Publications by authors named "Ashok Srinivasan"

166 Publications

Adapting Scientific Conferences to the Realities Imposed by COVID-19.

Radiol Imaging Cancer 2020 07 12;2(4):e204020. Epub 2020 Jun 12.

Department of Radiology, University of Michigan, Ann Arbor, Mich (V.K., A.S., G.D.L.) and Department of Radiology and Medical Imaging, University of Virginia, Charlottesville, Va (L.W.).

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http://dx.doi.org/10.1148/rycan.2020204020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7294822PMC
July 2020

Outcomes of pediatric patients who relapse after first HCT for acute leukemia or MDS.

Bone Marrow Transplant 2021 Mar 19. Epub 2021 Mar 19.

Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, Memphis, TN, USA.

Disease relapse remains a major cause of treatment failure in patients receiving allogeneic hematopoietic cell transplantation (alloHCT) for high-risk acute leukemias or myelodysplastic syndromes (MDS). Comprehensive data on outcomes after post-transplant relapse are lacking, especially in pediatric patients. Our objective was to assess the impact of various transplant-, patient-, and disease-related variables on survival and outcomes in patients who relapse after alloHCT. We describe our institutional experience with 221 pediatric patients who experienced disease relapse after their first alloHCT for acute leukemias or MDS between 1990 and 2018. In a multivariable model, being in first complete remission at first alloHCT, longer duration of remission after alloHCT, experiencing GVHD and receiving a transplant in a more recent time period were significantly associated with a higher likelihood of receiving a second alloHCT after post-transplant relapse. Of these variables, only longer interval from alloHCT to relapse, receiving a second alloHCT or DLI, and receiving a transplant in a more recent time period were associated with improved overall survival. Our data support pursuing second alloHCT for patients who have experienced relapse after their first transplant, as that remains the only salvage modality with a reasonable chance of inducing long-term remission.
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http://dx.doi.org/10.1038/s41409-021-01267-0DOI Listing
March 2021

Relevance of Molecular Groups in Children with Newly Diagnosed Atypical Teratoid Rhabdoid Tumor: Results from Prospective St. Jude Multi-institutional Trials.

Clin Cancer Res 2021 Mar 18. Epub 2021 Mar 18.

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

Purpose: Report relevance of molecular groups to clinicopathologic features, germline alterations (GLA), and survival of children with atypical teratoid rhabdoid tumor (ATRT) treated in two multi-institutional clinical trials.

Materials And Methods: Seventy-four participants with newly diagnosed ATRT were treated in two trials: infants (SJYC07: age < 3 years; = 52) and children (SJMB03: age 3-21 years; = 22), using surgery, conventional chemotherapy (infants), or dose-dense chemotherapy with autologous stem cell rescue (children), and age- and risk-adapted radiotherapy [focal (infants) and craniospinal (CSI; children)]. Molecular groups ATRT-MYC (MYC), ATRT-SHH (SHH), and ATRT-TYR (TYR) were determined from tumor DNA methylation profiles.

Results: Twenty-four participants (32%) were alive at time of analysis at a median follow-up of 8.4 years (range, 3.1-14.1 years). Methylation profiling classified 64 ATRTs as TYR ( = 21), SHH ( = 30), and MYC ( = 13), SHH group being associated with metastatic disease. Among infants, TYR group had the best overall survival (OS; = 0.02). However, outcomes did not differ by molecular groups among infants with nonmetastatic (M0) disease. Children with M0 disease and <1.5 cm residual tumor had a 5-year progression-free survival (PFS) of 72.7 ± 12.7% and OS of 81.8 ± 11%. Infants with M0 disease had a 5-year PFS of 39.1 ± 11.5% and OS of 51.8 ± 12%. Those with metastases fared poorly [5-year OS 25 ± 12.5% (children) and 0% (infants)]. GLAs were not associated with PFS.

Conclusions: Among infants, those with ATRT-TYR had the best OS. ATRT-SHH was associated with metastases and consequently with inferior outcomes. Children with nonmetastatic ATRT benefit from postoperative CSI and adjuvant chemotherapy.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-4731DOI Listing
March 2021

Prediction of Disease Free Survival in Laryngeal and Hypopharyngeal Cancers Using CT Perfusion and Radiomic Features: A Pilot Study.

Tomography 2021 Mar 5;7(1):10-19. Epub 2021 Feb 5.

Department of Radiology, Michigan Medicine, University of Michigan, Ann Arbor, MI 48109, USA; (S.W.); (A.V.); (L.H.); (K.C.); (H.-P.C.).

(1) Purpose: The objective was to evaluate CT perfusion and radiomic features for prediction of one year disease free survival in laryngeal and hypopharyngeal cancer. (2) Method and Materials: This retrospective study included pre and post therapy CT neck studies in 36 patients with laryngeal/hypopharyngeal cancer. Tumor contouring was performed semi-autonomously by the computer and manually by two radiologists. Twenty-six radiomic features including morphological and gray-level features were extracted by an internally developed and validated computer-aided image analysis system. The five perfusion features analyzed included permeability surface area product (PS), blood flow (flow), blood volume (BV), mean transit time (MTT), and time-to-maximum (Tmax). One year persistent/recurrent disease data were obtained following the final treatment of definitive chemoradiation or after total laryngectomy. We performed a two-loop leave-one-out feature selection and linear discriminant analysis classifier with generation of receiver operating characteristic (ROC) curves and confidence intervals (CI). (3) Results: 10 patients (28%) had recurrence/persistent disease at 1 year. For prediction, the change in blood flow demonstrated a training AUC of 0.68 (CI 0.47-0.85) and testing AUC of 0.66 (CI 0.47-0.85). The best features selected were a combination of perfusion and radiomic features including training AUC of 0.68 (CI 0.5-0.85) and testing AUC of 0.69 (CI 0.5-0.85). The laryngoscopic percent change in volume was a poor predictor with a testing AUC of 0.4 (CI 0.16-0.57). (4) Conclusions: A combination of CT perfusion and radiomic features are potential predictors of one-year disease free survival in laryngeal and hypopharyngeal cancer patients.
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http://dx.doi.org/10.3390/tomography7010002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7934704PMC
March 2021

Outcomes by Clinical and Molecular Features in Children With Medulloblastoma Treated With Risk-Adapted Therapy: Results of an International Phase III Trial (SJMB03).

J Clin Oncol 2021 Mar 6;39(7):822-835. Epub 2021 Jan 6.

Division of Brain Tumor Research, Department of Developmental Neurobiology, St Jude Children's Research Hospital, Memphis, TN.

Purpose: SJMB03 (ClinicalTrials.gov identifier: NCT00085202) was a phase III risk-adapted trial that aimed to determine the frequency and clinical significance of biological variants and genetic alterations in medulloblastoma.

Patients And Methods: Patients 3-21 years old were stratified into average-risk and high-risk treatment groups based on metastatic status and extent of resection. Medulloblastomas were molecularly classified into subgroups (Wingless [WNT], Sonic Hedgehog [SHH], group 3, and group 4) and subtypes based on DNA methylation profiles and overlaid with gene mutations from next-generation sequencing. Coprimary study end points were (1) to assess the relationship between ERBB2 protein expression in tumors and progression-free survival (PFS), and (2) to estimate the frequency of mutations associated with WNT and SHH tumors. Clinical and molecular risk factors were evaluated, and the most robust were used to model new risk-classification categories.

Results: Three hundred thirty eligible patients with medulloblastoma were enrolled. Five-year PFS was 83.2% (95% CI, 78.4 to 88.2) for average-risk patients (n = 227) and 58.7% (95% CI, 49.8 to 69.1) for high-risk patients (n = 103). No association was found between ERBB2 status and PFS in the overall cohort ( = .74) or when patients were stratified by clinical risk ( = .71). Mutations in (96%), (37%), and (24%) were most common in WNT tumors and (38%), (21%), and (19%) in SHH tumors. Methylome profiling classified 53 WNT (17.4%), 48 SHH (15.7%), 65 group 3 (21.3%), and 139 group 4 (45.6%) tumors. A comprehensive clinicomolecular risk factor analysis identified three low-risk groups (WNT, low-risk SHH, and low-risk combined groups 3 and 4) with excellent (5-year PFS > 90%) and two very high-risk groups (high-risk SHH and high-risk combined groups 3 and 4) with poor survival (5-year PFS < 60%).

Conclusion: These results establish a new risk stratification for future medulloblastoma trials.
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http://dx.doi.org/10.1200/JCO.20.01372DOI Listing
March 2021

Discriminating pseudoprogression and true progression in diffuse infiltrating glioma using multi-parametric MRI data through deep learning.

Sci Rep 2020 11 23;10(1):20331. Epub 2020 Nov 23.

Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA.

Differentiating pseudoprogression from true tumor progression has become a significant challenge in follow-up of diffuse infiltrating gliomas, particularly high grade, which leads to a potential treatment delay for patients with early glioma recurrence. In this study, we proposed to use a multiparametric MRI data as a sequence input for the convolutional neural network with the recurrent neural network based deep learning structure to discriminate between pseudoprogression and true tumor progression. In this study, 43 biopsy-proven patient data identified as diffuse infiltrating glioma patients whose disease progressed/recurred were used. The dataset consists of five original MRI sequences; pre-contrast T1-weighted, post-contrast T1-weighted, T2-weighted, FLAIR, and ADC images as well as two engineered sequences; T1post-T1pre and T2-FLAIR. Next, we used three CNN-LSTM models with a different set of sequences as input sequences to pass through CNN-LSTM layers. We performed threefold cross-validation in the training dataset and generated the boxplot, accuracy, and ROC curve, AUC from each trained model with the test dataset to evaluate models. The mean accuracy for VGG16 models ranged from 0.44 to 0.60 and the mean AUC ranged from 0.47 to 0.59. For CNN-LSTM model, the mean accuracy ranged from 0.62 to 0.75 and the mean AUC ranged from 0.64 to 0.81. The performance of the proposed CNN-LSTM with multiparametric sequence data was found to outperform the popular convolutional CNN with a single MRI sequence. In conclusion, incorporating all available MRI sequences into a sequence input for a CNN-LSTM model improved diagnostic performance for discriminating between pseudoprogression and true tumor progression.
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http://dx.doi.org/10.1038/s41598-020-77389-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7683728PMC
November 2020

Administration of valproic acid in clinically approved dose improves neurologic recovery and decreases brain lesion size in swine subjected to hemorrhagic shock and traumatic brain injury.

J Trauma Acute Care Surg 2021 02;90(2):346-352

From the Department of Surgery (G.K.W., B.E.B., M.T.K., R.L.O., A.M.W., K.C., A.Z.S., U.F.B., C.A.V., H.B.A.), Department of Clinical Pharmacy (M.P.P.), and Section of Neuroradiology, Department of Radiology (A.S.), Michigan Medicine, University of Michigan, Ann Arbor, Michigan.

Background: Traumatic brain injury (TBI) and hemorrhage remain the leading causes of death after trauma. We have previously shown that a dose of valproic acid (VPA) at (150 mg/kg) can decrease brain lesion size and hasten neurologic recovery. The current Food and Drug Administration-approved dose of VPA is 60 mg/kg. We evaluate neurologic outcomes and brain lesion size of a single dose of VPA at a level currently within Food and Drug Administration-approved dose in swine subjected to TBI and hemorrhagic shock.

Methods: Swine (n = 5/group) were subjected to TBI and 40% blood volume hemorrhage. Animals remained in shock for 2 hours before randomization to normal saline (NS) resuscitation alone (control), NS-VPA 150 mg/kg (VPA 150), or NS-VPA 50 mg/kg (VPA 50). Neurologic severity scores (range, 0-32) were assessed daily for 14 days, and brain lesion size was measured via magnetic resonance imaging on postinjury day (PID) 3.

Results: Shock severity and laboratory values were similar in all groups. Valproic acid-treated animals demonstrated significantly less neurologic impairment on PID 1 and returned to baseline faster (PID 1 mean neurologic severity score, control = 22 ± 3 vs. VPA 150 mg/kg = 8 ± 7 or VPA 50 mg/kg = 6 ± 6; p = 0.02 and 0.003). Valproic acid-treated animals had significantly smaller brain lesion sizes (mean volume in mm3, control = 1,268.0 ± 241.2 vs. VPA 150 mg/kg = 620.4 ± 328.0 or VPA 50 mg/kg = 438.6 ± 234.8; p = 0.007 and 0.001).

Conclusion: In swine subjected to TBI and hemorrhagic shock, VPA treatment, in a dose that is approved for clinical use, decreases brain lesion size and reduces neurologic impairment compared with resuscitation alone.
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http://dx.doi.org/10.1097/TA.0000000000003036DOI Listing
February 2021

Texture analysis of T2-weighted MRI predicts SDH mutation in paraganglioma.

Neuroradiology 2021 Apr 19;63(4):547-554. Epub 2020 Nov 19.

Division of Neuroradiology, Department of Radiology, University of Michigan, 1500 E. Medical Center Dr., UH B2A209K, Ann Arbor, MI, 48109, USA.

Purpose: Texture analysis can quantify sophisticated imaging characteristics. We hypothesized that 2D textures computed with T2-weighted and post-contrast T1-weighted MRI can predict succinate dehydrogenase (SDH) mutation status in head and neck paragangliomas.

Methods: Our retrospective study included 21 patients (1 to 4 tumors/patient) with 24 pathologically proven paragangliomas in the head and neck. Fourteen lesions (58%) were SDH mutation-positive. All patients underwent T2-weighted and post-contrast T1-weighted MRI sequences. Three 2D texture features of dependence non-uniformity normalized (DNN), small dependence high gray level emphasis (SDHGLE), and small dependence low gray level emphasis (SDLGLE) were calculated. Computed textures between SDH mutants and non-mutants were compared using Mann-Whitney U test. Area under the receiver operating characteristic (AUROC) curve was used to quantify the predictive power of each texture.

Results: Only T2-based SDLGLE was statistically significant (p = 0.048), and AUROC was 0.71. Diagnostic accuracy was 70.8%.

Conclusion: 2D texture parameter of T2-based SDLGLE predicts SDH mutation in head and neck paragangliomas. This noninvasive technique can potentially facilitate further genetic workup.
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http://dx.doi.org/10.1007/s00234-020-02607-5DOI Listing
April 2021

Neratinib-Plus-Cetuximab in Quadruple-WT () Metastatic Colorectal Cancer Resistant to Cetuximab or Panitumumab: NSABP FC-7, A Phase Ib Study.

Clin Cancer Res 2021 Mar 17;27(6):1612-1622. Epub 2020 Nov 17.

NSABP Foundation, Inc., Pittsburgh, Pennsylvania.

Purpose: In metastatic colorectal cancer (mCRC), () gene amplification is implicated in anti-EGFR therapy resistance. We sought to determine the recommended phase II dose (RP2D) and efficacy of neratinib, a pan-ERBB kinase inhibitor, combined with cetuximab, in patients with progressive disease (PD) on anti-EGFR treatment.

Patients And Methods: Twenty-one patients with quadruple-wild-type, refractory mCRC enrolled in this 3+3 phase Ib study. Standard dosage cetuximab was administered with neratinib at 120 mg, 160 mg, 200 mg, and 240 mg/day orally in 28-day cycles. Samples were collected for molecular and pharmacokinetic studies.

Results: Sixteen patients were evaluable for dose-limiting toxicity (DLT). 240 mg was determined to be the RP2D wherein a single DLT occurred (1/7 patients). Treatment-related DLTs were not seen at lower doses. Best response was stable disease (SD) in 7 of 16 (44%) patients. amplification (chromogenic IHC) was detected in 2 of 21 (9.5%) treatment-naïve tumors and 4 of 16 (25%) biopsies upon trial enrollment (post-anti-EGFR treatment and progression). Compared with matched enrollment biopsies, 6 of 8 (75%) blood samples showed concordance for CNV in circulating cell-free DNA. Five SD patients had amplification in either treatment-naïve or enrollment biopsies. Examination of gene-expression, total protein, and protein phosphorylation levels showed relative upregulation of ≥2 members of the HER-family receptors or ligands upon enrollment versus matched treatment-naïve samples.

Conclusions: The RP2D of neratinib in this combination was 240 mg/day, which was well tolerated with low incidence of G3 AEs. There were no objective responses; SD was seen at all neratinib doses. amplification, detectable in both tissue and blood, was more frequent post-anti-EGFR therapy.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-1831DOI Listing
March 2021

Pulmonary Complications of Pediatric Hematopoietic Cell Transplantation. A National Institutes of Health Workshop Summary.

Ann Am Thorac Soc 2021 03;18(3):381-394

National Heart, Lung, Blood Institute, Bethesda, Maryland; and.

Approximately 2,500 pediatric hematopoietic cell transplants (HCTs), most of which are allogeneic, are performed annually in the United States for life-threatening malignant and nonmalignant conditions. Although HCT is undertaken with curative intent, post-HCT complications limit successful outcomes, with pulmonary dysfunction representing the leading cause of nonrelapse mortality. To better understand, predict, prevent, and/or treat pulmonary complications after HCT, a multidisciplinary group of 33 experts met in a 2-day National Institutes of Health Workshop to identify knowledge gaps and research strategies most likely to improve outcomes. This summary of Workshop deliberations outlines the consensus focus areas for future research.
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http://dx.doi.org/10.1513/AnnalsATS.202001-006OTDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7919149PMC
March 2021

Automated Segmentation and Severity Analysis of Subdural Hematoma for Patients with Traumatic Brain Injuries.

Diagnostics (Basel) 2020 Sep 30;10(10). Epub 2020 Sep 30.

Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA.

Detection and severity assessment of subdural hematoma is a major step in the evaluation of traumatic brain injuries. This is a retrospective study of 110 computed tomography (CT) scans from patients admitted to the Michigan Medicine Neurological Intensive Care Unit or Emergency Department. A machine learning pipeline was developed to segment and assess the severity of subdural hematoma. First, the probability of each point belonging to the hematoma region was determined using a combination of hand-crafted and deep features. This probability provided the initial state of the segmentation. Next, a 3D post-processing model was applied to evolve the initial state and delineate the hematoma. The recall, precision, and Dice similarity coefficient of the proposed segmentation method were 78.61%, 76.12%, and 75.35%, respectively, for the entire population. The Dice similarity coefficient was 79.97% for clinically significant hematomas, which compared favorably to an inter-rater Dice similarity coefficient. In volume-based severity analysis, the proposed model yielded an F1, recall, and specificity of 98.22%, 98.81%, and 92.31%, respectively, in detecting moderate and severe subdural hematomas based on hematoma volume. These results show that the combination of classical image processing and deep learning can outperform deep learning only methods to achieve greater average performance and robustness. Such a system can aid critical care physicians in reducing time to intervention and thereby improve long-term patient outcomes.
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http://dx.doi.org/10.3390/diagnostics10100773DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7600198PMC
September 2020

Haemophagocytic lymphohistiocytosis restricted to the central nervous system.

Arch Dis Child 2020 Sep 9. Epub 2020 Sep 9.

St. Jude Children's Research Hospital, Memphis, TN, United States.

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http://dx.doi.org/10.1136/archdischild-2020-319088DOI Listing
September 2020

The use of imaging to identify immunocompromised children requiring biopsy for invasive fungal rhinosinusitis.

Pediatr Blood Cancer 2020 11 29;67(11):e28676. Epub 2020 Aug 29.

Department of Bone Marrow Transplantation and Cellular Therapy, St Jude Children's Research Hospital, Memphis, Tennessee.

Background And Purpose: Children with severe immunocompromise due to cancer therapy or hematopoietic cell transplant are at risk both for potentially lethal invasive fungal rhinosinusitis (IFRS), and for complications associated with gold-standard biopsy diagnosis. We investigated whether early imaging could reliably identify or exclude IFRS in this population, thereby reducing unnecessary biopsy.

Methods: We reviewed clinical/laboratory data and cross-sectional imaging from 31 pediatric patients evaluated for suspicion of IFRS, 19 without (age 11.8 ± 5.4 years) and 12 with proven IFRS (age 11.9 ± 4.6 years). Imaging examinations were graded for mucosal thickening (Lund score), for fungal-specific signs (FSS) of bone destruction, extra-sinus inflammation, and nasal mucosal ulceration. Loss of contrast enhancement (LoCE) was assessed separately where possible. Clinical and imaging findings were compared with parametric or nonparametric tests as appropriate. Diagnostic accuracy was assessed by receiver operating characteristic (ROC) analysis. Positive (+LR) and negative likelihood ratios (-LR) and probabilities were calculated.

Results: Ten of 12 patients with IFRS and one of 19 without IFRS had at least one FSS on early imaging (83% sensitive, 95% specific, +LR = 15.83, -LR = 0.18; P < .001). Absolute neutrophil count (ANC) ≤ 200/mm was 100% sensitive and 58% specific for IFRS (+LR = 2.38, -LR = 0; P = .001). Facial pain was the only discriminating symptom of IFRS (P < .001). In a symptomatic child with ANC ≤ 200/m , the presence of at least one FSS indicated high (79%) probability of IFRS; absence of FSS suggested low (<4%) probability.

Conclusion: In symptomatic, severely immunocompromised children, the presence or absence of fungal-specific imaging findings may effectively rule in or rule out early IFRS, potentially sparing some patients the risks associated with biopsy.
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http://dx.doi.org/10.1002/pbc.28676DOI Listing
November 2020

Effectiveness of Bath Wipes After Hematopoietic Cell Transplantation: A Randomized Trial.

J Pediatr Oncol Nurs 2020 Nov/Dec;37(6):390-397. Epub 2020 Jul 24.

St. Jude Children's Research Hospital, Memphis, TN, USA.

Bacteremia is a leading cause of morbidity and mortality in children undergoing hematopoietic cell transplantation (HCT). Infections of vancomycin-resistant enterococci (VRE) and multidrug resistant (MDR) gram-negative rods (GNRs) are common in this population. Our objective was to assess whether experimental bath wipes containing silver were more effective than standard bath wipes containing soap at reducing skin colonization by VRE and MDR GNRs, and nonmucosal barrier injury bacteremia. Patients undergoing autologous or allogeneic HCT in a tertiary referral center were randomized to receive experimental or standard bath wipes for 60 days post-HCT. Skin swabs were collected at baseline, discharge, and day +60 post-HCT. The rate of VRE colonization was chosen as the marker for efficacy. Experimental bath wipes were well tolerated. Before the study, the rate of colonization with VRE in HCT recipients was 25%. In an interim analysis of 127 children, one (2%) patient in the experimental arm and two (3%) in the standard arm were colonized with VRE. Two (3%) patients had nonmucosal barrier injury bacteremia in the standard arm, with none in the experimental arm. MDR GNRs were not isolated. The trial was halted because the interim analyses indicated equivalent efficacy of the two methods. Skin cleansing with silver-containing or standard bath wipes resulted in very low and equivalent rates of bacteremia and colonization with VRE and MDR GNRs in children post-HCT. Future studies in other high-risk populations are needed to confirm these results.
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http://dx.doi.org/10.1177/1043454220944061DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7802025PMC
March 2021

Multiscale model for the optimal design of pedestrian queues to mitigate infectious disease spread.

PLoS One 2020 9;15(7):e0235891. Epub 2020 Jul 9.

Computer Science, University of West Florida, Pensacola, Florida, United States of America.

There is direct evidence for the spread of infectious diseases such as influenza, SARS, measles, and norovirus in locations where large groups of people gather at high densities e.g. theme parks, airports, etc. The mixing of susceptible and infectious individuals in these high people density man-made environments involves pedestrian movement which is generally not taken into account in modeling studies of disease dynamics. We address this problem through a multiscale model that combines pedestrian dynamics with stochastic infection spread models. The pedestrian dynamics model is utilized to generate the trajectories of motion and contacts between infected and susceptible individuals. We incorporate this information into a stochastic infection dynamics model with infection probability and contact radius as primary inputs. This generic model is applicable for several directly transmitted diseases by varying the input parameters related to infectivity and transmission mechanisms. Through this multiscale framework, we estimate the aggregate numbers and probabilities of newly infected people for different winding queue configurations. We find that the queue configuration has a significant impact on disease spread for a range of infection radii and transmission probabilities. We quantify the effectiveness of wall separators in suppressing the disease spread compared to rope separators. Further, we find that configurations with short aisles lower the infection spread when rope separators are used.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0235891PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7347216PMC
September 2020

Head and Neck Imaging in the Twenty-First Century.

Authors:
Ashok Srinivasan

Neuroimaging Clin N Am 2020 Aug 11;30(3):xvii. Epub 2020 Jun 11.

Michigan Medicine, Department of Radiology, B2-A209D, University of Michigan, 1500 East Medical Center Drive, Ann Arbor, MI 48109, USA. Electronic address:

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http://dx.doi.org/10.1016/j.nic.2020.05.004DOI Listing
August 2020

Magnetic Resonance Spectroscopy of the Head and Neck: Principles, Applications, and Challenges.

Neuroimaging Clin N Am 2020 Aug 11;30(3):283-293. Epub 2020 Jun 11.

Department of Radiology, Boston Medical Center, Boston University School of Medicine, One Boston Medical Center Place, Boston, MA 02118, USA; Department of Radiation Oncology, Boston Medical Center, Boston University School of Medicine, One Boston Medical Center Place, Boston, MA 02118, USA; Department of Otolaryngology-Head and Neck Surgery, Boston Medical Center, Boston University School of Medicine, One Boston Medical Center Place, Boston, MA 02118, USA. Electronic address:

Several investigations have revealed the utility of magnetic resonance spectroscopy (MRS) as an adjunct in the evaluation of lesions of the head and neck. This technique remains a challenge in the head and neck because of its low signal-to-noise ratio and long acquisition times. In this review article, the basics of image acquisition technique and reported clinical utilities of head and neck MRS are presented.
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http://dx.doi.org/10.1016/j.nic.2020.04.006DOI Listing
August 2020

Mechanisms and Origins of Spinal Pain: from Molecules to Anatomy, with Diagnostic Clues and Imaging Findings.

Radiographics 2020 Jul-Aug;40(4):1163-1181. Epub 2020 Jun 5.

From the Division of Neuroradiology, Department of Radiology, University of Michigan, 1500 E Medical Center Dr, UH B2, Ann Arbor, MI 48109.

Spinal pain, especially low back pain (LBP), is a widespread clinical and diagnostic problem for both patients and physicians, because back pain has an equivalently wide variety of causes and provocations. Because of its variable nature and manifestations, back pain is challenging to diagnose and treat correctly. In addition, the pain is induced not only by direct mechanical pressure such as a herniated disk or degenerated bone but also by inflammation and associated proinflammatory cytokines. To help guide further diagnostic workup or the next step in management, radiologists should be familiar with the causes, mechanisms, and diagnostic clues provided by MRI. The authors review the microscopic and macroscopic mechanisms for each category of LBP and depict the relationship between imaging findings and pain mechanisms. This review focuses on the detailed anatomy related to the pain-signaling pathway and the roles of chemicals in inducing different mechanisms of LBP. MRI findings that serve as representative examples of key concepts are demonstrated according to each mechanism, and treatment options are reviewed on the basis of different causes of LBP. By knowing these concepts, radiologists can help correlate imaging findings with potential underlying mechanisms and help guide clinicians in the management of LBP. RSNA, 2020.
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http://dx.doi.org/10.1148/rg.2020190185DOI Listing
June 2020

Multiphase CT Angiography for Evaluation and Diagnosis of Complex Spinal Dural Arteriovenous Fistula.

Can J Neurol Sci 2020 09 14;47(5):681-682. Epub 2020 May 14.

Department of Neurosurgery, University of Michigan, Ann Arbor, MI, USA.

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http://dx.doi.org/10.1017/cjn.2020.94DOI Listing
September 2020

Comprehensive review of Wernicke encephalopathy: pathophysiology, clinical symptoms and imaging findings.

Jpn J Radiol 2020 Sep 10;38(9):809-820. Epub 2020 May 10.

The Division of Neuroradiology, Department of Radiology, University of Michigan, 1500 E Medical Center Dr, UH B2, Ann Arbor, MI, 48109, USA.

Wernicke's encephalopathy (WE) is a severe and life-threatening illness resulting from vitamin B1 (thiamine) deficiency. The prevalence of WE has been estimated from 0.4 to 2.8%. If not treated properly, severe neurologic disorders such as Korsakoff psychosis and even death may occur. The classical triad of clinical symptoms (abnormal mental state, ataxia, and ophthalmoplegia) is found in only 16-33% of patients on initial examination. The originally described underlying condition of WE is alcoholism, but it accounts for about 50% of causes of WE. Nonalcoholic patients are also affected by WE and likely to present symptoms and radiological imaging findings different from patients with alcoholism, which further complicates the diagnosis of WE. Being familiar with predisposing causes, symptoms and radiological imaging findings of WE is important for radiologists and clinicians when making the diagnosis to start immediate treatment. This review discusses pathophysiologies, underlying causes, clinical symptoms, imaging findings and their mimics.
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http://dx.doi.org/10.1007/s11604-020-00989-3DOI Listing
September 2020

Splenial Restricted Diffusion as MRI Correlate of Diaschisis in a Blind Infant With Unilateral Posterior Cerebral Artery Stroke.

J Neuroophthalmol 2021 Mar;41(1):e119-e121

Department of Ophthalmology and Visual Sciences (EAE, TPP, JDT), Kellogg Eye Center, University of Michigan, Ann Arbor, Michigan; Department of Radiology (Neuroradiology) (AS, TM), University of Michigan, Ann Arbor, Michigan; and Department of Neurology (JDT), University of Michigan, Ann Arbor, Michigan.

Abstract: A 3-month-old male infant appeared on multiple clinical examinations to have acutely developed bilateral retrogeniculate blindness. Electroencephalography showed focal status epilepticus confined to the left posterior cerebral hemisphere. MRI demonstrated restricted diffusion in the domain of the left posterior cerebral artery consistent with acute stroke. Notably, the restricted diffusion extended across the midline in the splenium of the corpus callosum. This splenial sign may be the imaging correlate of cerebral diaschisis, a well-described phenomenon in which patients with new brain lesions develop acutely impaired neurologic function in related but nonlesioned brain regions. Diaschisis has been posited as the explanation for the temporary bilateral blindness in adult patients suffering from unilateral occipital infarctions.
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http://dx.doi.org/10.1097/WNO.0000000000000954DOI Listing
March 2021

Pre- and post-magnetic resonance imaging of hips and knees for detecting osteonecrosis in children and adolescents undergoing hematopoietic cell transplantation.

Bone Marrow Transplant 2020 09 7;55(9):1837-1839. Epub 2020 Apr 7.

Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, Memphis, TN, USA.

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http://dx.doi.org/10.1038/s41409-020-0882-9DOI Listing
September 2020

Constrained Linear Movement Model (CALM): Simulation of passenger movement in airplanes.

PLoS One 2020 5;15(3):e0229690. Epub 2020 Mar 5.

Aerospace Engineering Department, Embry-Riddle Aeronautical University, Daytona Beach, Florida, United States of America.

Pedestrian dynamics models the walking movement of individuals in a crowd. It has recently been used in the analysis of procedures to reduce the risk of disease spread in airplanes, relying on the SPED model. This is a social force model inspired by molecular dynamics; pedestrians are treated as point particles, and their trajectories are determined in a simulation. A parameter sweep is performed to address uncertainties in human behavior, which requires a large number of simulations. The SPED model's slow speed is a bottleneck to performing a large parameter sweep. This is a severe impediment to delivering real-time results, which are often required in the course of decision meetings, especially during emergencies. We propose a new model, called CALM, to remove this limitation. It is designed to simulate a crowd's movement in constrained linear passageways, such as inside an aircraft. We show that CALM yields realistic results while improving performance by two orders of magnitude over the SPED model.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0229690PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7058282PMC
June 2020

Prospective Imaging Trial Assessing Gadoteridol Retention in the Deep Brain Nuclei of Women Undergoing Breast MRI.

Acad Radiol 2020 12 24;27(12):1734-1741. Epub 2020 Feb 24.

Department of Radiology, University of Michigan, C415 MIB, 1500 E. Medical Center Drive, Ann Arbor, MI, 48109.

Rationale And Objectives: To assess for indirect evidence of gadoteridol retention in the deep brain nuclei of women undergoing serial screening breast MRI.

Methods: This HIPAA-compliant prospective observational noninferiority imaging trial was approved by the IRB. From December 2016 to March 2018, 12 consented subjects previously exposed to 0-1 doses of gadoteridol (group 1) and 7 consented subjects previously exposed to ≥4 doses of gadoteridol (group 2) prospectively underwent research-specific unenhanced brain MRI including T1w spin echo imaging and T1 mapping. Inclusion criteria were: (1) planned breast MRI with gadoteridol, (2) no gadolinium exposure other than gadoteridol, (3) able to undergo MRI, (4) no neurological illness, (5) no metastatic disease, (6) no chemotherapy. Regions of interest were manually drawn in the globus pallidus, thalamus, dentate nucleus, and pons. Globus pallidus/thalamus and dentate nucleus/pons signal intensities and T1-time ratios were calculated using established methods and correlated with cumulative gadoteridol dose (mL).

Results: All subjects were female (mean age: 50 ± 12 years) and previously had received an average of 0.5 ± 0.5 (group 1) and 5.9 ± 2.1 (group 2) doses of gadoteridol (cumulative dose: 8 ± 8 and 82 ± 31 mL, respectively), with the last dose an average of 492 ± 299 days prior to scanning. There was no significant correlation between cumulative gadoteridol dose (mL) and deep brain nuclei signal intensity at T1w spin echo imaging (p = 0.365-0.512) or T1 mapping (p = 0.197-0.965).

Conclusion: We observed no indirect evidence of gadolinium retention in the deep brain nuclei of women undergoing screening breast MRI with gadoteridol.
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http://dx.doi.org/10.1016/j.acra.2020.01.007DOI Listing
December 2020

Differences in Outcomes Associated With Individual Radiologists for Emergency Department Patients With Headache Imaged With CT: A Retrospective Cohort Study of 25,596 Patients.

AJR Am J Roentgenol 2020 05 11;214(5):1122-1130. Epub 2020 Feb 11.

Department of Radiology, Michigan Medicine, 1500 E Medical Center Dr B2-A209A, Ann Arbor, MI 48109.

The purpose of this study was to determine whether diagnostic radiologists impart variation into resource use and patient outcomes in emergency department (ED) patients undergoing CT for headache. This was a single-institution retrospective quality assurance cohort study of 25,596 unique adult ED patients undergoing head CT for headache from January 2012 to October 2017. CT examinations were interpreted by 55 attending radiologists (25 neuroradiologists, 30 radiologists of other specialties) who each interpreted a mean of 1469.8 ± 787.9 CT examinations. Risk adjustment for variables thought to influence outcome included baseline risk (demographics, Elixhauser comorbidity score), clinical factors (vital signs, ED triage and pain scores, laboratory data, hydrocephalus, prior intracranial hemorrhage, neurosurgical consultation within last 12 months), and system factors (time of CT, physician experience, neuroradiology training). Multivariable models were built to analyze the effect of individual radiologists on subsequent outcomes. Any value less than 0.007 was considered significant after Bonferroni correction. The study found 57.5% (14,718/25,596) of CT interpretations were performed by neuroradiologists, and most patients (98.1% [25,119/25,596]) had no neurosurgical history. After risk adjustment, individual radiologists were not an independent predictor of hospital admission ( = 0.49), 30-day readmission ( = 0.30), 30-day mortality ( = 0.14), or neurosurgical intervention ( = 0.04) but did predict MRI use ( < 0.001; odds ratio [OR] range among radiologists, 0.009-38.2), neurology consultation ( < 0.001; OR range, 0.4-3.2), and neurosurgical consultation ( < 0.001; OR range, 0.1-9.9). Radiologists with different skills, experience, and practice patterns appear interchangeable for major clinical outcomes when interpreting CT for headache in the ED, but their differences predict differential use of downstream health care resources. Resource use measures are potential quality indicators in this cohort.
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http://dx.doi.org/10.2214/AJR.19.22189DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8029644PMC
May 2020

CSF flow jet: novel CT myelogram finding of CSF leak through dural tear in traumatic pseudomeningocele.

Clin Imaging 2020 May 20;61:33-35. Epub 2019 Nov 20.

Department of Radiology, University of Michigan Health System, Ann Arbor, MI, USA.

Determining the exact location of dural violation after traumatic pre-ganglionic (avulsion) injury of the brachial plexus with associated progressively enlarging pseudomeningocele is critical for treatment, but current imaging by MR and CT myelogram remains inadequate as there are often only indirect imaging features. We present a case of a 25-year-old man with history of motorcycle accident and left brachial plexus injury, who was found to have an extensive anterior epidural CSF collection, resulting in the contralateral neurologic deficit. Surgical treatment relies upon the identification of the site of the dural violation. On dynamic CT myelogram images, a thin hyperdense line of contrast was seen, representing "CSF flow jet" extravasating into the pseudomeningocele. Subsequent laminectomy and foraminotomy revealed a left avulsed nerve root and a dural tear at the site localized on the CT myelogram. To our knowledge, this is the first case of using dynamic CT myelography to visualize "CSF flow jet," revealing the exact location of dural violation resulting in the expanding pseudomeningocele, providing crucial information for perioperative planning.
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http://dx.doi.org/10.1016/j.clinimag.2019.09.010DOI Listing
May 2020

LOX-1, the Common Therapeutic Target in Hypercholesterolemia: A New Perspective of Antiatherosclerotic Action of Aegeline.

Oxid Med Cell Longev 2019 30;2019:8285730. Epub 2019 Nov 30.

Department of Medical Biochemistry, Dr. ALM Post Graduate Institute for Basic Medical Sciences, University of Madras, Chennai, India.

Background: Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is the major receptor for oxidized low-density lipoprotein (Ox-LDL) in the aorta of aged rats. Ox-LDL initiates LOX-1 activation in the endothelium of lipid-accumulating sites of both animal and human subjects of hypercholesterolemia. Targeting LOX-1 may provide a novel diagnostic strategy towards hypercholesterolemia and vascular diseases.

Hypothesis: This study was planned to address whether aegeline (AG) could bind to LOX-1 with a higher affinity and modulate the uptake of Ox-LDL in hypercholesterolemia.

Study Design: Thirty-six Wistar rats were divided into six groups. The pathology group rats were fed with high-cholesterol diet (HCD) for 45 days, and the treatment group rats were fed with HCD and aegeline/atorvastatin (AV) for the last 30 days. and experiments were carried out to assay the markers of atherosclerosis like Ox-LDL and LOX-1 levels. Histopathological examination was performed. Oil Red O staining was carried out in the IC-21 cell line. Docking studies were performed.

Results: AG administration effectively brought down the lipid levels induced by HCD. The lowered levels of Ox-LDL and LOX-1 in AG-administered rats deem it to be a potent antihypercholesterolemic agent. Compared to AV, AG had a pronounced effect in downregulating the expression of lipids evidenced by Oil Red O staining. AG binds with LOX-1 at a higher affinity validated by docking.

Conclusion: This study validates AG to be an effective stratagem in bringing down the lipid stress induced by HCD and can be deemed as an antihypercholesterolemic agent.
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http://dx.doi.org/10.1155/2019/8285730DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6914969PMC
June 2020

NSABP FB-7: a phase II randomized neoadjuvant trial with paclitaxel + trastuzumab and/or neratinib followed by chemotherapy and postoperative trastuzumab in HER2 breast cancer.

Breast Cancer Res 2019 12 3;21(1):133. Epub 2019 Dec 3.

NSABP Foundation, Inc., Nova Tower 2, Two Allegheny Center - Ste 1200, Pittsburgh, PA, 15212, USA.

Purpose: The primary aim of NSABP FB-7 was to determine the pathologic complete response (pCR) rate in locally advanced HER2-positive (HER2) breast cancer patients treated with neoadjuvant trastuzumab or neratinib or the combination and weekly paclitaxel followed by standard doxorubicin plus cyclophosphamide. The secondary aims include biomarker analyses.

Experimental Design: pCR was tested for association with treatment, gene expression, and a single nucleotide polymorphism (SNP) in the Fc fragment of the IgG receptor IIIa-158V/F (FCGR3A). Pre-treatment biopsies and residual tumors were also compared to identify molecular changes.

Results: The numerical pCR rate in the trastuzumab plus neratinib arm (50% [95%CI 34-66%]) was greater than that for single-targeted therapies with trastuzumab (38% [95%CI 24-54]) or neratinib (33% [95%CI 20-50]) in the overall cohort but was not statistically significant. Hormone receptor-negative (HR) tumors had a higher pCR rate than HR tumors in all three treatment arms, with the highest pCR rate in the combination arm. Diarrhea was the most frequent adverse event and occurred in virtually all patients who received neratinib-based therapy. Grade 3 diarrhea was reported in 31% of patients; there were no grade 4 events. Our 8-gene signature, previously validated for trastuzumab benefit in two different clinical trials in the adjuvant setting, was correlated with pCR across all arms of NSABP FB-7. Specifically, patients predicted to receive no trastuzumab benefit had a significantly lower pCR rate than did patients predicted to receive the most benefit (P = 0.03). FCGR genotyping showed that patients who were homozygous for the Fc low-binding phenylalanine (F) allele for FCGR3A-158V/F were less likely to achieve pCR.

Conclusions: Combining trastuzumab plus neratinib with paclitaxel increased the absolute pCR rate in the overall cohort and in HR patients. The 8-gene signature, which is validated for predicting trastuzumab benefit in the adjuvant setting, was associated with pCR in the neoadjuvant setting, but remains to be validated as a predictive marker in a larger neoadjuvant clinical trial. HR status, and the FCGR3A-158V/F genotype, also warrant further investigation to identify HER2 patients who may benefit from additional anti-HER2 therapies beyond trastuzumab. All of these markers will require further validation in the neoadjuvant setting.

Trials Registration: ClinicalTrials.gov, NCT01008150. Retrospectively registered on October 5, 2010.
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http://dx.doi.org/10.1186/s13058-019-1196-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6892191PMC
December 2019