Publications by authors named "John Lucas"

190 Publications

Artificial Intelligence-Assisted Prediction of Late-Onset Cardiomyopathy Among Childhood Cancer Survivors.

JCO Clin Cancer Inform 2021 Apr;5:459-468

Department of Epidemiology and Cancer Control, St Jude Children's Research Hospital, Memphis, TN.

Purpose: Early identification of childhood cancer survivors at high risk for treatment-related cardiomyopathy may improve outcomes by enabling intervention before development of heart failure. We implemented artificial intelligence (AI) methods using the Children's Oncology Group guideline-recommended baseline ECG to predict cardiomyopathy.

Material And Methods: Seven AI and signal processing methods were applied to 10-second 12-lead ECGs obtained on 1,217 adult survivors of childhood cancer prospectively followed in the St Jude Lifetime Cohort (SJLIFE) study. Clinical and echocardiographic assessment of cardiac function was performed at initial and follow-up SJLIFE visits. Cardiomyopathy was defined as an ejection fraction < 50% or an absolute drop from baseline ≥ 10%. Genetic algorithm was used for feature selection, and extreme gradient boosting was applied to predict cardiomyopathy during the follow-up period. Model performance was evaluated by five-fold stratified cross-validation.

Results: The median age at baseline SJLIFE evaluation was 31.7 years (range 18.4-66.4), and the time between baseline and follow-up evaluations was 5.2 years (0.5-9.5). Two thirds (67.1%) of patients were exposed to chest radiation, and 76.6% to anthracycline chemotherapy. One hundred seventeen (9.6%) patients developed cardiomyopathy during follow-up. In the model based solely on ECG features, the cross-validation area under the curve (AUC) was 0.87 (95% CI, 0.83 to 0.90), whereas the model based on clinical features had an AUC of 0.69 (95% CI, 0.64 to 0.74). In the model based on ECG and clinical features, the cross-validation AUC was 0.89 (95% CI, 0.86 to 0.91), with a sensitivity of 78% and a specificity of 81%.

Conclusion: AI using ECG data may assist in the identification of childhood cancer survivors at increased risk for developing future cardiomyopathy.
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http://dx.doi.org/10.1200/CCI.20.00176DOI Listing
April 2021

Excellent Outcome for Pediatric Patients With High-Risk Hodgkin Lymphoma Treated With Brentuximab Vedotin and Risk-Adapted Residual Node Radiation.

J Clin Oncol 2021 Apr 7:JCO2003286. Epub 2021 Apr 7.

Department of Radiation Oncology, St Jude Children's Research Hospital, Memphis, TN.

Purpose: Brentuximab vedotin, an effective anti-CD30 antibody-drug conjugate approved for use in adults with classical Hodgkin lymphoma (HL), was introduced in this frontline trial to reduce prescribed radiation in children and adolescents with classical HL.

Methods: Open-label, single-arm, multicenter trial for patients (age ≤ 18 years) with stage IIB, IIIB, or IV classical HL was conducted. Brentuximab vedotin replaced each vincristine in the OEPA/COPDac (vincristine, etoposide, prednisone, and doxorubicin/cyclophosphamide, vincristine, prednisone, and dacarbazine) regimen according to GPOH-HD2002 treatment group 3 (TG3); two cycles of AEPA and four cycles of CAPDac. Residual node radiotherapy (25.5 Gy) was given at the end of all chemotherapy only to nodal sites that did not achieve a complete response (CR) at the early response assessment (ERA) after two cycles of therapy. Primary objectives were to evaluate the safety and efficacy (complete remission at ERA) of this combination and the 3-year event-free (EFS) and overall survival (OS). The trials are registered at ClinicalTrials.gov identifier: NCT01920932.

Results: Of the 77 patients enrolled in the study, 27 (35%) achieved complete remission at ERA and were spared radiation. Patients who were irradiated received radiation to individual residual nodal tissue. At a median follow-up of 3.4 years, the 3-year EFS was 97.4% (SE 2.3%) and the OS was 98.7% (SE 1.6%). One irradiated patient experienced disease progression at the end of therapy and now remains disease free more than 6 years following salvage therapy, and one unexpected death occurred. Only 4% of patients experienced grade 3 neuropathy.

Conclusion: The integration of brentuximab vedotin in the frontline treatment of pediatric high-risk HL is highly tolerable, facilitated significant reduction in radiation exposure, and yielded excellent outcomes.
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http://dx.doi.org/10.1200/JCO.20.03286DOI Listing
April 2021

Neuroblastoma.

Pediatr Blood Cancer 2021 May;68 Suppl 2:e28473

Department of Radiation Oncology University of Pennsylvania and the Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.

The survival of patients with high-risk neuroblastoma has improved significantly with the use of intensive multimodality treatment regimens, including chemotherapy, surgery, radiation therapy, myeloablative chemotherapy followed by stem cell rescue, and immunotherapy. This report summarizes the current treatment strategies used in the COG and SIOP for children with neuroblastoma. The improved global collaboration and the adoption of a uniform International Neuroblastoma Risk Group Staging System will help facilitate comparison of homogeneous pretreatment cohorts across clinical trials. Future research strategies regarding the indications for and dosages of radiation therapy to the primary and metastatic sites, and the integration of meta-iodobenzyl guanidine therapy into the multimodal treatment program, are discussed.
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http://dx.doi.org/10.1002/pbc.28473DOI Listing
May 2021

Non-invasive image-based cytometry for high throughput NK cell cytolysis analysis.

J Immunol Methods 2021 Apr 9;491:112992. Epub 2021 Feb 9.

Department of Biomedical Engineering, Rutgers University, Piscataway, NJ 08854, USA; Department of Medicine, Rutgers Biomedical Health Sciences, New Brunswick, NJ 088, USA. Electronic address:

Natural Killer (NK) cells are lymphocytes that are the first line of defense against malignantly transformed cells, virally infected cells and other stressed cell types. To study the cytolytic function of NK cells in vitro, a cytotoxicity assay is normally conducted against a target cancerous cell line. Current assay methods are typically performed in mixed 2D cocultures with destructive endpoints and low throughput, thereby limiting the scale, time-resolution, and relevance of the assay to in vivo conditions. Here, we evaluated a novel, non-invasive, quantitative image-based cytometry (qIBC) assay for detection of NK-mediated killing of target cells in 2D and 3D environments in vitro and compared its performance to two common flow cytometry- and fluorescence-based cytotoxicity assays. Similar to the other methods evaluated, the qIBC assay allowed for reproducible detection of target cell killing across a range of effector-to-target ratios with reduced variability. The qIBC assay also allowed for detection of NK cytolysis in 3D spheroids, which enabled scalable measurements of cell cytotoxicity in 3D models. Our findings suggest that quantitative image-based cytometry would be suitable for rapid, high-throughput screening of NK cytolysis in vitro, including in quasi-3D structures that model tissue environments in vivo.
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http://dx.doi.org/10.1016/j.jim.2021.112992DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8112353PMC
April 2021

Understanding the role of cultural factors in the risk of mild cognitive impairment in diverse populations.

Int Psychogeriatr 2021 Jan;33(1):11-13

Department of Psychiatry and Psychology, Mayo Clinic, Jacksonville, FL, USA.

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http://dx.doi.org/10.1017/S1041610220000435DOI Listing
January 2021

PATENCY-2 trial of vonapanitase to promote radiocephalic fistula use for hemodialysis and secondary patency.

J Vasc Access 2021 Jan 22:1129729820985626. Epub 2021 Jan 22.

Akebia Therapeutics, Cambridge, MA 02142.

Objective: Arteriovenous fistulas created for hemodialysis often fail to become usable and are frequently abandoned. This prospective trial evaluated the efficacy of vonapanitase, a recombinant human elastase, in increasing radiocephalic fistula use for hemodialysis and secondary patency.

Methods: PATENCY-2 was a randomized, double-blind, placebo-controlled trial in patients on or approaching the need for hemodialysis undergoing radiocephalic arteriovenous fistula creation. Of 696 screened, 613 were randomized, and 603 were treated (vonapanitase  = 405, placebo  = 208). The study drug solution was applied topically to the artery and vein for 10 min immediately after fistula creation. The primary endpoints were fistula use for hemodialysis and secondary patency (fistula survival without abandonment). Other efficacy endpoints included unassisted fistula use for hemodialysis, primary unassisted patency, fistula maturation and unassisted maturation by ultrasound criteria, and fistula procedure rates.

Results: The proportions of patients with fistula use for hemodialysis was similar between groups, 70% vonapanitase and 65% placebo, ( = 0.33). The Kaplan-Meier estimates of 12-month secondary patency were 78% (95% confidence interval [CI], 73-82) for vonapanitase and 76% (95% CI, 70-82) for placebo ( = 0.93). The proportions with unassisted fistula use for hemodialysis were 46% vonapanitase and 37% placebo ( = 0.054). The Kaplan-Meier estimates of 12-month primary unassisted patency were 50% (95% CI, 44-55) for vonapanitase and 43% (95% CI, 35-50) for placebo ( = 0.18). There were no differences in the proportion of patients with fistula maturation or in fistula procedure rates. Adverse events were similar between groups. Vonapanitase was not immunogenic.

Conclusions: Vonapanitase treatment did not achieve clinical or statistical significance to meaningfully improve radiocephalic fistula surgical outcomes. Outcome in the placebo group were better than in historical controls. Vonapanitase was well-tolerated and safe.

Trial Registration: clinicaltrials.gov: NCT02414841 (https://clinicaltrials.gov/ct2/show/NCT02414841).
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http://dx.doi.org/10.1177/1129729820985626DOI Listing
January 2021

The Multi-Fungicide Resistance Status of Populations in Arable Soils and the Wider European Environment.

Front Microbiol 2020 15;11:599233. Epub 2020 Dec 15.

Rothamsted Research, Harpenden, United Kingdom.

The evolution and spread of pan-azole resistance alleles in clinical and environmental isolates of is a global human health concern. The identification of hotspots for azole resistance development in the wider environment can inform optimal measures to counteract further spread by minimizing exposure to azole fungicides and reducing inoculum build-up and pathogen dispersal. We investigated the fungicide sensitivity status of soil populations sampled from arable crops and the wider environment and compared these with urban airborne populations. Low levels of azole resistance were observed for isolates carrying the CYP51A variant F46Y/M172V/E427K, all belonging to a cluster of related cell surface protein (CSP) types which included t07, t08, t13, t15, t19, and t02B, a new allele. High levels of resistance were found in soil isolates carrying CYP51A variants TR/L98H and TR/Y121F/T289A, all belonging to CSP types t01, t02, t04B, or t11. TR/Y121F/M172V/T289A/G448S (CSP t01) and TR/Y121F/T289A/S363P/I364V/G448S (CSP t01), a new haplotype associated with high levels of resistance, were isolated from Dutch urban air samples, indicating azole resistance evolution is ongoing. Based on low numbers of pan-azole resistant isolates and lack of new genotypes in soils of fungicide-treated commercial and experimental wheat crops, we consider arable crop production as a coldspot for azole resistance development, in contrast to previously reported flower bulb waste heaps. This study also shows that, in addition to azole resistance, several lineages of carrying TR-based CYP51A variants have also developed acquired resistance to methyl benzimidazole carbamate, quinone outside inhibitor and succinate dehydrogenase (Sdh) inhibitor fungicides through target-site alterations in the corresponding fungicide target proteins; beta-tubulin (F200Y), cytochrome (G143A), and Sdh subunit B (H270Y and H270R), respectively. Molecular typing showed that several multi-fungicide resistant strains found in agricultural soils in this study were clonal as identical isolates have been found earlier in the environment and/or in patients. Further research on the spread of different fungicide-resistant alleles from the wider environment to patients and can inform optimal practices to tackle the further spread of antifungal resistance in populations and to safeguard the efficacy of azoles for future treatment of invasive aspergillosis.
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http://dx.doi.org/10.3389/fmicb.2020.599233DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7770239PMC
December 2020

Stereotactic Body Radiation Therapy for Metastatic and Recurrent Solid Tumors in Children and Young Adults.

Int J Radiat Oncol Biol Phys 2021 Apr 28;109(5):1396-1405. Epub 2020 Nov 28.

Department of Radiation Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee.

Purpose: The use of stereotactic body radiation therapy (SBRT) in pediatric patients has been underreported. We reviewed practice patterns, outcomes, and toxicity of SBRT in this population.

Methods And Materials: In this multi-institutional study, 55 patients with 107 non-central nervous system lesions treated with SBRT between 2010 and 2016 were reviewed. Treatment response was evaluated by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 and modified RECIST v1.1 criteria for soft-tissue and bone lesions, respectively. Patterns of local failure (LF) were assessed dosimetrically. The cumulative incidence of LF and toxicity were estimated accounting for the competing risk event of death. Predictors of LF were identified through joint frailty models for clustered competing risks.

Results: The median (range) dose/fraction was 7 (4.5-25) Gy, the total (range) dose/site was 35 (12-45), and the median (range) number of fractions was 5 (1-9). The radiographic response rates of bone and soft-tissue lesions were 90.6% and 76.7%, respectively. Symptom improvement was observed for 62% of symptomatic sites. A total of 27 LFs were documented, with 14 in-field, 9 marginal, and 4 out-of-field LFs. The 1-year estimated cumulative LF rate, progression-free survival, and overall survival were 25.2% (95% confidence interval [CI], 17.2%-36.1%), 17.5% (95% CI, 9.0%-34.1%), and 61% (95% CI, 48.9%-76.1%), respectively. Lesion type (soft tissue vs bone) was the only significant predictor of LF on multivariable analysis (P = .04), with increased hazard for soft-tissue lesions. No acute or late toxicity of grade 4 or higher was observed; the estimated 1-year cumulative incidence of late toxicity of any grade was 7.5% (95% CI, 3.6%-12.1%).

Conclusions: The SBRT was well tolerated and resulted in radiographic response and symptom palliation in most pediatric patients with advanced disease. The 1-year cumulative LF rate of 25% will serve as a benchmark for further modifications to radiation therapy indications, parameters, and combination therapy.
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http://dx.doi.org/10.1016/j.ijrobp.2020.11.054DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7965242PMC
April 2021

Plasma Biomarkers of Alzheimer's Disease in African Americans.

J Alzheimers Dis 2021 ;79(1):323-334

Mayo Clinic, Department of Neuroscience, Jacksonville, FL, USA.

Background/objective: The aim of this study was to determine if plasma concentrations of 5 surrogate markers of Alzheimer's disease (AD) pathology and neuroinflammation are associated with disease status in African Americans.

Methods: We evaluated 321 African Americans (159 AD, 162 controls) from the Florida Consortium for African-American Alzheimer's Disease Studies (FCA3DS). Five plasma proteins reflecting AD neuropathology or inflammation (Aβ42, tau, IL6, IL10, TNFα) were tested for associations with AD, age, sex, APOE and MAPT genotypes, and for pairwise correlations.

Results: Plasma tau levels were higher in AD when adjusted for biological and technical covariates. APOEɛ4 was associated with lower plasma Aβ42 and tau levels. Older age was associated with higher plasma Aβ42, tau, and TNFα. Females had lower IL10 levels. Inflammatory proteins had strong pairwise correlations amongst themselves and with Aβ42.

Conclusion: We identified effects of demographic and genetic variants on five potential plasma biomarkers in African Americans. Plasma inflammatory biomarkers and Aβ42 may reflect correlated pathologies and elevated plasma tau may be a biomarker of AD in this population.
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http://dx.doi.org/10.3233/JAD-200828DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7902984PMC
January 2021

Association of ABI3 and PLCG2 missense variants with disease risk and neuropathology in Lewy body disease and progressive supranuclear palsy.

Acta Neuropathol Commun 2020 10 22;8(1):172. Epub 2020 Oct 22.

Department of Neuroscience, Mayo Clinic Florida, Jacksonville, FL, 32224, USA.

Missense variants ABI3_rs616338-T and PLCG2_rs72824905-G were previously associated with elevated or reduced risk of Alzheimer's disease (AD), respectively. Despite reports of associations with other neurodegenerative diseases, there are few studies of these variants in purely neuropathologically diagnosed cohorts. Further, the effect of these mutations on neurodegenerative disease pathologies is unknown. In this study, we tested the effects of ABI3_rs616338-T and PLCG2_rs72824905-G on disease risk in autopsy cohorts comprised of 973 patients diagnosed neuropathologically with Lewy body disease (LBD-NP) and 1040 with progressive supranuclear palsy (PSP), compared to 3351 controls. LBD-NP patients were further categorized as high, intermediate and low likelihood of clinical dementia with Lewy bodies (DLB-CL) based on DLB Consortium criteria. We also tested for association with both Braak neurofibrillary tau tangle (n = 2008, n = 1037, n = 971) and Thal phase amyloid plaque scores (n = 1786, n = 1018, n = 768). Additionally, 841 PSP patients had quantitative tau neuropathology measures that were assessed for genetic associations. There was no statistically significant association with disease risk for either LBD-NP or PSP in our study. LBD intermediate category disease risk was significantly associated with ABI3_rs616338-T (OR = 2.65, 95% CI 1.46-4.83, p = 0.001). PLCG2_rs72824905-G was associated with lower Braak stage (ß = - 0.822, 95% CI - 1.439 to - 0.204, p = 0.009). This effect was more pronounced in the PSP (ß = - 0.995, 95% CI - 1.773 to - 0.218, p = 0.012) than LBD-NP patients (ß = - 0.292, 95% CI - 1.283 to 0.698, p = 0.563). PLCG2_rs72824905-G also showed association with reduced quantitative tau pathology for each lesion type and overall tau burden in PSP (ß = - 0.638, 95% CI - 1.139 to - 0.136, p = 0.013). These findings support a role for PLCG2_rs72824905-G in suppressing tau neuropathology. ABI3_rs616338-T may influence disease risk specifically in the LBD-NP intermediate category comprised of patients with diffuse neocortical or limbic LB, concurrently with moderate or high AD neuropathology, respectively. Our study provides a potential mechanism of action for the missense PLCG2 variant and suggests a differential disease risk effect for ABI3 in a distinct LBD-NP neuropathologic category.
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http://dx.doi.org/10.1186/s40478-020-01050-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7579984PMC
October 2020

Improving the Pediatric Patient Experience During Radiation Therapy-A Children's Oncology Group Study.

Int J Radiat Oncol Biol Phys 2021 Feb 12;109(2):505-514. Epub 2020 Sep 12.

Department of Radiation Oncology, University of Colorado, Aurora, Colorado.

Purpose: Treatment with radiation therapy (RT) can cause anxiety and distress for pediatric patients and their families. Radiation oncology teams have developed strategies to reduce the negative psychological impact. This survey study aimed to characterize these methods.

Methods And Materials: A 37-item questionnaire was sent to all radiation oncology members of the Children's Oncology Group to explore strategies to improve the pediatric patient experience. The Wilcoxon rank-sum test was used to assess factors associated with use of anesthesia for older children.

Results: Surveys were completed by 106 individuals from 84/210 institutions (40%). Respondents included 89 radiation oncologists and 17 supportive staff. Sixty-one percent of centers treated ≤50 children per year. Respondents described heterogenous interventions. The median age at which most children no longer required anesthesia was 6 years (range: ≤3 years to ≥8 years). Routine anesthesia use at an older age was associated with physicians' lack of awareness of these strategies (P = .04) and <10 years of pediatric radiation oncology experience (P = .04). Fifty-two percent of respondents reported anesthesia use added >45 minutes in the radiation oncology department daily. Twenty-six percent of respondents planned to implement new strategies, with 65% focusing on video-based distraction therapy and/or augmented reality/virtual reality.

Conclusions: Many strategies are used to improve children's experience during RT. Lack of awareness of these interventions is a barrier to their implementation and is associated with increased anesthesia use. This study aims to disseminate these methods with the goal of raising awareness, facilitating implementation, and, ultimately, improving the experience of pediatric cancer patients and their caregivers.
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http://dx.doi.org/10.1016/j.ijrobp.2020.09.002DOI Listing
February 2021

Products and mechanism of thermal decomposition of chlorpyrifos under inert and oxidative conditions.

Environ Sci Process Impacts 2020 Oct 10;22(10):2084-2094. Epub 2020 Sep 10.

Faculty of Engineering and Built Environment, Discipline of Chemical Engineering, School of Engineering, University of Newcastle, Callaghan, NSW 2308, Australia.

Chlorpyrifos (CPF) is a widely used pesticide; however, limited experimental work has been completed on its thermal decomposition. CPF is known to decompose into 3,5,6-trichloro-2-pyridinol (TCpyol) together with ethylene and HOPOS. Under oxidative conditions TCpyol can decompose into the dioxin-like 2,3,7,8-tetrachloro-[1,4]-dioxinodipyridine (TCDDPy). With CPF on the cusp of being banned in several jurisdictions worldwide, the question might arise as to how to safely eliminate large stockpiles of this pesticide. Thermal methods such as incineration or thermal desorption of pesticide-contaminated soils are often employed. To assess the safety of thermal methods, information about the toxicants arising from thermal treatment is essential. The present flow reactor study reports the products detected under inert and oxidative conditions from the decomposition of CPF representative of thermal treatments and of wildfires in CPF-contaminated vegetation. Ethylene and TCpyol are the initial products formed at temperatures between 550 and 650 °C, although the detection of HOPOS as a reaction product has proven to be elusive. During pyrolysis of CPF in an inert gas, the dominant sulfur-containing product detected from CPF is carbon disulfide. Quantum chemical analysis reveals that ethylene and HOPOS undergo a facile reaction to form thiirane (c-CHS) which subsequently undergoes ring opening reactions to form precursors of CS. At elevated temperatures (>650 °C), TCpyol undergoes both decarbonylation and dehydroxylation reactions together with decomposition of its primary product, TCpyol. A substantial number of toxicants is observed, including HCN and several nitriles, including cyanogen. No CS is observed under oxidative conditions - sulfur dioxide is the fate of S in oxidation of CPF, and quantum chemical studies show that SO formation is initiated by the reaction between HOPOS and O. The range of toxicants produced in thermal decomposition of CPF is summarised.
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http://dx.doi.org/10.1039/d0em00295jDOI Listing
October 2020

Results of a third Gamma Knife radiosurgery for trigeminal neuralgia.

J Neurosurg 2020 Apr 24:1-7. Epub 2020 Apr 24.

Departments of1Radiation Oncology and.

Objective: Gamma Knife radiosurgery (GKRS) is a commonly used procedure for medically refractory trigeminal neuralgia (TN), with repeat GKRS routinely done in cases of pain relapse. The results of a third GKRS in cases of further pain relapse have not been well described. In this study, the authors report the largest series of patients treated with a third GKRS for TN to date.

Methods: Retrospective review of institutional electronic medical records and a GKRS database was performed to identify patients who had been treated with a third GKRS at the authors' institution in the period from 2010 to 2018. Telephone interviews were used to collect long-term follow-up data. Pain outcomes were measured using the Barrow Neurological Institute (BNI) pain intensity scale, with a score ≤ IIIb indicating successful treatment.

Results: Twenty-two nerves in 21 patients had sufficient follow-up to determine BNI pain score outcomes. Eighteen of 22 cases had a successful third GKRS, with a median durability of pain relief of 3.88 years. There was no significant difference in the durability of pain relief after a third GKRS compared with those of institutional historical controls of prior series of first and second GKRS procedures. Ten cases had new or worsening facial numbness, with 1 case being bothersome. Four cases of toxicity other than facial numbness were reported, including 1 case of corneal abrasions and possible neurotrophic keratopathy. No cases of anesthesia dolorosa were reported. No factors predicting treatment success or the durability of pain relief were identified. Nonnumbness toxicity was more common in those with a proximally placed shot at the third GKRS.

Conclusions: A third GKRS is an effective treatment option for TN patients who have pain relapse after repeat GKRS. Pain outcomes of a third GKRS are similar to those following a first or second GKRS. Toxicity is tolerable in patients with a distally placed shot at the third GKRS.
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http://dx.doi.org/10.3171/2020.2.JNS192876DOI Listing
April 2020

Pediatric bithalamic gliomas have a distinct epigenetic signature and frequent EGFR exon 20 insertions resulting in potential sensitivity to targeted kinase inhibition.

Acta Neuropathol 2020 06 17;139(6):1071-1088. Epub 2020 Apr 17.

Division of Hematology/Oncology, Department of Pediatrics, Nicklaus Children's Hospital, Miami, FL, USA.

Brain tumors are the most common solid tumors of childhood, and the genetic drivers and optimal therapeutic strategies for many of the different subtypes remain unknown. Here, we identify that bithalamic gliomas harbor frequent mutations in the EGFR oncogene, only rare histone H3 mutation (in contrast to their unilateral counterparts), and a distinct genome-wide DNA methylation profile compared to all other glioma subtypes studied to date. These EGFR mutations are either small in-frame insertions within exon 20 (intracellular tyrosine kinase domain) or missense mutations within exon 7 (extracellular ligand-binding domain) that occur in the absence of accompanying gene amplification. We find these EGFR mutations are oncogenic in primary astrocyte models and confer sensitivity to specific tyrosine kinase inhibitors dependent on location within the kinase domain or extracellular domain. We initiated treatment with targeted kinase inhibitors in four children whose tumors harbor EGFR mutations with encouraging results. This study identifies a promising genomically-tailored therapeutic strategy for bithalamic gliomas, a lethal and genetically distinct brain tumor of childhood.
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http://dx.doi.org/10.1007/s00401-020-02155-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7792550PMC
June 2020

Wada testing and fMRI in a polyglot evaluated for epilepsy surgery.

Epileptic Disord 2020 Apr;22(2):207-213

Department of Neurology.

Despite advancements in the neurophysiology of language and presurgical evaluation for epilepsy surgery, there is a paucity of information in the literature regarding presurgical evaluation of multilingual patients. We present a case of a 52-year-old right-handed woman with refractory epilepsy who was fluent in six languages and underwent subsequent trilingual presurgical evaluation which included neuropsychological testing, Wada testing, functional magnetic resonance imaging (fMRI), and electrocortical stimulation. These studies suggested a seizure focus in the left temporal lobe and language localization that was predominantly right-hemispheric; she subsequently underwent left temporal laser interstitial thermal therapy without clinical disturbance in language function while remaining seizure-free. A multidisciplinary effort was integral in providing an optimal outcome for this patient.
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http://dx.doi.org/10.1684/epd.2020.1145DOI Listing
April 2020

Treatment-related calvarial lesions in pediatric brain tumor survivors.

Pediatr Blood Cancer 2020 06 14;67(6):e28189. Epub 2020 Apr 14.

Department of Neurosurgery, LeBonheur Children's Hospital, Memphis, Tennessee.

Background: Despite improved survival, many pediatric brain tumor survivors receiving radiation therapy (RT) experience late effects.

Procedure: To study calvarial lesions in this population, we retrospectively reviewed records of patients undergoing neurosurgical evaluation for calvarial bone lesions detected in posttreatment follow-up imaging at St. Jude Children's Research Hospital. Primary tumor diagnosis, treatment, imaging, surgical intervention, and histopathology from patients with radiographic evidence of lesions followed for ≥2 years post-RT were studied.

Results: For 17 patients with 18 index lesions, median time to lesion manifestation was 2.34 years. Medulloblastoma patients developed lesions at a shorter interval from RT than ependymoma patients (P = .05). Twelve of 14 lesions requiring surgery were benign fibro-osseous or sclerotic. Two malignant lesions distinct from the primary tumor had genetic predisposition to malignancy.

Conclusion: Most calvarial lesions arising post-RT are benign and fibro-osseous. Serial imaging is recommended, and high index of suspicion for malignant lesions is warranted for patients genetically predisposed to cancer.
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http://dx.doi.org/10.1002/pbc.28189DOI Listing
June 2020

A versatile dual-use RT-PCR control for use in assays for the detection of peste des petits ruminants virus.

J Virol Methods 2020 03 16;277:113799. Epub 2019 Dec 16.

U.S. Department of Agriculture, Animal and Plant Health Inspection Service, National Veterinary Services Laboratories, Foreign Animal Disease Diagnostic Laboratory, Plum Island Animal Disease Center, Greenport, NY, 11944, USA. Electronic address:

Peste des petits ruminants (PPR) is an acute and highly contagious disease with high mortality in small ruminants and significant socioeconomic impact in developing countries. The causative agent is peste des petits ruminants virus (PPRV). The Food and Agriculture Organization of the United Nations (FAO) and the World Organization for Animal Health (OIE) have set up a goal for the global eradication of PPR by 2030. To assist in this effort, an easily produced, specific, non-pathogenic bacteriophage Qβ based real-time RT-PCR (qRT-PCR) PPRV positive control was developed. This control is compatible for use with two previously described PPRV qRT-PCR assays either as singleplex or multiplex platform. Additionally, the control can also be used for assembling proficiency testing panels for competency testing in diagnostic laboratories. Use of the Qβ phage based PPRV control as a positive control or in proficiency testing panels reduces the risk of inadvertent release of pathogenic PPRV from diagnostic laboratories, which would be especially important should PPR be eradicated in the future.
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http://dx.doi.org/10.1016/j.jviromet.2019.113799DOI Listing
March 2020

Defining Optimal Target Volumes of Conformal Radiation Therapy for Diffuse Intrinsic Pontine Glioma.

Int J Radiat Oncol Biol Phys 2020 03 27;106(4):838-847. Epub 2019 Nov 27.

Department of Radiation Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee.

Purpose: Optimal radiation therapy (RT) target margins for diffuse intrinsic pontine glioma (DIPG) are unknown. We sought to define disease progression patterns in a contemporary cohort treated with conformal RT using different clinical target volume (CTV) margins.

Methods And Materials: We reviewed 105 patients with newly diagnosed DIPG treated with conformal conventionally fractionated RT at our institution from 2006 to 2014. CTV margins were classified as standard (1 cm) for 60 patients and extended (2-3 cm) for 45 patients. Survival and cumulative incidence of progression in treatment groups were compared by log-rank and Gray's tests, respectively. Cox proportional hazard models identified predictors of survival.

Results: For 97 patients evaluated with magnetic resonance imaging at progression, the cumulative incidences of isolated local, isolated distant, and synchronous disease progression at 1 year were 62.6%, 12.3%, and 7.2%, respectively, and did not differ significantly according to the CTV margin. Central dosimetric progression (V95% ≥95%) was observed in 80 of 81 evaluable patients. Median progression-free survival and overall survival (OS) were 7.6 months (95% confidence interval, 6.9-8.2) and 11.3 months (95% confidence interval, 10.0-12.8), respectively, and did not differ significantly according to margin status. DIPG survival prediction risk group (standard vs high, P = .02; intermediate vs high, P = .009) and development of distant metastasis (P = .003) were independent predictors of OS. For the 41 patients (39%) with a pathologic diagnosis, H3.3 K27M mutation was associated with shorter OS (hazard ratio [HR], 0.41; P =.02), whereas H3.1 K27M and ACVR1 mutations were associated with longer OS (HR, 3.56; P =.004 and HR, 2.58; P =.04, respectively).

Conclusions: All patients who experienced local failure showed progression within the high-dose volume, and there was no apparent survival or tumor-control benefit to extending the CTV margins beyond 1 cm. Given the increasing use of reirradiation, standardizing the CTV margin to 1 cm may improve retreatment tolerance.
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http://dx.doi.org/10.1016/j.ijrobp.2019.11.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7042090PMC
March 2020

Propofol Total Intravenous Anesthesia as an Intervention for Severe Radiation-Induced Phantosmia in an Adolescent with Ependymoma.

J Adolesc Young Adult Oncol 2020 04 23;9(2):299-302. Epub 2019 Oct 23.

Department of Anesthesiology, St. Jude Children's Research Hospital, Memphis, Tennessee.

Radiation-induced phantosmia has been reported both in children and adults. A fraction of these patients have nausea and vomiting triggered by phantosmia. Radiation-induced phantosmia, although transient, can be distressing enough to prevent a patient from staying still during radiation therapy. To date, specific interventions for radiation-induced phantosmia, including anesthesia, have not been reported. We report for the first time anesthesia as an intervention for transient severe radiation-induced phantosmia, in a 16-year-old girl with ependymoma undergoing proton therapy, and we discuss the pros and cons of techniques for anesthesia and airway management.
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http://dx.doi.org/10.1089/jayao.2019.0103DOI Listing
April 2020

Decreasing Accuracy of the eFAST Examination-Another Challenge Due to Morbid Obesity.

Am Surg 2019 Aug;85(8):923-926

The extended focused assessment with sonography for trauma (eFAST) ultrasound examination is an essential step in the initial assessment of trauma patients. Its accuracy depends on the ability to acquire high-quality ultrasound images, and we hypothesized that increasing BMI was associated with increased odds for incorrect eFAST. All adult blunt trauma activations at a high-volume urban trauma center in 2016 that underwent eFAST and CT chest, abdomen, and pelvis were included (n = 446). Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of the eFAST were calculated with CT results as reference. The association of BMI and eFAST accuracy was determined using univariate analyses. Sensitivity and specificity of the eFAST examination were 27.1 per cent and 91.7 per cent, respectively, with an overall 76.2 per cent accuracy. At BMI 36 kg/m², the odds of having incorrect eFAST results increased to odds ratio (OR) = 1.85 (95% confidence interval, 1.03-3.32; = 0.05). For those with BMI > 40 kg/m², the OR increased to OR = 3.12 (95% confidence interval, 1.45-6.69; = 0.01). One-third of patients in this study were obese or morbidly obese. The latter was associated with increased odds for incorrect eFAST results, particularly the abdominal examination component.
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August 2019

Optimal dosing of cyclophosphamide in rhabdomyosarcoma: It's complicated.

Cancer 2019 09 7;125(18):3107-3110. Epub 2019 Jun 7.

Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee.

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http://dx.doi.org/10.1002/cncr.32205DOI Listing
September 2019

Gamma Knife Radiosurgery for Multiple Sclerosis-Associated Trigeminal Neuralgia.

Neurosurgery 2019 11;85(5):E933-E939

Department of Radiation Oncology, Wake Forest Baptist Medical Center, Winston-Salem, North Carolina.

Background: Trigeminal neuralgia in the setting of multiple sclerosis (MS-TN) is a challenging condition to manage that is commonly treated with Gamma Knife radiosurgery (GKRS; Elekta AB). However, data regarding the efficacy of this treatment are somewhat limited, particularly for repeat GKRS.

Objective: To report outcomes of GKRS for MS-TN from a cohort study.

Methods: Retrospective review of our GKRS database identified 77 cases of unilateral MS-TN (UMSTN) in 74 patients treated with GKRS between 2001 and 2016, with 37 cases undergoing repeat GKRS. Background medical history, treatment outcomes and complications, and dosimetric data were obtained by retrospective chart reviews and telephone interviews.

Results: Eighty-two percent of UMSTN cases achieved Barrow Neurological Institute (BNI) IIIb or better pain relief following initial GKRS for a median duration of 1.1 yr. Estimated rates of pain relief at 1, 3, and 5 yr were 51, 39, and 29% respectively. Eighty-eight percent achieved BNI IIIb or better pain relief after repeat GKRS for a median duration of 4.0 yr. Estimated rates of pain relief at 1 and 3 yr were 70 and 54%, respectively. Median doses for initial and repeat GKRS were 85 and 80 Gy to the 100% isodose line, respectively. Those with MS-TN had a shorter duration of BNI IIIb or better pain relief after initial (4.6 vs 1.1 yr), but not repeat GKRS (3.8 vs 4.0 yr) compared to a historical cohort from our institution.

Conclusion: GKRS is an effective, well-tolerated treatment for patients with MS-TN. More durable relief is often achieved with repeat GKRS.
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http://dx.doi.org/10.1093/neuros/nyz182DOI Listing
November 2019

Creating arteriovenous fistulas for children in Guatemala.

J Vasc Surg 2019 11 21;70(5):1635-1641. Epub 2019 May 21.

Private Practice, Beverly Hills, Calif.

Objective: The Guatemalan Foundation for Children with Kidney Diseases was established in 2003 as the first and only comprehensive pediatric nephrology program and hemodialysis unit in Guatemala. Bridge of Life (BOL) is a not-for-profit charitable organization focused on chronic kidney disease and supplied equipment, training and support during formation of the hemodialysis unit. Pediatric permanent vascular access (VA) expertise had not been established and noncuffed dialysis catheters provided almost all VA, many through subclavian vein access sites. BOL assistance was requested for establishing a VA surgical program, resulting in recurring BOL surgical missions to create arteriovenous fistulas (AVF) in these children. This study analyzes the BOL pediatric VA missions to Guatemala.

Methods: Three surgical pediatric VA missions were conducted in Guatemala from 2015 to 2017. Each mission was led by two or three surgeons. All supplies and equipment (including ultrasound units) were taken as part of each mission. The BOL surgical VA mission teams work with local pediatric surgeons, pediatric nephrologists, and dialysis nurses to establish collegial relationships and foster teaching interactions. We retrospectively reviewed the patient demographic data, procedures, and outcomes for these missions.

Results: AVFs were created in 54 new pediatric patients. Ages were 8 to 19 years (13.4 ± 2.8 years) and 29 patients (54%) were male. Patient weights were 28 to 50 kg (30.8 ± 8.3 kg) with body mass indexes of 12 to 25 kg/m (17.9 ± 2.9 kg/m). Radiocephalic AVFs were created in 21 children (39%), proximal radial artery AVFs in 12 (22%). and brachial artery inflow AVFs in 5 (9%). Sixteen patients (30%) required transpositions and one a translocation; two of these were femoral procedures. Primary and cumulative patency rates were 83% and 85% at 12 months and 62% and 85% at 36 months, respectively. The median follow-up was 17 months. Interventions with fistulagram and balloon angioplasty options were not available for AVF dysfunction or access salvage during the study period. However, six patients underwent an AVF revision and salvage during subsequent missions or by one of the Guatemalan surgeons (R.S.). Four individuals underwent successful transplantation during the study period. There were no operative deaths or major complications.

Conclusions: Pediatric VA missions to Guatemala created safe and functional AVFs in concert with local pediatric surgeons and pediatric nephrologists. Three surgical missions included access operations in 54 new patients. Cumulative AVF patency was 85% at 36 months.
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http://dx.doi.org/10.1016/j.jvs.2019.02.022DOI Listing
November 2019

Low-Cost Carbon Fibre Derived from Sustainable Coal Tar Pitch and Polyacrylonitrile: Fabrication and Characterisation.

Materials (Basel) 2019 Apr 18;12(8). Epub 2019 Apr 18.

Department of Chemical Engineering, The University of Newcastle, Callaghan, NSW 2308, Australia.

Preparation of high-value pitch-based carbon fibres (CFs) from mesophase pitch precursor is of great importance towards low-cost CFs. Herein, we developed a method to reduce the cost of CFs precursor through incorporating high loading of coal tar pitch (CTP) into polyacrylonitrile (PAN) polymer solution. The CTP with a loading of 25% and 50% was blended with PAN and their spinnability was examined by electrospinning process. The effect of CTP on thermal stabilization and carbonisation of PAN fibres was investigated by thermal analyses methods. Moreover, electrospun PAN/CTP fibres were carbonised at two different temperatures i.e., 850 °C and 1200 °C and their crystallographic structures of resulting such low-cost PAN/CTP CFs were studied through X-ray diffraction (XRD) and Raman analyses. Compared to pure PAN CFs, the electrical resistivity of PAN/25% CTP CFs significantly decreased by 92%, reaching 1.6 kΩ/sq. The overall results showed that PAN precursor containing 25% CTP resulted in balanced properties in terms of spinnability, thermal and structural properties. It is believed that CTP has a great potential to be used as an additive for PAN precursor and will pave the way for cost-reduced and high-performance CFs.
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http://dx.doi.org/10.3390/ma12081281DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6515280PMC
April 2019

Association between hippocampal dose and memory in survivors of childhood or adolescent low-grade glioma: a 10-year neurocognitive longitudinal study.

Neuro Oncol 2019 09;21(9):1175-1183

Department of Radiation Oncology, St Jude Children's Research Hospital, Memphis, Tennessee.

Background: Hippocampal avoidance has been suggested as a strategy to reduce short-term memory decline in adults receiving whole-brain radiation therapy (RT). The purpose of this study was to determine whether the hippocampal dose in children and adolescents undergoing RT for low-grade glioma was associated with memory, as measured by verbal recall.

Methods: Eighty patients aged at least 6 years but less than 21 years with low-grade glioma were treated with RT to 54 Gy on a phase II protocol. Patients underwent age-appropriate cognitive testing at baseline, 6 months posttreatment, yearly through 5 years posttreatment, year 7 or 8, and year 10 posttreatment. Random coefficient models were used to estimate the longitudinal trends in cognitive assessment scores.

Results: Median neurocognitive follow-up was 9.8 years. There was a significant decline in short-delay recall (slope = -0.01 standard deviation [SD]/year, P < 0.001), total recall (slope = -0.09 SD/y, P = 0.005), and long-delay recall (slope = -0.01 SD/y, P  = 0.002). On multivariate regression, after accounting for hydrocephalus, decline in short-delay recall was associated with the volume of right (slope = -0.001 SD/y, P = 0.019) or left hippocampus (slope = -0.001 SD/y, P = 0.025) receiving 40 Gy (V40 Gy). On univariate regression, decline in total recall was only associated with right hippocampal dosimetry (V40 Gy slope = -0.002, P = 0.025). In children <12 years, on univariate regression, decline in long-delay recall was only associated with right (V40 Gy slope = -0.002, P = 0.013) and left (V40 Gy slope = -0.002, P = 0.014) hippocampal dosimetry.

Conclusion: In this 10-year longitudinal study, greater hippocampal dose was associated with a greater decline in delayed recall. Such findings might be informative for radiation therapy planning, warranting prospective evaluation.
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http://dx.doi.org/10.1093/neuonc/noz068DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7594551PMC
September 2019

Desmoplastic Small Round Cell Tumor: Long-Term Complications After Cytoreduction and Hyperthermic Intraperitoneal Chemotherapy.

Ann Surg Oncol 2020 Jan 8;27(1):171-178. Epub 2019 Apr 8.

Division of Surgical Oncology, Department of Surgery, University of Tennessee Health Science Center, Memphis, TN, 38163, USA.

Background: Desmoplastic small round cell tumor (DSRCT) is a rare intra-abdominal soft tissue sarcoma affecting adolescents and young adults. Cytoreduction, hyperthermic intraperitoneal chemotherapy (CRS/HIPEC), and adjuvant radiotherapy may improve local control. We review our experience with patients who undergo CRS/HIPEC and adjuvant radiotherapy for DSRCT.

Methods: A retrospective review was performed for patients with DSRCT from 2013 to 2017 who underwent CRS/HIPEC. Clinicopathologic, operative, and outcome data were reviewed.

Results: Ten CRS/HIPEC procedures were performed for nine patients (7 males, 6 Caucasian, median age 19 years (range 10-24)). Four patients presented with extra-abdominal disease; five had liver involvement. The median peritoneal cancer index was 16 (range 5-20). All received neoadjuvant chemotherapy. CCR 0/1 resection was possible in nine patients. Major complications occurred in four with no operative mortalities. All received adjuvant chemotherapy, seven received radiation therapy, and three received stem-cell transplant. All but one patient recurred after treatment. The median recurrence-free and overall survival (OS) were 12 and 45 months (95% confidence interval 35.1-54.9) respectively, with a 3-year OS of 55%. Long-term parenteral nutrition was required in eight for a median of 261 days (range 37-997). Clinically significant long-term complications requiring further surgery included gastroparesis (N = 1), small bowel obstruction (N = 3) and hemorrhagic cystitis (N = 2).

Conclusions: Multimodal therapy for DSRCT consisting of multiagent neoadjuvant chemotherapy, CRS/HIPEC, adjuvant chemotherapy, and radiation therapy is associated with potential cumulative toxicity. Recurrence after resection is common. Prolonged parenteral nutrition may be necessary, and late gastrointestinal and genitourinary complications may require additional treatment.
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http://dx.doi.org/10.1245/s10434-019-07339-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7424843PMC
January 2020

Automatic image processing pipeline for tracking longitudinal vessel changes in magnetic resonance angiography.

J Magn Reson Imaging 2019 10 7;50(4):1063-1074. Epub 2019 Mar 7.

Department of Radiation Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA (Work Origin).

Background: Cerebral vessel diameter changes objectively and automatically derived from longitudinal magnetic resonance angiography (MRA) facilitate quantification of vessel changes and further modeling.

Purpose: To characterize longitudinal changes in intracranial vessel diameter using time-of-flight (TOF) MRA.

Study Type: Retrospective longitudinal study.

Subject Population: IN all, 112 pediatric patients, aged 9.96 ± 4.59 years, with craniopharyngioma from 2006-2011 scanned annually.

Field Strength/sequence: 1.5T and 3T TOF MRA.

Statistical Tests: Chi-square and Wilcoxon-Mann-Whitney tests.

Assessment: Manual measurements using interventional angiography was established as a reference standard for diameter measurements. Constant and linear quantile regression with absolute difference, percentage difference, and relative difference was used for outlier detection.

Results: Major vessels surrounding the circle of Willis were successfully segmented except for posterior communicating arteries, mostly due to disease-related hypoplasia. Diameter measurements were calculated at 1-mm segments with a median computed vessel diameter of 1.25 mm. Diameter distortion due to registration was within 0.04 mm for 99% of vessel segments. Outlier detection using quantile regression detected less than 4.34% as being outliers. Outliers were more frequent in smaller vessels and proximity to bifurcations (P < 0.001).

Data Conclusion: Using the proposed method, objective changes in vessel diameter can be acquired noninvasively from routine longitudinal imaging. High-throughput analyses of imaging-derived vascular trees combined with clinical and treatment parameters will allow rigorous modeling of vessel diameter changes.

Level Of Evidence: 2 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2019;50:1063-1074.
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http://dx.doi.org/10.1002/jmri.26699DOI Listing
October 2019

Ethnoracial differences in Alzheimer's disease from the FLorida Autopsied Multi-Ethnic (FLAME) cohort.

Alzheimers Dement 2019 05 18;15(5):635-643. Epub 2019 Feb 18.

Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA. Electronic address:

Introduction: Our primary goal was to examine demographic and clinicopathologic differences across an ethnoracially diverse autopsy-confirmed cohort of Alzheimer's disease cases.

Methods: A retrospective study was conducted in the Florida Autopsied Multi-Ethnic cohort on 1625 Alzheimer's disease cases, including decedents who self-reported as Hispanic/Latino (n = 67), black/African American (n = 19), and white/European American (n = 1539).

Results: Hispanic decedents had a higher frequency of family history of cognitive impairment (58%), an earlier age at onset (median age of 70 years), longer disease duration (median of 12 years), and lower MMSE proximal to death (median of 4 points) compared with the other ethnoracial groups. Black decedents had a lower Braak tangle stage (stage V) and higher frequency of coexisting hippocampal sclerosis (21%); however, only hippocampal sclerosis differences survived adjustment for sex, age at onset, and disease duration. Neither Thal amyloid phase nor coexisting Lewy body disease differed across ethnoracial groups.

Discussion: Despite a smaller sample size, Hispanics demonstrated longer disease duration with Alzheimer's disease, but not greater lifespan. Neuropathologic differences across ethnoracial groups supported differences in tau pathology distribution and coexisting hippocampal sclerosis, which may impact biomarker studies.
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http://dx.doi.org/10.1016/j.jalz.2018.12.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6511501PMC
May 2019

Implications of Image-Defined Risk Factors and Primary-Site Response on Local Control and Radiation Treatment Delivery in the Management of High-Risk Neuroblastoma: Is There a Role for De-escalation of Adjuvant Primary-Site Radiation Therapy?

Int J Radiat Oncol Biol Phys 2019 03 26;103(4):869-877. Epub 2018 Nov 26.

Department of Surgery, St. Jude Children's Research Hospital, Memphis, Tennessee.

Purpose: The predictive value of Image-Defined Risk Factors (IDRFs) developed by the International Neuroblastoma Risk Group Task Force as it relates to primary-site management is undefined and may aid patient selection for de-escalation of adjuvant radiation therapy to the primary site in high-risk neuroblastoma.

Methods And Materials: Patients (N = 76) with high-risk neuroblastoma treated on prospective trials at our institution from 1997 to 2014 were eligible for inclusion. IDRFs were defined based on pretherapy imaging. Overall survival, progression-free survival, and locoregional failure-free survival (LRFFS) were described using the Kaplan-Meier estimator and tested across strata by using the log-rank test.

Results: Twenty of 76 patients (26%) experienced local (n = 6), regional (n = 6), or combined locoregional failure (n = 8) with or without distant failure. Ten (50%) of the locoregional failures had concurrent distant relapse. Of patients who completed all therapy, both those with no IDRFs and those with >90% resection had a 3-year LRFFS of 100%, with or without radiation therapy. Patients with either ≥1 IDRF or 
Conclusions: Patients with >90% tumor resection and no primary site IDRFs at diagnosis may be candidates for de-escalation of adjuvant primary-site radiation therapy, although validation of these findings in future studies is required.
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http://dx.doi.org/10.1016/j.ijrobp.2018.11.041DOI Listing
March 2019