Publications by authors named "Thomas Ernst"

276 Publications

Associations of the Dietary Inflammatory Index with total adiposity and ectopic fat through the gut microbiota, lipopolysaccharides, and C-reactive protein in the Multiethnic Cohort-Adiposity Phenotype Study.

Am J Clin Nutr 2021 Dec 6. Epub 2021 Dec 6.

Fred Hutchinson Cancer Research Center.

Background Mechanisms linking a pro-inflammatory diet to obesity remain under investigation. The ability of diet to influence the gut microbiome (GM) in creating chronic low-grade systemic inflammation provides a plausible connection to adiposity.

Methods: In the cross-sectional Multiethnic Cohort Adiposity Phenotype Study (812 men, 843 women, 60 to 77 years) we tested whether associations between the energy-adjusted Dietary Inflammatory Index (E-DIITM) score and total adiposity, visceral adipose tissue (VAT), and liver fat (% volume) function through the GM, lipopolysaccharides (LPS), and high-sensitivity C-reactive protein (hs-CRP). Dual energy X-ray absorptiometry (DXA)-derived total fat mass, MRI-measured VAT, and MRI-based liver fat were measured. Participants provided stool and fasting blood samples and completed a food frequency questionnaire (FFQ). Stool bacterial DNA was amplified and the 16S rRNA gene was sequenced at the V1-V3 region. E-DII score was computed from FFQ data, with a higher E-DII representing a more pro-inflammatory diet. The associations between E-DII score, GM (10 phyla, 28 genera, alpha diversity), and adiposity phenotypes were examined using linear regression and mediation analyses, adjusting for confounders.

Results: There were positive total effects (c) between E-DII and total fat mass (c = 0.68; 95% CI = 0.47, 0.90), VAT (c = 4.61; 95% CI = 2.95, 6.27), and liver fat (c = 0.40; 95% CI = 0.27, 0.53). The association between E-DII score and total fat mass was mediated by LPS, Flavonifractor, [Ruminococcus] gnavus group, and Tyzzerella. The association between E-DII score and ectopic fat occurred indirectly through Fusobacteria, Christensenellaceae R-7 group, Coprococcus 2, Escherichia- Shigella, [Eubacterium] xylanophilum group, Flavonifractor, Lachnoclostridium, [Ruminococcus] gnavus group, Tyzzerella, [Ruminococcus] gnavus group (VAT only), and alpha diversity (liver fat only). There was no significant association between E-DII score and adiposity phenotype through hs-CRP.

Conclusion: Associations found between E-DII and adiposity phenotypes occurred through the GM and LPS.
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http://dx.doi.org/10.1093/ajcn/nqab398DOI Listing
December 2021

Contributions of chronic tobacco smoking to HIV-associated brain atrophy and cognitive deficits.

AIDS 2021 Dec 2. Epub 2021 Dec 2.

Department of Diagnostic Radiology and Nuclear Medicine, University of Maryland School of Medicine, Baltimore, MD, USA Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA Department of Neurology, University of Maryland School of Medicine, Baltimore, MD, USA Department of Medicine, John A. Burns School of Medicine, University of Hawaii at Manoa, Honolulu, HI, USA.

Objectives: Tobacco smoking is linked to cognitive deficits and greater white matter (WM) abnormalities in people with HIV disease (PWH). Whether tobacco smoking additionally contributes to brain atrophy in PWH is unknown and was evaluated in this study.

Design: We used a 2 × 2 design that included 83 PWH (43 nonsmokers, 40 smokers) and 171 HIV-seronegative (SN, 106 nonsmokers, 65 smokers) participants and assessed their brain structure and cognitive function.

Methods: Selected subcortical volumes, voxel-wise cortical volumes and thickness, and total WM volume were analyzed using FreeSurfer. Independent and interactive effects of HIV and smoking were evaluated with two-way analysis of covariance on cognitive domain Z-scores and morphometric measures on T1-weighted MRI.

Results: Regardless of smoking status, relative to SN, PWH had smaller brain volumes [basal ganglia, thalami, hippocampi, subcortical gray matter (GM) and cerebral WM volumes (p = 0.002-0.042)], steeper age-related declines in the right superior-parietal (interaction-p < 0.001) volumes, and poorer attention/working memory and learning (p = 0.016-0.027). Regardless of HIV serostatus, smokers tended to have smaller hippocampi than nonsmokers (-0.6%, p = 0.055). PWH smokers had the smallest total and regional subcortical GM and cortical WM volume and poorest cognitive performance.

Conclusions: Tobacco smoking additionally contributed to brain atrophy and cognitive deficits in PWH. The greater brain atrophy in PWH smokers may be due to greater neuronal damage or myelin loss in various brain regions, leading to their poor cognitive performance. Therefore, tobacco smoking may exacerbate or increase the risk for HIV-associated neurocognitive disorders.
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http://dx.doi.org/10.1097/QAD.0000000000003138DOI Listing
December 2021

The log odds of positive neck lymph nodes is a superior lymph node predictor for overall survival in head and neck cancer: a population-based analysis in Germany.

Eur Arch Otorhinolaryngol 2021 Nov 22. Epub 2021 Nov 22.

Department of Otorhinolaryngology, Jena University Hospital, Am Klinikum 1, 07747, Jena, Germany.

Background: This population-based study investigated the influence of different lymph node (LN) classifications on overall survival (OS) in head and neck cancer (HNC).

Methods: 401 patients (median age: 57 years; 47% stage IV) of the Thuringian cancer registries with diagnosis of a primary HNC receiving a neck dissection (ND) in 2009 and 2010 were included. OS was assessed in relation to total number of LN removed, number of positive LN, LN ratio, and log odds of positive LN (LODDS).

Results: Mean number of LODDS was 0-0.96 ± 0.57. When limiting the multivariate analysis to TNM stage, only the UICC staging (stage IV: HR 9.218; 95% CI 2.721-31.224; p < 0.001) and LODDS >  - 1.0 (HR 2.120; 95% CI 1.129-3.982; p = 0.019) were independently associated with lower OS.

Conclusion: LODDS was an independent and superior predictor for OS in HNC in a population-based setting with representative real-life data.
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http://dx.doi.org/10.1007/s00405-021-07176-8DOI Listing
November 2021

Publisher Correction: SIRT7: an influence factor in healthy aging and the development of age-dependent myeloid stem-cell disorders.

Leukemia 2021 Dec;35(12):3632

Klinik für Innere Medizin II, Abteilung Hämatologie und Internistische Onkologie, Universitätsklinikum Jena, Jena, Germany.

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http://dx.doi.org/10.1038/s41375-021-01365-4DOI Listing
December 2021

Race/ethnicity-associated blood DNA methylation differences between Japanese and European American women: an exploratory study.

Clin Epigenetics 2021 10 11;13(1):188. Epub 2021 Oct 11.

Population Sciences in the Pacific Program, University of Hawaii Cancer Center, University of Hawaii at Manoa, Honolulu, HI, USA.

Background: Racial/ethnic disparities in health reflect a combination of genetic and environmental causes, and DNA methylation may be an important mediator. We compared in an exploratory manner the blood DNA methylome of Japanese Americans (JPA) versus European Americans (EUA).

Methods: Genome-wide buffy coat DNA methylation was profiled among healthy Multiethnic Cohort participant women who were Japanese (JPA; n = 30) or European (EUA; n = 28) Americans aged 60-65. Differentially methylated CpGs by race/ethnicity (DM-CpGs) were identified by linear regression (Bonferroni-corrected P < 0.1) and analyzed in relation to corresponding gene expression, a priori selected single nucleotide polymorphisms (SNPs), and blood biomarkers of inflammation and metabolism using Pearson or Spearman correlations (FDR < 0.1).

Results: We identified 174 DM-CpGs with the majority of hypermethylated in JPA compared to EUA (n = 133), often in promoter regions (n = 48). Half (51%) of the genes corresponding to the DM-CpGs were involved in liver function and liver disease, and the methylation in nine genes was significantly correlated with gene expression for DM-CpGs. A total of 156 DM-CpGs were associated with rs7489665 (SH2B1). Methylation of DM-CpGs was correlated with blood levels of the cytokine MIP1B (n = 146). We confirmed some of the DM-CpGs in the TCGA adjacent non-tumor liver tissue of Asians versus EUA.

Conclusion: We found a number of differentially methylated CpGs in blood DNA between JPA and EUA women with a potential link to liver disease, specific SNPs, and systemic inflammation. These findings may support further research on the role of DNA methylation in mediating some of the higher risk of liver disease among JPA.
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http://dx.doi.org/10.1186/s13148-021-01171-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8507376PMC
October 2021

Diet and Liver Adiposity in Older Adults: The Multiethnic Cohort Adiposity Phenotype Study.

J Nutr 2021 Nov;151(11):3579-3587

Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.

Background: Diet plays a key role in the pathogenesis of nonalcoholic fatty liver disease. Limited data exist regarding specific nutrients and food groups and liver fat continuously, particularly among different ethnicities.

Objectives: We aimed to determine the relationship between usual dietary intake and accurately measured liver fat content in a multiethnic population.

Methods: Participants from the Multiethnic Cohort were recruited into the cross-sectional Adiposity Phenotype Study including women and men aged 60-77 y and 5 race/ethnic groups (African American, Japanese American, Latino, Native Hawaiian, and white). They filled out a detailed FFQ and underwent abdominal MRI for liver fat quantification and whole-body DXA for total adiposity. Intake of a priori-selected dietary factors (total and macronutrient energy, specific micronutrients, and food groups) was analyzed in relation to liver fat by estimating the mean percentage liver fat for quartiles of each dietary factor in a general linear model that adjusted for age, sex, race/ethnicity, percentage body fat, and daily energy intake (kcal/d).

Results: In total, 1682 participants (mean age: 69.2 y; 51% female) were included. Mean ± SD liver fat percentage was 5.7 ± 4.6. A significant positive association with liver fat was found across quartiles of percentage energy from fat, saturated fat, cholesterol, total red meat, red meat excluding processed red meat, and coffee (Bonferroni-adjusted P-trend < 0.05). A significant inverse association was observed for dietary fiber, vitamin C, and vitamin E (Bonferroni-adjusted P-trend < 0.05).

Conclusions: This study of ethnically diverse older adults shows that certain dietary factors, in particular red meat and saturated fat from red meat, were strongly associated with liver fat, whereas dietary fiber was inversely associated with liver fat, replicating some of the previous studies conducted mostly in whites.
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http://dx.doi.org/10.1093/jn/nxab300DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8564699PMC
November 2021

Associations of the gut microbiome with hepatic adiposity in the Multiethnic Cohort Adiposity Phenotype Study.

Gut Microbes 2021 Jan-Dec;13(1):1965463

Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, U.S.A.

Nonalcoholic fatty liver disease (NAFLD) is a risk factor for liver cancer and prevalence varies by ethnicity. Along with genetic and lifestyle factors, the gut microbiome (GM) may contribute to NAFLD and its progression to advanced liver disease. Our cross-sectional analysis assessed the association of the GM with hepatic adiposity among African American, Japanese American, White, Latino, and Native Hawaiian participants in the Multiethnic Cohort. We used MRI to measure liver fat and determine nonalcoholic fatty liver disease (NAFLD) status (n = 511 cases) in 1,544 participants, aged 60-77 years, with 12-53% overall adiposity (BMI of 17.8-46.2 kg/m). The GM was measured by 16S rRNA gene sequencing and, on a subset, by metagenomic sequencing. Alpha diversity was lower overall with NAFLD and in certain ethnicities (African Americans, Whites, and Latinos). In models regressing genus on NAFLD status, 62 of 149 genera (40%) exhibited a significant interaction between NAFLD and ethnicity stratified analysis found 69 genera significantly associated with NAFLD in at least one ethnic group. No single genus was significantly associated with NAFLD across all ethnicities. In contrast, the same bacterial metabolic pathways were over-represented in participants with NAFLD regardless of ethnicity. Imputed secondary bile acid and carbohydrate pathways were associated with NAFLD, the latter of which was corroborated by metagenomics, although different genera in different ethnicities were associated with these pathways. Overall, we found that NAFLD was associated with altered bacterial composition and metabolism, and that bacterial endotoxin, assessed by plasma lipopolysaccharide binding protein (LBP), may mediate liver fat-associated systemic inflammation in a manner that seems to vary by ethnicity.
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http://dx.doi.org/10.1080/19490976.2021.1965463DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8425768PMC
September 2021

Genome-wide association study of pancreatic fat: The Multiethnic Cohort Adiposity Phenotype Study.

PLoS One 2021 30;16(7):e0249615. Epub 2021 Jul 30.

University of Hawaii Cancer Center, University of Hawaii at Mānoa, Honolulu, Hawaii, United States of America.

Several studies have found associations between higher pancreatic fat content and adverse health outcomes, such as diabetes and the metabolic syndrome, but investigations into the genetic contributions to pancreatic fat are limited. This genome-wide association study, comprised of 804 participants with MRI-assessed pancreatic fat measurements, was conducted in the ethnically diverse Multiethnic Cohort-Adiposity Phenotype Study (MEC-APS). Two genetic variants reaching genome-wide significance, rs73449607 on chromosome 13q21.2 (Beta = -0.67, P = 4.50x10-8) and rs7996760 on chromosome 6q14 (Beta = -0.90, P = 4.91x10-8) were associated with percent pancreatic fat on the log scale. Rs73449607 was most common in the African American population (13%) and rs79967607 was most common in the European American population (6%). Rs73449607 was also associated with lower risk of type 2 diabetes (OR = 0.95, 95% CI = 0.89-1.00, P = 0.047) in the Population Architecture Genomics and Epidemiology (PAGE) Study and the DIAbetes Genetics Replication and Meta-analysis (DIAGRAM), which included substantial numbers of non-European ancestry participants (53,102 cases and 193,679 controls). Rs73449607 is located in an intergenic region between GSX1 and PLUTO, and rs79967607 is in intron 1 of EPM2A. PLUTO, a lncRNA, regulates transcription of an adjacent gene, PDX1, that controls beta-cell function in the mature pancreas, and EPM2A encodes the protein laforin, which plays a critical role in regulating glycogen production. If validated, these variants may suggest a genetic component for pancreatic fat and a common etiologic link between pancreatic fat and type 2 diabetes.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0249615PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8323875PMC
October 2021

Biomarker-based visceral adiposity score and incident type 2 diabetes in the multiethnic cohort.

Ann Epidemiol 2021 11 21;63:29-34. Epub 2021 Jul 21.

University of Hawaii Cancer Center, Honolulu, HI. Electronic address:

Purpose: Visceral adipose tissue (VAT) may be more important than subcutaneous fat in type 2 diabetes (T2D) etiology. We examined a VAT score developed in reference to MRI measurement of VAT in the Multiethnic Cohort (MEC) as a risk factor for incident T2D.

Methods: Two nested case-control studies of cancer allowed calculation of the VAT score based on anthropometric measures and 8 biomarkers among 2,556 participants without T2D. Incident cases were identified from Medicare linkages and self-reports after blood draws in 2001-2006. Cox regression with age as time metric was applied to estimate the association of the VAT score with T2D.

Results: During 10.1 ± 2.4 years, 355 incident T2D cases were identified. VAT scores were higher in T2D cases than among those without disease (5.06±0.43 vs. 4.95±0.41; P<0.0001) and significantly associated with T2D (HR = 2.70; 95%CI 1.60, 4.58 per unit) with similar values in men (HR = 2.99; 95%CI 1.03, 8.73) and women (HR = 2.61; 95%CI 1.39, 4.91). A significant association was observed in all five ethnic groups but only statistically significant among Japanese Americans (HR = 6.24; 95%CI 2.34, 16.68).

Conclusion: These findings support that VAT as estimated by a biomarker-based score predicts T2D incidence beyond BMI in particular among older adults of Japanese ancestry.
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http://dx.doi.org/10.1016/j.annepidem.2021.07.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8500936PMC
November 2021

Complementary and alternative medicine (CAM) supplements in cancer outpatients: analyses of usage and of interaction risks with cancer treatment.

J Cancer Res Clin Oncol 2021 Jul 6. Epub 2021 Jul 6.

Klinik für Innere Medizin II, Hämatologie und Internistische Onkologie, Integrative Onkologie, Universitätsklinikum Jena, Am Klinikum 1, 07747, Jena, Germany.

Purpose: The aim of our study was to analyze the use of complementary and alternative medicine (CAM) supplements, identify possible predictors, and analyze and compile potential interactions of CAM supplements with conventional cancer therapy.

Methods: We included outpatient cancer patients treated at a German university hospital in March or April 2020. Information was obtained from questionnaires and patient records. CAM-drug interactions were identified based on literature research for each active ingredient of the supplements consumed by the patients.

Results: 37.4% of a total of 115 patients consumed CAM supplements. Potential interactions with conventional cancer treatment were identified in 51.2% of these patients. All types of CAM supplements were revealed to be a potential source for interactions: vitamins, minerals, food and plant extracts, and other processed CAM substances. Younger age (< 62 years) (p = 0.020, φc = 0.229) and duration of individual cancer history of more than 1 year (p = 0.006, φc = 0.264) were associated with increased likelihood of CAM supplement use. A wide range of different CAM supplement interactions were reviewed: effects of antioxidants, cytochrome (CYP) interactions, and specific agonistic or antagonistic effects with cancer treatment.

Conclusion: The interaction risks of conventional cancer therapy with over-the-counter CAM supplements seem to be underestimated. Supplements without medical indication, as well as overdoses, should be avoided, especially in cancer patients. To increase patient safety, physicians should address the risks of interactions in physician-patient communication, document the use of CAM supplements in patient records, and check for interactions.
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http://dx.doi.org/10.1007/s00432-021-03675-7DOI Listing
July 2021

Integration of Ultra-Low Volume Pneumatic Microfluidics with a Three-Dimensional Electrode Network for On-Chip Biochemical Sensing.

Micromachines (Basel) 2021 Jun 28;12(7). Epub 2021 Jun 28.

Laboratory of Life Sciences Electronics, École Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland.

This paper reports a novel miniaturized pseudo reference electrode (RE) design for biasing Ion Sensitive Field Effect Transistors (ISFETs). It eliminates the need for post-CMOS processing and can scale up in numbers with the CMOS scaling. The presented design employs silane-mediated transfer of patterned gold electrode lines onto PDMS microfluidics such that the gold conformally coats the inside of microfluidic channel. Access to this electrode network is made possible by using "through-PDMS-vias" (TPV), which consist of high metal-coated SU-8 pillars manufactured by a novel process that employs a patterned positive resist layer as SU-8 adhesion depressor. When integrated with pneumatic valves, TPV and pseudo-RE network were able to bias 1.5 nanoliters (nL) of isolated electrolyte volumes. We present a detailed characterization of our pseudo-RE design demonstrating ISFET operation and its DC characterization. The stability of pseudo-RE is investigated by measuring open circuit potential (OCP) against a commercial Ag/AgCl reference electrode.
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http://dx.doi.org/10.3390/mi12070762DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8306664PMC
June 2021

Long-Term Facial Nerve Outcome in Primary Parotid Cancer Surgery: A Population-Based Analysis.

Laryngoscope 2021 12 29;131(12):2694-2700. Epub 2021 May 29.

Department of Otorhinolaryngology, Jena University Hospital, Jena, Germany.

Objectives/hypothesis: To determine immediate postoperative and long-term facial nerve dysfunction after parotid cancer surgery, risk factors, and the role of facial reanimation surgery.

Study Design: Population-based long-term analysis for all new primary parotid carcinoma cases in Thuringia from 1996 to 2019.

Methods: Data of the cancer registries of Thuringia, a federal state in Germany, were analyzed in combination with hospital-based data on facial function.

Results: About 477 patients (42.3% women; median age: 68 years) were included. It was observed that 6.7% had a preoperative facial nerve dysfunction, 11.7% received a radical parotidectomy, that is, that 5% had a normal preoperative facial function but needed radical surgery because of intraoperative detection of tumor infiltration into the facial nerve. About 10.2% received facial nerve reconstruction surgery. Immediate postoperative facial nerve dysfunction in the other patients was observed in 34.4% of the patients. Advanced T classification (odds ratio [OR] = 2.140; confidence interval [CI] = 1.268-3.611; P = .004) and neck dissection (OR = 2.012; CI = 1.027-3.940; P = .041) were independent risk factors for immediate postoperative facial nerve dysfunction. In addition, 22.0% showed no recovery during follow-up. Advanced T classification (OR = 2.177; CI = 1.147-4.133; P = .017) and postoperative radiotherapy (OR = 2.695; CI = 1.244-5.841; P = .012) were independent risk factors for permanent postoperative facial nerve dysfunction.

Conclusion: Patients with primary parotid cancer are at high risk for long-term facial nerve dysfunction. It seems that the possibilities of facial reanimation surgery needs to be utilized even more effectively.

Level Of Evidence: 3 Laryngoscope, 131:2694-2700, 2021.
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http://dx.doi.org/10.1002/lary.29666DOI Listing
December 2021

Metabolic syndrome screening using visceral adipose tissue (VAT) from opportunistic MRI locations in a multi-ethnic population.

Obes Res Clin Pract 2021 May-Jun;15(3):227-234. Epub 2021 May 21.

University of Hawaii Cancer Center, 701 Ilalo Street, Honolulu, HI, 96813, USA. Electronic address:

Objective: To determine if visceral adipose tissue (VAT) area measured through MRI can be used opportunistically to assess the presence of cardiometabolic risk factors and compare its performance to simpler adiposity measures.

Methods: A cross-sectional analysis was carried out on a subset of 1683 participants (856 women) from the Adiposity Phenotype Study (mean age=69.2y; range 59.9-77.4). The association of total VAT area (sum of four cross sections, L1-L2, L2-L3, L3-L4, L4-L5) and each location, as well as BMI and body fat % (per SD) with the metabolic syndrome (MetSx) or its components was evaluated through logistic regression analysis.

Results: Total VAT can be accurately predicted using all sites evaluated (R range=0.82-0.96). In men, VAT did not show a superior association to MetSx compared to BMI in men. However, in women, VAT was consistently superior to BMI and body fat % in its association to MetSx, independent of ethnicity [odds ratio for BMI, body fat %and total VAT area=2.25 (95% CI: 1.93-2.62); 1.66 (95% CI: 1.36-2.03); 6.20 (95% CI: 4.69-8.21) respectively in all women]. Ethnic-specific odds ratios to MetSx in women ranged from 5.38 to 8.63 for total VAT area and 2.12-4.08 for BMI.

Conclusion: Total VAT area can be accurately predicted from individual VAT regions in men and women and offers superior association to BMI for MetSx in women but not in men for five ethnicities. Therefore, opportunistic screening for elevated VAT area in women may be warranted across multiple ethnic groups.
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http://dx.doi.org/10.1016/j.orcp.2021.03.007DOI Listing
September 2021

Interactions in cancer treatment considering cancer therapy, concomitant medications, food, herbal medicine and other supplements.

J Cancer Res Clin Oncol 2021 Apr 17. Epub 2021 Apr 17.

Klinik für Innere Medizin II, Hämatologie und Internistische Onkologie, Integrative Onkologie, Universitätsklinikum Jena, Am Klinikum 1, 07747, Jena, Germany.

Purpose: The aim of our study was to analyse the frequency and severity of different types of potential interactions in oncological outpatients' therapy. Therefore, medications, food and substances in terms of complementary and alternative medicine (CAM) like dietary supplements, herbs and other processed ingredients were considered.

Methods: We obtained data from questionnaires and from analysing the patient records of 115 cancer outpatients treated at a German university hospital. Drug-drug interactions were identified using a drug interaction checking software. Potential CAM-drug interactions and food-drug interactions were identified based on literature research.

Results: 92.2% of all patients were at risk of one or more interaction of any kind and 61.7% of at least one major drug-drug interaction. On average, physicians prescribed 10.4 drugs to each patient and 6.9 interactions were found, 2.5 of which were classified as major. The most prevalent types of drug-drug interactions were a combination of QT prolonging drugs (32.3%) and drugs with a potential for myelotoxicity (13.4%) or hepatotoxicity (10.1%). In 37.2% of all patients using CAM supplements the likelihood of interactions with medications was rated as likely. Food-drug interactions were likely in 28.7% of all patients.

Conclusion: The high amount of interactions could not be found in literature so far. We recommend running interaction checks when prescribing any new drug and capturing CAM supplements in medication lists too. If not advised explicitly in another way drugs should be taken separately from meals and by using nonmineralized water to minimize the risk for food-drug interactions.
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http://dx.doi.org/10.1007/s00432-021-03625-3DOI Listing
April 2021

Associations between frontal lobe structure, parent-reported obstructive sleep disordered breathing and childhood behavior in the ABCD dataset.

Nat Commun 2021 04 13;12(1):2205. Epub 2021 Apr 13.

Department of Diagnostic Radiology and Nuclear Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.

Parents frequently report behavioral problems among children who snore. Our understanding of the relationship between symptoms of obstructive sleep disordered breathing (oSDB) and childhood behavioral problems associated with brain structural alterations is limited. Here, we examine the associations between oSDB symptoms, behavioral measures such as inattention, and brain morphometry in the Adolescent Brain Cognitive Development (ABCD) study comprising 10,140 preadolescents. We observe that parent-reported symptoms of oSDB are associated with composite and domain-specific problem behaviors measured by parent responses to the Child Behavior Checklist. Alterations of brain structure demonstrating the strongest negative associations with oSDB symptoms are within the frontal lobe. The relationships between oSDB symptoms and behavioral measures are mediated by significantly smaller volumes of multiple frontal lobe regions. These results provide population-level evidence for an association between regional structural alterations in cortical gray matter and problem behaviors reported in children with oSDB.
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http://dx.doi.org/10.1038/s41467-021-22534-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8044120PMC
April 2021

A Wearable Low-Power Sensing Platform for Environmental and Health Monitoring: The Convergence Project.

Sensors (Basel) 2021 Mar 5;21(5). Epub 2021 Mar 5.

NanoLab, Ecole Polytechnique Federale de Lausanne (EPFL), 1015 Lausanne, Switzerland.

The low-power sensing platform proposed by the Convergence project is foreseen as a wireless, low-power and multifunctional wearable system empowered by energy-efficient technologies. This will allow meeting the strict demands of life-style and healthcare applications in terms of autonomy for quasi-continuous collection of data for early-detection strategies. The system is compatible with different kinds of sensors, able to monitor not only health indicators of individual person (physical activity, core body temperature and biomarkers) but also the environment with chemical composition of the ambient air (NO, CO, NH particles) returning meaningful information on his/her exposure to dangerous (safety) or pollutant agents. In this article, we introduce the specifications and the design of the low-power sensing platform and the different sensors developed in the project, with a particular focus on pollutant sensing capabilities and specifically on NO sensor based on graphene and CO sensor based on polyaniline ink.
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http://dx.doi.org/10.3390/s21051802DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7961452PMC
March 2021

Rates of Incidental Findings in Brain Magnetic Resonance Imaging in Children.

JAMA Neurol 2021 May;78(5):578-587

Department of Psychiatry, University of Maryland, Baltimore.

Importance: Incidental findings (IFs) are unexpected abnormalities discovered during imaging and can range from normal anatomic variants to findings requiring urgent medical intervention. In the case of brain magnetic resonance imaging (MRI), reliable data about the prevalence and significance of IFs in the general population are limited, making it difficult to anticipate, communicate, and manage these findings.

Objectives: To determine the overall prevalence of IFs in brain MRI in the nonclinical pediatric population as well as the rates of specific findings and findings for which clinical referral is recommended.

Design, Setting, And Participants: This cohort study was based on the April 2019 release of baseline data from 11 810 children aged 9 to 10 years who were enrolled and completed baseline neuroimaging in the Adolescent Brain Cognitive Development (ABCD) study, the largest US population-based longitudinal observational study of brain development and child health, between September 1, 2016, and November 15, 2018. Participants were enrolled at 21 sites across the US designed to mirror the demographic characteristics of the US population. Baseline structural MRIs were centrally reviewed for IFs by board-certified neuroradiologists and findings were described and categorized (category 1, no abnormal findings; 2, no referral recommended; 3; consider referral; and 4, consider immediate referral). Children were enrolled through a broad school-based recruitment process in which all children of eligible age at selected schools were invited to participate. Exclusion criteria were severe sensory, intellectual, medical, or neurologic disorders that would preclude or interfere with study participation. During the enrollment process, demographic data were monitored to ensure that the study met targets for sex, socioeconomic, ethnic, and racial diversity. Data were analyzed from March 15, 2018, to November 20, 2020.

Main Outcomes And Measures: Percentage of children with IFs in each category and prevalence of specific IFs.

Results: A total of 11 679 children (52.1% boys, mean [SD] age, 9.9 [0.62] years) had interpretable baseline structural MRI results. Of these, 2464 participants (21.1%) had IFs, including 2013 children (17.2%) assigned to category 2, 431 (3.7%) assigned to category 3, and 20 (0.2%) assigned to category 4. Overall rates of IFs did not differ significantly between singleton and twin gestations or between monozygotic and dizygotic twins, but heritability analysis showed heritability for the presence or absence of IFs (h2 = 0.260; 95% CI, 0.135-0.387).

Conclusions And Relevance: Incidental findings in brain MRI and findings with potential clinical significance are both common in the general pediatric population. By assessing IFs and concurrent developmental and health measures and following these findings over the longitudinal study course, the ABCD study has the potential to determine the significance of many common IFs.
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http://dx.doi.org/10.1001/jamaneurol.2021.0306DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7985817PMC
May 2021

Ultra-precise quantification of mRNA targets across a broad dynamic range with nanoreactor beads.

PLoS One 2021 18;16(3):e0242529. Epub 2021 Mar 18.

BLINK AG, Jena, Germany.

Precise quantification of molecular targets in a biological sample across a wide dynamic range is a key requirement in many diagnostic procedures, such as monitoring response to therapy or detection of measurable residual disease. State of the art digital PCR assays provide for a dynamic range of four orders of magnitude. However digital assays are complex and require sophisticated microfluidic tools. Here we present an assay format that enables ultra-precise quantification of RNA targets in a single measurement across a dynamic range of more than six orders of magnitude. The approach is based on hydrogel beads that provide for microfluidic free compartmentalization of the sample as they are used as nanoreactors for reverse transcription, PCR amplification and combined real time and digital detection of gene transcripts. We have applied these nanoreactor beads for establishing an assay for the detection and quantification of BCR-ABL1 fusion transcripts. The assay has been characterized for its precision and linear dynamic range. A comparison of the new method against conventional real time RT-PCR analysis (reference method) with clinical samples from patients with chronic myeloid leukemia (CML) revealed excellent concordance with Pearsons correlation coefficient of 0.983 and slope of 1.08.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0242529PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7971518PMC
August 2021

Motion-insensitive diffusion imaging of the brain using optical tracking and dynamic sequence updates.

Magn Reson Med 2021 08 15;86(2):926-934. Epub 2021 Mar 15.

Department of Diagnostic Radiology and Nuclear Medicine, University of Maryland, Baltimore, MD, USA.

Purpose: Diffusion-weighted imaging (DWI) is sensitive to head movements, which may cause signal losses because of motion-induced gradient imbalances. Prospective motion correction using fast optical tracking can attenuate these artifacts. Approaches include quasicontinuous updates of gradients and radiofrequency (RF) pulses or dynamically applying a rebalancing gradient to restore the gradient balance, but these prior methods used bipolar diffusion gradients. The goal of this project was to develop and evaluate a motion-insensitive implementation for the more common monopolar diffusion sequence.

Methods: A monopolar diffusion sequence was developed with motion updates before each RF pulse and each diffusion-weighting gradient. The sequence was tested in a phantom and human brain at b = 1000 s/mm and rotational velocities up to 20°/s. Motion sensitivity, signal losses, and in vivo image profiles were compared between scans with and without intrasequence motion updates.

Results: With typical motion parameters, intrasequence motion updates with optimal parameters reduced the motion sensitivity of DWI (motion-induced gradient moment imbalance) sevenfold. Optimal results were achieved by matching the echo time of the pulse sequence to an even multiple of the tracking system frame-to-frame period. Average signal losses and the frequency of signal dropouts in phantom and in vivo measurements were reduced when intrasequence updates were enabled, and quality measures of DTI analyses were improved.

Conclusion: A correction scheme for the monopolar DWI sequence can reduce the motion sensitivity of brain DWI up to sevenfold compared with an implementation without intrasequence updates.
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http://dx.doi.org/10.1002/mrm.28747DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8211393PMC
August 2021

Correspondence Between Perceived Pubertal Development and Hormone Levels in 9-10 Year-Olds From the Adolescent Brain Cognitive Development Study.

Front Endocrinol (Lausanne) 2020 18;11:549928. Epub 2021 Feb 18.

Department of Pediatrics, University of Minnesota, Minneapolis, MN, United States.

Aim: To examine individual variability between perceived physical features and hormones of pubertal maturation in 9-10-year-old children as a function of sociodemographic characteristics.

Methods: Cross-sectional metrics of puberty were utilized from the baseline assessment of the Adolescent Brain Cognitive Development (ABCD) Study-a multi-site sample of 9-10 year-olds (n = 11,875)-and included perceived physical features the pubertal development scale (PDS) and child salivary hormone levels (dehydroepiandrosterone and testosterone in all, and estradiol in females). Multi-level models examined the relationships among sociodemographic measures, physical features, and hormone levels. A group factor analysis (GFA) was implemented to extract latent variables of pubertal maturation that integrated both measures of perceived physical features and hormone levels.

Results: PDS summary scores indicated more males (70%) than females (31%) were prepubertal. Perceived physical features and hormone levels were significantly associated with child's weight status and income, such that more mature scores were observed among children that were overweight/obese or from households with low-income. Results from the GFA identified two latent factors that described individual differences in pubertal maturation among both females and males, with factor 1 driven by higher hormone levels, and factor 2 driven by perceived physical maturation. The correspondence between latent factor 1 scores (hormones) and latent factor 2 scores (perceived physical maturation) revealed synchronous and asynchronous relationships between hormones and concomitant physical features in this large young adolescent sample.

Conclusions: Sociodemographic measures were associated with both objective hormone and self-report physical measures of pubertal maturation in a large, diverse sample of 9-10 year-olds. The latent variables of pubertal maturation described a complex interplay between perceived physical changes and hormone levels that hallmark sexual maturation, which future studies can examine in relation to trajectories of brain maturation, risk/resilience to substance use, and other mental health outcomes.
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http://dx.doi.org/10.3389/fendo.2020.549928DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7930488PMC
May 2021

Assessment of individual molecular response in chronic myeloid leukemia patients with atypical BCR-ABL1 fusion transcripts: recommendations by the EUTOS cooperative network.

J Cancer Res Clin Oncol 2021 Oct 7;147(10):3081-3089. Epub 2021 Mar 7.

Abteilung Hämatologie/Onkologie, Klinik für Innere Medizin II, Universitätsklinikum Jena, Am Klinikum 1, 07747, Jena, Germany.

Purpose: Approximately 1-2% of chronic myeloid leukemia (CML) patients harbor atypical BCR-ABL1 transcripts that cannot be monitored by real-time quantitative PCR (RT-qPCR) using standard methodologies. Within the European Treatment and Outcome Study (EUTOS) for CML we established and validated robust RT-qPCR methods for these patients.

Methods: BCR-ABL1 transcripts were amplified and sequenced to characterize the underlying fusion. Residual disease monitoring was carried out by RT-qPCR with specific primers and probes using serial dilutions of appropriate BCR-ABL1 and GUSB plasmid DNA calibrators. Results were expressed as log reduction of the BCR-ABL1/GUSB ratio relative to the patient-specific baseline value and evaluated as an individual molecular response (IMR).

Results: In total, 330 blood samples (2-34 per patient, median 8) from 33 CML patients (19 male, median age 62 years) were analyzed. Patients expressed seven different atypical BCR-ABL1 transcripts (e1a2, n = 6; e6a2, n = 1; e8a2, n = 2; e13a3, n = 4; e14a3, n = 6; e13a3/e14a3, n = 2; e19a2, n = 12). Most patients (61%) responded well to TKI therapy and achieved an IMR of at least one log reduction 3 months after diagnosis. Four patients relapsed with a significant increase of BCR-ABL1/GUSB ratios.

Conclusions: Characterization of atypical BCR-ABL1 transcripts is essential for adequate patient monitoring and to avoid false-negative results. The results cannot be expressed on the International Scale (IS) and thus the common molecular milestones and guidelines for treatment are difficult to apply. We, therefore, suggest reporting IMR levels in these cases as a time-dependent log reduction of BCR-ABL1 transcript levels compared to baseline prior to therapy.
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http://dx.doi.org/10.1007/s00432-021-03569-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8397658PMC
October 2021

Improved gene delivery to K-562 leukemia cells by lipoic acid modified block copolymer micelles.

J Nanobiotechnology 2021 Mar 6;19(1):70. Epub 2021 Mar 6.

Laboratory of Organic and Macromolecular Chemistry (IOMC), Friedrich Schiller University Jena, Humboldtstrasse 10, 07743, Jena, Germany.

Although there has been substantial progress in the research field of gene delivery, there are some challenges remaining, e.g. there are still cell types such as primary cells and suspension cells (immune cells) known to be difficult to transfect. Cationic polymers have gained increasing attention due to their ability to bind, condense and mask genetic material, being amenable to scale up and highly variable in their composition. In addition, they can be combined with further monomers exhibiting desired biological and chemical properties, such as antioxidative, pH- and redox-responsive or biocompatible features. By introduction of hydrophobic monomers, in particular as block copolymers, cationic micelles can be formed possessing an improved chance of transfection in otherwise challenging cells. In this study, the antioxidant biomolecule lipoic acid, which can also be used as crosslinker, was incorporated into the hydrophobic block of a diblock copolymer, poly{[2-(dimethylamino)ethyl methacrylate]-b-[n-(butyl methacrylate)-co-(lipoic acid methacrylate)]} (P(DMAEMA-b-[nBMA-co-LAMA])), synthesized by RAFT polymerization and assembled into micelles (LAMA-mic). These micelles were investigated regarding their pDNA binding, cytotoxicity mechanisms and transfection efficiency in K-562 and HEK293T cells, the former representing a difficult to transfect, suspension leukemia cell line. The LAMA-mic exhibited low cytotoxicity at applied concentrations but demonstrated superior transfection efficiency in HEK293T and especially K-562 cells. In-depth studies on the transfection mechanism revealed that transfection efficiency in K-562 cells does not depend on the specific oncogenic fusion gene BCR-ABL alone. It is independent of the cellular uptake of polymer-pDNA complexes but correlates with the endosomal escape of the LAMA-mic. A comparison of the transfection efficiency of the LAMA-mic with structurally comparable micelles without lipoic acid showed that lipoic acid is not solely responsible for the superior transfection efficiency of the LAMA-mic. More likely, a synergistic effect of the antioxidative lipoic acid and the micellar architecture was identified. Therefore, the incorporation of lipoic acid into the core of hydrophobic-cationic micelles represents a promising tailor-made transfer strategy, which can potentially be beneficial for other difficult to transfect cell types.
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http://dx.doi.org/10.1186/s12951-021-00801-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7936509PMC
March 2021

Body Fat Distribution, Glucose Metabolism, and Diabetes Status among Older Adults: The Multiethnic Cohort Adiposity Phenotype Study.

J Epidemiol 2021 Feb 27. Epub 2021 Feb 27.

University of Hawaii Cancer Center.

Aims: As the proportion of visceral (VAT) to subcutaneous adipose tissue (SAT) may contribute to type 2 diabetes (T2D) development, we examined this relation in a cross-sectional design within the Multiethnic Cohort that includes Japanese Americans known to have high VAT. The aim was to understand how ectopic fat accumulation differs by glycemic status across ethnic groups with disparate rates of obesity, T2D, and propensity to accumulate VAT.

Methods: In 2013-16, 1,746 participants aged 69.2 (2.7) years from five ethnic groups completed questionnaires, blood collections, and whole-body DXA and abdominal MRI scans. Participants with self-reported T2D and/or medication were classified as T2D, those with fasting glucose >125 and 100-125 mg/dL as undiagnosed cases (UT2D) and prediabetes (PT2D), respectively. Using linear regression, we estimated adjusted means of adiposity measures by T2D status.

Results: Overall, 315 (18%) participants were classified as T2D, 158 (9%) as UT2D, 518 (30%) as PT2D, and 755 (43%) as normoglycemic (NG) with significant ethnic differences (p<0.0001). In fully adjusted models, VAT, VAT/SAT, and percent liver fat increased significantly from NG, PT2D, UT2D, to T2D (p<0.001). Across ethnic groups, the VAT/SAT ratio was lowest for NG participants and highest for T2D cases. Positive trends were observed in all groups except African Americans, with highest VAT/SAT in Japanese Americans.

Conclusions: These findings indicate that VAT plays an important role in T2D etiology, in particular among Japanese Americans with high levels of ectopic adipose tissue, which drives the development of T2D to a greater degree than in other ethnic groups.
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http://dx.doi.org/10.2188/jea.JE20200538DOI Listing
February 2021

Association Between Habitual Snoring and Cognitive Performance Among a Large Sample of Preadolescent Children.

JAMA Otolaryngol Head Neck Surg 2021 05;147(5):426-433

Department of Diagnostic Radiology and Nuclear Medicine, University of Maryland School of Medicine, Baltimore.

Importance: Previous studies have identified an association between habitual snoring and lower cognitive performance in children. However, whether and to what extent this association is confounded by pertinent demographic, anthropometric, and socioeconomic characteristics is unknown.

Objective: To assess the extent to which potential confounding factors modify the association between parent-reported habitual snoring and cognitive outcomes among a large and diverse sample of typically developing preadolescent children.

Design, Setting, And Participants: This cross-sectional analysis used a baseline data set (version 2.0.1) from children enrolled in the ongoing Adolescent Brain Cognitive Development study between September 1, 2016, and October 15, 2018. Children aged 9 to 10 years without serious psychiatric or neurological comorbidities were recruited at 21 research sites in the US. Study recruitment was designed to approximate the racial and socioeconomic diversity of the US population. Data were analyzed from February 1 to March 31, 2020.

Exposures: Parent-reported habitual snoring in children that occurs 3 or more nights per week.

Main Outcomes And Measures: Associations between habitual snoring and cognitive performance were assessed using the Sleep Disturbance Scale for Children and the National Institutes of Health Toolbox Cognition Battery, which includes 7 domain-specific and 3 composite (total cognitive function, fluid cognition, and crystallized cognition) standard scores that are uncorrected for covariates. Cognitive performance was examined before and after adjustment for covariates, which included age, sex, body mass index percentile, annual household income before taxes, and highest educational level of caregiver. The extent of confounding was assessed by the effect size, represented by Cohen d, before and after inclusion of covariates using linear mixed-effects models.

Results: A total of 11 873 children aged 9 to 10 years (6187 boys [52.1%]; 6174 White [52.0%]) with available data were included in the study. Of those, habitual snoring (≥3 nights per week) was reported in 810 children (6.8%), and nonhabitual snoring (1-2 nights per week) was reported in 4058 children (34.2%). In the unadjusted models, the total cognitive function composite score among children who habitually snored was significantly lower compared with children who never snored (Cohen d, 0.35; 95% CI, 0.28-0.42). Differences were also identified in the crystallized cognition (Cohen d, 0.34; 95% CI, 0.26-0.41) and fluid cognition (Cohen d, 0.28; 95% CI, 0.21-0.35) composite scores. The association between habitual snoring and cognitive performance was substantially attenuated after adjustment for covariates (Cohen d, 0.16 [95% CI, 0.09 to 0.24] for total cognitive function, 0.14 [95% CI, 0.07 to 0.21] for crystallized cognition, and 0.13 [95% CI, 0.06 to 0.21] for fluid cognition). Similar mitigation was also observed for all domain-specific scores.

Conclusions: In this cross-sectional study, when adjusted for baseline demographic, anthropometric, and socioeconomic characteristics, the association between parent-reported habitual snoring and cognitive performance was substantially attenuated among children aged 9 to 10 years.
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http://dx.doi.org/10.1001/jamaoto.2020.5712DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7907984PMC
May 2021

Quality of life, symptoms and dietary habits in oncology outpatients with malnutrition: A cross-sectional study.

Med Oncol 2021 Feb 4;38(2):20. Epub 2021 Feb 4.

Klinik für Innere Medizin II, University Hospital Jena, Jena, Germany.

Cancer-related malnutrition has a high prevalence, reduces survival and increases side effects. The aim of this study was to assess oncology outpatients and risk of malnutrition. Reported symptoms and quality of life (QoL) in patients found to be at risk of malnutrition or malnourished were compared to patients without malnutrition. Using a standardized questionnaire, the European Organization for Research and Treatment of Cancer Questionnaire for Quality of Life and the Mini Nutritional Assessment (MNA), patients in an outpatient cancer clinic undergoing chemotherapy treatment at a German University Hospital were assessed for nutrition, risk of malnutrition and quality of life. Based on the MNA, 39 (45.9%) patients were categorized as malnourished or at risk for malnutrition. Loss of appetite (n = 37.6%, p < 0.001) and altered taste sensation (n = 30,3%, p < 0.001) were the symptoms most frequently associated with reduced food intake. Patients with risk of malnutrition scored lower on the global health status (n = 48.15%, p = 0.001). Side effects of cancer treatments lead to a higher risk of malnutrition and as a consequence lower QoL. These side effects should be addressed more efficiently in cancer care.
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http://dx.doi.org/10.1007/s12032-021-01460-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7862192PMC
February 2021

Systemic therapy for recurrent and/or metastatic head and neck cancer: a population-based healthcare research study in Thuringia, Germany.

J Cancer Res Clin Oncol 2021 Sep 31;147(9):2625-2635. Epub 2021 Jan 31.

Department of Otorhinolaryngology, Jena University Hospital, Friedrich Schiller University, Am Klinikum 1, 07740, Jena, Germany.

Purpose: Systemic therapy choice for patients with recurrent and/or metastatic head and neck cancer (R/M HNC) is a challenge. Not much is known about systemic therapies used in daily clinical routine and their outcome.

Methods: Data of all 283 patients with R/M HNC (89.4% male, median age: 60 years) registered for first-line systemic therapy between 2015 and 2018 in the cancer registries of Thuringia, a federal state in Germany, were included. Patient characteristics and treatment patterns were summarized. Exploratory univariate and multivariate analyses were conducted on select of systemic therapy and prognostic factors for overall survival.

Results: The most frequent first-line regimens were platinum-based combinations (71.4%), mainly cetuximab + platinum + 5-fluorouracil (32.5%). 32.5, 13.1, 4.9, and 1.1%, respectively, received, a second, third, fourth, and fifth line of systemic therapy. Median follow-up was 5.5 months. Median real-world overall survival was 16.8 months [95% confidence interval (CI) 11.1-22.6]. Alcohol drinking [hazard ratio (HR) 2.375, CI 1.471-3.831; p < 0.001], no second-line therapy (HR 3.425, CI 2.082-5.635, p < 0.001), and application of three agents compared to one agent in first-line therapy (HR 2.798, CI 1.374-5.697; p = 0.005) were associated to decreased overall survival after start of first-line systemic therapy. Termination of second-line treatment because of deterioration of the general condition was the only independent negative prognostic factor (HR 4.202, CI 1.091-16.129; p = 0.037) after start of second-line systemic therapy.

Conclusions: This study offers useful information, mainly prior to the availability of immunotherapy, on patient characteristics, treatment patterns, and survival in a German real-world population.
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http://dx.doi.org/10.1007/s00432-021-03535-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8310840PMC
September 2021

Brain-derived neurotrophic factor Val66Met variant on brain volumes in infants.

Brain Struct Funct 2021 Apr 20;226(3):919-925. Epub 2021 Jan 20.

Department of Medicine, John A. Burns School of Medicine, University of Hawaii, Honolulu, HI, USA.

The brain-derived neurotrophic factor (BDNF) has many important roles in neurogenesis and neuronal health. BDNF is also involved in learning and memory. Individuals with BDNF-Val66Met variant (Met +) are at higher risk for neuropsychiatric disorders and have smaller hippocampi and amgydalae compared to those without this variant (Met -). Whether these smaller brain volumes are already present at birth is unknown and were evaluated. 66 newborn infants were genotyped for BDNF-rs6265 and had brain MRI scans. The T1-weighted images were automatically parcellated for hippocampus and amygdala, as well as the intracranial volume (ICV), total brain volume, total gray and white matter, using a multi-atlas label fusion method implemented in the MRICloud ( https://braingps.anatomyworks.org ). The segmented brain volumes were normalized to the ICV for group comparisons. The two infant groups were not different in their demographics and birth characteristics. However, compared to Met - infants, the Met + infants had smaller hippocampi (p = 0.013), smaller amygdalae (p = 0.041), and less steep age-related declines in total brain volume and % white matter volume. The smaller relative hippocampal and amygdala volumes in Met + infants suggest that the Met + genotype affected prenatal developmental processes. In addition, the slower age-dependent declines in the relative total brain and white matter volumes of the Met + group in this cross-sectional dataset suggest the BDNF-Val66Met variant might have an ongoing negative influence on the postnatal developmental processes.
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http://dx.doi.org/10.1007/s00429-020-02207-2DOI Listing
April 2021

Association of Immunosuppression and Viral Load With Subcortical Brain Volume in an International Sample of People Living With HIV.

JAMA Netw Open 2021 01 4;4(1):e2031190. Epub 2021 Jan 4.

Imaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California, Marina del Rey.

Importance: Despite more widely accessible combination antiretroviral therapy (cART), HIV-1 infection remains a global public health challenge. Even in treated patients with chronic HIV infection, neurocognitive impairment often persists, affecting quality of life. Identifying the neuroanatomical pathways associated with infection in vivo may delineate the neuropathologic processes underlying these deficits. However, published neuroimaging findings from relatively small, heterogeneous cohorts are inconsistent, limiting the generalizability of the conclusions drawn to date.

Objective: To examine structural brain associations with the most commonly collected clinical assessments of HIV burden (CD4+ T-cell count and viral load), which are generalizable across demographically and clinically diverse HIV-infected individuals worldwide.

Design, Setting, And Participants: This cross-sectional study established the HIV Working Group within the Enhancing Neuro Imaging Genetics Through Meta Analysis (ENIGMA) consortium to pool and harmonize data from existing HIV neuroimaging studies. In total, data from 1295 HIV-positive adults were contributed from 13 studies across Africa, Asia, Australia, Europe, and North America. Regional and whole brain segmentations were extracted from data sets as contributing studies joined the consortium on a rolling basis from November 1, 2014, to December 31, 2019.

Main Outcomes And Measures: Volume estimates for 8 subcortical brain regions were extracted from T1-weighted magnetic resonance images to identify associations with blood plasma markers of current immunosuppression (CD4+ T-cell counts) or detectable plasma viral load (dVL) in HIV-positive participants. Post hoc sensitivity analyses stratified data by cART status.

Results: After quality assurance, data from 1203 HIV-positive individuals (mean [SD] age, 45.7 [11.5] years; 880 [73.2%] male; 897 [74.6%] taking cART) remained. Lower current CD4+ cell counts were associated with smaller hippocampal (mean [SE] β = 16.66 [4.72] mm3 per 100 cells/mm3; P < .001) and thalamic (mean [SE] β = 32.24 [8.96] mm3 per 100 cells/mm3; P < .001) volumes and larger ventricles (mean [SE] β = -391.50 [122.58] mm3 per 100 cells/mm3; P = .001); in participants not taking cART, however, lower current CD4+ cell counts were associated with smaller putamen volumes (mean [SE] β = 57.34 [18.78] mm3 per 100 cells/mm3; P = .003). A dVL was associated with smaller hippocampal volumes (d = -0.17; P = .005); in participants taking cART, dVL was also associated with smaller amygdala volumes (d = -0.23; P = .004).

Conclusions And Relevance: In a large-scale international population of HIV-positive individuals, volumes of structures in the limbic system were consistently associated with current plasma markers. Our findings extend beyond the classically implicated regions of the basal ganglia and may represent a generalizable brain signature of HIV infection in the cART era.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.31190DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7811179PMC
January 2021

Resection of cerebellar tumours causes widespread and functionally relevant white matter impairments.

Hum Brain Mapp 2021 04 7;42(6):1641-1656. Epub 2021 Jan 7.

Department of Neurology, Essen University Hospital, University of Duisburg-Essen, Essen, Germany.

Several diffusion tensor imaging studies reveal that white matter (WM) lesions are common in children suffering from benign cerebellar tumours who are treated with surgery only. The clinical implications of WM alterations that occur as a direct consequence of cerebellar disease have not been thoroughly studied. Here, we analysed structural and diffusion imaging data from cerebellar patients with chronic surgical lesions after resection for benign cerebellar tumours. We aimed to elucidate the impact of focal lesions of the cerebellum on WM integrity across the entire brain, and to investigate whether WM deficits were associated with behavioural impairment in three different motor tasks. Lesion symptom mapping analysis suggested that lesions in critical cerebellar regions were related to deficits in savings during an eyeblink conditioning task, as well as to deficits in motor action timing. Diffusion imaging analysis of cerebellar WM indicated that better behavioural performance was associated with higher fractional anisotropy (FA) in the superior cerebellar peduncle, cerebellum's main outflow path. Moreover, voxel-wise analysis revealed a global pattern of WM deficits in patients within many cerebral WM tracts critical for motor and non-motor function. Finally, we observed a positive correlation between FA and savings within cerebello-thalamo-cortical pathways in patients but not in controls, showing that saving effects partly depend on extracerebellar areas, and may be recruited for compensation. These results confirm that the cerebellum has extended connections with many cerebral areas involved in motor/cognitive functions, and the observed WM changes likely contribute to long-term clinical deficits of posterior fossa tumour survivors.
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http://dx.doi.org/10.1002/hbm.25317DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7978119PMC
April 2021
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