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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.




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Alcohol and Tobacco Use in Relation to Mammographic Density in 23,456 Women

Background:

Percent density (PD) is a strong risk factor for breast cancer that is potentially modifiable by lifestyle factors. PD is a composite of the dense (DA) and nondense (NDA) areas of a mammogram, representing predominantly fibroglandular or fatty tissues, respectively. Alcohol and tobacco use have been associated with increased breast cancer risk. However, their effects on mammographic density (MD) phenotypes are poorly understood.

Methods:

We examined associations of alcohol and tobacco use with PD, DA, and NDA in a population-based cohort of 23,456 women screened using full-field digital mammography machines manufactured by Hologic or General Electric. MD was measured using Cumulus. Machine-specific effects were estimated using linear regression, and combined using random effects meta-analysis.

Results:

Alcohol use was positively associated with PD (Ptrend = 0.01), unassociated with DA (Ptrend = 0.23), and inversely associated with NDA (Ptrend = 0.02) adjusting for age, body mass index, reproductive factors, physical activity, and family history of breast cancer. In contrast, tobacco use was inversely associated with PD (Ptrend = 0.0008), unassociated with DA (Ptrend = 0.93), and positively associated with NDA (Ptrend<0.0001). These trends were stronger in normal and overweight women than in obese women.

Conclusions:

These findings suggest that associations of alcohol and tobacco use with PD result more from their associations with NDA than DA.

Impact:

PD and NDA may mediate the association of alcohol drinking, but not tobacco smoking, with increased breast cancer risk. Further studies are needed to elucidate the modifiable lifestyle factors that influence breast tissue composition, and the important role of the fatty tissues on breast health.




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Red and Processed Meat, Poultry, Fish, and Egg Intakes and Cause-Specific and All-Cause Mortality among Men with Nonmetastatic Prostate Cancer in a U.S. Cohort

Background:

Research on the relationship of meat, fish, and egg consumption and mortality among prostate cancer survivors is limited.

Methods:

In the Cancer Prevention Study-II Nutrition Cohort, men diagnosed with nonmetastatic prostate cancer between baseline in 1992/1993 and 2015 were followed for mortality until 2016. Analyses of pre- and postdiagnosis intakes of red and processed meat, poultry, fish, and eggs included 9,286 and 4,882 survivors, respectively. Multivariable-adjusted RRs and 95% confidence intervals (CI) were estimated using Cox proportional hazards models.

Results:

A total of 4,682 and 2,768 deaths occurred during follow-up in pre- and postdiagnosis analyses, respectively. Both pre- and postdiagnosis intakes of total red and processed meat were positively associated with all-cause mortality (quartile 4 vs. 1: RR = 1.13; 95% CI, 1.03–1.25; Ptrend = 0.02; RR = 1.22; 95% CI, 1.07–1.39; Ptrend = 0.03, respectively), and both pre- and postdiagnosis poultry intakes were inversely associated with all-cause mortality (quartile 4 vs. 1 RR = 0.90; 95% CI, 0.82–0.98; Ptrend = 0.04; RR = 0.84; 95% CI, 0.75–0.95; Ptrend = 0.01, respectively). No associations were seen for prostate cancer–specific mortality, except that higher postdiagnosis unprocessed red meat intake was associated with lower risk.

Conclusions:

Higher red and processed meat, and lower poultry, intakes either before or after prostate cancer diagnosis were associated with higher risk of all-cause mortality.

Impact:

Our findings provide additional evidence that prostate cancer survivors should follow the nutrition guidelines limiting red and processed meat consumption to improve overall survival. Additional research on the relationship of specific meat types and mortality is needed.




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Circulating Biomarker Score for Visceral Fat and Risks of Incident Colorectal and Postmenopausal Breast Cancer: The Multiethnic Cohort Adiposity Phenotype Study

Background:

Visceral adipose tissue (VAT) may play a greater role than subcutaneous fat in increasing cancer risk but is poorly estimated in epidemiologic studies.

Methods:

We developed a VAT prediction score by regression equations averaged across 100 least absolute shrinkage and selection operator models in a cross-sectional study of 1,801 older adults in the Multiethnic Cohort (MEC). The score was then used as proxy for VAT in case–control studies of postmenopausal breast (950 case–control pairs) and colorectal (831 case–control pairs) cancer in an independent sample in MEC. Abdominal MRI–derived VAT; circulating biomarkers of metabolic, hormonal, and inflammation dysfunctions; and ORs for incident cancer adjusted for BMI and other risk factors were assessed.

Results:

The final score, composed of nine biomarkers, BMI, and height, explained 11% and 15% more of the variance in VAT than BMI alone in men and women, respectively. The area under the receiver operator curve for VAT >150 cm2 was 0.90 in men and 0.86 in women. The VAT score was associated with risk of breast cancer [OR (95% confidence interval [CI]) by increasing tertiles: 1.00, 1.09 (0.86–1.39), 1.48 (1.16–1.89); Ptrend = 0.002] but not with colorectal cancer (P = 0.84), although an association [1.00, 0.98 (0.68–1.39), 1.24 (0.88–1.76); Ptrend = 0.08] was suggested for this cancer after excluding cases that occurred within 7 years of blood draw (Pheterogeneity = 0.06).

Conclusions:

The VAT score predicted risks of postmenopausal breast cancer and can be used for risk assessment in diverse populations.

Impact:

These findings provide specific evidence for a role of VAT in breast cancer.




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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.




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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.




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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.




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Assessing Cancer Treatment Information Using Medicare and Hospital Discharge Data among Women with Non-Hodgkin Lymphoma in a Los Angeles County Case-Control Study

Background:

We assessed the ability to supplement existing epidemiologic/etiologic studies with data on treatment and clinical outcomes by linking to publicly available cancer registry and administrative databases.

Methods:

Medical records were retrieved and abstracted for cases enrolled in a Los Angeles County case–control study of non-Hodgkin lymphoma (NHL). Cases were linked to the Los Angeles County cancer registry (CSP), the California state hospitalization discharge database (OSHPD), and the SEER-Medicare database. We assessed sensitivity, specificity, and positive predictive value (PPV) of cancer treatment in linked databases, compared with medical record abstraction.

Results:

We successfully retrieved medical records for 918 of 1,004 participating NHL cases and abstracted treatment for 698. We linked 59% of cases (96% of cases >65 years old) to SEER-Medicare and 96% to OSHPD. Chemotherapy was the most common treatment and best captured, with the highest sensitivity in SEER-Medicare (80%) and CSP (74%); combining all three data sources together increased sensitivity (92%), at reduced specificity (56%). Sensitivity for radiotherapy was moderate: 77% with aggregated data. Sensitivity of BMT was low in the CSP (42%), but high for the administrative databases, especially OSHPD (98%). Sensitivity for surgery reached 83% when considering all three datasets in aggregate, but PPV was 60%. In general, sensitivity and PPV for chronic lymphocytic leukemia/small lymphocytic lymphoma were low.

Conclusions:

Chemotherapy was accurately captured by all data sources. Hospitalization data yielded the highest performance values for BMTs. Performance measures for radiotherapy and surgery were moderate.

Impact:

Various administrative databases can supplement epidemiologic studies, depending on treatment type and NHL subtype of interest.




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Li-Fraumeni Exploration Consortium Data Coordinating Center: Building an Interactive Web-Based Resource for Collaborative International Cancer Epidemiology Research for a Rare Condition

Background:

The success of multisite collaborative research relies on effective data collection, harmonization, and aggregation strategies. Data Coordination Centers (DCC) serve to facilitate the implementation of these strategies. The utility of a DCC can be particularly relevant for research on rare diseases where collaboration from multiple sites to amass large aggregate datasets is essential. However, approaches to building a DCC have been scarcely documented.

Methods:

The Li-Fraumeni Exploration (LiFE) Consortium's DCC was created using multiple open source packages, including LAM/G Application (Linux, Apache, MySQL, Grails), Extraction-Transformation-Loading (ETL) Pentaho Data Integration Tool, and the Saiku-Mondrian client. This document serves as a resource for building a rare disease DCC for multi-institutional collaborative research.

Results:

The primary scientific and technological objective to create an online central repository into which data from all participating sites could be deposited, harmonized, aggregated, disseminated, and analyzed was completed. The cohort now include 2,193 participants from six contributing sites, including 1,354 individuals from families with a pathogenic or likely variant in TP53. Data on cancer diagnoses are also available. Challenges and lessons learned are summarized.

Conclusions:

The methods leveraged mitigate challenges associated with successfully developing a DCC's technical infrastructure, data harmonization efforts, communications, and software development and applications.

Impact:

These methods can serve as a framework in establishing other collaborative research efforts. Data from the consortium will serve as a great resource for collaborative research to improve knowledge on, and the ability to care for, individuals and families with Li-Fraumeni syndrome.




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Further Guidance in Implementing the Standardized 2018 World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) Score

The 2018 World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) Score was developed to establish a simple, standardized scoring system for researchers to quantify adherence to the 2018 WCRF/AICR Cancer Prevention Recommendations and assess its impact on cancer risk and other health-related outcomes. The aim of this commentary is to clarify potential points of ambiguity in its application, focusing on aspects related to specific subscore components (physical activity, fast foods, alcohol, and sugar-sweetened drinks), how to address different data needs due to varied data collection instruments, and future exploratory score approaches. Overall, we encourage researchers to utilize the standardized score to enhance comparability across populations and countries. Researchers who may adapt or augment the 2018 WCRF/AICR Score are strongly encouraged to provide detailed descriptions of their methods to promote transparency and reproducibility.




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E. coli DNA Polymerase I and the Klenow Fragment

Escherichia coli DNA Pol I can carry out three enzymatic reactions: It possesses 5' -> 3' DNA polymerase activity and 3' -> 5' and 5' -> 3' exonuclease activity. Pol I can be cleaved by mild treatment with subtilisin into two fragments; the larger fragment is known as the Klenow fragment. The Klenow fragment retains the polymerizing activity and the 3' -> 5' exonuclease of the holo-enzyme but lacks its powerful 5' -> 3' exonuclease activity. These enzymes and their applications in molecular cloning are introduced here.




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Labeling 3' Termini of Double-Stranded DNA Using the Klenow Fragment of E. coli DNA Polymerase I

The Klenow fragment, which retains the template-dependent deoxynucleotide polymerizing activity and the 3' -> 5' exonuclease of the holo-enzyme but lacks its powerful 5' -> 3' exonuclease activity, is used to fill recessed 3' termini of dsDNA. In this protocol, fragments suitable as templates for the end-filling reaction are produced by digestion of DNA with an appropriate restriction enzyme. The Klenow enzyme is then used to catalyze the attachment of dNTPs to the recessed 3'-hydroxyl groups.




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The Impact of One-week Dietary Supplementation with Kava on Biomarkers of Tobacco Use and Nitrosamine-based Carcinogenesis Risk among Active Smokers

Tobacco smoking is the primary risk factor for lung cancer, driven by the addictive nature of nicotine and the indisputable carcinogenicity of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) as well as other compounds. The integration of lung cancer chemoprevention with smoking cessation is one potential approach to reduce this risk and mitigate lung cancer mortality. Experimental data from our group suggest that kava, commonly consumed in the South Pacific Islands as a beverage to promote relaxation, may reduce lung cancer risk by enhancing NNK detoxification and reducing NNK-derived DNA damage. Building upon these observations, we conducted a pilot clinical trial to evaluate the effects of a 7-day course of kava on NNK metabolism in active smokers. The primary objective was to compare urinary total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL plus its glucuronides, major metabolites of NNK) before and after kava administration as an indicator of NNK detoxification. Secondary objectives included determining kava's safety, its effects on DNA damage, tobacco use, and cortisol (a biomarker of stress). Kava increased urinary excretion of total NNAL and reduced urinary 3-methyladenine in participants, suggestive of its ability to reduce the carcinogenicity of NNK. Kava also reduced urinary total nicotine equivalents, indicative of its potential to facilitate tobacco cessation. Plasma cortisol and urinary total cortisol equivalents were reduced upon kava use, which may contribute to reductions in tobacco use. These results demonstrate the potential of kava intake to reduce lung cancer risk among smokers.




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Adiposity Change Over the Life Course and Mammographic Breast Density in Postmenopausal Women

Mammographic breast density is a strong risk factor for breast cancer. We comprehensively investigated the associations of body mass index (BMI) change from ages 10, 18, and 30 to age at mammogram with mammographic breast density in postmenopausal women. We used multivariable linear regression models, adjusted for confounders, to investigate the associations of BMI change with volumetric percent density, dense volume, and nondense volume, assessed using Volpara in 367 women. At the time of mammogram, the mean age was 57.9 years. Compared with women who had a BMI gain of 0.1–5 kg/m2 from age 10, women who had a BMI gain of 5.1–10 kg/m2 had a 24.4% decrease [95% confidence interval (CI), 6.0%–39.2%] in volumetric percent density; women who had a BMI gain of 10.1–15 kg/m2 had a 46.1% decrease (95% CI, 33.0%–56.7%) in volumetric percent density; and women who had a BMI gain of >15 kg/m2 had a 56.5% decrease (95% CI, 46.0%–65.0%) in volumetric percent density. Similar, but slightly attenuated associations were observed for BMI gain from ages 18 and 30 to age at mammogram and volumetric percent density. BMI gain over the life course was positively associated with nondense volume, but not dense volume. We observed strong associations between BMI change over the life course and mammographic breast density. The inverse associations between early-life adiposity change and volumetric percent density suggest that childhood adiposity may confer long-term protection against postmenopausal breast cancer via its effect of mammographic breast density.




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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.




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Dasatinib Is an Effective Treatment for Angioimmunoblastic T-cell Lymphoma

Recurrent hotspot (p.Gly17Val) mutations in RHOA encoding a small GTPase, together with loss-of-function mutations in TET2 encoding an epigenetic regulator, are genetic hallmarks of angioimmunoblastic T-cell lymphoma (AITL). Mice expressing the p.Gly17Val RHOA mutant on a Tet2-null background succumbed to AITL-like T-cell lymphomas due to deregulated T-cell receptor (TCR) signaling. Using these mice to investigate therapeutics for AITL, we found that dasatinib, a multikinase inhibitor prolonged their survival through inhibition of hyperactivated TCR signaling. A phase I clinical trial study of dasatinib monotherapy in 5 patients with relapsed/refractory AITL was performed. Dasatinib was started at a dose of 100 mg/body once a day and continued until days 10–78 (median day 58). All the evaluable patients achieved partial responses. Our findings suggest that AITL is highly dependent on TCR signaling and that dasatinib could be a promising candidate drug for AITL treatment.Significance:Deregulated T-cell receptor signaling is a critical molecular event in angioimmunoblastic T-cell lymphoma and can be targeted with dasatinib.




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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.




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Immunotherapeutic Response in Tumors Is Affected by Microenvironmental ROS

Carcinoma-associated fibroblasts (CAF) are a potential therapeutic target for both direct and indirect regulation of cancer progression and therapy response. In this issue of Cancer Research, Ford and colleagues investigate the influence of CAF on the immune environment of tumors, specifically focusing on the regulation of CD8+ T cells, required for immune therapy response. Their work suggests a role for stromally expressed NADPH oxidase 4 (NOX4) as a modulator of reactive oxygen species that in turn can reduce the number of CD8+ T cells locally. Inhibition of NOX4 increased CD8+ T cells and restored responsiveness to immune therapy, suggesting an indirect stromally targeted avenue for therapy resensitization.See related article by Ford et al., p. 1846




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Postpartum Involution and Cancer: An Opportunity for Targeted Breast Cancer Prevention and Treatments?

Childbirth at any age confers a transient increased risk for breast cancer in the first decade postpartum and this window of adverse effect extends over two decades in women with late-age first childbirth (>35 years of age). Crossover to the protective effect of pregnancy is dependent on age at first pregnancy, with young mothers receiving the most benefit. Furthermore, breast cancer diagnosis during the 5- to 10-year postpartum window associates with high risk for subsequent metastatic disease. Notably, lactation has been shown to be protective against breast cancer incidence overall, with varying degrees of protection by race, multiparity, and lifetime duration of lactation. An effect for lactation on breast cancer outcome after diagnosis has not been described. We discuss the most recent data and mechanistic insights underlying these epidemiologic findings. Postpartum involution of the breast has been identified as a key mediator of the increased risk for metastasis in women diagnosed within 5–10 years of a completed pregnancy. During breast involution, immune avoidance, increased lymphatic network, extracellular matrix remodeling, and increased seeding to the liver and lymph node work as interconnected pathways, leading to the adverse effect of a postpartum diagnosis. We al discuss a novel mechanism underlying the protective effect of breastfeeding. Collectively, these mechanistic insights offer potential therapeutic avenues for the prevention and/or improved treatment of postpartum breast cancer.




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Involvement of the Olfactory Apparatus by Gliomas [HEAD & NECK]

SUMMARY:

The olfactory bulbs and tracts are central nervous system white matter tracts maintained by central neuroglia. Although rare, gliomas can originate from and progress to involve the olfactory apparatus. Through a Health Insurance Portability and Accountability Act–compliant retrospective review of the institutional teaching files and brain MR imaging reports spanning 10 years, we identified 12 cases of gliomas involving the olfactory bulbs and tracts, including 6 cases of glioblastoma, 2 cases of anaplastic oligodendroglioma, and 1 case each of pilocytic astrocytoma, diffuse (grade II) astrocytoma, anaplastic astrocytoma (grade III), and diffuse midline glioma. All except the pilocytic astrocytoma occurred in patients with known primary glial tumors elsewhere. Imaging findings of olfactory tumor involvement ranged from well-demarcated enhancing masses to ill-defined enhancing infiltrative lesions to nonenhancing masslike FLAIR signal abnormality within the olfactory tracts. Familiarity with the imaging findings of glioma involvement of the olfactory nerves is important for timely diagnosis and treatment of recurrent gliomas and to distinguish them from other disease processes.




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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.




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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.




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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.




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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.




men

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.




men

Complications of Endovascular Treatments for Brain Arteriovenous Malformations: A Nationwide Surveillance [INTERVENTIONAL]

BACKGROUND AND PURPOSE:

Embolization is widely performed to treat brain arteriovenous malformations, but little has been reported on factors contributing to complications. We retrospectively reviewed a nationwide surveillance to identify risk factors contributing to complications and short-term clinical outcomes in the endovascular treatment of brain arteriovenous malformations.

MATERIALS AND METHODS:

Data for endovascular treatment of brain arteriovenous malformations were extracted from the Japanese nationwide surveillance. Patient characteristics, brain arteriovenous malformation features, procedures, angiographic results, complications, and clinical outcomes at 30 days postprocedure were analyzed.

RESULTS:

A total of 1042 endovascular procedures (788 patients; mean, 1.43 ± 0.85 procedures per patient) performed in 111 institutions from 2010 to 2014 were reviewed. Liquid materials were used in 976 procedures (93.7%): to perform presurgical embolization in 638 procedures (61.2%), preradiosurgical embolization in 160 (15.4%), and as sole endovascular treatment in 231 (22.2%). Complete or near-complete obliteration of brain arteriovenous malformations was obtained in 386 procedures (37.0%). Procedure-related complications occurred in 136 procedures (13.1%), including hemorrhagic complications in 59 (5.7%) and ischemic complications in 57 (5.5%). Univariate analysis identified deep venous drainage, associated aneurysms, infratentorial location, and preradiosurgical embolization as statistically significant risk factors for complications. Multivariate analysis showed that embolization of brain arteriovenous malformations in the infratentorial location was significantly associated with complications. Patients with complications due to endovascular procedures had worse clinical outcomes 30 days after the procedures than those without complications.

CONCLUSIONS:

Complications arising after endovascular treatment of brain arteriovenous malformations are not negligible even though they may play a role in adjunctive therapy, especially in the management of infratentorial brain arteriovenous malformations.




men

Glasgow Coma Scale on Presentation Predicts Outcome in Endovascular Treatment for Acute Posterior Large-Vessel Occlusion [INTERVENTIONAL]

SUMMARY:

Use of mechanical thrombectomy for stroke has increased since the publication of trials describing outcome improvement when used in the anterior circulation. These results, however, cannot be directly translated to the posterior circulation. While a high NIHSS score has demonstrated an association with poor outcomes in posterior stroke, the NIHSS is weighted toward hemispheric disease, and complex scores potentially delay definitive imaging diagnosis. We performed a retrospective analysis to ascertain whether any rapidly obtainable demographic or clinical and imaging data have a correlation with patient outcome postthrombectomy. Seventy-three cases were audited between September 2010 and October 2017. Presenting with a Glasgow Coma Scale score of >13 meant that the odds of reaching the primary end point of functional independence (defined as a 90-day modified Rankin Scale score of 0–2) were 5.70 times greater; similarly, presenting with a posterior circulation ASPECTS of >9 resulted in the odds of reaching the primary end point being 4.03 times greater. Older age correlated to a lower odds of independence (0.97, p = .04).




men

Save the Brain First: CTA and Mechanical Thrombectomy in Patients at Risk for Contrast-Induced Nephropathy [article-commentary]




men

Contrast-Induced Acute Kidney Injury in Radiologic Management of Acute Ischemic Stroke in the Emergency Setting [INTERVENTIONAL]

BACKGROUND AND PURPOSE:

The use of invasive cerebral angiography with CTA for active treatment of patients with suspected ischemic strokes has been increasing recently. This study aimed to identify the incidence of postcontrast acute kidney injury using baseline renal function when CTA and cerebral angiography were performed sequentially.

MATERIALS AND METHODS:

This retrospective observational study evaluated adults (18 years of age or older) with ischemic stroke who underwent CTA and cerebral angiography sequentially between 2010 and 2018. The incidence of postcontrast acute kidney injury was determined using the baseline estimated glomerular filtration rate. The value of the baseline estimated glomerular filtration rate at which the occurrence of postcontrast acute kidney injury increased was also determined.

RESULTS:

Postcontrast acute kidney injury occurred in 57/601 (9.5%) patients. Those with a baseline estimated glomerular filtration rate of <30 mL/min/1.73 m2 showed a higher incidence of acute kidney injury. Age, chronic kidney disease, medication (nonsteroidal anti-inflammatory drugs, angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, β blockers, statins, and insulin) use following contrast media exposure, and serum albumin affected the incidence of postcontrast acute kidney injury. The incidence of postcontrast acute kidney injury increased when the baseline estimated glomerular filtration rate was <43 mL/min/1.73 m2.

CONCLUSIONS:

Patients with low baseline renal function had the highest incidence of postcontrast acute kidney injury after CTA and cerebral angiography, but no fatal adverse effects were documented. Thus, patients suspected of having a stroke should be actively managed with respect to neurovascular function.




men

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.




men

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.




men

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