ia

Timely News and Notes for Primary Care Providers from the American Diabetes Association




ia

Clinical Diabetes




ia

Lipid Trait Variants and the Risk of Non-Hodgkin Lymphoma Subtypes: A Mendelian Randomization Study

Background:

Lipid traits have been inconsistently linked to risk of non-Hodgkin lymphoma (NHL). We examined the association of genetically predicted lipid traits with risk of diffuse large B-cell lymphoma (DLBCL), chronic lymphocytic leukemia (CLL), follicular lymphoma (FL), and marginal zone lymphoma (MZL) using Mendelian randomization (MR) analysis.

Methods:

Genome-wide association study data from the InterLymph Consortium were available for 2,661 DLBCLs, 2,179 CLLs, 2,142 FLs, 824 MZLs, and 6,221 controls. SNPs associated (P < 5 x 10–8) with high-density lipoprotein (HDL, n = 164), low-density lipoprotein (LDL, n = 137), total cholesterol (TC, n = 161), and triglycerides (TG, n = 123) were used as instrumental variables (IV), explaining 14.6%, 27.7%, 16.8%, and 12.8% of phenotypic variation, respectively. Associations between each lipid trait and NHL subtype were calculated using the MR inverse variance–weighted method, estimating odds ratios (OR) per standard deviation and 95% confidence intervals (CI).

Results:

HDL was positively associated with DLBCL (OR = 1.14; 95% CI, 1.00–1.30) and MZL (OR = 1.09; 95% CI, 1.01–1.18), while TG was inversely associated with MZL risk (OR = 0.90; 95% CI, 0.83–0.99), all at nominal significance (P < 0.05). A positive trend was observed for HDL with FL risk (OR = 1.08; 95% CI, 0.99–1.19; P = 0.087). No associations were noteworthy after adjusting for multiple testing.

Conclusions:

We did not find evidence of a clear or strong association of these lipid traits with the most common NHL subtypes. While these IVs have been previously linked to other cancers, our findings do not support any causal associations with these NHL subtypes.

Impact:

Our results suggest that prior reported inverse associations of lipid traits are not likely to be causal and could represent reverse causality or confounding.




ia

Prediagnostic Circulating Levels of Sex Steroid Hormones and SHBG in Relation to Risk of Ductal Carcinoma In Situ of the Breast among UK Women

Background:

Sex steroid hormones and sex hormone–binding globulin (SHBG) have been implicated in the etiology of invasive breast cancer, but their associations with risk of the precursor lesion, ductal carcinoma in situ (DCIS) of the breast, remain unclear.

Methods:

We used Cox proportional hazards regression models to estimate the associations of serum levels of estradiol (premenopausal women only), testosterone, and/or SHBG with DCIS risk among 182,935 women. After a median follow-up of 7.1 years, 186 and 531 DCIS cases were ascertained in premenopausal and postmenopausal women, respectively.

Results:

Total and free estradiol were positively associated with risk of DCIS among premenopausal women. The HRs for the highest versus the lowest tertiles were 1.54 (1.06–2.23) and 1.72 [95% confidence interval (CI), 1.15–2.57], respectively. Among postmenopausal women, elevated levels of free testosterone (FT), and to a lesser extent, total testosterone, were positively associated with DCIS risk. The HRs for the highest versus the lowest quartiles were 1.42 (95% CI, 1.09–1.85) and 1.16 (95% CI, 0.91–1.48), respectively. Serum SHBG levels were inversely associated with risk of DCIS among postmenopausal women (HRq4 vs. q1: 0.75; 95% CI, 0.56–0.99).

Conclusions:

This study suggests that elevated levels of estradiol are associated with increased risk of DCIS among premenopausal women, and that among postmenopausal women, elevated levels of testosterone, and particularly those of FT, are associated with increased DCIS risk, while elevated levels of SHBG are associated with reduced risk.

Impact:

These findings may be helpful in developing prevention strategies aimed at reducing breast cancer risk among premenopausal and postmenopausal women.




ia

Total Antioxidant Capacity and Pancreatic Cancer Incidence and Mortality in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial

Background:

Total antioxidant capacity (TAC) reflects an individual's overall antioxidant intake. We sought to clarify whether higher TAC is associated with lower risks of pancreatic cancer incidence and mortality in the U.S. general population.

Methods:

A total of 96,018 American adults were identified from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. A ferric-reducing ability of plasma score was used to reflect an individual's TAC intake from diet and/or supplements. Cox regression was used to calculate hazard ratios (HR) for pancreatic cancer incidence, and competing risk regression was used to calculate subdistribution HRs for pancreatic cancer mortality. Restricted cubic spline regression was used to test nonlinearity.

Results:

A total of 393 pancreatic cancer cases and 353 pancreatic cancer–related deaths were documented. Total (diet + supplements) TAC was found to be inversely associated with pancreatic cancer incidence (HR quartile 4 vs. quartile 1 = 0.53; 95% confidence interval, 0.39–0.72; Ptrend = 0.0002) and mortality (subdistribution HR quartile 4 vs. quartile 1 = 0.52; 95% confidence interval 0.38–0.72; Ptrend = 0.0003) in a nonlinear dose–response manner (all Pnonlinearity < 0.01). Similar results were observed for dietary TAC. No association of supplemental TAC with pancreatic cancer incidence and mortality was found.

Conclusions:

In the U.S. general population, dietary but not supplemental TAC level is inversely associated with risks of pancreatic cancer incidence and mortality in a nonlinear dose–response pattern.

Impact:

This is the first prospective study indicating that a diet rich in antioxidants may be beneficial in decreasing pancreatic cancer incidence and mortality.




ia

Accuracy of Self-reported Colonic Polyps: Results from the Prostate, Lung, Colorectal, and Ovarian Screening Trial Study of Colonoscopy Utilization

Background:

Colonoscopy follow-up recommendations depend on the presence or absence of polyps, and if found, their number, size, and histology. Patients may be responsible for conveying results between primary and specialty care or providing medical information to family members; thus, accurate reporting is critical. This analysis assessed the accuracy of self-reported colonoscopy findings.

Methods:

3,986 participants from the Study of Colonoscopy Utilization, an ancillary study nested within the Prostate, Lung, Colorectal, and Ovarian Screening Trial, were included. Self-reports of polyp and adenoma were compared to medical records, and measures of sensitivity and specificity were calculated. Correlates of accurate self-report of polyp were assessed using logistic regression and weighted to account for study sampling.

Results:

The sensitivity and specificity of self-reported polyp findings were 88% and 85%, respectively, and for adenoma 11% and 99%, respectively. Among participants with a polyp, older age was associated with lower likelihood while polyp severity and non-white race were associated with increased likelihood of accurate recall. Among participants without a polyp, having multiple colonoscopies was associated with lower likelihood while family history of colorectal cancer was associated with increased likelihood of accurate recall. Among both groups, longer time since colonoscopy was associated with lower likelihood of accurate recall.

Conclusions:

Participants recalled with reasonable accuracy whether they had a prior polyp; however, recall of histology, specifically adenoma, was much less accurate.

Impact:

Identification of strategies to increase accurate self-report of colonic polyps are needed, particularly for patient–provider communications and patient reporting of results to family members.




ia

Prospective Association of Energy Balance Scores Based on Metabolic Biomarkers with Colorectal Cancer Risk

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.




ia

Associations of Abdominal Skeletal Muscle Mass, Fat Mass, and Mortality among Men and Women with Stage I-III Colorectal Cancer

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.




ia

Daily Time of Radiation Treatment Is Associated with Subsequent Oral Mucositis Severity during Radiotherapy in Head and Neck Cancer Patients

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.




ia

Age at Diagnosis and Patient Preferences for Treatment Outcomes in AML: A Discrete Choice Experiment to Explore Meaningful Benefits

Background:

The recent expansion of treatment options in acute myeloid leukemia (AML) has necessitated a greater understanding of patient preferences for treatment benefits, about which little is known.

Methods:

We sought to quantify and assess heterogeneity of the preferences of AML patients for treatment outcomes. An AML-specific discrete choice experiment (DCE) was developed involving multiple stakeholders. Attributes included in the DCE were event-free survival (EFS), complete remission (CR), time in the hospital, short-term side effects, and long-term side effects. Continuously coded conditional, stratified, and latent-class logistic regressions were used to model preferences of 294 patients with AML.

Results:

Most patients were white (89.4%) and in remission (95.0%). A 10% improvement in the chance of CR was the most meaningful offered benefit (P < 0.001). Patients were willing to trade up to 22 months of EFS or endure 8.7 months in the hospital or a two-step increase in long-term side effects to gain a 10% increase in chance of CR. Patients diagnosed at 60 years or older (21.6%) more strongly preferred to avoid short-term side effects (P = 0.03). Latent class analysis showed significant differences of preferences across gender and insurance status.

Conclusions:

In this national sample of mostly AML survivors, patients preferred treatments that maximized chance at remission; however, significant preference heterogeneity for outcomes was identified. Age and gender may affect patients' preferences.

Impact:

Survivor preferences for outcomes can inform patient-focused drug development and shared decision-making. Further studies are necessary to investigate the use of DCEs to guide treatment for individual patients.




ia

Harnessing Population Pedigree Data and Machine Learning Methods to Identify Patterns of Familial Bladder Cancer Risk

Background:

Relatives of patients with bladder cancer have been shown to be at increased risk for kidney, lung, thyroid, and cervical cancer after correcting for smoking-related behaviors that may concentrate in some families. We demonstrate a novel approach to simultaneously assess risks for multiple cancers to identify distinct multicancer configurations (multiple different cancer types that cluster in relatives) surrounding patients with familial bladder cancer.

Methods:

This study takes advantage of a unique population-level data resource, the Utah Population Database (UPDB), containing vast genealogy and statewide cancer data. Familial risk is measured using standardized incidence risk (SIR) ratios that account for sex, age, birth cohort, and person-years of the pedigree members.

Results:

We identify 1,023 families with a significantly higher bladder cancer rate than population controls (familial bladder cancer). Familial SIRs are then calculated across 25 cancer types, and a weighted Gower distance with K-medoids clustering is used to identify familial multicancer configurations (FMC). We found five FMCs, each exhibiting a different pattern of cancer aggregation. Of the 25 cancer types studied, kidney and prostate cancers were most commonly enriched in the familial bladder cancer clusters. Laryngeal, lung, stomach, acute lymphocytic leukemia, Hodgkin disease, soft-tissue carcinoma, esophageal, breast, lung, uterine, thyroid, and melanoma cancers were the other cancer types with increased incidence in familial bladder cancer families.

Conclusions:

This study identified five familial bladder cancer FMCs showing unique risk patterns for cancers of other organs, suggesting phenotypic heterogeneity familial bladder cancer.

Impact:

FMC configurations could permit better definitions of cancer phenotypes (subtypes or multicancer) for gene discovery and environmental risk factor studies.




ia

Screen to Save: Results from NCI's Colorectal Cancer Outreach and Screening Initiative to Promote Awareness and Knowledge of Colorectal Cancer in Racial/Ethnic and Rural Populations

Background:

The Center to Reduce Cancer Health Disparities (CRCHD), NCI, implemented Screen to Save, NCI's Colorectal Cancer Outreach and Screening Initiative to promote awareness and knowledge of colorectal cancer in racial/ethnic and rural populations.

Methods:

The initiative was implemented through CRCHD's National Outreach Network (NON). NON is a national network of Community Health Educators (CHE), aligned with NCI-designated Cancer Centers across the nation. In phases I and II, the CHEs focused on the dissemination of cancer-related information and implementation of evidence-based educational outreach.

Results:

In total, 3,183 pre/post surveys were obtained from male and female participants, ages 50 to 74 years, during the 347 educational events held in phase I. Results demonstrated all racial/ethnic groups had an increase in colorectal cancer–related knowledge, and each group strongly agreed that the educational event increased the likelihood that they would engage in colorectal cancer–related healthful behaviors (e.g., obtain colorectal cancer screening and increase physical activity). For phase II, Connections to Care, event participants were linked to screening. Eighty-two percent of the participants who obtained colorectal cancer screening during the 3-month follow-up period obtained their screening results.

Conclusions:

These results suggest that culturally tailored, standardized educational messaging and data collection tools are key change agents that can serve to inform the effectiveness of educational outreach to advance awareness and knowledge of colorectal cancer.

Impact:

Future initiatives should focus on large-scale national efforts to elucidate effective models of connections to care, related to colorectal cancer screening, follow-up, and treatments that are modifiable to meet community needs.




ia

One Size Does Not Fit All: Marked Heterogeneity in Incidence of and Survival from Gastric Cancer among Asian American Subgroups

Background:

Asian Americans are at higher risk for noncardia gastric cancers (NCGC) relative to non-Hispanic Whites (NHW). Asian Americans are genetically, linguistically, and culturally heterogeneous, yet have mostly been treated as a single population in prior studies. This aggregation may obscure important subgroup-specific cancer patterns.

Methods:

We utilized data from 13 regional United States cancer registries from 1990 to 2014 to determine secular trends in incidence and survivorship from NCGC. Data were analyzed for NHWs and the six largest Asian American subgroups: Chinese, Japanese, Filipino, Korean, Vietnamese, and South Asian (Indian/Pakistani).

Results:

There exists substantial heterogeneity in NCGC incidence between Asian subgroups, with Koreans (48.6 per 100,000 person-years) having seven-fold higher age-adjusted incidence than South Asians (7.4 per 100,000 person-years). Asians had generally earlier stages of diagnosis and higher rates of surgical resection compared with NHWs. All Asian subgroups also demonstrated higher 5-year observed survival compared with NHWs, with Koreans (41.3%) and South Asians (42.8%) having survival double that of NHWs (20.1%, P < 0.001). In multivariable regression, differences in stage of diagnosis and rates of resection partially explained the difference in survivorship between Asian subgroups.

Conclusions:

We find substantial differences in incidence, staging, histology, treatment, and survivorship from NCGC between Asian subgroups, data which challenge our traditional perceptions about gastric cancer in Asians. Both biological heterogeneity and cultural/environmental differences may underlie these findings.

Impact:

These data are relevant to the national discourse regarding the appropriate role of gastric cancer screening, and identifies high-risk racial/ethnic subgroups who many benefit from customized risk attenuation programs.




ia

Projected Reductions in Absolute Cancer-Related Deaths from Diagnosing Cancers Before Metastasis, 2006-2015

Background:

New technologies are being developed for early detection of multiple types of cancer simultaneously. To quantify the potential benefit, we estimated reductions in absolute cancer–related deaths that could occur if cancers diagnosed after metastasis (stage IV) were instead diagnosed at earlier stages.

Methods:

We obtained stage-specific incidence and survival data from the Surveillance, Epidemiology, and End Results Program for 17 cancer types for all persons diagnosed ages 50 to 79 years in 18 geographic regions between 2006 and 2015. For a hypothetical cohort of 100,000 persons, we estimated cancer-related deaths under assumptions that cancers diagnosed at stage IV were diagnosed at earlier stages.

Results:

Stage IV cancers represented 18% of all estimated diagnoses but 48% of all estimated cancer-related deaths within 5 years. Assuming all stage IV cancers were diagnosed at stage III, 51 fewer cancer-related deaths would be expected per 100,000, a reduction of 15% of all cancer-related deaths. Assuming one third of metastatic cancers were diagnosed at stage III, one third diagnosed at stage II, and one third diagnosed at stage I, 81 fewer cancer-related deaths would be expected per 100,000, a reduction of 24% of all cancer-related deaths, corresponding to a reduction in all-cause mortality comparable in magnitude to eliminating deaths due to cerebrovascular disease.

Conclusions:

Detection of multiple cancer types earlier than stage IV could reduce at least 15% of cancer-related deaths within 5 years, affecting not only cancer-specific but all-cause mortality.

Impact:

Detecting cancer before stage IV, including modest shifts to stage III, could offer substantial population benefit.




ia

Sensitive Determination of Infectious Titer of Recombinant Adeno-Associated Viruses (rAAVs) Using TCID50 End-Point Dilution and Quantitative Polymerase Chain Reaction (qPCR)

Adeno-associated virus (AAV) recombinants are currently the vector of choice for many gene therapy applications. As experimental therapies progress to clinical trials, the need to characterize recombinant adeno-associated viruses (rAAVs) accurately and reproducibly increases. Accurate determination of rAAV infectious titer is important for determining the activity of each vector lot and for ensuring lot-to-lot consistency. The following protocol developed in our laboratory uses a 96-well TCID50 format and quantitative polymerase chain reaction (qPCR) detection for the determination of rAAV infectious titer.




ia

Titration of Recombinant Adeno-Associated Virus (rAAV) Genome Copy Number Using Real-Time Quantitative Polymerase Chain Reaction (qPCR)

This protocol is used to determine the concentration of DNase-resistant vector genomes (i.e., packaged in the capsid) in purified recombinant adeno-associated virus (rAAV) preparations. The protocol begins with treatment of the vector stock with DNase I to eliminate unencapsidated AAV DNA or contaminating plasmid DNA. This is followed by a heat treatment to heat-inactivate DNase I, to disrupt the viral capsid, and to release the packaged vector genomes for quantification by real-time polymerase chain reaction (PCR) using a set of standards (linearized plasmid used for vector production) containing known copy numbers. To accomplish high-throughput titration, the primer and probe sets used in real-time PCR are usually designed to target common elements present in most rAAV genomes, such as promoters and poly(A) signals. This strategy significantly reduces the number of PCRs, controls, and turnaround time. Several important controls should be included in the assay as follows: The first two controls should have a known copy number of the rAAV genome plasmid treated or not treated with DNase I. This control tests the effectiveness of DNase treatment. To control for potential cross-contamination between samples during the preparation process, a blank control containing nuclease-free water only should be processed and tested in parallel. A validation vector sample with a known titer should be included in every assay to monitor interassay variability. Finally, for the PCR run, a no-template control (NTC) is included to indicate cross-contamination during PCR setup.




ia

Purification of Recombinant Adeno-Associated Virus 2 (rAAV2) by Heparin Column Affinity Chromatography

This protocol describes a simple single-step column purification (SSCP) of rAAV2 by gravity flow based on its affinity to heparin, without ultracentrifugation.




ia

Oral Microbiome Profiling in Smokers with and without Head and Neck Cancer Reveals Variations Between Health and Disease

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.




ia

A Systematic Review on Cost-effectiveness Studies Evaluating Ovarian Cancer Early Detection and Prevention Strategies

Ovarian cancer imposes a substantial health and economic burden. We systematically reviewed current health-economic evidence for ovarian cancer early detection or prevention strategies. Accordingly, we searched relevant databases for cost-effectiveness studies evaluating ovarian cancer early detection or prevention strategies. Study characteristics and results including quality-adjusted life years (QALY), and incremental cost-effectiveness ratios (ICER) were summarized in standardized evidence tables. Economic results were transformed into 2017 Euros. The included studies (N = 33) evaluated ovarian cancer screening, risk-reducing interventions in women with heterogeneous cancer risks and genetic testing followed by risk-reducing interventions for mutation carriers. Multimodal screening with a risk-adjusted algorithm in postmenopausal women achieved ICERs of 9,800–81,400 Euros/QALY, depending on assumptions on mortality data extrapolation, costs, test performance, and screening frequency. Cost-effectiveness of risk-reducing surgery in mutation carriers ranged from cost-saving to 59,000 Euros/QALY. Genetic testing plus risk-reducing interventions for mutation carriers ranged from cost-saving to 54,000 Euros/QALY in women at increased mutation risk. Our findings suggest that preventive surgery and genetic testing plus preventive surgery in women at high risk for ovarian cancer can be considered effective and cost-effective. In postmenopausal women from the general population, multimodal screening using a risk-adjusted algorithm may be cost-effective.




ia

TRPV6 as a Putative Genomic Susceptibility Locus Influencing Racial Disparities in Cancer

It is well established that African Americans exhibit higher incidence, higher mortality, and more aggressive forms of some cancers, including those of breast, prostate, colon, stomach, and cervix. Here we examine the ancestral haplotype of the TRPV6 calcium channel as a putative genomic factor in this racial divide. The minor (ancestral) allele frequency is 60% in people of African ancestry, but between 1% and 11% in all other populations. Research on TRPV6 structure/function, its association with specific cancers, and the evolutionary-ecological conditions that impacted selection of its haplotypes are synthesized to provide evidence for TRPV6 as a germline susceptibility locus in cancer. Recently elucidated mechanisms of TRPV6 channel deactivation are discussed in relation to the location of the allele favored in selection, suggesting a reduced capacity to inactivate the channel in those who have the ancestral haplotype. This could result in an excessively high cellular Ca2+, which has been implicated in cancer, for those in settings where calcium intake is far higher than in their ancestral environment. A recent report associating increasing calcium intake with a pattern of increase in aggressive prostate cancer in African-American but not European-American men may be related. If TRPV6 is found to be associated with cancer, further research would be warranted to improve risk assessment and examine interventions with the aim of improving cancer outcomes for people of African ancestry.




ia

Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer Is Associated with Indigenous American Ancestry in Latin American Women

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.




ia

MEF2c-Dependent Downregulation of Myocilin Mediates Cancer-Induced Muscle Wasting and Associates with Cachexia in Patients with Cancer

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.




ia

NOX4 Inhibition Potentiates Immunotherapy by Overcoming Cancer-Associated Fibroblast-Mediated CD8 T-cell Exclusion from Tumors

Determining mechanisms of resistance to αPD-1/PD-L1 immune-checkpoint immunotherapy is key to developing new treatment strategies. Cancer-associated fibroblasts (CAF) have many tumor-promoting functions and promote immune evasion through multiple mechanisms, but as yet, no CAF-specific inhibitors are clinically available. Here we generated CAF-rich murine tumor models (TC1, MC38, and 4T1) to investigate how CAFs influence the immune microenvironment and affect response to different immunotherapy modalities [anticancer vaccination, TC1 (HPV E7 DNA vaccine), αPD-1, and MC38] and found that CAFs broadly suppressed response by specifically excluding CD8+ T cells from tumors (not CD4+ T cells or macrophages); CD8+ T-cell exclusion was similarly present in CAF-rich human tumors. RNA sequencing of CD8+ T cells from CAF-rich murine tumors and immunochemistry analysis of human tumors identified significant upregulation of CTLA-4 in the absence of other exhaustion markers; inhibiting CTLA-4 with a nondepleting antibody overcame the CD8+ T-cell exclusion effect without affecting Tregs. We then examined the potential for CAF targeting, focusing on the ROS-producing enzyme NOX4, which is upregulated by CAF in many human cancers, and compared this with TGFβ1 inhibition, a key regulator of the CAF phenotype. siRNA knockdown or pharmacologic inhibition [GKT137831 (Setanaxib)] of NOX4 “normalized” CAF to a quiescent phenotype and promoted intratumoral CD8+ T-cell infiltration, overcoming the exclusion effect; TGFβ1 inhibition could prevent, but not reverse, CAF differentiation. Finally, NOX4 inhibition restored immunotherapy response in CAF-rich tumors. These findings demonstrate that CAF-mediated immunotherapy resistance can be effectively overcome through NOX4 inhibition and could improve outcome in a broad range of cancers.Significance:NOX4 is critical for maintaining the immune-suppressive CAF phenotype in tumors. Pharmacologic inhibition of NOX4 potentiates immunotherapy by overcoming CAF-mediated CD8+ T-cell exclusion.Graphical Abstract:http://cancerres.aacrjournals.org/content/canres/80/9/1846/F1.large.jpg.See related commentary by Hayward, p. 1799




ia

Glial TIM-3 Modulates Immune Responses in the Brain Tumor Microenvironment

T-cell immunoglobulin and mucin domain–containing molecule 3 (TIM-3), a potential immunotherapeutic target for cancer, has been shown to display diverse characteristics in a context-dependent manner. Thus, it would be useful to delineate the precise functional features of TIM-3 in a given situation. Here, we report that glial TIM-3 shows distinctive properties in the brain tumor microenvironment. TIM-3 was expressed on both growing tumor cells and their surrounding cells including glia and T cells in an orthotopic mouse glioma model. The expression pattern of TIM-3 was distinct from those of other immune checkpoint molecules in tumor-exposed and tumor-infiltrating glia. Comparison of cells from tumor-bearing and contralateral hemispheres of a glioma model showed that TIM-3 expression was lower in tumor-infiltrating CD11b+CD45mid glial cells but higher in tumor-infiltrating CD8+ T cells. In TIM-3 mutant mice with intracellular signaling defects and Cre-inducible TIM-3 mice, TIM-3 affected the expression of several immune-associated molecules including iNOS and PD-L1 in primary glia-exposed conditioned media (CM) from brain tumors. Further, TIM-3 was cross-regulated by TLR2, but not by TLR4, in brain tumor CM- or Pam3CSK4-exposed glia. In addition, following exposure to tumor CM, IFNγ production was lower in T cells cocultured with TIM-3–defective glia than with normal glia. Collectively, these findings suggest that glial TIM-3 actively and distinctively responds to brain tumor, and plays specific intracellular and intercellular immunoregulatory roles that might be different from TIM-3 on T cells in the brain tumor microenvironment.Significance:TIM-3 is typically thought of as a T-cell checkpoint receptor. This study demonstrates a role for TIM-3 in mediating myeloid cell responses in glioblastoma.




ia

Risk SNP-Mediated Enhancer-Promoter Interaction Drives Colorectal Cancer through Both FADS2 and AP002754.2

Although genome-wide association studies (GWAS) have identified more than 100 colorectal cancer risk loci, most of the biological mechanisms associated with these loci remain unclear. Here we first performed a comprehensive expression quantitative trait loci analysis in colorectal cancer tissues adjusted for multiple confounders to test the determinants of germline variants in established GWAS susceptibility loci on mRNA and long noncoding RNA (lncRNA) expression. Combining integrative functional genomic/epigenomic analyses and a large-scale population study consisting of 6,024 cases and 10,022 controls, we then prioritized rs174575 with a C>G change as a potential causal candidate for colorectal cancer at 11q12.2, as its G allele was associated with an increased risk of colorectal cancer (OR = 1.26; 95% confidence interval = 1.17–1.36; P = 2.57 × 10–9). rs174575 acted as an allele-specific enhancer to distally facilitate expression of both FADS2 and lncRNA AP002754.2 via long-range enhancer–promoter interaction loops, which were mediated by E2F1. AP002754.2 further activated a transcriptional activator that upregulated FADS2 expression. FADS2, in turn, was overexpressed in colorectal cancer tumor tissues and functioned as a potential oncogene that facilitated colorectal cancer cell proliferation and xenograft growth in vitro and in vivo by increasing the metabolism of PGE2, an oncogenic molecule involved in colorectal cancer tumorigenesis. Our findings represent a novel mechanism by which a noncoding variant can facilitate long-range genome interactions to modulate the expression of multiple genes including not only mRNA, but also lncRNA, which provides new insights into the understanding of colorectal cancer etiology.Significance:This study provides an oncogenic regulatory circuit among several oncogenes including E2F1, FADS2, and AP002754.2 underlying the association of rs174575 with colorectal cancer risk, which is driven by long-range enhancer–promoter interaction loops.Graphical Abstract:http://cancerres.aacrjournals.org/content/canres/80/9/1804/F1.large.jpg.




ia

[PERSPECTIVES] Toward Systems Pathology for PTEN Diagnostics

Germline alterations of the tumor suppressor PTEN have been extensively characterized in patients with PTEN hamartoma tumor syndromes, encompassing subsets of Cowden syndrome, Bannayan–Riley–Ruvalcaba syndrome, Proteus and Proteus-like syndromes, as well as autism spectrum disorder. Studies have shown an increase in the risk of developing specific cancer types in the presence of a germline PTEN mutation. Furthermore, outside of the familial setting, somatic variants of PTEN occur in numerous malignancies. Here we introduce and discuss the prospect of moving toward a systems pathology approach for PTEN diagnostics, incorporating clinical and molecular pathology data with the goal of improving the clinical management of patients with a PTEN mutation. Detection of a germline PTEN mutation can inform cancer surveillance and in the case of somatic mutation, have value in predicting disease course. Given that PTEN functions in the PI3K/AKT/mTOR pathway, identification of a PTEN mutation may highlight new therapeutic opportunities and/or inform therapeutic choices.




ia

[PERSPECTIVES] RNA Regulators in Leukemia and Lymphoma

Posttranscriptional regulation of mRNA is a powerful and tightly controlled process in which cells command the integrity, diversity, and abundance of their protein products. RNA-binding proteins (RBPs) are the principal players that control many intermediary steps of posttranscriptional regulation. Recent advances in this field have discovered the importance of RBPs in hematological diseases. Herein we will review a number of RBPs that have been determined to play critical functions in leukemia and lymphoma. Furthermore, we will discuss the potential therapeutic strategies that are currently being studied to specifically target RBPs in these diseases.




ia

Thalamic Massa Intermedia in Children with and without Midline Brain Malformations [PEDIATRICS]

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.




ia

Increased Notching of the Corpus Callosum in Fetal Alcohol Spectrum Disorder: A Callosal Misunderstanding? [PEDIATRICS]

BACKGROUND AND PURPOSE:

In the medicolegal literature, notching of the corpus callosum has been reported to be associated with fetal alcohol spectrum disorders. Our purpose was to analyze the prevalence of notching of the corpus callosum in a fetal alcohol spectrum disorders group and a healthy population to determine whether notching occurs with increased frequency in the fetal alcohol spectrum disorders population.

MATERIALS AND METHODS:

We performed a multicenter search for cases of fetal alcohol spectrum disorders and included all patients who had a sagittal T1-weighted brain MR imaging. Patients with concomitant intracranial pathology were excluded. The corpus callosum was examined for notches using previously published methods. A 2 test was used to compare the fetal alcohol spectrum disorders and healthy groups.

RESULTS:

Thirty-three of 59 patients with fetal alcohol spectrum disorders (0–44 years of age) identified across all centers had corpus callosum notching. Of these, 8 had an anterior corpus callosum notch (prevalence, 13.6%), 23 had a posterior corpus callosum notch (prevalence, 39%), and 2 patients demonstrated undulated morphology (prevalence, 3.4%). In the healthy population, the anterior notch prevalence was 139/875 (15.8%), posterior notch prevalence was 378/875 (43.2%), and undulating prevalence was 37/875 (4.2%). There was no significant difference among the anterior (P = .635), posterior (P = .526), and undulating (P = .755) notch prevalence in the fetal alcohol spectrum disorders and healthy groups.

CONCLUSIONS:

There was no significant difference in notching of the corpus callosum between patients with fetal alcohol spectrum disorders and the healthy population. Although reported to be a marker of fetal alcohol spectrum disorders, notching of the corpus callosum should not be viewed as a specific finding associated with fetal alcohol spectrum disorders.




ia

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]

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.




ia

Comparison of Enhancement of the Vestibular Perilymph between Variable and Constant Flip Angle-Delayed 3D-FLAIR Sequences in Meniere Disease [HEAD & NECK]

BACKGROUND AND PURPOSE:

Endolymphatic hydrops in patients with Menière disease relies on delayed postcontrast 3D-FLAIR sequences. The purpose of this study was to compare the degree of perilymphatic enhancement and the detection rate of endolymphatic hydrops using constant and variable flip angles sequences.

MATERIALS AND METHODS:

This was a retrospective study performed in 16 patients with Menière disease who underwent 3T MR imaging 4 hours after gadolinium injection using two 3D-FLAIR sequences with a constant flip angle at 140° for the first and a heavily-T2 variable flip angle for the second. The signal intensity ratio was measured using the ROI method. We graded endolymphatic hydrops and evaluated the cochlear blood-labyrinth barrier impairment.

RESULTS:

Both for symptomatic and asymptomatic ears, the median signal intensity ratio was significantly higher with the constant flip angle than with the heavily-T2 variable flip angle (7.16 versus 1.54 and 7.00 versus 1.45, P < .001). Cochlear blood-labyrinth barrier impairment was observed in 4/18 symptomatic ears with the heavily-T2 variable flip angle versus 8/19 with constant flip angle sequences. With heavily-T2 variable flip angle sequences, endolymphatic hydrops was observed in 7–10/19 symptomatic ears versus 12/19 ears with constant flip angle sequences. We found a significant association between the clinical symptomatology and the presence of endolymphatic hydrops with constant flip angle but not with heavily-T2 variable flip angle sequences. Interreader agreement was always perfect with constant flip angle sequences while it was fair-to-moderate with heavily-T2 variable flip angle sequences.

CONCLUSIONS:

3D-FLAIR constant flip angle sequences provide a higher signal intensity ratio and are superior to heavily-T2 variable flip angle sequences in reliably evaluating the cochlear blood-labyrinth barrier impairment and the endolymphatic space.




ia

Assessment of Apparent Internal Carotid Tandem Occlusion on High-Resolution Vessel Wall Imaging: Comparison with Digital Subtraction Angiography [EXTRACRANIAL VASCULAR]

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.




ia

Facial Nerve Arterial Arcade Supply in Dural Arteriovenous Fistulas: Anatomy and Treatment Strategies [INTERVENTIONAL]

BACKGROUND AND PURPOSE:

Endovascular treatment of petrous dural AVFs may carry a risk of iatrogenic facial nerve palsy if the facial nerve arterial arcade, an anastomotic arterial arch that supplies the geniculate ganglion, is not respected or recognized. Our purpose was to demonstrate that the use of a treatment strategy algorithm incorporating detailed angiographic anatomic assessment allows identification of the facial nerve arterial arcade and therefore safe endovascular treatment.

MATERIALS AND METHODS:

This was a retrospective cohort study of consecutive petrous dural AVF cases managed at Toronto Western Hospital between 2006 and 2018. Our standard of care consists of detailed angiographic assessment followed by multidisciplinary discussion on management. Arterial supply, primary and secondary treatments undertaken, angiographic outcomes, and clinical outcomes were assessed by 2 independent fellowship-trained interventional neuroradiologists.

RESULTS:

Fifteen patients had 15 fistulas localized over the petrous temporal bone. Fistulas in all 15 patients had direct cortical venous drainage and received at least partial supply from the facial nerve arterial arcade. Following multidisciplinary evaluation, treatment was performed by endovascular embolization in 8 patients (53%) and microsurgical disconnection in 7 patients (47%). All patients had long-term angiographic cure, and none developed iatrogenic facial nerve palsy.

CONCLUSIONS:

By means of our treatment strategy based on detailed angiographic assessment and multidisciplinary discussion, approximately half of our patients with petrous AVFs were cured by endovascular treatment, half were cured by an operation, and all had preserved facial nerve function.




ia

Intermixed Dimethyl-Sulfoxide-Based Nonadhesive Liquid Embolic Agents Delivered Serially via the Same Microcatheter for Cerebral AVM Treatment [INTERVENTIONAL]

BACKGROUND AND PURPOSE:

Conventional nonadhesive liquid embolic agents currently are the criterion standard for endovascular embolization of cerebral AVMs. However, inadequate distal penetration into the nidus and unstable proximal plug formation are the major limitations of this approach and of the currently available embolic materials. The aim of this study was to evaluate the hypothetic efficacy of combining liquid embolic agents with different properties and viscosities for use in endovascular embolization of cerebral AVMs.

MATERIALS AND METHODS:

From March 2018 to March 2019, sixteen patients with cerebral AVMs (12 women, 4 men; age range, 33–61 years) underwent endovascular embolization with combined liquid embolic agents delivered serially via a single microcatheter. The procedure consists of initial embolization with PHIL 30%, followed by Menox 18 through the same microcatheter. According to the Spetzler-Martin scale, 11 (68.75%) AVMs were grades I–II, 4 (25%) were grade III, and 1 (6.25%) was grade IV. Angiographic, technical, and clinical outcomes were analyzed independently.

RESULTS:

Combined PHIL and Menox embolization through the same microcatheter via 21 pedicles was performed in these 16 patients. Once the length of the reflux reached approximately 2 cm, PHIL 30% was switched to Menox 18. Antegrade flow and distal penetration of the serially applied liquid embolic agents were observed in all 16 cases. The ability to completely control the flow of the materials and avoid any dangerous proximal reflux was noted in all performed embolizations. The estimated average size reduction of the treated AVMs was 85%, ranging from 50% to 100%. Complete embolization was achieved in 10/16 or 62.5% of the cases. There was no procedure-related complication during or after the embolization. No mortality or postprocedural clinical worsening was seen. Clinical success and complete obliteration were confirmed with at least 1 follow-up angiography in 10/16 patients.

CONCLUSIONS:

Serial delivery of nonadhesive liquid embolic agents via the same microcatheter was safe and effective in our study and may be a potential technique for routine AVM treatment. However, further investigations are required to validate the safety and the efficacy of the method.




ia

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]

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.




ia

MRI Vessel Wall Imaging after Intra-Arterial Treatment for Acute Ischemic Stroke [INTERVENTIONAL]

BACKGROUND AND PURPOSE:

Vessel wall imaging is increasingly performed in the diagnostic work-up of patients with ischemic stroke. The aim of this study was to compare vessel wall enhancement after intra-arterial thrombosuction with that in patients not treated with thrombosuction.

MATERIALS AND METHODS:

From 2009 to 2017, forty-nine patients with an ischemic stroke underwent 7T MR imaging within 3 months after symptom onset as part of a prospective intracranial vessel wall imaging study. Fourteen of these patients underwent intra-arterial treatment using thrombosuction (intra-arterial treatment group). In the intra-arterial treatment group, vessel walls were evaluated for major vessel wall changes. All patients underwent pre- and postcontrast vessel wall imaging to assess enhancing foci of the vessel wall using coregistered subtraction images. A Wilcoxon signed rank test was performed to test for differences.

RESULTS:

In the intra-arterial treatment group, 11 of 14 patients (79%) showed vessel wall enhancement compared with 17 of 35 patients without intra-arterial treatment (49%). In the intra-arterial treatment group, more enhancing foci were detected on the ipsilateral side (n = 18.5) compared with the contralateral side (n = 3, P = .005). Enhancement was more often concentric on the ipsilateral side (n = 8) compared with contralateral side (n = 0, P = .01). No differences were found in the group without intra-arterial treatment between the number and configuration of ipsilateral and contralateral enhancing foci.

CONCLUSIONS:

Patients with intra-arterial treatment by means of thrombosuction showed more (concentric) enhancing foci of the vessel wall ipsilateral compared with contralateral to the treated artery than the patients without intra-arterial treatment, suggesting reactive changes of the vessel wall. This finding should be taken into account when assessing vessel wall MR images in patients with stroke.




ia

Suspected Metallic Embolization Distal to Coiled Intracranial Aneurysms Detectable by Susceptibility-Weighted MR Imaging [INTERVENTIONAL]

BACKGROUND AND PURPOSE:

After endovascular coiling of intracranial aneurysms, round dark parenchymal lesions believed to be particulate metal are sometimes encountered in MR imaging studies of the brain. We used SWI to assess the frequency of such occurrences, in addition to exploring likely causes and clinical implications.

MATERIALS AND METHODS:

We reviewed 700 MR imaging studies performed between September 2018 and March 2019 at our institution as follow-up monitoring of coiled intracranial aneurysms. Any sizeable (>5 mm) rounded dark-signal lesions encountered were presumed to be metallic. The magnitudes and locations of such lesions were recorded. In patients with these lesions, pertinent procedural documentation was screened for devices used, including coils, microcatheters, microguidewires, and stents. Medical records were also examined to determine whether any related symptoms ensued.

RESULTS:

Twenty patients (2.8%) exhibited a total of 25 lesions on SWI. Diameters ranged from 5 to 11 mm (median, 8 mm). All except 2 lesions were located in brain regions downstream from aneurysms, but all lesions occupied vascular territories of vessels used to place guiding catheters. Other than the Synchro 14, which was routinely deployed, no device was regularly used in patients with SWI-detectable lesions; and none of the affected patients developed focal neurologic symptoms as a consequence.

CONCLUSIONS:

Although the origins remain unclear, distal embolization of particulate metal distal to coiled cerebral aneurysms is occasionally observed on follow-up MR imaging studies. Such lesions, however, seem to have no apparent clinical impact.




ia

Reliability of CT Angiography in Cerebral Vasospasm: A Systematic Review of the Literature and an Inter- and Intraobserver Study [INTERVENTIONAL]

BACKGROUND AND PURPOSE:

Computed tomography angiography offers a non-invasive alternative to DSA for the assessment of cerebral vasospasm following subarachnoid hemorrhage but there is limited evidence regarding its reliability. Our aim was to perform a systematic review (Part I) and to assess (Part II) the inter- and intraobserver reliability of CTA in the diagnosis of cerebral vasospasm.

MATERIALS AND METHODS:

In Part I, articles reporting the reliability of CTA up to May 2018 were systematically searched and evaluated. In Part II, 11 raters independently graded 17 arterial segments in each of 50 patients with SAH for the presence of vasospasm using a 4-category scale. Raters were additionally asked to judge the presence of any moderate/severe vasospasm (≥ 50% narrowing) and whether findings would justify augmentation of medical treatment or conventional angiography ± balloon angioplasty. Four raters took part in the intraobserver reliability study.

RESULTS:

In Part I, the systematic review revealed few studies with heterogeneous vasospasm definitions. In Part II, we found interrater reliability to be moderate at best ( ≤ 0.6), even when results were stratified according to specialty and experience. Intrarater reliability was substantial ( > 0.6) in 3/4 readers. In the per arterial segment analysis, substantial agreement was reached only for the middle cerebral arteries, and only when senior raters’ judgments were dichotomized (presence or absence of ≥50% narrowing). Agreement on the medical or angiographic management of vasospasm based on CTA alone was less than substantial ( ≤ 0.6).

CONCLUSIONS:

The diagnosis of vasospasm using CTA alone was not sufficiently repeatable among observers to support its general use to guide decisions in the clinical management of patients with SAH.




ia

CT Angiography in Evaluating Large-Vessel Occlusion in Acute Anterior Circulation Ischemic Stroke: Factors Associated with Diagnostic Error in Clinical Practice [INTERVENTIONAL]

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.




ia

Polymorphous Low-Grade Neuroepithelial Tumor of the Young as a Partially Calcified Intra-Axial Mass in an Adult [RADIOLOGY-PATHOLOGY CORRELATION]

SUMMARY:

Polymorphous low-grade neuroepithelial tumors of the young (PLNTYs) are recently described CNS tumors. Classically, PLNTYs are epileptogenic and are a subtype of a heterogeneous group of low-grade neuroepithelial tumors that cause refractory epilepsy, such as angiocentric gliomas, oligodendrogliomas, gangliogliomas, and pleomorphic xanthoastrocytomas. Although they are a relatively new entity, a number of imaging and histologic characteristics of PLNTYs are already known. We present the imaging and pathologic findings of such a tumor as well as the surgical approach and clinical management.




ia

The Lateral Ventricles: A Detailed Review of Anatomy, Development, and Anatomic Variations [review-article]

SUMMARY:

The cerebral ventricles have been studied since the fourth century BC and were originally thought to harbor the soul and higher executive functions. During the infancy of neuroradiology, alterations to the ventricular shape and position on pneumoencephalography and ventriculography were signs of mass effect or volume loss. However, in the current era of high-resolution cross-sectional imaging, variation in ventricular anatomy is more easily detectable and its clinical significance is still being investigated. Interpreting radiologists must be aware of anatomic variations of the ventricular system to prevent mistaking normal variants for pathology. We will review of the anatomy and development of the lateral ventricles and discuss several ventricular variations.




ia

Novel Coronavirus: What Neuroradiologists as Citizens of the World Need to Know [EDITORIALS]




ia

Bán suất ngoại giao kiot DV - 08 TSG Lotus chỉ từ 3,3 tỷ ký HĐMB trực tiếp CĐT, bàn giao ngay

Bán suất ngoại giao kiot DV - 08 dự án TSG Lotus chỉ từ 3,3 tỷ ký HĐMB trực tiếp CĐT, bàn giao ngay sau khi ký HĐ. * Liên hệ ngay 0961.169.169. -------------------- - Bàn giao ngay Tháng 5/2020. - Giá chỉ 3,3 tỷ (cam kết giá hợp lý nhất dự án và trong khu vực). - Mặt tiền rộng 5m. - Diện tích: 80 m2 (đã gồm tổng diện tích 2 tầng). - 2 tầng full kính, vừa có thể để ở, v...




ia

Ra mắt shophouse 2 mặt tiền hot nhất Ecopark, Văn Giang, Hưng Yên

Mở bán Shophouse 2 Mặt tiền dự án Sky Oasis thuộc khu đô thị Ecopark. Nhanh tay sở hữu ngay shop chân đế vĩnh viễn. Diện tích 40 - 150m2. Nằm trên tuyến phố đi bộ 2.5km thiết kế phong cách Hàn, Nhật theo chủ đề. Phố shoping, giải trí, Check - in... Lưu lượng 10 tòa chung cư với h...




ia

Bán shop office, kiot chân khối đế mặt đường Hàm Nghi, Vinhomes Gardenia. LH 0983786378

Bán shop office Vinhomes Gardenia, bán shop chân khối đế mặt Hàm Nghi 3 tòa chung cư A1, A2, A3 Vinhomes Gardenia Mỹ Đình, Nam từ Liêm. Bán kiot mặt Hàm nghi Gardenia. 1. Shop Diện tích 112.8 m2. Đang cho thuê 100 triệu/th, hợp đồng thuê còn 5 năm, thanh toán 12 tháng/ lần....




ia

Senturia Nam Sài Gòn

Senturia Nam Sài Gòn là dự án có quy mô 19,8ha nằm trên đường Nguyễn Văn Linh, Bình Hưng, Bình Chánh.




ia

Piania City

Piania City do Phúc Sơn Group đầu tư xây dựng có quy mô 65,63ha, gồm 1.300 lô đất nhà ở và hàng trăm căn biệt thự đơn lập, nhà liền kề và nhà phố thương mại.




ia

Kallias Complex City

Kallias Complex City do Công ty Cổ phần NDMREAL đầu tư với quy mô 5.03ha theo mô hình tổ hợp thương mại - du lịch gồm các sản phẩm khách sạn, căn hộ du lịch, shophouse tại Tuy Hòa, Phú Yên.




ia

Green Diamond

Green Diamond là dự án tổ hợp chung cư, nhà liền kề và shophouse được đầu tư bởi Công Ty Cổ Phần Đầu Tư Và Phát Triển Nhà Số 6 Hạ Long (thuộc Công Ty Cổ Phần Đầu Tư Và Phát Triển Nhà Số 6 Hà Nội).




ia

Nhận nhà ở ngay - vay 0% lãi suất tại HC Golden City - quà tặng tân gia 80tr - liên hệ 0896677736

HC Golden City được giới chuyên gia bất động sản đánh giá cao về vị trí, cũng như chất lượng xây dựng, chất lượng sống cao cấp căn cứ theo các tiêu chuẩn sau:- Dự án HC Golden City được coi là độc nhất vô nhị trên tuyến đường dát vàng Hồng Tiến - tuyến đường Cổ Linh kéo dài kết n...