wit Adduct Formation of Delamanid with NAD in Mycobacteria [Mechanisms of Action] By aac.asm.org Published On :: 2020-04-21T08:01:09-07:00 Delamanid (DLM), a nitro-dihydroimidazooxazole derivative currently approved for pulmonary multidrug-resistant tuberculosis (TB) therapy, is a prodrug activated by mycobacterial 7,8-didemethyl-8-hydroxy 5-deazaflavin electron transfer coenzyme (F420)-dependent nitroreductase (Ddn). Despite inhibiting the biosynthesis of a subclass of mycolic acids, the active DLM metabolite remained unknown. Comparative liquid chromatography-mass spectrometry (LC-MS) analysis of DLM metabolites revealed covalent binding of reduced DLM with a nicotinamide ring of NAD derivatives (oxidized form) in DLM-treated Mycobacterium tuberculosis var. Bacille de Calmette et Guérin. Isoniazid-resistant mutations in the type II NADH dehydrogenase gene (ndh) showed a higher intracellular NADH/NAD ratio and cross-resistance to DLM, which were restored by complementation of the mutants with wild-type ndh. Our data demonstrated for the first time the adduct formation of reduced DLM with NAD in mycobacterial cells and its importance in the action of DLM. Full Article
wit Erratum for Asempa et al., "In Vitro Activity of Imipenem-Relebactam Alone or in Combination with Amikacin or Colistin against Pseudomonas aeruginosa" [Errata] By aac.asm.org Published On :: 2020-04-21T08:01:09-07:00 Full Article
wit Compounds with Therapeutic Potential against Novel Respiratory 2019 Coronavirus [Minireviews] By aac.asm.org Published On :: 2020-04-21T08:01:09-07:00 Currently, the expansion of the novel human respiratory coronavirus (known as SARS-CoV-2 [severe acute respiratory syndrome coronavirus 2], COVID-2019 [coronavirus disease 2019], or 2019-nCoV [2019 novel coronavirus]) has stressed the need for therapeutic alternatives to alleviate and stop this new epidemic. The previous epidemics of infections by high-morbidity human coronaviruses, such as SARS-CoV in 2003 and the Middle East respiratory syndrome coronavirus (MERS-CoV) in 2012, prompted the characterization of compounds that could be potentially active against the currently emerging novel coronavirus, SARS-CoV-2. The most promising compound is remdesivir (GS-5734), a nucleotide analog prodrug currently in clinical trials for treating Ebola virus infections. Remdesivir inhibited the replication of SARS-CoV and MERS-CoV in tissue cultures, and it displayed efficacy in nonhuman animal models. In addition, a combination of the human immunodeficiency virus type 1 (HIV-1) protease inhibitors lopinavir/ritonavir and interferon beta (LPV/RTV–IFN-β) was shown to be effective in patients infected with SARS-CoV. LPV/RTV–IFN-β also improved clinical parameters in marmosets and mice infected with MERS-CoV. Remarkably, the therapeutic efficacy of remdesivir appeared to be superior to that of LPV/RTV–IFN-β against MERS-CoV in a transgenic humanized mouse model. The relatively high mortality rates associated with these three novel human coronavirus infections, SARS-CoV, MERS-CoV, and SARS-CoV-2, have suggested that proinflammatory responses might play a role in the pathogenesis. It remains unknown whether the generated inflammatory state should be targeted. Therapeutics that target the coronavirus alone might not be able to reverse highly pathogenic infections. This minireview aims to provide a summary of therapeutic compounds that have shown potential in fighting SARS-CoV-2 infections. Full Article
wit Accumulation of Major Linezolid Metabolites in Patients with Renal Impairment [Pharmacology] By aac.asm.org Published On :: 2020-04-21T08:01:09-07:00 In patients with renal impairment (n = 22 of 39), the median serum concentrations of linezolid, PNU-142300, and PNU-142586 were 1.6-, 3.3-, 2.8-fold higher, respectively, than in patients without renal impairment. Metabolite concentrations in paired samples were poorly correlated with linezolid concentrations (r2 = 0.26 for PNU-142300 and 0.06 for PNU-142586). Linezolid and its metabolites share potential toxicophores that deserve characterization to mitigate higher myelosuppression risk in patients with renal impairment. Full Article
wit Noncoding Variants Connect Enhancer Dysregulation with Nuclear Receptor Signaling in Hematopoietic Malignancies [Research Articles] By cancerdiscovery.aacrjournals.org Published On :: 2020-05-01T00:05:26-07:00 Mutations in protein-coding genes are well established as the basis for human cancer, yet how alterations within noncoding genome, a substantial fraction of which contain cis-regulatory elements (CRE), contribute to cancer pathophysiology remains elusive. Here, we developed an integrative approach to systematically identify and characterize noncoding regulatory variants with functional consequences in human hematopoietic malignancies. Combining targeted resequencing of hematopoietic lineage–associated CREs and mutation discovery, we uncovered 1,836 recurrently mutated CREs containing leukemia-associated noncoding variants. By enhanced CRISPR/dCas9–based CRE perturbation screening and functional analyses, we identified 218 variant-associated oncogenic or tumor-suppressive CREs in human leukemia. Noncoding variants at KRAS and PER2 enhancers reside in proximity to nuclear receptor (NR) binding regions and modulate transcriptional activities in response to NR signaling in leukemia cells. NR binding sites frequently colocalize with noncoding variants across cancer types. Hence, recurrent noncoding variants connect enhancer dysregulation with nuclear receptor signaling in hematopoietic malignancies. Significance: We describe an integrative approach to identify noncoding variants in human leukemia, and reveal cohorts of variant-associated oncogenic and tumor-suppressive cis-regulatory elements including KRAS and PER2 enhancers. Our findings support a model in which noncoding regulatory variants connect enhancer dysregulation with nuclear receptor signaling to modulate gene programs in hematopoietic malignancies. See related commentary by van Galen, p. 646. This article is highlighted in the In This Issue feature, p. 627 Full Article
wit Targeting HER2 with Trastuzumab Deruxtecan: A Dose-Expansion, Phase I Study in Multiple Advanced Solid Tumors [Research Articles] By cancerdiscovery.aacrjournals.org Published On :: 2020-05-01T00:05:26-07:00 HER2-targeted therapies are approved only for HER2-positive breast and gastric cancers. We assessed the safety/tolerability and activity of the novel HER2-targeted antibody–drug conjugate trastuzumab deruxtecan (T-DXd) in 60 patients with pretreated, HER2-expressing (IHC ≥ 1+), non-breast/non-gastric or HER2-mutant solid tumors from a phase I trial (NCT02564900). Most common (>50%) treatment-emergent adverse events (TEAE) were nausea, decreased appetite, and vomiting. Two drug-related TEAEs were associated with fatal outcomes. The confirmed objective response rate (ORR) was 28.3% (17/60). Median progression-free survival (PFS) was 7.2 [95% confidence interval (CI), 4.8–11.1] months. In HER2-mutant non–small cell lung cancer (NSCLC), ORR was 72.7% (8/11), and median PFS was 11.3 (95% CI, 8.1–14.3) months. Confirmed responses were observed in six tumor types, including HER2-expressing NSCLC, colorectal cancer, salivary gland cancer, biliary tract cancer, endometrial cancer, and HER2-mutant NSCLC and breast cancer. Results suggest T-DXd holds promise for HER2-expressing/mutant solid tumors. Significance: T-DXd demonstrated promising activity in a heterogeneous patient population with heavily pretreated HER2-expressing or HER2-mutant solid tumors, especially HER2-mutant NSCLC. The safety profile was generally acceptable. Interstitial lung disease can be severe and requires prompt monitoring and intervention. Further research of T-DXd is warranted to address these unmet medical needs. See related commentary by Rolfo and Russo, p. 643. This article is highlighted in the In This Issue feature, p. 627 Full Article
wit Strong HPV Vaccine Response Predicts Better Survival with Chemotherapy [Clinical Trials] By cancerdiscovery.aacrjournals.org Published On :: 2020-05-01T00:05:26-07:00 Patients with HPV16+ cervical cancer and high T-cell responses to an HPV16 vaccine survived longer. Full Article
wit Comparative single-cell RNA sequencing (scRNA-seq) reveals liver metastasis-specific targets in a patient with small intestinal neuroendocrine cancer [RESEARCH REPORT] By molecularcasestudies.cshlp.org Published On :: 2020-04-01T06:30:17-07:00 Genomic analysis of a patient's tumor is the cornerstone of precision oncology, but it does not address whether metastases should be treated differently. Here we tested whether comparative single-cell RNA sequencing (scRNA-seq) of a primary small intestinal neuroendocrine tumor to a matched liver metastasis could guide the treatment of a patient's metastatic disease. Following surgery, the patient was put on maintenance treatment with a somatostatin analog. However, the scRNA-seq analysis revealed that the neuroendocrine epithelial cells in the liver metastasis were less differentiated and expressed relatively little SSTR2, the predominant somatostatin receptor. There were also differences in the tumor microenvironments. RNA expression of vascular endothelial growth factors was higher in the primary tumor cells, reflected by an increased number of endothelial cells. Interestingly, vascular expression of the major VEGF receptors was considerably higher in the liver metastasis, indicating that the metastatic vasculature may be primed for expansion and susceptible to treatment with angiogenesis inhibitors. The patient eventually progressed on Sandostatin, and although consideration was given to adding an angiogenesis inhibitor to her regimen, her disease progression involved non-liver metastases that had not been characterized. Although in this specific case comparative scRNA-seq did not alter treatment, its potential to help guide therapy of metastatic disease was clearly demonstrated. Full Article
wit RNA sequencing profiles and diagnostic signatures linked with response to ramucirumab in gastric cancer [RESEARCH REPORT] By molecularcasestudies.cshlp.org Published On :: 2020-04-01T06:30:17-07:00 Gastric cancer (GC) is the fifth-ranked cancer type by associated mortality. The proportion of early diagnosis is low, and most patients are diagnosed at the advanced stages. First-line therapy standardly includes fluoropyrimidines and platinum compounds with trastuzumab for HER2-positive cases. For recurrent disease, there are several alternative options including ramucirumab, a monoclonal therapeutic antibody that inhibits VEGF-mediated tumor angiogenesis by binding with VEGFR2, alone or in combination with other cancer drugs. However, overall response rate following ramucirumab or its combinations is 30%–80% of the patients, suggesting that personalization of drug prescription is needed to increase efficacy of treatment. We report here original tumor RNA sequencing profiles for 15 advanced GC patients linked with data on clinical response to ramucirumab or its combinations. Three genes showed differential expression in the tumors for responders versus nonresponders: CHRM3, LRFN1, and TEX15. Of them, CHRM3 was up-regulated in the responders. Using the bioinformatic platform Oncobox we simulated ramucirumab efficiency and compared output model results with actual tumor response data. An agreement was observed between predicted and real clinical outcomes (AUC ≥ 0.7). These results suggest that RNA sequencing may be used to personalize the prescription of ramucirumab for GC and indicate potential molecular mechanisms underlying ramucirumab resistance. The RNA sequencing profiles obtained here are fully compatible with the previously published Oncobox Atlas of Normal Tissue Expression (ANTE) data. Full Article
wit The diagnostic challenges and clinical course of a myeloid/lymphoid neoplasm with eosinophilia and ZBTB20-JAK2 gene fusion presenting as B-lymphoblastic leukemia [RESEARCH REPORT] By molecularcasestudies.cshlp.org Published On :: 2020-04-01T06:30:17-07:00 We report the diagnostic challenges and the clinical course of a patient with an extraordinary presentation of B-lymphoblastic leukemia (B-ALL) with eosinophilia. We identified a novel ZBTB20-JAK2 gene fusion as a chimeric RNA transcript using the Archer platform. This gene fusion from the same patient was recently identified by Peterson et al. (2019) at the genomic level using a different sequencing technology platform. The configuration of this gene fusion predicts the production of a kinase-activating JAK2 fusion protein, which would normally lead to a diagnosis of Philadelphia chromosome–like B-ALL (Ph-like B-ALL). However, the unusual presentation of eosinophilia led us to demonstrate the presence of this gene fusion in nonlymphoid hematopoietic cells by fluorescence in situ hybridization (FISH) studies with morphologic correlation. Therefore, we believe this disease, in fact, represents blast crisis arising from an underlying myeloid neoplasm with JAK2 rearrangements. This case illustrates the difficulty in differentiating Ph-like B-ALL and myeloid/lymphoid neoplasm with eosinophilia and gene rearrangements (MLN-EGR) in blast crisis. As currently defined, the diagnosis of MLN-EGR relies on the hematologic presentations and the identification of marker gene fusions (including PCM1-JAK2, ETV6-JAK2, and BCR-JAK2). However, these same gene fusions, when limited to B-lymphoblasts, also define Ph-like B-ALL. Yet, our case does not conform to either condition. Therefore, the assessment for lineage restriction of gene rearrangements to reflect the pathophysiologic difference between B-ALL and MLN-EGR in blast crisis is likely a more robust diagnostic approach and allows the inclusion of MLN-EGR with novel gene fusions. Full Article
wit BRAF V600E-mutated metastatic pediatric Wilms tumor with complete response to targeted RAF/MEK inhibition [RESEARCH REPORT] By molecularcasestudies.cshlp.org Published On :: 2020-04-01T06:30:17-07:00 Wilms tumor (WT) is the most common renal malignancy of childhood and accounts for 6% of all childhood malignancies. With current therapies, the 5-yr overall survival (OS) for children with unilateral favorable histology WT is greater than 85%. The prognosis is worse, however, for the roughly 15% of patients who relapse, with only 50%–80% OS reported in those with recurrence. Herein, we describe the extended and detailed clinical course of a rare case of a child with recurrent, pulmonary metastatic, favorable histology WT harboring a BRAF V600E mutation. The BRAF V600E mutation, commonly found in melanoma and other cancers, and previously undescribed in WT, has recently been reported by our group in a subset of epithelial-predominant WT. This patient, who was included in that series, presented with unilateral, stage 1, favorable histology WT and was treated with standard chemotherapy. Following the completion of therapy, the patient relapsed with pulmonary metastatic disease, that then again recurred despite an initial response to salvage chemotherapy and radiation. Next-generation sequencing (NGS) on the metastatic pulmonary nodule revealed a BRAF V600E mutation. After weighing the therapeutic options, a novel approach with dual BRAF/MEK inhibitor combination therapy was initiated. Complete radiographic response was observed following 4 months of therapy with dabrafenib and trametinib. At 12 months following the start of BRAF/MEK combination treatment, the patient continues with a complete response and has experienced minimal treatment-related side effects. This represents the first case, to our knowledge, of effective treatment with BRAF/MEK molecularly targeted therapy in a pediatric Wilms tumor patient. Full Article
wit A Case of Euglycemic Diabetic Ketoacidosis Triggered by a Ketogenic Diet in a Patient With Type 2 Diabetes Using a Sodium-Glucose Cotransporter 2 Inhibitor By clinical.diabetesjournals.org Published On :: 2020-04-15T12:00:21-07:00 Full Article
wit Optimizing Diabetes Care With the Standardized Continuous Glucose Monitoring Report By clinical.diabetesjournals.org Published On :: 2020-04-15T12:00:21-07:00 Full Article
wit Distribution of Highly Prevalent Musculoskeletal Disorders and Their Association With Diabetes Complications in a Population of 140 Individuals With Type 1 Diabetes: A Retrospective Study in a French Diabetes Center By clinical.diabetesjournals.org Published On :: 2020-04-15T12:00:21-07:00 Although they are usually not considered to be diabetes complications, musculoskeletal disorders (MSKDs) are common in individuals with type 1 or type 2 diabetes and can strongly interfere with daily diabetes care, especially in people using diabetes technologies. The authors of this retrospective study in a population of 140 patients with type 1 diabetes report the distribution of subtypes of MSKDs and speculate about the mechanisms involved. The authors emphasize the need for multidisciplinary care involving not only the diabetes care team but also orthopedic surgeons. This report should lead to large, prospective studies to increase knowledge about these under-studied complications. Full Article
wit Beneficial Agents for Patients With Type 2 Diabetes and Cardiovascular Disease or Obesity: Utilization in an Era of Accumulating Evidence By clinical.diabetesjournals.org Published On :: 2020-04-15T12:00:21-07:00 This study was an analysis of a national sample of U.S. medical office visits from 2014 to 2016, a period when evidence of effectiveness was emerging for a variety of beneficial type 2 diabetes agents with regard to potential reduction in diabetes comorbidities. Ideal therapy was defined as an American Diabetes Association–identified beneficial agent plus metformin. The associations between atherosclerotic cardiovascular disease or obesity and use of these agents were explored. Full Article
wit “What’s the Point?”: Understanding Why People With Type 2 Diabetes Decline Structured Education By clinical.diabetesjournals.org Published On :: 2020-04-15T12:00:21-07:00 Structured diabetes education (SDE) is an evidence-based intervention that supports self-management in people with type 2 diabetes. In the United Kingdom, health care providers working in primary care settings are responsible for referring people with type 2 diabetes to SDE programs. However, national audits record a high percentage of nonattenders. We explored the personal experience of living with type 2 diabetes that led to individuals declining invitations to attend SDE programs. The themes suggested that emotional, cognitive, and social issues related to diagnosis and living with diabetes may be responsible for declining to attend SDE and that these factors may be masked by explanations of practical barriers. A person-centered approach to understanding the personal meaning of being diagnosed and living with type 2 diabetes may help to identify individuals’ psychosocial barriers to attending SDE. Full Article
wit Flash Continuous Home Glucose Monitoring to Improve Adherence to Self-Monitoring of Blood Glucose and Self-Efficacy in Adolescents With Type 1 Diabetes By clinical.diabetesjournals.org Published On :: 2020-04-15T12:00:21-07:00 Adolescents with type 1 diabetes face self-management challenges that make it difficult for them to achieve good glycemic control. In our population of adolescents with poorly controlled type 1 diabetes, the use of continuous glucose monitoring (CGM) improved patients’ glycemic time in range (TIR) and identified hypoglycemia more frequently than with intermittent self-monitoring of blood glucose throughout a 4-week interval. However, the adolescents were unable to synthesize this information to problem-solve or reduce the frequency of hypoglycemic events. Setting SMART (specific, measurable, achievable, relevant, and time-bound) diabetes management goals and providing intensive diabetes education and support could increase adolescents’ TIR and prevent hypoglycemia. Full Article
wit Operative Intervention Does Not Change Pain Perception in Patients With Diabetic Foot Ulcers By clinical.diabetesjournals.org Published On :: 2020-04-15T12:00:21-07:00 Researchers investigated pain perception in patients with diabetic foot ulcers (DFUs) by analyzing pre- and postoperative physical function (PF), pain interference (PI), and depression domains of the Patient-Reported Outcome Measurement Information System (PROMIS). They hypothesized that 1) because of painful diabetic peripheral neuropathy (DPN), a majority of patients with DFUs would have high PROMIS PI scores unchanged by operative intervention, and 2) the initially assessed PI, PF, and depression levels would be correlated with final outcomes. Seventy-five percent of patients with DFUs reported pain, most likely because of painful DPN. Those who reported high PI and low PF were likely to report depression. PF, PI, and depression levels were unchanged after operative intervention or healing of DFUs. Full Article
wit Red and Processed Meat, Poultry, Fish, and Egg Intakes and Cause-Specific and All-Cause Mortality among Men with Nonmetastatic Prostate Cancer in a U.S. Cohort By cebp.aacrjournals.org Published On :: 2020-05-01T00:05:36-07:00 Background: Research on the relationship of meat, fish, and egg consumption and mortality among prostate cancer survivors is limited. Methods: In the Cancer Prevention Study-II Nutrition Cohort, men diagnosed with nonmetastatic prostate cancer between baseline in 1992/1993 and 2015 were followed for mortality until 2016. Analyses of pre- and postdiagnosis intakes of red and processed meat, poultry, fish, and eggs included 9,286 and 4,882 survivors, respectively. Multivariable-adjusted RRs and 95% confidence intervals (CI) were estimated using Cox proportional hazards models. Results: A total of 4,682 and 2,768 deaths occurred during follow-up in pre- and postdiagnosis analyses, respectively. Both pre- and postdiagnosis intakes of total red and processed meat were positively associated with all-cause mortality (quartile 4 vs. 1: RR = 1.13; 95% CI, 1.03–1.25; Ptrend = 0.02; RR = 1.22; 95% CI, 1.07–1.39; Ptrend = 0.03, respectively), and both pre- and postdiagnosis poultry intakes were inversely associated with all-cause mortality (quartile 4 vs. 1 RR = 0.90; 95% CI, 0.82–0.98; Ptrend = 0.04; RR = 0.84; 95% CI, 0.75–0.95; Ptrend = 0.01, respectively). No associations were seen for prostate cancer–specific mortality, except that higher postdiagnosis unprocessed red meat intake was associated with lower risk. Conclusions: Higher red and processed meat, and lower poultry, intakes either before or after prostate cancer diagnosis were associated with higher risk of all-cause mortality. Impact: Our findings provide additional evidence that prostate cancer survivors should follow the nutrition guidelines limiting red and processed meat consumption to improve overall survival. Additional research on the relationship of specific meat types and mortality is needed. Full Article
wit Prospective Association of Energy Balance Scores Based on Metabolic Biomarkers with Colorectal Cancer Risk By cebp.aacrjournals.org Published On :: 2020-05-01T00:05:36-07:00 Background: Energy balance–related factors, such as body mass index (BMI), diet, and physical activity, may influence colorectal cancer etiology through interconnected metabolic pathways, but their combined influence is less clear. Methods: We used reduced rank regression to derive three energy balance scores that associate lifestyle factors with combinations of prediagnostic, circulating levels of high-sensitivity C-reactive protein (hsCRP), C-peptide, and hemoglobin A1c (HbA1c) among 2,498 participants in the Cancer Prevention Study-II Nutrition Cohort. Among 114,989 participants, we verified 2,228 colorectal cancer cases. We assessed associations of each score with colorectal cancer incidence and by tumor molecular phenotypes using Cox proportional hazards regression. Results: The derived scores comprised BMI, physical activity, screen time, and 14 food groups, and explained 5.1% to 10.5% of the variation in biomarkers. The HR and 95% confidence interval (CI) for quartile 4 versus 1 of the HbA1c+C peptide–based score and colorectal cancer was 1.30 (1.15–1.47), the hsCRP-based score was 1.35 (1.19–1.53), and the hsCRP, C-peptide, and HbA1c-based score was 1.35 (1.19–1.52). The latter score was associated with non-CIMP tumors (HRQ4vsQ1: 1.59; 95% CI: 1.17–2.16), but not CIMP-positive tumors (Pheterogeneity = 0.04). Conclusions: These results further support hypotheses that systemic biomarkers of metabolic health—inflammation and abnormal glucose homeostasis—mediate part of the relationship between several energy balance–related modifiable factors and colorectal cancer risk. Impact: Results support cancer prevention guidelines for maintaining a healthful body weight, consuming a healthful diet, and being physically active. More research is needed on these clusters of exposures with molecular phenotypes of tumors. Full Article
wit Associations of Abdominal Skeletal Muscle Mass, Fat Mass, and Mortality among Men and Women with Stage I-III Colorectal Cancer By cebp.aacrjournals.org Published On :: 2020-05-01T00:05:36-07:00 Background: The associations of abdominal skeletal muscle mass index (SMI), visceral and subcutaneous adipose tissue (VAT and SAT, respectively), and mortality among patients with stage I–III colorectal cancer may differ for men and women, but only few studies stratified their data into men and women. We investigated associations of abdominal SMI, VAT, and SAT with overall mortality among men and among women with stage I–III colorectal cancer. Methods: SMI, VAT, and SAT were assessed from abdominal CT images for 1,998 patients with stage I–III colorectal cancer diagnosed between 2006 and 2015. Restricted cubic splines (RCS) were used to investigate associations of SMI, VAT, and SAT with overall mortality. Results: Average age of the participants was 67.9 ± 10.6 years and 58% were men. During a median follow-up of 4.3 years, 546 (27%) patients died. Among men, the association of SMI and mortality was statistically significant in a nonlinear way in the RCS analyses, with lower SMI levels associated with higher mortality. SMI was not associated with mortality among women. SAT was associated with mortality in a nonlinear way for men and for women, with lower SAT levels being associated with higher mortality. VAT was not significantly associated with mortality in men or women. Conclusion: Associations of abdominal skeletal muscle mass with mortality among patients with colorectal cancer were not the same for men and for women. Impact: This study stresses the importance for more attention on sex-related differences in body composition and cancer outcomes. Full Article
wit Daily Time of Radiation Treatment Is Associated with Subsequent Oral Mucositis Severity during Radiotherapy in Head and Neck Cancer Patients By cebp.aacrjournals.org Published On :: 2020-05-01T00:05:36-07:00 Background: Limited treatment options are available for oral mucositis, a common, debilitating complication of cancer therapy. We examined the association between daily delivery time of radiotherapy and the severity of oral mucositis in patients with head and neck cancer. Methods: We used electronic medical records of 190 patients with head and neck squamous cell carcinoma who completed radiotherapy, with or without concurrent chemotherapy, at Roswell Park Comprehensive Cancer Center (Buffalo, NY) between 2015 and 2017. Throughout a 7-week treatment course, patient mouth and throat soreness (MTS) was self-reported weekly using a validated oral mucositis questionnaire, with responses 0 (no) to 4 (extreme). Average treatment times from day 1 until the day before each mucositis survey were categorized into seven groups. Multivariable-adjusted marginal average scores (LSmeans) were estimated for the repeated- and maximum-MTS, using a linear-mixed model and generalized-linear model, respectively. Results: Radiation treatment time was significantly associated with oral mucositis severity using both repeated-MTS (n = 1,156; P = 0.02) and maximum-MTS (n = 190; P = 0.04), with consistent patterns. The severity was lowest for patients treated during 8:30 to <9:30 am (LSmeans for maximum-MTS = 2.24; SE = 0.15), increased at later treatment times and peaked at early afternoon (11:30 am to <3:00 pm, LSmeans = 2.66–2.71; SEs = 0.16/0.17), and then decreased substantially after 3 pm. Conclusions: We report a significant association between radiation treatment time and oral mucositis severity in patients with head and neck cancer. Impact: Although additional studies are needed, these data suggest a potential simple treatment time solution to limit severity of oral mucositis during radiotherapy without increasing cost. Full Article
wit Assessing Cancer Treatment Information Using Medicare and Hospital Discharge Data among Women with Non-Hodgkin Lymphoma in a Los Angeles County Case-Control Study By cebp.aacrjournals.org Published On :: 2020-05-01T00:05:36-07:00 Background: We assessed the ability to supplement existing epidemiologic/etiologic studies with data on treatment and clinical outcomes by linking to publicly available cancer registry and administrative databases. Methods: Medical records were retrieved and abstracted for cases enrolled in a Los Angeles County case–control study of non-Hodgkin lymphoma (NHL). Cases were linked to the Los Angeles County cancer registry (CSP), the California state hospitalization discharge database (OSHPD), and the SEER-Medicare database. We assessed sensitivity, specificity, and positive predictive value (PPV) of cancer treatment in linked databases, compared with medical record abstraction. Results: We successfully retrieved medical records for 918 of 1,004 participating NHL cases and abstracted treatment for 698. We linked 59% of cases (96% of cases >65 years old) to SEER-Medicare and 96% to OSHPD. Chemotherapy was the most common treatment and best captured, with the highest sensitivity in SEER-Medicare (80%) and CSP (74%); combining all three data sources together increased sensitivity (92%), at reduced specificity (56%). Sensitivity for radiotherapy was moderate: 77% with aggregated data. Sensitivity of BMT was low in the CSP (42%), but high for the administrative databases, especially OSHPD (98%). Sensitivity for surgery reached 83% when considering all three datasets in aggregate, but PPV was 60%. In general, sensitivity and PPV for chronic lymphocytic leukemia/small lymphocytic lymphoma were low. Conclusions: Chemotherapy was accurately captured by all data sources. Hospitalization data yielded the highest performance values for BMTs. Performance measures for radiotherapy and surgery were moderate. Impact: Various administrative databases can supplement epidemiologic studies, depending on treatment type and NHL subtype of interest. Full Article
wit The Impact of One-week Dietary Supplementation with Kava on Biomarkers of Tobacco Use and Nitrosamine-based Carcinogenesis Risk among Active Smokers By cancerpreventionresearch.aacrjournals.org Published On :: 2020-05-04T05:35:14-07:00 Tobacco smoking is the primary risk factor for lung cancer, driven by the addictive nature of nicotine and the indisputable carcinogenicity of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) as well as other compounds. The integration of lung cancer chemoprevention with smoking cessation is one potential approach to reduce this risk and mitigate lung cancer mortality. Experimental data from our group suggest that kava, commonly consumed in the South Pacific Islands as a beverage to promote relaxation, may reduce lung cancer risk by enhancing NNK detoxification and reducing NNK-derived DNA damage. Building upon these observations, we conducted a pilot clinical trial to evaluate the effects of a 7-day course of kava on NNK metabolism in active smokers. The primary objective was to compare urinary total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL plus its glucuronides, major metabolites of NNK) before and after kava administration as an indicator of NNK detoxification. Secondary objectives included determining kava's safety, its effects on DNA damage, tobacco use, and cortisol (a biomarker of stress). Kava increased urinary excretion of total NNAL and reduced urinary 3-methyladenine in participants, suggestive of its ability to reduce the carcinogenicity of NNK. Kava also reduced urinary total nicotine equivalents, indicative of its potential to facilitate tobacco cessation. Plasma cortisol and urinary total cortisol equivalents were reduced upon kava use, which may contribute to reductions in tobacco use. These results demonstrate the potential of kava intake to reduce lung cancer risk among smokers. Full Article
wit Oral Microbiome Profiling in Smokers with and without Head and Neck Cancer Reveals Variations Between Health and Disease By cancerpreventionresearch.aacrjournals.org Published On :: 2020-05-04T05:35:14-07:00 While smoking is inextricably linked to oral/head and neck cancer (HNSCC), only a small fraction of smokers develop HNSCC. Thus, we have sought to identify other factors, which may influence the development of HNSCC in smokers including microbiology. To determine microbial associations with HNSCC among tobacco users, we characterized oral microbiome composition in smokers with and without HNSCC. 16S rRNA MiSeq sequencing was used to examine the oral mucosa microbiome of 27 smokers with (cases) and 24 without HNSCC (controls). In addition, we correlated previously reported levels of DNA damage with the microbiome data. Smokers with HNSCC showed lower microbiome richness compared with controls (q = 0.012). Beta-diversity analyses, assessed as UniFrac (weighted and unweighted) and Bray–Curtis distances, showed significant differences in oral mucosal microbiome signatures between cases and controls (r2 = 0.03; P = 0.03) and higher interindividual microbiome heterogeneity in the former (q ≤ 0.01). Higher relative abundance of Stenotrophomonas and Comamonadaceae and predicted bacterial pathways mainly involved in xenobiotic and amine degradation were found in cases compared with controls. The latter, in contrast, exhibited higher abundance of common oral commensals and predicted sugar degradation pathways. Finally, levels of DNA damage in the oral cavity were correlated with the microbiome profiles above. Oral microbiome traits differ in smokers with and without HNSCC, potentially informing the risk of eventual HNSCC and shedding light into possible microbially mediated mechanisms of disease. These findings present data that may be useful in screening efforts for HNSCC among smokers who are unable to quit. Full Article
wit Maternal Epigenetic Regulation Contributes to Prevention of Estrogen Receptor-negative Mammary Cancer with Broccoli Sprout Consumption By cancerpreventionresearch.aacrjournals.org Published On :: 2020-05-04T05:35:14-07:00 Cruciferous vegetables have been of special interest due to the rich presence of bioactive compounds such as sulforaphane which show promising potential on cancer prevention and therapy as an epigenetic dietary strategy. Abnormal epigenetic alteration as one of the primary contributors to tumor development is closely related to breast cancer initiation and progression. In the present study, we investigated the effect of dietary broccoli sprouts (BSp), a common cruciferous vegetable, on prevention of estrogen receptor (ER)-negative mammary tumors at three different temporal exposure windows using a spontaneous breast cancer mouse model. Our findings indicate that maternal BSp treatment exhibited profound inhibitory and preventive effects on mammary cancer formation in the nontreated mouse offspring. The BSp diet administered to adult mice also showed suppressive effects on mammary cancer but was not as profound as the maternal BSp preventive effects. Moreover, such protective effects were linked with differentially expressed tumor- and epigenetic-related genes, as well as altered global histone acetylation, DNA methylation, and DNA hydroxymethylation levels. We also found that the expression changes of tumor-related genes were associated with the levels of histone methylation of H3K4 and H3K9 in the gene promoter regions. In addition, BSp-enriched sulforaphane was shown to increase protein expression of tumor suppressor genes such as p16 and p53 and inhibit the protein levels of Bmi1, DNA methyltransferases, and histone deacetylases in ERα-negative breast cancer cell lines. Collectively, these results suggest that maternal exposure to key phytochemicals may contribute to ER-negative mammary tumor prevention in their offspring through epigenetic regulations. Full Article
wit Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer Is Associated with Indigenous American Ancestry in Latin American Women By cancerres.aacrjournals.org Published On :: 2020-05-04T05:35:17-07:00 Women of Latin American origin in the United States are more likely to be diagnosed with advanced breast cancer and have a higher risk of mortality than non-Hispanic White women. Studies in U.S. Latinas and Latin American women have reported a high incidence of HER2 positive (+) tumors; however, the factors contributing to this observation are unknown. Genome-wide genotype data for 1,312 patients from the Peruvian Genetics and Genomics of Breast Cancer Study (PEGEN-BC) were used to estimate genetic ancestry. We tested the association between HER2 status and genetic ancestry using logistic and multinomial logistic regression models. Findings were replicated in 616 samples from Mexico and Colombia. Average Indigenous American (IA) ancestry differed by subtype. In multivariate models, the odds of having an HER2+ tumor increased by a factor of 1.20 with every 10% increase in IA ancestry proportion (95% CI, 1.07–1.35; P = 0.001). The association between HER2 status and IA ancestry was independently replicated in samples from Mexico and Colombia. Results suggest that the high prevalence of HER2+ tumors in Latinas could be due in part to the presence of population-specific genetic variant(s) affecting HER2 expression in breast cancer.Significance:The positive association between Indigenous American genetic ancestry and HER2+ breast cancer suggests that the high incidence of HER2+ subtypes in Latinas might be due to population and subtype-specific genetic risk variants. Full Article
wit MEF2c-Dependent Downregulation of Myocilin Mediates Cancer-Induced Muscle Wasting and Associates with Cachexia in Patients with Cancer By cancerres.aacrjournals.org Published On :: 2020-05-04T05:35:17-07:00 Skeletal muscle wasting is a devastating consequence of cancer that contributes to increased complications and poor survival, but is not well understood at the molecular level. Herein, we investigated the role of Myocilin (Myoc), a skeletal muscle hypertrophy-promoting protein that we showed is downregulated in multiple mouse models of cancer cachexia. Loss of Myoc alone was sufficient to induce phenotypes identified in mouse models of cancer cachexia, including muscle fiber atrophy, sarcolemmal fragility, and impaired muscle regeneration. By 18 months of age, mice deficient in Myoc showed significant skeletal muscle remodeling, characterized by increased fat and collagen deposition compared with wild-type mice, thus also supporting Myoc as a regulator of muscle quality. In cancer cachexia models, maintaining skeletal muscle expression of Myoc significantly attenuated muscle loss, while mice lacking Myoc showed enhanced muscle wasting. Furthermore, we identified the myocyte enhancer factor 2 C (MEF2C) transcription factor as a key upstream activator of Myoc whose gain of function significantly deterred cancer-induced muscle wasting and dysfunction in a preclinical model of pancreatic ductal adenocarcinoma (PDAC). Finally, compared with noncancer control patients, MYOC was significantly reduced in skeletal muscle of patients with PDAC defined as cachectic and correlated with MEF2c. These data therefore identify disruptions in MEF2c-dependent transcription of Myoc as a novel mechanism of cancer-associated muscle wasting that is similarly disrupted in muscle of patients with cachectic cancer.Significance:This work identifies a novel transcriptional mechanism that mediates skeletal muscle wasting in murine models of cancer cachexia that is disrupted in skeletal muscle of patients with cancer exhibiting cachexia. Full Article
wit Thalamic Massa Intermedia in Children with and without Midline Brain Malformations [PEDIATRICS] By www.ajnr.org Published On :: 2020-04-09T06:30:48-07:00 BACKGROUND AND PURPOSE: The massa intermedia is a normal midline transventricular thalamic connection. Massa intermedia aberrations are common in schizophrenia, Chiari II malformation, X-linked hydrocephalus, Cornelia de Lange syndrome, and diencephalic-mesencephalic junction dysplasia, among others. We have noticed that massa intermedia abnormalities often accompany other midline malformations. The massa intermedia has never been formally evaluated in a group of exclusively pediatric patients, to our knowledge. We sought to compare and contrast the prevalence, size, and location of the massa intermedia in pediatric patients with and without congenital midline brain abnormalities. MATERIALS AND METHODS: Successive 3T brain MR imaging examinations from pediatric patients with and without midline malformations were procured from the imaging data base at a pediatric hospital. Massa intermedia presence, size, morphology, and position were determined using 3D-TIWI with 1-mm isotropic resolution. The brain commissures, septum pellucidum, hypothalamus, hippocampus, vermis, and brain stem were evaluated to determine whether alterations were related to or predictive of massa intermedia abnormalities. RESULTS: The massa intermedia was more frequently absent, dysmorphic, and/or displaced in patients with additional midline abnormalities than in those without. The massa intermedia was absent in 40% of patients with midline malformations versus 12% of patients with normal findings (P < .001). Massa intermedia absence, surface area, and morphology were predictable by various attributes and alterations of the commissures, hippocampus, hypothalamus, vermis, brain stem, and third ventricle. CONCLUSIONS: Most pediatric patients have a thalamic massa intermedia centered in the anterior/superior third ventricle. Massa intermedia abnormalities are commonly associated with other midline malformations. Normal-variant massa intermedia absence is a diagnosis of exclusion. Full Article
wit Advanced ADC Histogram, Perfusion, and Permeability Metrics Show an Association with Survival and Pseudoprogression in Newly Diagnosed Diffuse Intrinsic Pontine Glioma: A Report from the Pediatric Brain Tumor Consortium [FUNCTIONAL] By www.ajnr.org Published On :: 2020-04-09T06:30:48-07:00 BACKGROUND AND PURPOSE: Diffuse intrinsic pontine glioma is a lethal childhood brain cancer with dismal prognosis and MR imaging is the primary methodology used for diagnosis and monitoring. Our aim was to determine whether advanced diffusion, perfusion, and permeability MR imaging metrics predict survival and pseudoprogression in children with newly diagnosed diffuse intrinsic pontine glioma. MATERIALS AND METHODS: A clinical trial using the poly (adenosine diphosphate ribose) polymerase (PARP) inhibitor veliparib concurrently with radiation therapy, followed by maintenance therapy with veliparib + temozolomide, in children with diffuse intrinsic pontine glioma was conducted by the Pediatric Brain Tumor Consortium. Standard MR imaging, DWI, dynamic contrast-enhanced perfusion, and DSC perfusion were performed at baseline and approximately every 2 months throughout treatment. ADC histogram metrics of T2-weighted FLAIR and enhancing tumor volume, dynamic contrast-enhanced permeability metrics for enhancing tumors, and tumor relative CBV from DSC perfusion MR imaging were calculated. Baseline values, post-radiation therapy changes, and longitudinal trends for all metrics were evaluated for associations with survival and pseudoprogression. RESULTS: Fifty children were evaluable for survival analyses. Higher baseline relative CBV was associated with shorter progression-free survival (P = .02, Q = 0.089) and overall survival (P = .006, Q = 0.055). Associations of higher baseline mean transfer constant from the blood plasma into the extravascular extracellular space with shorter progression-free survival (P = .03, Q = 0.105) and overall survival (P = .03, Q = 0.102) trended toward significance. An increase in relative CBV with time was associated with shorter progression-free survival (P < .001, Q < 0.001) and overall survival (P = .004, Q = 0.043). Associations of longitudinal mean extravascular extracellular volume fraction with progression-free survival (P = .03, Q = 0.104) and overall survival (P = .03, Q = 0.105) and maximum transfer constant from the blood plasma into the extravascular extracellular space with progression-free survival (P = .03, Q = 0.102) trended toward significance. Greater increases with time were associated with worse outcomes. True radiologic progression showed greater post-radiation therapy decreases in mode_ADC_FLAIR compared with pseudoprogression (means, –268.15 versus –26.11, P = .01.) CONCLUSIONS: ADC histogram, perfusion, and permeability MR imaging metrics in diffuse intrinsic pontine glioma are useful in predicting survival and pseudoprogression. Full Article
wit Assessment of Apparent Internal Carotid Tandem Occlusion on High-Resolution Vessel Wall Imaging: Comparison with Digital Subtraction Angiography [EXTRACRANIAL VASCULAR] By www.ajnr.org Published On :: 2020-04-09T06:30:48-07:00 BACKGROUND AND PURPOSE: Not all tandem occlusions diagnosed on traditional vascular imaging modalities, such as MRA, represent actual complete ICA occlusion. This study aimed to explore the utility of high-resolution vessel wall imaging in identifying true ICA tandem occlusions and screening patients for their suitability for endovascular recanalization. MATERIALS AND METHODS: Patients with no signal in the ICA on MRA were retrospectively reviewed. Two neuroradiologists independently reviewed their high-resolution vessel wall images to assess whether there were true tandem occlusions and categorized all cases into intracranial ICA occlusion, extracranial ICA occlusion, tandem occlusion, or near-occlusion. DSA classified patient images into the same 4 categories, which were used as the comparison with high-resolution vessel wall imaging. The suitability for recanalization of occluded vessels was evaluated on high-resolution vessel wall imaging compared with DSA. RESULTS: Forty-five patients with no ICA signal on MRA who had available high-resolution vessel wall imaging and DSA images were included. Among the 34 patients (34/45, 75.6%) with tandem occlusions on DSA, 18 cases also showed tandem occlusions on high-resolution vessel wall imaging. The remaining 16 patients, intracranial ICA, extracranial ICA occlusions and near-occlusions were found in 2, 6, and 8 patients, respectively, on the basis of high-resolution vessel wall imaging. A total of 20 cases (20/45, 44.4%) were considered suitable for recanalization on the basis of both DSA and high-resolution vessel wall imaging. Among the 25 patients deemed unsuitable for recanalization by DSA, 11 were deemed suitable for recanalization by high-resolution vessel wall imaging. CONCLUSIONS: High-resolution vessel wall imaging could allow identification of true ICA tandem occlusion in patients with an absence of signal on MRA. Findings on high-resolution vessel wall imaging can be used to screen more suitable candidates for recanalization therapy. Full Article
wit Treatment Outcomes of Endovascular Embolization Only in Patients with Unruptured Brain Arteriovenous Malformations: A Subgroup Analysis of ARUBA (A Randomized Trial of Unruptured Brain Arteriovenous Malformations) [INTERVENTIONAL] By www.ajnr.org Published On :: 2020-04-09T06:30:48-07:00 BACKGROUND AND PURPOSE: Endovascular embolization only has been advocated for treatment of brain arteriovenous malformations in recent trials. Our aim was to evaluate the results of embolization only in a cohort of patients who were enrolled in the A Randomized Trial of Unruptured Brain Arteriovenous Malformations (ARUBA) study at 39 clinical sites in 9 countries. MATERIALS AND METHODS: We analyzed the rates and severity of stroke and death in patients who underwent embolization only. Events were identified through in-person neurologic follow-up visits performed at 6-month intervals during the first 2 years and annually, with telephone contact every 6 months thereafter. All event-related data were reviewed by independent adjudicators. RESULTS: Among 30 patients who had embolization planned, 26 underwent embolization only. A total of 13 stroke events were reported in the follow-up period among 26 subjects (ischemic, hemorrhagic, or both in 4, 7, and 2 subjects, respectively). The adverse event occurred after the first embolization in 11 of 13 patients. One patient had a major motor deficit, and 2 patients developed major visual field deficits. One event was fatal. The modified Rankin Scale score was 0–2 at last follow-up in 11 of the 12 stroke survivors. Estimated stroke-free survival was 46% at 12 months. CONCLUSIONS: Although the rates of stroke and/or death were high in patients treated with embolization only in ARUBA, the rates of favorable outcomes following stroke were high during follow-up. Full Article
wit CT Angiography in Evaluating Large-Vessel Occlusion in Acute Anterior Circulation Ischemic Stroke: Factors Associated with Diagnostic Error in Clinical Practice [INTERVENTIONAL] By www.ajnr.org Published On :: 2020-04-09T06:30:48-07:00 BACKGROUND AND PURPOSE: It is currently not completely clear how well radiologists perform in evaluating large-vessel occlusion on CTA in acute ischemic stroke. The purpose of this study was to investigate potential factors associated with diagnostic error. MATERIALS AND METHODS: Five hundred twenty consecutive patients with a clinical diagnosis of acute ischemic stroke (49.4% men; mean age, 72 years) who underwent CTA to evaluate large-vessel occlusion of the proximal anterior circulation were included. CTA scans were retrospectively reviewed by a consensus panel of 2 neuroradiologists. Logistic regression analysis was performed to investigate the association between several variables and missed large-vessel occlusion at the initial CTA interpretation. RESULTS: The prevalence of large-vessel occlusion was 16% (84/520 patients); 20% (17/84) of large-vessel occlusions were missed at the initial CTA evaluation. In multivariate analysis, non-neuroradiologists were more likely to miss large-vessel occlusion compared with neuroradiologists (OR = 5.62; 95% CI, 1.06–29.85; P = .04), and occlusions of the M2 segment were more likely to be missed compared with occlusions of the distal internal carotid artery and/or M1 segment (OR = 5.69; 95% CI, 1.44–22.57; P = .01). There were no calcified emboli in initially correctly identified large-vessel occlusions. However, calcified emboli were present in 4 of 17 (24%) initially missed or misinterpreted large-vessel occlusions. CONCLUSIONS: Several factors may have an association with missing a large-vessel occlusion on CTA, including the CTA interpreter (non-neuroradiologists versus neuroradiologists), large-vessel occlusion location (M2 segment versus the distal internal carotid artery and/or M1 segment), and large-vessel occlusion caused by calcified emboli. Awareness of these factors may improve the accuracy in interpreting CTA and eventually improve stroke outcome. Full Article
wit Anoxic Brain Injury Detection with the Normalized Diffusion to ASL Perfusion Ratio: Implications for Blood-Brain Barrier Injury and Permeability [FUNCTIONAL] By www.ajnr.org Published On :: 2020-04-09T06:30:48-07:00 BACKGROUND AND PURPOSE: Anoxic brain injury is a result of prolonged hypoxia. We sought to describe the nonquantitative arterial spin-labeling perfusion imaging patterns of anoxic brain injury, characterize the relationship of arterial spin-labeling and DWI, and evaluate the normalized diffusion-to-perfusion ratio to differentiate patients with anoxic brain injury from healthy controls. MATERIALS AND METHODS: We identified all patients diagnosed with anoxic brain injuries from 2002 to 2019. Twelve ROIs were drawn on arterial spin-labeling with coordinate-matched ROIs identified on DWI. Linear regression analysis was performed to examine the relationship between arterial spin-labeling perfusion and diffusion signal. Normalized diffusion-to-perfusion maps were generated using a custom-built algorithm. RESULTS: Thirty-five patients with anoxic brain injuries and 34 healthy controls were identified. Linear regression analysis demonstrated a significant positive correlation between arterial spin-labeling and DWI signal. By means of a combinatory cutoff of slope of >0 and R2 of > 0.78, linear regression using arterial spin-labeling and DWI showed a sensitivity of 0.86 (95% CI, 0.71–0.94) and specificity of 0.82 (95% CI, 0.66–0.92) for anoxic brain injuries. A normalized diffusion-to-perfusion color map demonstrated heterogeneous ratios throughout the brain in healthy controls and homogeneous ratios in patients with anoxic brain injuries. CONCLUSIONS: In anoxic brain injuries, a homogeneously positive correlation between qualitative perfusion and DWI signal was identified so that areas of increased diffusion signal showed increased ASL signal. By exploiting this relationship, the normalized diffusion-to-perfusion ratio color map may be a valuable imaging biomarker for diagnosing anoxic brain injury and potentially assessing BBB integrity. Full Article
wit Hippocampal Sclerosis Detection with NeuroQuant Compared with Neuroradiologists [FUNCTIONAL] By www.ajnr.org Published On :: 2020-04-09T06:30:48-07:00 BACKGROUND AND PURPOSE: NeuroQuant is an FDA-approved software that performs automated MR imaging quantitative volumetric analysis. This study aimed to compare the accuracy of NeuroQuant analysis with visual MR imaging analysis by neuroradiologists with expertise in epilepsy in identifying hippocampal sclerosis. MATERIALS AND METHODS: We reviewed 144 adult patients who underwent presurgical evaluation for temporal lobe epilepsy. The reference standard for hippocampal sclerosis was defined by having hippocampal sclerosis on pathology (n = 61) or not having hippocampal sclerosis on pathology (n = 83). Sensitivities, specificities, positive predictive values, and negative predictive values were compared between NeuroQuant analysis and visual MR imaging analysis by using a McNemar paired test of proportions and the Bayes theorem. RESULTS: NeuroQuant analysis had a similar specificity to neuroradiologist visual MR imaging analysis (90.4% versus 91.6%; P = .99) but a lower sensitivity (69.0% versus 93.0%, P < .001). The positive predictive value of NeuroQuant analysis was comparable with visual MR imaging analysis (84.0% versus 89.1%), whereas the negative predictive value was not comparable (79.8% versus 95.0%). CONCLUSIONS: Visual MR imaging analysis by a neuroradiologist with expertise in epilepsy had a higher sensitivity than did NeuroQuant analysis, likely due to the inability of NeuroQuant to evaluate changes in hippocampal T2 signal or architecture. Given that there was no significant difference in specificity between NeuroQuant analysis and visual MR imaging analysis, NeuroQuant can be a valuable tool when the results are positive, particularly in centers that lack neuroradiologists with expertise in epilepsy, to help identify and refer candidates for temporal lobe epilepsy resection. In contrast, a negative test could justify a case referral for further evaluation to ensure that false-negatives are detected. Full Article
wit Apartment 3 bedrooms with river view fully furnished in Diamond Island for rent By batdongsan.com.vn Published On :: Mon, 23 Mar 2020 23:00:00 GMT Diamond Island apartment for rent, CA-XX.01, designed with 3 bedrooms, 2 bathrooms, living room, kitchen, fully furnished, total area 117m2, airy river view.Price: $ 1,500 / MonthDiamond Island apartment is the most high-class apartment project in Ho Chi Minh City at present, spe... Full Article
wit Nice house for rent on street 4, Ha Quang 2 urban area, Nha Trang city with the best price. By batdongsan.com.vn Published On :: Sat, 04 Apr 2020 16:26:05 GMT - Nice house located on the road No. 4 urban area Ha Quang 2, Phuoc Hai Ward, City of Nha Trang. - With an area of 110m2 per floor, horizontal 5m, the house has 4 floors and terrace, used area up to 500m2. - 1st floor, 2nd floor, 3rd floor smoothly built, suitable for opening com... Full Article
wit Need to rent a big house on A2 street, urban area in Nha Trang city with cheapest price in the area By batdongsan.com.vn Published On :: Sat, 04 Apr 2020 16:28:50 GMT The house is located on A2, beautiful shimmering, suitable for opening a company, Restaurant, spa, showroom ... In Urban Area, Phuoc Hai Industrial Area, Nha Trang City. - With an area of 220m2 per floor, the house has 4 floors, the usable area is up to 900m2 - The ground floor... Full Article
wit Villa Riviera An Phu for sale includes 1 ground floor, 2 floors, 5 bedrooms with garden By batdongsan.com.vn Published On :: Mon, 24 Feb 2020 09:27:00 GMT Villa Rivierais a high-class compound, a luxury villa near the Saigon river with modern and high-class architectural villas. Villa Riviera An Phu villa for salehas an architecture of 1 ground floor, 2 floors with a total area of 350m2, land area of 300m2, including 5 bedrooms, 5 ... Full Article
wit Luxury villa need for sale at Villa Riviera, 5 bedrooms, 3 floors with large garden By batdongsan.com.vn Published On :: Mon, 24 Feb 2020 09:28:06 GMT Villa Riviera needs for sale villa in District 2located at An Phu ward, land area of 289m2, built with 1 ground floor, 2 floors, including 1 large living room, 5 bedrooms, 1 working room, 1 main room (with WC), 2 kitchens, 6 bathrooms. Price:45 Billion VND~1,937,000 USD.Hotline: ... Full Article
wit Room with fully furnished and clean for rent, suitable for short/long term, office-159/9 Bach Dang By batdongsan.com.vn Published On :: Mon, 16 Mar 2020 23:00:25 GMT Studio room http://www.mkhome.vn at 159/9 Bach Dang Street, Ward 2, Tan Binh District is cool, full of light. 3 minutes from the airport by motorbike The house is kept clean. Quiet space, suitable for IT staff, foreign teachers, flight attendants, pilots, long-term business trav... Full Article
wit Room with full furniture and clean for lease at 159/9 Bach Dang Street By batdongsan.com.vn Published On :: Thu, 26 Mar 2020 20:57:04 GMT Studio Room at 159/9 Bach Dang Street, Ward 2, Tan Binh District http://www.mkhome.vn - 3 minutes from the airport by motorbike, right next to the greenest park in Saigon, next to Market and Supermarket. - The house is kept clean. - Quiet space, suitable for IT staff, business ... Full Article
wit SMART APARTMENT WITH 1 BEDROOM IN CENTER DISTRICT 7 (JAMONA HEIGHT) By batdongsan.com.vn Published On :: Thu, 07 May 2020 16:35:00 GMT Recently, TTC Land has officially launched the first service office line at Jamona Heights apartment in District 7, office apartments designed according to Korean standards designed by GanSam Corporation (Korean). , with a prime location in the heart of South Saigon. Project loca... Full Article
wit Mini apartment with an area of 30m2, 1.2 billion price, 5 star facilities, riverside habitat-Jamona By batdongsan.com.vn Published On :: Thu, 07 May 2020 16:44:00 GMT Smart 1-to-2 investment opportunity with TTC Land's Smartel Jamona Heights.Just working at the office of the company - just staying.Diverse area of 30m2 - 79m2.OCB bank borrows 50%.Payment in 18 months.There are 650 million still can invest in real estate in the center.50 year sa... Full Article
wit City Garden apartment for sale with 2 bedrooms, 108m2, fully furnished luxurious By batdongsan.com.vn Published On :: Thu, 07 May 2020 21:11:00 GMT City Garden apartment for sale areas 108m2, located on the 19th-floor Phase 2 Promenade designed with 2 bedrooms and 2 bathrooms, is an ideal solution for families who want to work and study. near the center of District 1. The apartment is designed to be open modern, natural ligh... Full Article
wit Condo with 2BR for sales at Sunwah Pearl - closing to City center - high rental yields +84911130135 By batdongsan.com.vn Published On :: Fri, 08 May 2020 16:21:06 GMT DEVELOPER: Sunwah Group is a highly diversified conglomerate with businesses in seven principal areas: Seafood & Foodstuff, Real Estate, Financial Services, Technology, Media, Infrastructure and Education and training. Activities extend deep into Mainland China as well as to the ... Full Article
wit Need for rent Shophouse 170m2 with 3 floors Song Hanh facade in Masteri An Phu By batdongsan.com.vn Published On :: Thu, 07 May 2020 21:11:00 GMT Shophouse for rent Masteri An Phu, frontage Song Hanh Street, District 2, parallel to Hanoi Highway, right at An Phu Metro Station (No. 7), Area: 170.4m2 (5.8110.73m) Shophouse consists of 3 floors, above is the high-class facilities of residents. Rough house Price: 141 millio... Full Article
wit Townhouse with 2 frontages, Corner intersection; Great for Business & Offices By batdongsan.com.vn Published On :: Mon, 25 Nov 2019 10:39:00 GMT + Townhouse for lease with Two Fronts, corner intersection, 30m from Au Co St., 6m wide road, convenient traffic cars. + Crowded residential area, surrounded by many offices, schools, apartments, mini supermarkets, cafes ... + An awesome deal for trading in pharmacies, cafes, min... Full Article
wit How to avoid drowning in real estate debt with average income? By batdongsan.com.vn Published On :: 10:48 22/10/2019 [Having appointment with real estate experts #5] While buying a home is quite easy for high-income households, it is another story for the middle-class. With a wise and specific financial plan, the chances of owning a home can still lie within reach even if an average income. Full Article
wit Legal framework for condotels must be completed within this year: PM By batdongsan.com.vn Published On :: 11:40 24/10/2019 Prime Minister Nguyen Xuan Phuc has just asked the Ministry of Construction (MoC) to promulgate regulations on amendments and supplements to construction standards and rules for condominiums, condotels, resort villas, officetels and rooms for rent. Full Article