overcrowded city in Vietnam. Therefore, the aim of this study was to estimate the prevalence of H. pylori and its geographical spread among school-aged children. Methods: A school-based cross-sectional study was conducted among 1854 pupils across 24 districts of HCMC in 2019. Multiple-stage sampling method was used to enroll pupils. We built a four-points index for geographical division based on population density and employees density to evaluate the link between H. pylori and crowded level. Stool samples were analyzed by monoclonal enzyme-immunoassay stool antigen-test to assess the infection status. Logistic regression was performed to assess possible factors related to H. pylori infection. Results: The overall prevalence of H. pylori was 87.7%. There was a linear increasing trend in the infection rate ( p < 0.001) across the 4-points index of HCMC and this trend maintained within both age and gender subgroups ( p = 0.02). Conclusion: Prevalence of H. pylori was high and it increased with population density or employees density. Therefore, it is crucial to plan and implement the reduction of H. pylori infection programs by targeting the highly concentrated population areas of HCMC., Competing Interests: The 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 © 2022 Che, Nguyen, Ngo, Nguyen, Vo, Ngo, Truong, Bontems, Robert and Nguyen.)

Purpose: We sought to analyze biologic, clinical, and prognostic differences according to pattern of failure at the time of first relapse in neuroblastoma., Patients and Methods: Children <21 years diagnosed with neuroblastoma between 1989 and 2017 with known site of first relapse (isolated local vs. distant only vs. combined local and distant sites) were identified from the International Neuroblastoma Risk Group (INRG) database. Data were compared between sites of relapse according to clinical features, biologic features, initial treatment, time to first relapse, and overall survival (OS) from time of first relapse., Results: Pattern of first relapse among 1833 children was 19% isolated local; 65% distant only; and 16% combined sites. All evaluated clinical and biologic variables with exception of tumor diagnosis differed statistically by relapse pattern, with patients with isolated local failure having more favorable prognostic features. Patients with stage 3 disease were more likely to have isolated local failure compared to all other stages (49% vs. 16%; p < .001). OS significantly differed by relapse pattern (5-year OS ± SE): isolated local: 64% ± 3%; distant only: 23% ± 2%; and combined: 26% ± 4% (p < .001). After controlling for age, stage, and MYCN status, patients with isolated local failure (adjusted hazard ratio [HR] = 0.46; 95% confidence interval [CI]: 0.33-0.62; p < .001) and distant-only failure (adjusted HR = 0.57; 95% CI: 0.45-0.71; p < .001) remained at decreased risk for death as compared to patients with combined failure., Conclusion: Patients with distant-only and combined failures have a higher proportion of unfavorable clinical and biological features, and a lower survival than those with isolated local relapse., (© 2022 Wiley Periodicals LLC.)

Neuroblastoma is one of the most common pediatric cancers. This study used machine learning (ML) to predict the mortality and a few other investigated intermediate outcomes of neuroblastoma patients non-invasively from CT images. Performances of multiple ML algorithms over retrospective CT images of 65 neuroblastoma patients are analyzed. An artificial neural network (ANN) is used on tumor radiomic features extracted from 3D CT images. A pre-trained 2D convolutional neural network (CNN) is used on slices of the same images. ML models are trained for various pathologically investigated outcomes of these patients. A subspecialty-trained pediatric radiologist independently reviewed the manually segmented primary tumors. Pyradiomics library is used to extract 105 radiomic features. Six ML algorithms are compared to predict the following outcomes: mortality, presence or absence of metastases, neuroblastoma differentiation, mitosis-karyorrhexis index (MKI), presence or absence of MYCN gene amplification, and presence of image-defined risk factors (IDRF). The prediction ranges over multiple experiments are measured using the area under the receiver operating characteristic (ROC-AUC) for comparison. Our results show that the radiomics-based ANN method slightly outperforms the other algorithms in predicting all outcomes except classification of the grade of neuroblastic differentiation, for which the elastic regression model performed the best. Contributions of the article are twofold: (1) noninvasive models for the prognosis from CT images of neuroblastoma, and (2) comparison of relevant ML models on this medical imaging problem., (© 2022. The Author(s) under exclusive licence to Society for Imaging Informatics in Medicine.)

Purpose: 131 I-metaiodobenzylguanidine (MIBG) is an active radiotherapeutic for neuroblastoma. The primary aim of this trial was to identify which of three MIBG regimens was likely associated with the highest true response rate., Patients and Methods: Patients 1-30 years were eligible if they had relapsed or refractory neuroblastoma, at least one MIBG-avid site, and adequate autologous stem cells. Patients received MIBG 18 mCi/kg on day 1 and autologous stem cell on day 15. Patients randomly assigned to arm A received only MIBG; patients randomly assigned to arm B received intravenous vincristine on day 0 and irinotecan daily on days 0-4; patients randomly assigned to arm C received vorinostat (180 mg/m 2 /dose) orally once daily on days 1 to 12. The primary end point was response after one course by New Approaches to Neuroblastoma Therapy criteria. The trial was designed with 105 patients to ensure an 80% chance that the arm with highest response rate was selected., Results: One hundred fourteen patients were enrolled, with three ineligible and six unevaluable, leaving 105 eligible and evaluable patients (36 in arm A, 35 in arm B, and 34 in arm C; 55 boys; and median age 6.5 years). After one course, the response rates (partial response or better) on arms A, B, and C were 14% (95% CI, 5 to 30), 14% (5 to 31), and 32% (18 to 51). An additional five, five, and four patients met New Approaches to Neuroblastoma Therapy Minor Response criteria on arms A, B, and C, respectively. On arms A, B, and C, rates of any grade 3+ nonhematologic toxicity after first course were 19%, 49%, and 35%., Conclusion: Vorinostat and MIBG is likely the arm with the highest true response rate, with manageable toxicity. Vincristine and irinotecan do not appear to improve the response rate to MIBG and are associated with increased toxicity., Competing Interests: Steven G. DuBoisConsulting or Advisory Role: BayerResearch Funding: Merck, Roche/Genentech, Lilly, Curis, Loxo, BMS, Eisai, Pfizer, Turning Point Therapeutics, Bayer, Salarius PharmaceuticalsTravel, Accommodations, Expenses: Roche/Genentech, Salarius PharmaceuticalsUncompensated Relationships: Ymabs Therapeutics Inc Susan GroshenEmployment: Pfizer Scarlett CzarneckiSpeakers' Bureau: United Therapeutics Yael P. MosseConsulting or Advisory Role: ASCO, Pfizer, Lilly, Auron Therapeutics, JumoResearch Funding: Pfizer John M. MarisStock and Other Ownership Interests: Tantigen BIO IncConsulting or Advisory Role: Auron Therapeutics, Illumina Radiopharmaceuticals, Jubilant DraxImagePatents, Royalties, Other Intellectual Property: GPC2 binders and CARs, Neuroblastoma antigens Suzanne ShustermanStock and Other Ownership Interests: Bristol Myers Squibb, GlaxoSmithKline, Intuitive Surgical, Kindred Biosciences, Merck, Nuvasive, OPKO Health, Regeneron, Surgalign, Amgen, BioTelemetry, RTI Surgical Holdings, EFOFEM biosciences, InVitae Susan L. CohnStock and Other Ownership Interests: Merck, Stryker, Amgen, Pfizer, AbbVie, Amgen, Lilly, Sanofi, Accelerated Medical Diagnostics, Novo Nordisk, Gilead Sciences, United Health Group, TevaHonoraria: Y-mAbs TherapeuticsResearch Funding: United Therapeutics, MerckOpen Payments Link: https://openpaymentsdata.cms.gov/physician/46569/summary Brian WeissResearch Funding: Novartis, Genentech, ExelixisTravel, Accommodations, Expenses: Exelixis, RocheOpen Payments Link: https://openpaymentsdata.cms.gov/physician/620363 Gregory A. YanikResearch Funding: Jazz Pharmaceuticals Meredith S. IrwinHonoraria: Bayer Daphne A. Haas-KoganConsulting or Advisory Role: Leidos Biomedical Research, SRA International, Gerson Lehrman Group, Guidepoint Global Araz MarachelianResearch Funding: Pfizer, United Therapeutics Katherine K. MatthayConsulting or Advisory Role: Resonance HealthNo other potential conflicts of interest were reported.

Most circulating tumor DNA (ctDNA) assays are designed to detect recurrent mutations. Pediatric sarcomas share few recurrent mutations but rather are characterized by translocations and copy-number changes. We applied Cancer Personalized Profiling by deep Sequencing (CAPP-Seq) for detection of translocations found in the most common pediatric sarcomas. We also applied ichorCNA to the combined off-target reads from our hybrid capture to simultaneously detect copy-number alterations (CNA). We analyzed 64 prospectively collected plasma samples from 17 patients with pediatric sarcoma. Translocations were detected in the pretreatment plasma of 13 patients and were confirmed by tumor sequencing in 12 patients. Two of these patients had evidence of complex chromosomal rearrangements in their ctDNA. We also detected copy-number changes in the pretreatment plasma of 7 patients. We found that ctDNA levels correlated with metastatic status and clinical response. Furthermore, we detected rising ctDNA levels before relapse was clinically apparent, demonstrating the high sensitivity of our assay. This assay can be utilized for simultaneous detection of translocations and CNAs in the plasma of patients with pediatric sarcoma. While we describe our experience in pediatric sarcomas, this approach can be applied to other tumors that are driven by structural variants., (©2021 The Authors; Published by the American Association for Cancer Research.)

Background: Clinical, molecular, and histopathologic features guide treatment for neuroblastoma, but obtaining tumor tissue may cause complications and is subject to sampling error due to tumor heterogeneity. We hypothesized that image-defined risk factors (IDRFs) would reflect molecular features, histopathology, and clinical outcomes in neuroblastoma., Methods: We performed a retrospective cohort study of 76 patients with neuroblastoma or ganglioneuroblastoma. Diagnostic CT scans were reviewed for 20 IDRFs, which were consolidated into five IDRF groups (involvement of multiple body compartments, vascular encasement, tumor infiltration of adjacent organs/structures, airway compression, or intraspinal extension). IDRF groups were analyzed for association with clinical, molecular, and histopathologic features of neuroblastoma., Results: Patients with more IDRF groups had a higher risk of surgical complications (OR = 3.1, p = 0.001). Tumor vascular encasement was associated with increased risk of surgical complications (OR = 5.40, p = 0.009) and increased risk of undifferentiated/poorly differentiated histologic grade (OR = 11.11, p = 0.013). Tumor infiltration of adjacent organs and structures was associated with decreased survival (HR = 8.90, p = 0.007), MYCN amplification (OR = 9.91, p = 0.001), high MKI (OR = 6.20, p = 0.003), and increased risk of International Neuroblastoma Staging System stage 4 disease (OR = 8.96, p < 0.001)., Conclusions: The presence of IDRFs at diagnosis was associated with high-risk clinical, molecular, and histopathologic features of neuroblastoma. The IDRF group tumor infiltration into adjacent organs and structures was associated with decreased survival. Collectively, these findings may assist surgical planning and medical management for neuroblastoma patients., (© 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Nucleotide-binding leucine-rich repeat (NLR) proteins play critical roles in plant immunity. However, how NLRs are regulated and activate defense signaling is not fully understood. The rice (Oryza sativa) NLR receptor Piz-t confers broad-spectrum resistance to the fungal pathogen Magnaporthe oryzae and the RING-type E3 ligase AVRPIZ-T INTERACTING PROTEIN 10 (APIP10) negatively regulates Piz-t accumulation. In this study, we found that APIP10 interacts with two rice transcription factors, VASCULAR PLANT ONE-ZINC FINGER 1 (OsVOZ1) and OsVOZ2, and promotes their degradation through the 26S proteasome pathway. OsVOZ1 displays transcriptional repression activity while OsVOZ2 confers transcriptional activation activity in planta. The osvoz1 and osvoz2 single mutants display modest but opposite M. oryzae resistance in the non-Piz-t background. However, the osvoz1 osvoz2 double mutant exhibits strong dwarfism and cell death, and silencing of both genes via RNA interference also leads to dwarfism, mild cell death, and enhanced resistance to M. oryzae in the non-Piz-t background. Both OsVOZ1 and OsVOZ2 interact with Piz-t. Double silencing of OsVOZ1 and OsVOZ2 in the Piz-t background decreases Piz-t protein accumulation and transcription, reactive oxygen species-dependent cell death, and resistance to M. oryzae containing AvrPiz-t. Taken together, these results indicate that OsVOZ1 and OsVOZ2 negatively regulate basal defense but contribute positively to Piz-t-mediated immunity., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

The metaiodobenzylguanidine (MIBG) scan is one of the most sensitive noninvasive lesion detection modalities for neuroblastoma. Unlike 123 I-MIBG, 124 I-MIBG allows high-resolution PET. We evaluated 124 I-MIBG PET/CT for its diagnostic performance as directly compared with paired 123 I-MIBG scans. Methods: Before 131 I-MIBG therapy, standard 123 I-MIBG imaging (5.2 MBq/kg) was performed on 7 patients, including whole-body (anterior-posterior) planar imaging, focused-field-of-view SPECT/CT, and whole-body 124 I-MIBG PET/CT (1.05 MBq/kg). After therapy, 2 of 7 patients also completed 124 I-MIBG PET/CT as well as paired 123 I-MIBG planar imaging and SPECT/CT. One patient underwent 124 I-MIBG PET/CT only after therapy. We evaluated all 8 patients who showed at least 1 123 I-MIBG-positive lesion with a total of 10 scans. In 8 pairs, 123 I-MIBG and 124 I-MIBG were performed within 1 mo of each other. The locations of identified lesions, the number of total lesions, and the curie scores were recorded for the 123 I-MIBG and 124 I-MIBG scans. Finally, for 5 patients who completed at least 3 PET/CT scans after administration of 124 I-MIBG, we estimated the effective dose of 124 I-MIBG. Results: 123 I-MIBG whole-body planar scans, focused-field-of-view SPECT/CT scans, and whole-body 124 I-MIBG PET scans found 25, 32, and 87 total lesions, respectively. There was a statistically significant difference in lesion detection for 124 I-MIBG PET/CT versus 123 I-MIBG planar imaging ( P < 0.0001) and 123 I-MIBG SPECT/CT ( P < 0.0001). The curie scores were also higher for 124 I-MIBG PET/CT than for 123 I-MIBG planar imaging and SPECT/CT in 6 of 10 patients. 124 I-MIBG PET/CT demonstrated better detection of lesions throughout the body, including the chest, spine, head and neck, and extremities. The effective dose estimated for patient-specific 124 I-MIBG was approximately 10 times that of 123 I-MIBG; however, given that we administered a very low activity of 124 I-MIBG (1.05 MBq/kg), the effective dose was only approximately twice that of 123 I-MIBG despite the large difference in half-lives (100 vs. 13.2 h). Conclusion: The first-in-humans use of low-dose 124 I-MIBG PET for monitoring disease burden demonstrated tumor detection capability superior to that of 123 I-MIBG planar imaging and SPECT/CT., (© 2021 by the Society of Nuclear Medicine and Molecular Imaging.)

Background: The optimal observation time period with respect to seizures after venlafaxine overdose is unclear. We conducted a 10-year retrospective review of calls to the California Poison Control System to describe the time of onset of seizures in adult and pediatric overdose of venlafaxine. Methods: Inclusion criteria included adult and pediatric patients with exposure to venlafaxine, who were admitted to a health care facility and who had at least one seizure. We did not exclude cases in which co-ingestions of other drugs were reported. Data extraction of a priori defined variables was recorded. Descriptive statistics were used to characterize the cohort of patients, including means, medians, and interquartile ranges. Results: The total number of cases included in the data analysis was 123 (12.9% of all venlafaxine ingestions). The longest time to last seizure was 24 h. Twenty-five percent of participants had a seizure from hour 7 to 24 h. This did not differ significantly between IR and XR formulations. Conclusions: Optimal observation time with respect to seizures after overdose of immediate-release formulation of venlafaxine is 18 h (24 h if ingested with other medications), and 21 h for patients who are poisoned with the sustained-release formulation.

Improvements in outcome have been seen in children and adolescents with cancer. Nevertheless, challenges remain in trying to improve the outcomes for all children diagnosed with cancer, particularly in patients with metastatic disease or with cancers that are resistant or recur after standard treatment. Precision medicine trials using individualized tumor molecular profiling for selection of targeted therapies are ongoing in adult malignancies. Similar approaches are being applied to children and adolescents with cancer. This article describes how precision medicine is being applied to pediatric oncology and the unique challenges being faced with these efforts., (Published by Elsevier Inc.)

High-risk neuroblastoma has a poor prognosis, and research studies have shown that increasing the intensity of therapy improves outcomes. Autologous hematopoietic cell transplant (aHCT) as consolidation therapy confers a significant survival advantage but is accompanied by significant morbidity. Transplant-associated thrombotic microangiopathy (TA-TMA) is a life-threatening complication caused by endothelial injury that often leads to hemolytic anemia, microthrombotic platelet consumption, and renal injury. Here we investigated the incidence, potential risk factors, and sequelae of TA-TMA in patients with high-risk neuroblastoma. We conducted a retrospective chart review of all patients (n = 141) with neuroblastoma in our institutions who underwent aHCT from 2000 to 2017. Ten patients (7%) developed TA-TMA. The patients in the TA-TMA group were similar to the rest of the subjects in demographics, disease burden, prior therapies, renal function, and timing of transplant. The type of conditioning regimen was the only statistically significant pretransplant variable (P < .001). Six of 15 patients (40%) intended to receive tandem transplants (cyclophosphamide/thiotepa and then carboplatin/etoposide/melphalan (CEM)), 4 of 68 patients (6%) who received conditioning with single CEM, and none of the 56 patients who received busulfan/melphalan were diagnosed with TA-TMA. Patients with TA-TMA were more likely to require intensive care unit transfer, have a longer length of stay in the hospital, and experience a delay or change in their subsequent therapy. In our cohort overall, patients with a delay in therapy after transplant appeared to have a worse overall survival, although the difference was not statistically significant. Because of this high incidence and significant morbidity, we have implemented standardized screening for TA-TMA during and after transplant. We anticipate that screening will lead to earlier intervention and decreased severity of disease., (Copyright © 2019 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Purpose: Radiation dose calculated on tumors for radiopharmaceutical therapy varies significantly from tumor to tumor and from patient to patient. Accurate estimation of radiation dose requires multiple time point measurements using radionuclide imaging modalities such as SPECT or PET. In this report, we show our technical development of reducing the number of scans needed for reasonable estimation of tumor and normal organ dose in our pretherapy imaging and dosimetry platform of 124 I-metaiodobenzylguanidine (MIBG) positron emission tomography/computed tomography (PET/CT) for 131 I-MIBG therapy of neuroblastoma., Methods: We analyzed the simplest kinetic data, areas of two-time point data for five patients with neuroblastoma who underwent 3 or 4 times of 124 I-MIBG PET/CT scan prior to 131 I-MIBG therapy. The data for which we derived areas were percent of injected activity (%IA) and standardized uptake value of tumors. These areas were correlated with time-integrated activity coefficients (TIACs) from full data (3 or 4 time points). TIACs are direct correlates with radiation dose as long as the volume and the radionuclide are known., Results: The areas of %IAs between data obtained from all the two-time points with time points 1 and 2 (day 0 and day 1), time points 2 and 3 (day 1 and day 2), and time points 1 and 3 (day 0 and day 2) showed reasonable correlation (Pearson's correlation coefficient |r| > 0.5) with not only tumor and organ TIACs but also tumor and organ absorbed doses. The tumor and organ doses calculated using %IA areas of time point 1 and time point 2 were our best fits at about 20% individual percent difference compared to doses calculated using 3 or 4 time points., Conclusions: We could achieve reasonable accuracy of estimating tumor doses for subsequent radiopharmaceutical therapy using only the two-time point imaging sessions. Images obtained from these time points (within the 48-h after administration of radiopharmaceutical) were also viewed as useful for diagnostic reading. Although our analysis was specific to 124 I-MIBG PET/CT pretherapy imaging data for 131 I-MIBG therapy of neuroblastoma and the number of imaging datasets was not large, this feasible methodology would generally be applicable to other imaging and therapeutic radionuclides with an appropriate data analysis similar to our analysis to other imaging and therapeutic radiopharmaceuticals., (© 2019 American Association of Physicists in Medicine.)

Approximately 75 MAP kinase kinase kinases (MAPKKKs) have been identified in the rice genome. However, only a few of them have been functionally characterized. In this paper, we report the function of a rice MAPKKK, OsMAPKKK63. OsMAPKKK63 was found to be induced by several abiotic stresses, including high salinity, chilling and drought. Our data indicate that OsMAPKKK63 possesses in vitro kinase activity and that it interacts with rice MAP kinase kinase OsMKK1 and OsMKK6. The two rice MKKs are known mediator of the salt stress response, implying that OsMAPKKK63 may be involved in the high salinity response. Our analysis of an OsMAPKKK63 knockout mutant indeed demonstrated that it is necessary for normal response to high salt. On the other hand, OsMAPKKK63 OX lines exhibited viviparous phenotype in both rice and Arabidopsis. The result suggests that OsMAPKKK63 may also be involved in seed dormancy control.

Background: New prognostic markers are needed to identify patients with Ewing sarcoma (EWS) and osteosarcoma unlikely to benefit from standard therapy. We describe the incidence and association with outcome of circulating tumour DNA (ctDNA) using next-generation sequencing (NGS) assays., Methods: A NGS hybrid capture assay and an ultra-low-pass whole-genome sequencing assay were used to detect ctDNA in banked plasma from patients with EWS and osteosarcoma, respectively. Patients were coded as positive or negative for ctDNA and tested for association with clinical features and outcome., Results: The analytic cohort included 94 patients with EWS (82% from initial diagnosis) and 72 patients with primary localised osteosarcoma (100% from initial diagnosis). ctDNA was detectable in 53% and 57% of newly diagnosed patients with EWS and osteosarcoma, respectively. Among patients with newly diagnosed localised EWS, detectable ctDNA was associated with inferior 3-year event-free survival (48.6% vs. 82.1%; p = 0.006) and overall survival (79.8% vs. 92.6%; p = 0.01). In both EWS and osteosarcoma, risk of event and death increased with ctDNA levels., Conclusions: NGS assays agnostic of primary tumour sequencing results detect ctDNA in half of the plasma samples from patients with newly diagnosed EWS and osteosarcoma. Detectable ctDNA is associated with inferior outcomes.

Insulin degludec/aspart (IDegAsp) is the first soluble insulin co-formulation, combining a long-acting insulin degludec (IDeg) and rapid-acting insulin aspart (IAsp). In type 2 diabetes patients with oral antidiabetes agent (OAD) inadequacy, insulin initiation with IDegAsp once daily provides superior long-term glycemic control compared to insulin glargine, with similar fasting plasma glucose (FPG) and insulin doses, and numerically lower rates of overall and nocturnal hypoglycemia. Furthermore, in patients with uncontrolled type 2 diabetes previously treated with insulins, IDegAsp twice daily effectively improves glycated hemoglobin and FPG, with fewer hypoglycemic episodes versus premix insulins and basal bolus therapy. In patients with type 1 diabetes mellitus, IDegAsp once daily with two doses of IAsp is a convenient, yet effective, regimen as compared to the conventional 4-5 injection-based basal bolus therapy. IDegAsp is an appropriate and reasonable option for initiation of insulin therapy in both type 1 and type 2 diabetes.

Deaths from opioid use are increasing in the US, with a growing proportion due to synthetic opioids. Until 2013, sporadic outbreaks of fentanyl and fentanyl analogs contaminating the heroin supply caused some deaths in heroin users. Since then, fentanyl has caused deaths in every state and fentanyl and its analogs have completely infiltrated the North American heroin supply. In 2014, the first illicit pills containing fentanyl, fentanyl analogs, and other novel synthetic opioids such as U-47700 were detected. These pills, which look like known opioids or benzodiazepines, have introduced synthetic opioids to more unsuspecting customers. As soon as these drugs are regulated by various countries, new compounds quickly appear on the market, making detection difficult and the number of cases likely underreported. Standard targeted analytical techniques such as GC-MS (gas chromatography mass spectrometry) and LC-MS/MS (liquid chromatography tandem mass spectrometry) can detect these drugs, but novel compound identification is aided by nontargeted testing with LC-HRMS (liquid chromatography high resolution mass spectrometry). Fentanyl, fentanyl analogs and other novel synthetic opioids are all full agonists of varying potencies at the μ-opioid receptor, leading to typical clinical effects of miosis and respiratory and central nervous system depression. Due to their high affinity for μ-opioid receptors, larger doses of naloxone are required to reverse the effects than are commonly used. Synthetic opioids are an increasingly major public health threat requiring vigilance from multiple fields including law enforcement, government agencies, clinical chemists, pharmacists, and physicians, to name a few, in order to stem its tide. This article is part of the Special Issue entitled 'Designer Drugs and Legal Highs.', (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Study Objective: Cannabis and its principal active constituent, Δ9-tetrahydrocannabinol (THC), are increasingly available as edibles resembling commercially available food products. In this case series, we describe a population of predominantly pediatric patients who were inadvertently exposed to a THC-containing product in San Francisco., Methods: Twelve children and 9 adults were identified, with 16 patients having detectable serum THC and THC metabolites. All patients presented to hospitals with a variety of constitutional symptoms and all were discharged home within 12 hours., Results: In general, pediatric patients had more severe symptoms and longer hospital length of stay, and, uniquely, a majority presented with leukocytosis and elevated lactic acid levels., Conclusion: We recommend that efforts be made to increase general public awareness in regard to the potential hazards of THC-containing edibles resembling commercially available food products., (Copyright © 2017 American College of Emergency Physicians. Published by Elsevier Inc. All rights reserved.)

Introduction: Bismuth salts have been used to treat gastroenterological disorders and are readily available over-the-counter and via the internet. Even though generally considered safe, bismuth compounds can cause a syndrome of subacute, progressive encephalopathy when taken in large quantities., Case Report: We present the case of woman who developed progressive encephalopathy, aphasia, myoclonus, and gait instability after chronically ingesting large amounts of bismuth subgallate purchased from a major online marketing website to control symptoms of irritable bowel syndrome. After extensive neurological work-up, elevated bismuth levels in her blood, urine, and cerebrospinal fluid confirmed the diagnosis of bismuth-related neurotoxicity. She improved slowly following cessation of exposure., Conclusion: This case highlights bismuth subgallate as a neurotoxic bismuth formulation and reminds providers of the potential for safety misconceptions of positively reviewed online supplements.

Amanita phalloides, colloquially known as the "death cap," belongs to the Phalloideae section of the Amanita family of mushrooms and is responsible for most deaths following ingestion of foraged mushrooms worldwide (1). On November 28, 2016, members of the Bay Area Mycological Society notified personnel at the California Poison Control System (CPCS) of an unusually large A. phalloides bloom in the greater San Francisco Bay Area, coincident with the abundant rainfall and recent warm weather. Five days later, CPCS received notification of the first human A. phalloides poisoning of the season. Over the following 2 weeks, CPCS was notified of an additional 13 cases of hepatotoxicity resulting from A. phalloides ingestion. In the past few years before this outbreak, CPCS received reports of only a few mushroom poisoning cases per year. A summary of 14 reported cases is presented here. Data extracted from patient medical charts revealed a pattern of delayed gastrointestinal manifestations of intoxication leading to dehydration and hepatotoxicity. Three patients received liver transplants and all but one recovered completely. The morbidity and potential lethality associated with A. phalloides ingestion are serious public health concerns and warrant medical provider education and dissemination of information cautioning against consuming foraged wild mushrooms.

Background: Carisoprodol, a centrally acting muscle relaxant with a high abuse potential, has barbiturate-like properties at the GABA-A receptor, leading to central nervous system depression and desired effects. Its tolerance and dependence has been previously demonstrated in an animal model, and withdrawal has been described in several recent case reports. Many cases can be effectively managed with a short course of benzodiazepines or antipsychotic agents. However, abrupt cessation in a patient with a history of long-term and high-dose carisoprodol abuse may result in symptoms that are more difficult for providers to treat., Case Report: We present a case of a 34-year-old man with a long history of carisoprodol abuse who was found unresponsive after having ingested 7.5 grams of carisoprodol. He was intubated and admitted to the intensive care unit. He was given propofol, dexmedetomidine, fentanyl, ketamine, lorazepam, midazolam, quetiapine, and haloperidol, some at high-dose infusions, before his agitation and ventilator asynchrony could be controlled. His improvement coincided with the addition of carisoprodol and phenobarbital to his treatment regimen. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Trends show increasing emergency department presentations for drug-related disorders and treatment. This case highlights an uncommon case of carisoprodol withdrawal that may be encountered by emergency physicians, and demonstrates that benzodiazepines may not be sufficient to suppress severe withdrawal symptoms. Treatment with carisoprodol and phenobarbital provided additional benefit and can be considered in cases of severe carisoprodol withdrawal., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Purpose: To determine the maximum tolerated dose (MTD), toxicities, and pharmacodynamics effects of sirolimus combined with oral metronomic topotecan and cyclophosphamide in a pediatric population., Materials and Methods: Patients who were 1 to 30 years of age with relapsed/refractory solid tumors (including CNS) were eligible. Patients received daily oral sirolimus and cyclophosphamide (25-50 mg/m2/dose) on days 1-21 and oral topotecan (0.8 mg/m2/dose) on days 1-14 in 28-day cycles. Sirolimus steady-state plasma trough concentrations of 3-7.9 ng/mL and 8-12.0 ng/mL were evaluated, with dose escalation based on a 3+3 phase 1 design. Biomarkers of angiogenesis were also evaluated., Results: Twenty-one patients were treated (median age 18 years; range 9-30). Dose-limiting toxicities included myelosuppression, ALT elevation, stomatitis, and hypertriglyceridemia. The MTD was sirolimus with trough goal of 8-12.0 ng/mL; cyclophosphamide 25 mg/m2/dose; and topotecan 0.8 mg/m2/dose. No objective responses were observed. Four patients had prolonged stable disease > 4 cycles (range 4-12). Correlative biomarker analyses demonstrated reductions in thrombospondin-1 (p=0.043) and soluble vascular endothelial growth factor receptor-2 plasma concentrations at 21 days compared to baseline., Conclusions: The combination of oral sirolimus, topotecan, and cyclophosphamide was well tolerated and biomarker studies demonstrated modulation of angiogenic pathways with this regimen.

Several reports of second malignant neoplasm (SMN) in patients with relapsed neuroblastoma after treatment with (131)I-MIBG suggest the possibility of increased risk. Incidence of and risk factors for SMN after (131)I-MIBG have not been defined. This is a multi-institutional retrospective review of patients with neuroblastoma treated with (131)I-MIBG therapy. A competing risk approach was used to calculate the cumulative incidence of SMN from time of first exposure to (131)I-MIBG. A competing risk regression was used to identify potential risk factors for SMN. The analytical cohort included 644 patients treated with (131)I-MIBG. The cumulative incidence of SMN was 7.6% (95% confidence interval [CI], 4.4-13.0%) and 14.3% (95% CI, 8.3-23.9%) at 5 and 10 years from first (131)I-MIBG, respectively. No increase in SMN risk was found with increased number of (131)I-MIBG treatments or higher cumulative activity per kilogram of (131)I-MIBG received (p = 0.72 and p = 0.84, respectively). Thirteen of the 19 reported SMN were haematologic. In a multivariate analysis controlling for variables with p < 0.1 (stage, age at first (131)I-MIBG, bone disease, disease status at time of first (131)I-MIBG), patients with relapsed/progressive disease had significantly lower risk of SMN (subdistribution hazard ratio 0.3, 95% CI, 0.1-0.8, p = 0.023) compared to patients with persistent/refractory neuroblastoma. The cumulative risk of SMN after (131)I-MIBG therapy for patients with relapsed or refractory neuroblastoma is similar to the greatest published incidence for high-risk neuroblastoma after myeloablative therapy, with no dose-dependent increase. As the number of patients treated and length of follow-up time increase, it will be important to reassess this risk., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

The Mildew resistance Locus O (MLO) family is unique to plants, containing genes that were initially identified as a susceptibility factor to powdery mildew pathogens. However, little is known about the roles and functional diversity of this family in rice, a model crop plant. The rice genome has 12 potential MLO family members. To achieve systematic functional assignments, we performed a phylogenomic analysis by integrating meta-expression data obtained from public sources of microarray data and real-time expression data into a phylogenic tree. Subsequently, we identified 12 MLO genes with various tissue-preferred patterns, including leaf, root, pollen, and ubiquitous expression. This suggested their functional diversity for morphological agronomic traits. We also used these integrated transcriptome data within a phylogenetic context to estimate the functional redundancy or specificity among OsMLO family members. Here, OsMLO12 showed preferential expression in mature pollen; OsMLO4 , in the root tips; Os MLO10 , throughout the roots except at the tips; and OsMLO8 , expression preferential to the leaves and trinucleate pollen. Of particular interest to us was the diurnal expression of OsMLO1, OsMLO3 , and OsMLO8 , which indicated that they are potentially significant in responses to environmental changes. In osdxr mutants that show defects in the light response, OsMLO1, OsMLO3, OsMLO8 , and four calmodulin genes were down-regulated. This finding provides insight into the novel functions of MLO proteins associated with the light-responsive methylerythritol 4-phosphate pathway. In addition, abiotic stress meta-expression data and real-time expression analysis implied that four and five MLO genes in rice are associated with responses to heat and cold stress, respectively. Upregulation of OsMLO3 by Magnaporthe oryzae infection further suggested that this gene participates in the response to pathogens. Our analysis has produced fundamental information that will enhance future studies of the diverse developmental or physiological phenomena mediated by the MLO family in this model plant system.

Purpose: Flow cytometry and RT-PCR can detect occult Ewing sarcoma cells in the blood and bone marrow. These techniques were used to evaluate the prognostic significance of micrometastatic disease in Ewing sarcoma., Experimental Design: Newly diagnosed patients with Ewing sarcoma were enrolled on two prospective multicenter studies. In the flow cytometry cohort, patients were defined as "positive" for bone marrow micrometastatic disease if their CD99(+)/CD45(-) values were above the upper limit in 22 control patients. In the PCR cohort, RT-PCR on blood or bone marrow samples classified the patients as "positive" or "negative" for EWSR1/FLI1 translocations. The association between micrometastatic disease burden with clinical features and outcome was assessed. Coexpression of insulin-like growth factor-1 receptor (IGF-1R) on detected tumor cells was performed in a subset of flow cytometry samples., Results: The median total bone marrow CD99(+)CD45(-) percent was 0.0012% (range 0%-1.10%) in the flow cytometry cohort, with 14 of 109 (12.8%) of Ewing sarcoma patients defined as "positive." In the PCR cohort, 19.6% (44/225) patients were "positive" for any EWSR1/FLI1 translocation in blood or bone marrow. There were no differences in baseline clinical features or event-free or overall survival between patients classified as "positive" versus "negative" by either method. CD99(+)CD45(-) cells had significantly higher IGF-1R expression compared with CD45(+) hematopoietic cells (mean geometric mean fluorescence intensity 982.7 vs. 190.9; P < 0.001)., Conclusions: The detection of micrometastatic disease at initial diagnosis by flow cytometry or RT-PCR is not associated with outcome in newly diagnosed patients with Ewing sarcoma. Flow cytometry provides a tool to characterize occult micrometastatic tumor cells for proteins of interest. Clin Cancer Res; 22(14); 3643-50. ©2016 AACR., (©2016 American Association for Cancer Research.)

Sarcomas are a heterogeneous group of mesenchymal malignancies. In recent years, studies have demonstrated that inhibition of angiogenic pathways or disruption of established vasculature can attenuate the growth of sarcomas. However, when used as monotherapy in the clinical setting, these targeted antiangiogenic agents have only provided modest survival benefits in some sarcoma subtypes, and have not been efficacious in others. Preclinical and early clinical data suggest that the addition of conventional chemotherapy to antiangiogenic agents may lead to more effective therapies for patients with these tumors. In the current review, the authors summarize the available evidence and possible mechanisms supporting this approach.

Purpose: Long-term survivors of Ewing sarcoma (EWS) are at considerable risk for future complications, including late relapse and death. Data on prognostic factors for late death in those who have survived beyond 5 years are lacking., Methods: We conducted a retrospective cohort study using the Surveillance, Epidemiology, and End Results database. We obtained clinical features and outcome data on 1,351 patients with EWS who had survived 60 months or more. From these data, we performed univariate and multivariable analyses of overall survival (OS) using log-rank tests and Cox proportional hazard models., Results: Of 1,351 patients in the cohort, there were 209 deaths, 144 (69%) of which were reported to be due to EWS. The OS for 5-year survivors at 10 years was 87.5% (95% confidence interval 85.4-89.3%). Univariate adverse prognostic factors for late death in 5-year survivors included age ≥ 18 years at initial diagnosis, male sex, and axial/pelvic primary site. Initial stage was not prognostic. Independent adverse prognostic factors for late death included black race (hazard ratio [HR] 2.16, P = 0.01), age ≥ 18 years at diagnosis (HR 2.02, P < 0.001), male sex (HR 1.43, P = 0.01), and axial/pelvic primary site (HR 1.43, P = 0.02)., Conclusions: The majority of late deaths in 5-year survivors are due to EWS. Black race, age ≥18 at diagnosis, male sex, and axial/pelvic primary site (but not stage at diagnosis) are independently associated with increased risk of late death., (© 2016 Wiley Periodicals, Inc.)

On March 28, 2016, two patients were evaluated at the Contra Costa Regional Medical Center emergency department (ED) in Contra Costa County, California, for nausea, vomiting, central nervous system depression, and respiratory depression, 30 minutes after ingesting what appeared to be Norco, a prescription opioid pain medication that contains acetaminophen and hydrocodone. The patients purchased the drug from a friend a few days earlier. The two cases of drug intoxication were reported to a Contra Costa County Health Department public health official who subsequently notified the California State Health Department.

Background: MYCN gene amplification (MNA) is a hallmark of aggressive neuroblastoma. This study was performed to determine univariate and multivariate predictors of tumor MNA., Methods: Data from the International Neuroblastoma Risk Group were analyzed for a subset of 7102 patients with known MYCN status. Chi-square testing and logistic regression were used to identify univariate and multivariate predictors of MYCN status. Recursive partitioning was used to identify groups of patients with maximal differences in rates of MNA., Results: All clinical features (age ≥ 18 months, high ferritin levels, high lactate dehydrogenase [LDH] levels, International Neuroblastoma Staging System stage 4, and adrenal sites) and pathological/biological features (DNA index ≤ 1, high mitosis-karyorrhexis index [MKI], undifferentiated/poorly differentiated grade, unfavorable histology according to the International Neuroblastoma Pathology Classification, and segmental chromosomal aberrations [SCAs]) were significantly associated with MNA. LDH (odds ratio [OR], 8.4; P < .001) and chromosomal 1p loss of heterozygosity (OR, 19.8; P < .001) were the clinical and biological variables, respectively, most strongly associated with MNA. In logistic regression, all variables except chromosome 17q aberration and pooled SCAs were independently predictive of MNA. Recursive partitioning identified subgroups with disparate rates of MNA, including subgroups with 85.7% MNA (patients with high LDH levels who had poorly differentiated adrenal tumors with chromosome 1p deletion) and 0.6% MNA (localized tumors having hyperdiploidy and low MKIs and lacking chromosome 1p aberrations)., Conclusions: MNA is strongly associated with other clinical and biological variables in neuroblastoma. Recursive partitioning has identified subgroups of neuroblastoma patients with highly disparate rates of MNA. These findings can be used to inform investigations of molecular mechanisms of MNA., (© 2015 American Cancer Society.)

Purpose: Neuroblastoma (NB) is a heterogeneous tumor arising from sympathetic tissues. The impact of primary tumor site in influencing the heterogeneity of NB remains unclear., Patients and Methods: Children younger than age 21 years diagnosed with NB or ganglioneuroblastoma between 1990 and 2002 and with known primary site were identified from the International Neuroblastoma Risk Group database. Data were compared between sites with respect to clinical and biologic features, as well as event-free survival (EFS) and overall survival (OS)., Results: Among 8,369 children, 47% had adrenal tumors. All evaluated clinical and biologic variables differed statistically between primary sites. The features that were > 10% discrepant between sites were stage 4 disease, MYCN amplification, elevated ferritin, elevated lactate dehydrogenase, and segmental chromosomal aberrations, all of which were more frequent in adrenal versus nonadrenal tumors (P < .001). Adrenal tumors were more likely than nonadrenal tumors (adjusted odds ratio, 2.09; 95% CI, 1.67 to 2.63; P < .001) and thoracic tumors were less likely than nonthoracic tumors (adjusted odds ratio, 0.20; 95% CI, 0.11 to 0.39; P < .001) to have MYCN amplification after controlling for age, stage, and histologic grade. EFS and OS differed significantly according to the primary site (P < .001 for both comparisons). After controlling for age, MYCN status, and stage, patients with adrenal tumors had higher risk for events (hazard ratio, 1.13 compared with nonadrenal tumors; 95% CI, 1.03 to 1.23; P = .008), and patients with thoracic tumors had lower risk for events (HR, 0.79 compared with nonthoracic; 95% CI, 0.67 to 0.92; P = .003)., Conclusion: Clinical and biologic features show important differences by NB primary site, with adrenal and thoracic sites associated with inferior and superior survival, respectively. Future studies will need to investigate the biologic origin of these differences., (© 2014 by American Society of Clinical Oncology.)

Heavy menstrual bleeding (HMB) is a frequent complaint in adolescence. Although HMB is often caused by immaturity of the hypothalamic-pituitary-ovarian axis, bleeding disorders are another common yet often unidentified cause. The aim of this study was to examine the bleeding patterns and prevalence of inherited bleeding disorders among females referred for HMB to a multidisciplinary adolescent haematology clinic. We retrospectively reviewed the first 105 patients (ages 8-18 years) referred to this specialty clinic from February 2009 to December 2011. Using menstrual bleeding questionnaires and medical records, data were extracted regarding demographics, bleeding patterns, frequency and types of bleeding disorders identified, and prescribed interventions. Sixty-two per cent of patients were diagnosed with a bleeding disorder, including platelet storage pool deficiency (36%), von Willebrand's disease (9%), other platelet function defect (8%), Ehlers-Danlos syndrome (7%) and combined bleeding disorders (2%). Comparison of the bleeding profiles for females with and without a bleeding disorder revealed only three factors that were significantly different, including the reported regularity of patients' periods (P = 0.02), description of period flow (P = 0.04) and number of days of each period that the bleeding was described as 'heavy' (P = 0.007). Bleeding disorders are prevalent in adolescent females presenting to a specialty clinic. Specifically, a relatively high proportion of adolescents were diagnosed with platelet storage pool deficiency. In our small population, menstrual bleeding profiles, as examined by a standardized questionnaire, could not identify females with an underlying bleeding disorder, demonstrating the important role of haemostasis testing in the evaluation of adolescents with HMB., (© 2012 Blackwell Publishing Ltd.)

Background: Although Vietnam is a region with a plant-based diet that has a high zinc deficiency, epidemiological data showing how this affects pregnant women are limited. This study explores the prevalence of zinc deficiency and possible correlates in pregnant Vietnamese women in Ho Chi Minh City., Methods: This was a cross-sectional study conducted at a general hospital in Ho Chi Minh City, Vietnam. All pregnant women who came to their first antenatal care visit from November 2011 to June 2012 were recruited. Those taking a vitamin and/or mineral supplement were excluded. Serum zinc concentrations, determined by a standard colorimetric method, of 10.7 μmol/L-17.5 μmol/L (70.0 g/dL-114 g/dL) were classified as normal and under 10.7 μmol/L (70.0 g/dL) as zinc deficient., Results: In total, 254 pregnant women were invited and 107 (42%) participated. The mean age of participants was 29 years, and mean gestational age was 10 weeks. Median zinc concentration in serum was 13.6 μmol/L, and the prevalence of zinc deficiency was 29% (95% CI=21%-39%). The daily intake of a milk product supplement was the only significant correlate of zinc deficiency of the items investigated (adjusted OR=0.40, 95% CI=0.16-0.99, p=0.049)., Discussion: This is the first study reporting that more than 25% of pregnant Vietnamese women in Ho Chi Minh City are zinc deficient. Further academic and clinical input is needed to confirm the scale of this neglected issue and to investigate the potential of milk product supplementation in this population.

Background: Notch receptors normally play a key role in guiding a variety of cell fate decisions during development and differentiation of metazoan organisms. On the other hand, dysregulation of Notch1 signaling is associated with many different types of cancer as well as tumor angiogenesis, making Notch1 a potential therapeutic target., Principal Findings: Here we report the in vitro activities of inhibitory Notch1 monoclonal antibodies derived from cell-based and solid-phase screening of a phage display library. Two classes of antibodies were found, one directed against the EGF-repeat region that encompasses the ligand-binding domain (LBD), and the second directed against the activation switch of the receptor, the Notch negative regulatory region (NRR). The antibodies are selective for Notch1, inhibiting Jag2-dependent signaling by Notch1 but not by Notch 2 and 3 in reporter gene assays, with EC(50) values as low as 5+/-3 nM and 0.13+/-0.09 nM for the LBD and NRR antibodies, respectively, and fail to recognize Notch4. While more potent, NRR antibodies are incomplete antagonists of Notch1 signaling. The antagonistic activity of LBD, but not NRR, antibodies is strongly dependent on the activating ligand. Both LBD and NRR antibodies bind to Notch1 on human tumor cell lines and inhibit the expression of sentinel Notch target genes, including HES1, HES5, and DTX1. NRR antibodies also strongly inhibit ligand-independent signaling in heterologous cells transiently expressing Notch1 receptors with diverse NRR "class I" point mutations, the most common type of mutation found in human T-cell acute lymphoblastic leukemia (T-ALL). In contrast, NRR antibodies failed to antagonize Notch1 receptors bearing rare "class II" or "class III" mutations, in which amino acid insertions generate a duplicated or constitutively sensitive metalloprotease cleavage site. Signaling in T-ALL cell lines bearing class I mutations is partially refractory to inhibitory antibodies as compared to cell-penetrating gamma-secretase inhibitors., Conclusions/significance: Antibodies that compete with Notch1 ligand binding or that bind to the negative regulatory region can act as potent inhibitors of Notch1 signaling. These antibodies may have clinical utility for conditions in which inhibition of signaling by wild-type Notch1 is desired, but are likely to be of limited value for treatment of T-ALLs associated with aberrant Notch1 activation.

A novel algorithm is presented for classification of four patterns of diffuse lung disease: normal, emphysema, honeycombing and ground glass opacity, on the basis of textural analysis of high resolution computed tomography (HRCT) lung images. The algorithm incorporates scale-space features based on Gaussian derivative filters and multi-dimensional multi-scale features based on wavelet and contourlet transforms of the original images. The mean, standard deviation, skewness and kurtosis along with generalized Gaussian density are used to model the output of filters and transforms, and construct feature vectors. Multi-class multiple kernel learning (m-MKL) classifier is used to evaluate the performance of the feature extraction scheme. The method is tested on a collection of 89 slices from 38 patients, each slice of size 512×512, 16 bits/pixel in DICOM format. The dataset contains 70,000 ROIs from slices already marked by experienced radiologists. The average sensitivity and specificity achieved is 94.16% and 98.68%, respectively.

This paper is concerned with the estimation of the height and width of freespace based on a Bayesian Recursive (BR) algorithm for an autonomous wheelchair using a stereoscopic camera system for disabled people. A 2D distance map for the purpose of freespace estimation is converted from a 3D point map using geometric projection and computation. The comparison of this 2D map to a 2D map obtained from Laser is carried out. Moreover, freespaces in the 2D map are estimated using a BR algorithm based on uncertainty information and control data. Given the average probability, a possible movement decision is then made for the mobile wheelchair. Experimental results obtained in an indoor environment prove the effectiveness of this estimation algorithm.

Gray matter atrophy observed by brain MRI is an important correlate to clinical disability and disease duration in multiple sclerosis. The objective of this study was to link brain atrophy visualized by neuroimaging to its underlying neuropathology using the MS model, experimental autoimmune encephalomyelitis (EAE). Volumetric changes in brains of EAE mice, as well as matched healthy normal controls, were quantified by collecting post-mortem high-resolution T2-weighted magnetic resonance microscopy and actively stained magnetic resonance histology images. Anatomical delineations demonstrated a significant decrease in the volume of the whole cerebellum, cerebellar cortex, and molecular layer of the cerebellar cortex in EAE as compared to normal controls. The pro-apoptotic marker caspase-3 was detected in Purkinje cells and a significant decrease in Purkinje cell number was found in EAE. Cross modality and temporal correlations revealed a significant association between Purkinje cell loss on neuropathology and atrophy of the molecular layer of the cerebellar cortex by neuroimaging. These results demonstrate the power of using combined population atlasing and neuropathology approaches to discern novel insights underlying gray matter atrophy in animal models of neurodegenerative disease.