Opportunities and Challenges in Implementation of Multiparameter Single Cell Analysis Platforms for Clinical Translation

Abstract

The high-content interrogation of single cells with platforms optimized for the multiparameter characterization of cells in liquid and solid biopsy samples can enable characterization of heterogeneous populations of cells ex vivo. Doing so will advance the diagnosis, prognosis, and treatment of cancer and other diseases. However, it is important to understand the unique issues in resolving heterogeneity and variability at the single cell level before navigating the validation and regulatory requirements in order for these technologies to impact patient care. Since 2013, leading experts representing industry, academia, and government have been brought together as part of the Foundation for the National Institutes of Health (FNIH) Biomarkers Consortium to foster the potential of high-content data integration for clinical translation.

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Fusion-Negative Rhabdomyosarcoma Can Arise from Endothelial Cells [Sarcoma]

Aberrant myogenic activation in endothelial cells can drive fusion-negative rhabdomyosarcoma (FN-RMS).

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Sugar-Sweetened Cigarettes: Added Sugars in American Cigarette Brands

Sugars are commonly added to American-blended cigarettes, and the presence of sugars in cigarettes increases the appeal, toxicity, and addictive potential of smoking. The purpose of this study was to identify the types and relative quantities of added sugars in the tobacco of popular American cigarette brands. Methods: We reviewed the company websites of Philip Morris USA (PMUSA) and RJ Reynolds Tobacco Company (RJR) for brand-specific ingredient lists for all PMUSA (n = 179) and RJR (n = 162) cigarette brand styles (combined 79% of US cigarette sales in 2016) and composite lists of all cigarette tobacco ingredients for both companies. From these lists, we identified known forms of saccharides (mono-, di-, and oligosaccharides). Results: All PMUSA and RJR cigarette brands contained at least one type of added sugar, except one RJR brand (6 brand styles), which contained no additives. By weight, sugars were the number one ingredient (excluding tobacco and water) in all PMUSA brands (e.g., Marlboro, Parliament, Virginia Slims). Examples of sugars added to PMUSA brands included high fructose corn syrup, sucrose, maltol, and ethyl maltol. Among RJR brands, sugar was the number two ingredient by weight (excluding tobacco and water) in most brands (e.g., Camel, Newport, Pall Mall). In some RJR brands, quantities of added sugar relative to other ingredients were more variable, ranging from the first to fourth most used ingredient by weight (e.g., Carlton, Doral, Kent, More). Types of sugars added to RJR brands included high fructose corn syrup, brown sugar, honey, glucose, and a variety of fruit juice concentrates (e.g., apple, fig, pineapple). Interestingly, many menthol cigarette brands (e.g., Newport, Marlboro Menthol, Camel Menthol) contained greater quantities of added sugar than menthol. Conclusions: A variety of sugars, including sugars routinely added to processed foods and beverages, are added to American cigarettes. Further, by weight, added sugars were the number one or number two ingredient in most cigarette brands. Given that added sugars increase the appeal, toxicity, and addictive potential of smoking, regulatory actions should be considered (e.g., a product standard for sugar) for the protection of public health.

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Using Social Media to Reduce Multiple Risk Factors for CRC in Rural Appalachians: #CRCFREE

Purpose: To examine the efficacy, acceptability, feasibility, and applicability of a Facebook (FB) intervention designed to reduce multiple colorectal cancer (CRC) risk factors in older adults residing in rural Appalachian Kentucky. Methods: We piloted a 12 week FB intervention culturally tailored for older adults residing in rural Eastern Kentucky to impact CRC risk factors, including: nutrition, physical activity, and screening. Participants were aged 50+, had internet access, and were at risk for CRC. During the 12 week study, the participants received three daily posts via secret FB group regarding CRC risk factors. Demographics, dietary measures, body mass index (BMI), and CRC screening were assessed at baseline and post intervention. FB engagement and physical activity were tracked throughout the intervention. Dietary measures included the Healthy Eating Index (HEI) and Dietary Inflammatory Index (DII). Physical activity was tracked using Fitbits. Post-intervention focus group interviews were conducted to assess feasibility and acceptability. Results: Participants (n = 57) were Caucasian, aged 58 ± 6 years, predominately female (67%), and the majority reported at least a high school education (77%). Post intervention, participants experienced significant increase in HEI scores (49.94 ± 9.84 vs. 58.60 ± 12.06, P = < 0.01). DII scores significantly decreased (2.44 ±1.12 vs. 1.60 ± 1.63, P = 0.003). There was no significant change in physical activity, BMI, or screening status. Participants, on average, viewed more than half of the posts. Focus group participants found FB posts to be useful and motivating. They reported that FB posts were educational and motivational. Conclusion: This pilot study shows promising preliminary data to support using a FB intervention in rural Appalachian older adults to decrease CRC risks. Participants were receptive to FB intervention, and FB provides a unique and accessible method for health promotion in hard to reach populations.

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Research Strategies for Nutritional and Physical Activity Epidemiology and Cancer Prevention

Very large international and ethnic differences in cancer rates exist, are minimally explained by genetic factors, and show the huge potential for cancer prevention. A substantial portion of the differences in cancer rates can be explained by modifiable factors, and many important relationships have been documented between diet, physical activity, and obesity, and incidence of important cancers. Other related factors, such as the microbiome and the metabolome, are emerging as important intermediary components in cancer prevention. It is possible with the incorporation of newer technologies and studies including long follow-up and evaluation of effects across the life cycle, additional convincing results will be produced. However, several challenges exist for cancer researchers; for example, measurement of diet and physical activity, and lack of standardization of samples for microbiome collection, and validation of metabolomic studies. The United States National Cancer Institute convened the Research Strategies for Nutritional and Physical Activity Epidemiology and Cancer Prevention Workshop on June 28–29, 2016, in Rockville, Maryland, during which the experts addressed the state of the science and areas of emphasis. This current paper reflects the state of the science and priorities for future research. Cancer Epidemiol Biomarkers Prev; 27(3); 233–44. ©2017 AACR.

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Breast Density and Risk of Invasive Breast Cancer among Older Women Undergoing Mammography: The Breast Cancer Surveillance Consortium Cohort Study

This study examined whether breast density is associated with risk of breast cancer in women age ≥65 years undergoing screening mammography in community practice. Methods: We used prospective cohort data between 1996 and 2012 from the Breast Cancer Surveillance Consortium (BCSC). We calculated separate cumulative incidence models for breast cancer incidence according to Breast Imaging Reporting and Data System (BI-RADS) breast density for women ages 65–74 and ages ≥75. Multivariable Cox proportional hazards regression models were fitted to determine the risk of invasive breast cancer adjusted for BCSC registry, race/ethnicity, BMI, hormone therapy use and benign breast disease. Results: Among the 403,268 women included in the study, approximately 40% were ages ≥75. The annual incidence rate of invasive breast cancer increased with increasing breast density among women ages 65–74 [BI- RADS fatty breasts: 2.2% (95% CI, 2.1%–2.4%) vs. heterogeneously or extremely dense breasts: 4.7% (95% CI, 4.6%–4.9%)] and women ages 75+ [BI-RADS fatty breasts: 2.3% (95% CI, 2.1%–2.5%) vs. heterogeneously or extremely dense: 4.3% (95% CI, 4.1%–4.5%)]. Women with BI-RADS fatty breasts had a decreased risk of breast cancer among women ages 65–74 [HR: 0.66 (95% CI: 0.58%–0.78%) and women ages ≥75 [HR: 0.73 (95% CI: 0.62%–0.87%). Women with BI-RADS heterogeneously or extremely dense breasts were found to have increased risk of breast cancer among women ages 65–74 [HR: 1.39 (95% CI: 1.28%–1.51%)] and women ages ≥75 [HR: 1.23 (95% CI: 1.10%–1.37%)]. Conclusions: Older women with higher BI-RADS density had a significantly increased risk of breast cancer. These findings add further evidence that breast density continues to be associated with an increased risk of breast cancer, even among women age ≥75 years.

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Multilevel Small-Area Estimation of Colorectal Cancer Screening in the United States

Background: The U.S. Preventive Services Task Force recommends routine screening for colorectal cancer for adults ages 50 to 75 years. We generated small-area estimates for being current with colorectal cancer screening to examine sociogeographic differences among states and counties. To our knowledge, nationwide county-level estimates for colorectal cancer screening are rarely presented.

Methods: We used county data from the 2014 Behavioral Risk Factor Surveillance System (BRFSS; n = 251,360 adults), linked it to the American Community Survey poverty data, and fitted multilevel logistic regression models. We post-stratified the data with the U.S. Census population data to run Monte Carlo simulations. We generated county-level screening prevalence estimates nationally and by race/ethnicity, mapped the estimates, and aggregated them into state and national estimates. We evaluated internal consistency of our modeled state-specific estimates with BRFSS direct state estimates using Spearman correlation coefficients.

Results: Correlation coefficients were ≥0.95, indicating high internal consistency. We observed substantial variations in current colorectal cancer screening estimates among the states and counties within states. State mean estimates ranged from 58.92% in Wyoming to 75.03% in Massachusetts. County mean estimates ranged from 40.11% in Alaska to 79.76% in Florida. Larger county variations were observed in various race/ethnicity groups.

Conclusions: State estimates mask county variations. However, both state and county estimates indicate that the country is far behind the "80% by 2018" target.

Impact: County-modeled estimates help identify variation in colorectal cancer screening prevalence in the United States and guide education and enhanced screening efforts in areas of need, including areas without BRFSS direct-estimates. Cancer Epidemiol Biomarkers Prev; 27(3); 245–53. ©2018 AACR.

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Family History of Melanoma and Lifetime Patterns of Daytime Hours Spent Outdoors in Melanoma-prone Families

Longer daytime hours spent outdoors reflect higher ultraviolet radiation exposure, which is a modifiable risk factor of melanoma. Among individuals of melanoma-prone families, we sought to describe lifetime patterns for hours spent outdoors, and to investigate whether having an affected family member with melanoma from an older generation was associated with patterning. Methods: Information on hours spent outdoors on weekdays, weekends, and holidays beginning at age 10 was obtained from individuals from melanoma-prone families. We determined time-weighted average hours outdoors for warmer months, colder months, and the entire year. K-means for longitudinal data was used to identify lifetime patterns. We created a variable to indicate whether there was an existing melanoma in a prior generation of an individual's family. Multinomial logistic regression models were used to examine the association between family history of melanoma and lifetime patterns of daytime hours spent outdoors, adjusting for covariates. Results: We analyzed 2540 individuals from 669 families ascertained across 15 countries, and four lifetime patterns were identified. Three patterns began with moderate hours that (B) decreased slowly (n = 1014); (C) decreased sharply until age 20 and then remained low (n = 572); or (D) increased at age 20 and remained high (n = 173). One pattern, (A) began with few hours that decreased at age 20 then remained very low (n = 781). Compared to individuals with the high (D) pattern, individuals with an existing melanoma in a prior family generation were more likely to have the low (A) pattern (OR = 1.92, 95% CI: 1.34–2.76), the moderate and slowly decreasing (B) pattern (OR = 1.72, 95% CI: 1.15–2.57), or the sharply decreasing (C) pattern (OR = 2.01, 95% CI: 1.40–2.87). Similar associations were observed separately in warmer and colder months. Examining lifetime patterns of hours spent outdoors during holidays, we noticed a stronger relationship with family history of melanoma in warmer months than in colder months. Conclusions: As expected, the diagnosis of a melanoma in a prior generation may impact family members' awareness of UVR exposure leading to reduced daytime hours spent outdoors.

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Comparison of Urine 4-(Methylnitrosamino)-1-(3)Pyridyl-1-Butanol and Cotinine for Assessment of Active and Passive Smoke Exposure in Urban Adolescents

Background: Many adolescents are exposed to tobacco smoke, from either active smoking (CS) or secondhand smoke (SHS) exposure. Tobacco-specific biomarkers of exposure include cotinine (detects use in past 2–4 days) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL; detects use for a month or longer). NNAL is expected to detect more intermittent tobacco exposure. We compared NNAL and cotinine as biomarkers of exposure to tobacco in urban adolescents and determined the optimal NNAL cutoff point to distinguish CS from SHS exposure.

Methods: Surplus urine samples, collected from 466 adolescents attending pediatric well or urgent care visits at Zuckerberg San Francisco General Hospital in 2013 to 2014, were assayed for cotinine and NNAL.

Results: Ninety-four percent of adolescents had measurable levels of NNAL compared with 87% for cotinine. The optimal NNAL cutoff point to distinguish CS from SHS was 9.6 pg/mL by latent class or 14.4 pg/mL by receiver-operating characteristic analysis. Cotinine and NNAL were strongly correlated, but the correlation slopes differed for active versus SHS-exposed adolescents. Among nonsmokers, NNAL levels were significantly higher in African American (median, 3.3 pg/mL) compared with other groups (0.9–1.9 pg/mL), suggesting greater exposure to SHS.

Conclusions: Urine NNAL screening finds a large majority (94%) of urban adolescents are exposed to tobacco. African Americans are exposed to higher levels of SHS than other ethnic/racial groups.

Impact: SHS is associated with significant medical morbidity in adolescents. Routine biochemical screening with NNAL or cotinine detects high prevalence of SHS exposure and should be considered as a tool to reduce SHS exposure in high-risk populations. Cancer Epidemiol Biomarkers Prev; 27(3); 254–61. ©2018 AACR.

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Highlights of This Issue

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Carcinogen Exposure among Canadian Tobacco Users: Changes in NNK Exposure from 2007-2009 through 2012-2013

Background: Tobacco-specific nitrosamines (TSNAs) are a class of carcinogens found in tobacco products, whose levels can vary considerably depending on tobacco blends and manufacturing processes. The current study examined whether recent increases in levels of the TSNA NNK [4-(methylnitrosamino-1-(3-pyridyl)-1-butanone] in Canadian cigarettes translated into differences in exposure among Canadian tobacco users.

Methods: Nationally representative data from the Canadian Health Measures Survey (CHMS) were used to measure levels of total urinary NNAL [4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol], a metabolite of the TSNA NNK, among tobacco users. Data from CHMS Cycle 3 (2012–13) were used to examine NNAL, and linear regression was used to examine predictors. Data from CHMS Cycle 1 (2007–09) and Cycle 3 (2012–13) were used to examine changes in NNAL over time.

Results: From 2007–2009 through 2012–2013, levels of creatinine-corrected NNAL increased by 64% (P < 0.0001). Levels of NNAL in 2012–2013 were higher among older respondents (P = 0.04), among females (P = 0.03), among respondents identifying as "white" and "Aboriginal" (P < 0.0001), and among those with greater daily cigarette consumption (P < 0.001), as well as greater levels of urinary free cotinine (P < 0.0001) and urinary creatinine (P < 0.0001).

Conclusions: The findings indicate that exposure to the TSNA NNK among Canadian tobacco users has increased considerably from 2007–2009 through 2012–2013, in parallel to changes in TSNA levels in Canadian cigarettes. In the absence of epidemiologic data, it is unclear whether this change translates into increased risk.

Impact: The study findings have potential implications for tobacco manufacturers, who bear a responsibility to reduce levels of tobacco carcinogens to the full extent possible. Cancer Epidemiol Biomarkers Prev; 27(3); 262–7. ©2018 AACR.

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Sleep and Cancer Incidence in Alberta's Tomorrow Project Cohort

We aimed to investigate the association between self-reported sleep duration and sleep timing midpoint with all- and site-specific cancer incidence in Alberta's Tomorrow Project (ATP) cohort. Methods: The analysis for sleep duration included 46,300 Albertans aged 35–65 years at baseline from the ATP cohort recruited from 2001–2015. Sleep timing midpoint (wake-time – 1/2 sleep duration) was assessed in a subset of ATP participants (n = 19,820). Cancer incidence was determined through record linkage with the Alberta Cancer Registry in December 2016. Cox proportional hazard regression models evaluated the effects of sleep duration and sleep timing midpoint categories on all- and site-specific (breast, colorectal, lung, prostate, endometrial and hematologic) cancer incidence. Models were adjusted for age, sex (non sex-specific cancers), highest level of education, total household income, marital status, alcohol intake, smoking status, body mass index, family history of cancer, presence of at least one medical condition/co-morbidity, menopausal status (female cancers only) and sleep duration (sleep timing midpoint analysis only). Results: By 2016, there were 3,034 incident cases of cancer in this cohort. A statistical trend was noted for an increased risk of all cancers in participants reporting > 9 hours of sleep/night compared to 7–9 hours of sleep/night (hazard ratio (HR) = 1.16, 95% confidence interval (CI): 0.98–1.36; P = 0.08). Reporting > 9 hours of sleep/night compared to 7–9 hours of sleep/night was also associated with an increased incidence of endometrial cancer (HR = 2.09, 95% CI: 1.16–3.76; P = 0.01). A later sleep timing midpoint (>4:08 AM) versus an intermediate sleep timing midpoint (3:47 AM–4:08 AM) was associated with an increased risk of all (HR = 1.19, 95% CI: 1.03–1.37; P = 0.02) and breast (HR = 1.64, 95% CI: 1.18–2.26; P = 0.003) cancer incidence. Conclusions: These novel findings provide evidence regarding the important role of sleep in cancer etiology. Interventions that put emphasis on proper sleep hygiene for cancer prevention are needed.

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Opium Use and Risk of Pancreatic Cancer: A Prospective Cohort Study

Background: We examined the association between opium consumption and pancreatic cancer incidence in a large-scale prospective cohort of the general population in northeastern Iran.

Methods: A total of 50,045 adults were systematically followed up (median of 7.4 years), and incident cases of pancreatic cancer were identified. Self-reported data on opium consumption was collected at baseline. Cumulative use (-year) was defined as number of nokhods (a local unit, approximately 0.2 g) of opium consumed per day multiplied by number of years consuming. Adjusted HRs and 95% confidence intervals (CIs) for the association between opium consumption and pancreatic cancer were calculated using Cox proportional hazards regression models.

Results: Overall, 54 confirmed cases of pancreatic cancer were identified. Opium use of more than 81 nokhod-years (high cumulative use), compared with never use, was strongly associated with pancreatic cancer even after adjustments for multiple potential confounding factors [HR = 3.01; 95% CI, 1.25–7.26]. High cumulative consumption of opium was significantly associated with risk of pancreatic cancer after adjusting for cumulative dose of cigarette smoking [HR = 3.56; 95% CI, 1.49–8.50]. In a sensitivity analysis, we excluded participants (including 2 pancreatic cancer cases) who were recruited within the first 5 years of starting opium consumption; high cumulative use of opium was still associated with pancreatic cancer risk [HR = 2.75; 95% CI, 1.14–6.64].

Conclusions: Our results showed a positive association between opium consumption and pancreatic cancer.

Impact: This is the first prospective large-scale study to show the association of opium consumption with pancreatic cancer as a risk factor. Cancer Epidemiol Biomarkers Prev; 27(3); 268–73. ©2017 AACR.

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Assessing the Feasibility of a Mentored Home-Based Vegetable Gardening Intervention among Breast Cancer Survivors in the Deep South

To assess the feasibility of a mentored home-based vegetable gardening intervention among Breast Cancer Survivors (BCS) residing in the Birmingham, Alabama metropolitan area. Methods: Using a wait-list control design, BCS were randomized to either a year-long vegetable gardening intervention or a wait-list control. Intervention participants were provided with necessary supplies and paired with a Master Gardener from the Cooperative Extension. Master Gardeners mentored participants in planning, planting, and maintaining 3 seasonal gardens over 12 months, conducted monthly home-visits, and checked in bi-weekly via telephone or email. Feasibility assessment criteria consisted of participant accrual, retention, and satisfaction rates of ≥80%. Target participant accrual was 100. Participant satisfaction data were collected after study completion via structured telephone debriefing. Descriptive statistics were conducted using SPSS V24. Results: 82 BCS (Mage = 60 (39–84); Msurvivorship = 5 years (0.5–23); Mco-morbidities = 3.5 (0–12); ≥2 functional limitations = 86.6%; Caucasian = 73.2%; African-American = 26.8%) enrolled (82% accrual). Of these, four did not complete the study (2 refused to be wait-listed due to not wanting to wait to garden, 1 withdrew due to family obligations, and 1 was lost to follow-up), resulting in an retention rate of 95% over a 1-year period. All BCS who completed the intervention (n = 42) rated their Harvest for Health experience as "Good to Excellent", reported that they would "do it again", and planned to "continue to garden." When asked to rate, on a scale of 1–10 (1 = not at all and 10 = very much), the influence of gardening on motivating behavior change, BCS reported that gardening motivated them to... "eat a healthier diet" (M = 8.38; SD = 2.07), "eat more vegetables" (M = 8.43; SD = 2.08), and "be more physically active" (M = 7.5; SD = 2.73). Conclusions: The vegetable gardening intervention proved to be feasible and provided new knowledge about the influence of gardening on motivating behavior change among BCS. Findings suggest that a mentored home-based vegetable gardening may offer an integrative approach to improve diet, vegetable consumption, and physical activity among BCS. Larger, future studies are warranted.

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Total Nut, Tree Nut, Peanut, and Peanut Butter Consumption and the Risk of Pancreatic Cancer in the Netherlands Cohort Study

Background: Nut intake has been associated with decreased cancer-related mortality, but few studies have examined the potential of nuts in the chemoprevention of pancreatic cancer. We prospectively investigated the association of total nut, tree nut, peanut, and peanut butter consumption with pancreatic cancer risk.

Methods: In the Netherlands Cohort Study, 120,852 men and women completed a baseline questionnaire, including a food frequency questionnaire, in 1986. After 20.3 years of follow-up, 583 incident pancreatic cancer cases, including 349 microscopically confirmed pancreatic cancer (MCPC) cases, were included in multivariable case–cohort analyses.

Results: Increased total nut consumption was associated with a nonsignificantly decreased MCPC risk in men [HR (95% confidence interval) for 10+ g/d vs. nonconsumers = 0.72 (0.47–1.11), P_trend = 0.163]. No clear association was found in women. For tree nut and peanut consumption, nonsignificant inverse associations were observed in men. In women, no or unclear associations were found for tree nut and peanut consumption. Peanut butter intake was related to a significantly reduced risk of MCPC in men [HR (95% confidence interval) for 5+ g/d vs. nonconsumers = 0.53 (0.28–1.00), P_trend = 0.047], but this relation was not clear in women. Evidence for a nonlinear dose–response relation with MCPC was found for tree nut intake only. The associations were weaker when looking at total pancreatic cancer.

Conclusions: Our results suggest that nuts and peanut butter might reduce pancreatic cancer risk in men. In women, no or unclear associations were found.

Impact: Nut consumption might reduce the risk of pancreatic cancer in men. Cancer Epidemiol Biomarkers Prev; 27(3); 274–84. ©2018 AACR.

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Race, Ethnicity, Socioeconomic Status and Site-specific Risk for Gastric Cancer

Differences in gastric cancer risk by race/ethnicity have been reported but data on risk by anatomic subsite are lacking. We assessed site-specific differences in gastric cancer risk according to race/ethnicity and socioeconomic status. Methods: Participants included incident cases of gastric adenocarcinoma age >18 years in the Surveillance Epidemiology and End Results Program 2000–2014. Primary outcome was risk for incident gastric cancer, overall, and by anatomic subsite (cardia vs. non-cardia). Age-adjusted incidence rates were used to estimate adjusted incidence rate ratios (IRR) and their 95% confidence intervals (CI). Risk was assessed by race/ethnicity and neighborhood socioeconomic status (nSES). Results: We identified 77,881 cases of incident gastric cancer (n = 23,651 cardia; n = 35,825 non-cardia; n = 18,405 other). For all gastric cancers, adjusted IRRs (95% CI) were higher for blacks [1.72 (95% CI: 1.68–1.76)], Hispanics [1.77 (1.73–1.80)], and Asian/Pacific Islanders [2.12 (2.08–2.17)] compared to non-Hispanic whites. Opposite trends in risk for cardia vs. non-cardia cancer by race/ethnicity were observed. Compared to non- Hispanic whites, cardia IRRs (95% CI) were 0.55 (0.52–0.59) for blacks, 0.63 (0.60–0.66) for Hispanics, and 0.59 (0.56–0.62) for Asians/Pacific Islanders. Non-cardia IRRs (95% CI) were 2.78 (2.69–2.87) for blacks, 2.83 (2.75- 2.91) for Hispanics, and 3.86 (3.75–3.97) for Asians/Pacific Islanders relative to non-Hispanic whites. Increasing risk with decreasing nSES was observed for all gastric cancers (p trend < 0.0001), with moderate variation for non- cardia cancer but no substantial variation observed for cardia cancer. Conclusions. Gastric cancer incidence varies substantially by race/ethnicity and nSES, but with markedly different associations by anatomic subsite. Non-cardia cancer risk is higher among minorities than non-Hispanic whites and varies only moderately by nSES; while cardia cancer risk is lower among minorities and does not vary by nSES. Unique opportunities for addressing disparities exist for cardia and non-cardia gastric cancer.

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Germline Variants in DNA Repair Genes, Diagnostic Radiation, and Risk of Thyroid Cancer

Background: Radiation exposure is a well-documented risk factor for thyroid cancer; diagnostic imaging represents an increasing source of exposure. Germline variations in DNA repair genes could increase risk of developing thyroid cancer following diagnostic radiation exposure. No studies have directly tested for interaction between germline mutations and radiation exposure.

Methods: Using data and DNA samples from a Connecticut population–based case–control study performed in 2010 to 2011, we genotyped 440 cases of incident thyroid cancer and 465 population-based controls for 296 SNPs in 52 DNA repair genes. We used multivariate unconditional logistic regression models to estimate associations between each SNP and thyroid cancer risk, as well as to directly estimate the genotype–environment interaction between each SNP and ionizing radiation.

Results: Three SNPs were associated with increased risk of thyroid cancer and with thyroid microcarcinoma: HUS rs2708896, HUS rs10951937, and MGMT rs12769288. No SNPs were associated with increased risk of larger tumor (>10 mm) in the additive model. The gene–environment interaction analysis yielded 24 SNPs with P_interaction < 0.05 for all thyroid cancer, 12 SNPs with P_interaction < 0.05 for thyroid microcarcinoma, and 5 SNPs with P_interaction < 0.05 for larger tumors.

Conclusions: Germline variants in DNA repair genes are associated with thyroid cancer risk and are differentially associated with thyroid microcarcinoma and large tumor size. Our study provides the first evidence that germline genetic variations modify the association between diagnostic radiation and thyroid cancer risk.

Impact: Thyroid microcarcinoma may represent a distinct subset of thyroid cancer. The effect of diagnostic radiation on thyroid cancer risk varies by germline polymorphism. Cancer Epidemiol Biomarkers Prev; 27(3); 285–94. ©2017 AACR.

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Clinical and Psychological Predictors of Switching from Active Surveillance to Active Treatment among Men with Low-Risk Prostate Cancer: the PREPARE Prospective Cohort Study

Numerous observational studies have assessed the clinical predictors of switching from active surveillance (AS) to active treatment (AT), but few have assessed psychological and decisional predictors. In a prospective, comparative effectiveness cohort study of men newly diagnosed with low-risk PCa, we assessed whether psychological and decisional factors predicted switching to AT after adjusting for clinical factors. We conducted pre-treatment telephone interviews (N = 1,139; 69.3% participation) with low-risk PCa patients (PSA < 10, Gleason < 7) and a follow-up assessment 6–10 months post-diagnosis (N = 1057; 93%). Clinical variables were obtained from the medical record. The current analysis included men who were on AS for up to 24 months (N = 515), compared to men on AS for >12 months who switched to AT between 12–24 months (N = 86). In Cox proportional hazard models, we included 2 time-dependent covariates measured between diagnosis and 24-months post-diagnosis: PSA (<4, 4–9.99, 10+) and Gleason score (<7, 7+, no surveillance biopsy). Baseline covariates included age (X = 62.3 (SD = 7.0), first degree relative with PCa (25%), number of positive cores (<2 = 75%), urologist initial treatment recommendation (14% AT). Covariates measured at 6 months included prostate- specific anxiety, decisional satisfaction, decisional uncertainty, and preference for shared vs. independent decisions. The fully adjusted model indicated that switching to an active treatment was more likely among those with a PSA > 10 (HR 5.6, 2.4–13.1), Gleason 7+ (HR 20.2, 12.2–33.4), and the urologist's initial recommendation of AT (HR 2.1, 1.04–4.2). The psychological variables, including preference for making independent treatment decisions (HR 2.7, 1.07–6.9) and concern that disease progression will not be detected (HR 1.5, 0.95–2.4), were independently associated with undergoing AT. After adjusting for clinical evidence of disease progression over the first two years post-diagnosis, men's concerns that disease progression will not be detected and preference for making their own treatment decision each independently predicted undergoing AT. These findings suggest the need to provide information and assistance to men who may be uncertain about remaining on AS, particularly when AS remains clinically indicated.

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Enhancing the Infrastructure of the Atherosclerosis Risk in Communities (ARIC) Study for Cancer Epidemiology Research: ARIC Cancer

Background: We describe the expansion of the Atherosclerosis Risk in Communities (ARIC) Study into a cancer cohort. In 1987 to 1989, ARIC recruited 15,792 participants 45 to 64 years old to be sex (55% female), race (27% black), and geographically diverse. ARIC has exceptional data collected during 6 clinical visits and calls every 6 months, repeated biospecimens, and linkage to Medicare claims data.

Methods: We established a Cancer Coordinating Center to implement infrastructure activities, convened a Working Group for data use, leveraged ARIC staff and procedures, and developed protocols. We initiated a cancer-specific participant contact, added questions to existing contacts, obtained permission to collect medical records and tissue, abstracted records, linked with state cancer registries, and adjudicated cases and characterizing data.

Results: Through 2012, we ascertained and characterized 4,743 incident invasive, first, and subsequent primary cancers among 4,107 participants and 1,660 cancer-related deaths. We generated a total cancer incidence and mortality analytic case file, and analytic case files for bladder, breast, colorectal, liver, lung, pancreas, and prostate cancer incidence, mortality, and case fatality. Adjudication of multiple data sources improved case records and identified cancers not identified via registries. From 2013 onward, we ascertain cases from self-report coupled with medical records. Additional cancer registry linkages are planned.

Conclusions: Compared with starting a new cohort, expanding a cardiovascular cohort into ARIC Cancer was an efficient strategy. Our efforts yielded enhanced case files with 25 years of follow-up.

Impact: Now that the cancer infrastructure is established, ARIC is contributing its unique features to modern cancer epidemiology research. Cancer Epidemiol Biomarkers Prev; 27(3); 295–305. ©2017 AACR.

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Overall and Visceral Adiposity Are Associated with Incident Cardiovascular Disease among Breast Cancer Patients: Results from the B-SCANS Study

It is assumed that total and visceral adiposity increase cardiovascular disease (CVD) risk among breast cancer survivors; yet, these associations have not been studied, and could differ from non-cancer populations due to the modifying effects of cancer treatment. METHODS: We studied 2,630 Stage I–III breast cancer patients without pre-existing CVD diagnosed at Kaiser Permanente (2006–2013). We quantified body composition from computed tomography scans taken at breast cancer diagnosis. The main exposures were total and visceral adiposity indices (cm2/m2), examined in tertiles. From ICD codes, we identified non-fatal stroke, coronary artery disease (CAD), and heart failure, and a composite outcome including CVD death (CVD). We estimated hazard ratios (HR) and 95% confidence intervals (CI) adjusting for age, smoking, tumor (stage, grade, and ER/PR and HER2 status) and treatment (chemotherapy and/or radiation) factors, skeletal muscle index (SMI), and body mass index (BMI) residuals. We assessed effect modification via product terms of adiposity with age (>=/<55 years), sarcopenia (SMI>=/<40 cm2/m2) and chemotherapy (yes/no). RESULTS: At diagnosis, mean (SD) age was 55 (11) years and BMI was 28 (6) kg/m2. Over a maximum follow-up of 11 years, 669 CVD events occurred. Independent of BMI and other covariates, women in the highest (v. lowest) tertile of total adiposity had a higher risk of CVD, heart failure, stroke and CAD; HRs (95%CI) were 1.45 (1.15–1.81), 1.78 (1.24–2.57), 1.89 (1.25–2.87), and 1.52 (0.83–2.79), respectively. Results were similar for visceral adiposity, and by age and sarcopenia, but were stronger for women receiving chemotherapy: e.g., the HR (95%CI) for the highest (v. lowest) tertile of total adiposity with CVD risk was 1.76 (1.33–2.33) for women who received chemotherapy versus 0.93 (0.63–1.38) for women who did not, p- interaction = 0.04. CONCLUSIONS: Women who enter a breast cancer diagnosis with greater total and visceral adiposity are at higher risk of subsequent CVD, particularly if they receive chemotherapy. Our results suggest that body composition - independent of BMI and other factors - can identify patients with high CVD risk for additional monitoring, tailored treatment plans and targeting of preventive interventions.

http://ift.tt/2FJ4s0r

Depression, Antidepressant Use, and Breast Cancer Risk in Pre- and Postmenopausal Women: A Prospective Cohort Study

Background: Depression and antidepressant use is highly prevalent among U.S. women and may be related to increased breast cancer risk. However, prior studies are not in agreement regarding an increase in risk.

Methods: We conducted a prospective cohort study within the Nurses' Health Study (NHS) and NHSII among females age 25 and older. Over more than 10 years of follow-up in each cohort, 4,014 incident invasive breast cancers were diagnosed. We used Cox proportional hazards regressions with updating of exposures and covariates throughout follow-up to estimate HRs and 95% confidence intervals (CIs) for associations between clinical depression and antidepressant use with invasive breast cancer risk. Analyses were repeated separately for in situ disease, as well as stratified by estrogen receptor (ER) subtype and menopausal status at diagnosis.

Results: No statistically significant associations were observed between clinical depression (HR for reporting ≥3 times vs. 0, 1.13; 95% CI, 0.85–1.49) or antidepressant use (HR for reporting ≥3 times vs. 0, 0.92; 95% CI, 0.80–1.05) and invasive breast cancer risk in multivariable analyses. Likewise, we observed no significant associations between clinical depression or antidepressant use and risk of in situ, ER⁺, ER^–, premenopausal, or postmenopausal breast cancer.

Conclusions: In the largest prospective study to date, we find no evidence that either depression or antidepressant use increase risk of breast cancer.

Impact: The results of this study are reassuring in that neither depression nor antidepressant use appear to be related to subsequent breast cancer risk. Cancer Epidemiol Biomarkers Prev; 27(3); 306–14. ©2017 AACR.

http://ift.tt/2FKELg3

Pre-treatment Dietary Patterns Are Associated with the Presence of Symptoms 1 Year after Diagnosis in Patients with Head and Neck Cancer

Ninety percent of head and neck cancer (HNC) survivors experience disease and treatment related symptoms. Diet has the potential to reduce inflammation, modulate epigenetic changes and affect biological processes involved in the pathogenesis of symptoms. The objective of this study was to determine if pre-treatment dietary patterns are associated with the presence of symptoms 1-year after diagnosis. Methods: This was a longitudinal study of 295 newly diagnosed HNC patients. All patients completed a food frequency questionnaire and epidemiologic health survey. Self-reported symptoms were assessed pre-treatment and 1-year after diagnosis using a Likert scale ranging from "1: not at all bothered" by symptom to "5: extremely bothered". Symptom scores were dichotomized as "not at all" vs. "slight - extremely". Principal component analysis was used to derive pre-treatment dietary patterns. Multivariable logistic regression models examined the association of derived dietary patterns (fit by quartiles) and seven symptoms (trismus, xerostomia, dysphagia of liquids, dysphagia of solids, difficulty chewing, taste and mucositis). An overall symptom summary score was calculated (range 8–39) and dichotomized as <17 vs. ≥17. This cut-off was chosen by examining the distribution of scores and categorizing into two distinct subgroups naturally present in the data. Results: Two dietary patterns emerged: Prudent (high intakes of vegetables, fruit, fish, poultry, and whole grains) and Western (high intakes of red and processed meats, refined grains, potatoes, and French fries). After adjusting for age, baseline symptoms, tumor site, cancer stage, smoking, calories and HPV status, significant inverse associations were observed between pre-treatment Prudent pattern score and dysphagia of liquids (P = 0.01), dysphagia of solids (P = 0.02) and difficulty chewing (P = 0.02) at 1 year post- diagnosis. A statistically significant inverse association was observed between the overall symptom summary score and the Prudent pattern (P < 0.001). No significant associations were observed between the Western pattern and symptoms. Conclusion: Consumption of a pre-treatment Prudent diet may help reduce the risk of symptoms such as dysphagia and difficulty chewing 1-year after diagnosis in HNC survivors.

http://ift.tt/2FL5h9l

Model-based recursive partitioning to identify risk clusters for metabolic syndrome and its components: findings from the International Mobility in Aging Study

Objective

Conceptual models underpinning much epidemiological research on ageing acknowledge that environmental, social and biological systems interact to influence health outcomes. Recursive partitioning is a data-driven approach that allows for concurrent exploration of distinct mixtures, or clusters, of individuals that have a particular outcome. Our aim is to use recursive partitioning to examine risk clusters for metabolic syndrome (MetS) and its components, in order to identify vulnerable populations.

Study design

Cross-sectional analysis of baseline data from a prospective longitudinal cohort called the International Mobility in Aging Study (IMIAS).

Setting

IMIAS includes sites from three middle-income countries—Tirana (Albania), Natal (Brazil) and Manizales (Colombia)—and two from Canada—Kingston (Ontario) and Saint-Hyacinthe (Quebec).

Participants

Community-dwelling male and female adults, aged 64–75 years (n=2002).

Primary and secondary outcome measures

We apply recursive partitioning to investigate social and behavioural risk factors for MetS and its components. Model-based recursive partitioning (MOB) was used to cluster participants into age-adjusted risk groups based on variabilities in: study site, sex, education, living arrangements, childhood adversities, adult occupation, current employment status, income, perceived income sufficiency, smoking status and weekly minutes of physical activity.

Results

43% of participants had MetS. Using MOB, the primary partitioning variable was participant sex. Among women from middle-incomes sites, the predicted proportion with MetS ranged from 58% to 68%. Canadian women with limited physical activity had elevated predicted proportions of MetS (49%, 95% CI 39% to 58%). Among men, MetS ranged from 26% to 41% depending on childhood social adversity and education. Clustering for MetS components differed from the syndrome and across components. Study site was a primary partitioning variable for all components except HDL cholesterol. Sex was important for most components.

Conclusion

MOB is a promising technique for identifying disease risk clusters (eg, vulnerable populations) in modestly sized samples.

http://ift.tt/2F7rsp1

Developing a UK registry to investigate the role of cardiovascular magnetic resonance (CMR) in patients who activate the primary percutaneous coronary intervention (PPCI) pathway: a multicentre, feasibility study linking routinely collected electronic patient data

Objectives

To determine whether it is feasible to set up a national registry, linking routinely collected data from hospital information systems (HIS), to investigate the role of cardiovascular magnetic resonance (CMR) in patients who activate the primary percutaneous coronary intervention (PPCI) pathway.

Design

Feasibility prospective cohort study, to establish whether: (1) consent can be implemented; (2) data linkage and extraction from multiple HIS can be achieved for >90% of consented patients; (3) local data can be successfully linked with hospital episode data (Hospital Episode Statistics, HES; Patient Episode Database for Wales, PEDW) for >90% of consented patients and (4) the proportion of patients activating the PPCI pathway who get a CMR scan is ≥10% in hospitals with dedicated CMR facilities.

Participants

Patients from four 24/7 PPCI hospitals in England and Wales (two with and two without a dedicated CMR facility) who activated the PPCI pathway and underwent an emergency coronary angiogram.

Results

Consent was successfully implemented at all hospitals (consent rates ranged from 59% to 74%) and 1670 participants were recruited. Data submission was variable: all hospitals submitted clinical data (for ≥82% of patients); only three hospitals submitted biochemistry data (for ≥98% of patients) and echocardiography data (for 34%–87% of patients); only one hospital submitted medications data (for 97% of patients). At the two CMR centres, 14% and 20% of patients received a CMR scan. Data submitted by hospitals were linked with HES and PEDW for 99% of all consented patients.

Conclusion

We successfully consented patients but obtaining individual, opt-in consent would not be feasible for a national registry. Linkage of data from HIS with hospital episode data was feasible. However, data from HIS are not uniformly available/exportable and, in centres with a dedicated CMR facility, some referrals for CMR were for research rather than clinical purposes.

http://ift.tt/2oDjAVS

Linkage of Maternity Hospital Episode Statistics data to birth registration and notification records for births in England 2005-2014: Quality assurance of linkage of routine data for singleton and multiple births

Objectives

To quality assure a Trusted Third Party linked data set to prepare it for analysis.

Setting

Birth registration and notification records from the Office for National Statistics for all births in England 2005–2014 linked to Maternity Hospital Episode Statistics (HES) delivery records by NHS Digital using mothers' identifiers.

Participants

All 6 676 912 births that occurred in England from 1 January 2005 to 31 December 2014.

Primary and secondary outcome measures

Every link between a registered birth and an HES delivery record for the study period was categorised as either the same baby or a different baby to the same mother, or as a wrong link, by comparing common baby data items and valid values in key fields with stepwise deterministic rules. Rates of preserved and discarded links were calculated and which features were more common in each group were assessed.

Results

Ninety-eight per cent of births originally linked to HES were left with one preserved link. The majority of discarded links were due to duplicate HES delivery records. Of the 4854 discarded links categorised as wrong links, clerical checks found 85% were false-positives links, 13% were quality assurance false negatives and 2% were undeterminable. Births linked using a less reliable stage of the linkage algorithm, births at home and in the London region, and with birth weight or gestational age values missing in HES were more likely to have all links discarded.

Conclusions

Linkage error, data quality issues, and false negatives in the quality assurance procedure were uncovered. The procedure could be improved by allowing for transposition in date fields, and more discrimination between missing and differing values. The availability of identifiers in the datasets supported clerical checking. Other research using Trusted Third Party linkage should not assume the linked dataset is error-free or optimised for their analysis, and allow sufficient resources for this.

http://ift.tt/2F7CBpH

Development of an English-language version of a Japanese iPad application to facilitate collaborative goal setting in rehabilitation: a Delphi study and field test

Objective

This study aimed to investigate the content of an English-language version of a Japanese iPad application designed to facilitate shared decision-making around goal setting in rehabilitation: Aid for Decision-making in Occupational Choice—English (ADOC-E).

Design

Phase 1: Delphi methods to reach consensus with an international group of expert occupational therapists on the text and images in ADOC-E. Phase 2: Testing correct recognition (unprompted and prompted) of images in ADOC-E by health service users in inpatient rehabilitation and residential care.

Setting

Phase 1: International, online. Phase 2: Three healthcare services in New Zealand—(1) a residential rehabilitation service for traumatic brain injury, (2) a nursing home for frail older adults and (3) an inpatient rehabilitation ward in a public hospital.

Participants

Phase 1: Fourteen experienced occupational therapists from New Zealand (4), Australia (4), UK (2) and USA (4). Phase 2: Twenty-four rehabilitation and residential care service users (10 men, 14 women; 20–95 years; Mini-Mental State Exam scores 13–30).

Results

Four Delphi rounds were required to reach consensus with the experienced occupational therapists on the content of ADOC-E, ending with 100 items covering daily activities that people do and social roles they participate in. Ninety-five per cent (95/100) of ADOC-E items could each be correctly identified by over 80% of service user participants with either unprompted or prompted recognition.

Conclusion

While a few of the more abstract concepts in ADOC-E (related to complex social roles) were less likely to be correctly recognised by all participants, the text and images ADOC-E were deemed to be fit for purpose overall and ready for future clinical testing.

http://ift.tt/2FbSf6X

Does physiological distribution of blood parameters in children depend on socioeconomic status? Results of a German cross-sectional study

Objectives

In the present study, we examined the relation between socioeconomic status (SES) and the physiological distribution of iron-related blood parameters.

Design

This is a cross-sectional analysis of longitudinal population-based cohort study.

Setting

Based on a sample of healthy participants from a German research centre, various blood parameters and values of clinical examinations and questionnaires were collected.

Participants

A total of 1206 healthy volunteers aged 2.5 to 19 years, one child per family randomly selected, were included.

Primary and secondary outcome measures

Associations between the SES of children by Winkler-Stolzenberg Index (WSI) and its dimensions (income, education, occupation) and iron-related blood parameters (haemoglobin, ferritin and transferrin) were analysed by linear regression analyses. Gender and pubertal stage were included as covariables. Additionally, associations between SES of children by WSI and physical activity (side-to-side jumps, push-ups) as well as body mass index (BMI) were analysed by linear regression analyses.

Results

Children with high WSI or family income showed significantly increased z-scores for haemoglobin (P=0.046; P<0.001). Children with increased WSI or family income showed significantly lower z-scores for transferrin (P<0.001). There was a significant correlation between haemoglobin and gender (P<0.001) and between transferrin and pubertal stage (P=0.024). Furthermore, physical activity was positively correlated and BMI was negatively correlated with WSI (P<0.001).

Discussion

Our data show an association between SES and the distribution of iron-dependent parameters. Lower SES is correlated with lower values for haemoglobin and higher values for transferrin. Furthermore, we demonstrate that physical activity and BMI are associated with SES. Whereas higher SES is correlated with higher values for physical activity and lower BMI. Our parameters are standardised as z-scores with the advantages that the results are comparable across different age groups and present physiological courses.

Trial registration number

NCT02550236; Results.

http://ift.tt/2GWg284

Realist evaluation of a complex integrated care programme: protocol for a mixed methods study

Introduction

The lack of understanding of how complex integrated care programmes achieve their outcomes due to the lack of acceptable methods leads to difficulties in the development, implementation, adaptation and scaling up of similar interventions. In this study, we evaluate an integrated care network, the National University Health System (NUHS) Regional Health System (RHS), consisting of acute hospitals, step down care, primary care providers, social services and community partners using a theory-driven realist evaluation approach. This study aims to examine how and for whom the NUHS-RHS works to improve healthcare utilisations, outcomes, care experiences and reduce healthcare costs. By using a realist approach that balances the needs of context-specific evaluation with international comparability, this study carries the potential to address current research gaps.

Methods and analysis

This evaluation will be conducted in three research phases: (1) development of initial programme theory (IPT) underlying the NUHS-RHS; (2) testing of programme theory using empirical data; and (3) refinement of IPT. IPT was elicited and developed through reviews of programme documents, informal discussions and in-depth interviews with relevant stakeholders. Then, a convergent parallel mixed method study will be conducted to assess context (C), mechanisms (M) and outcomes (O) to test the IPT. Findings will then be analysed according to the realist evaluation formula of CMO in which findings on the context, mechanisms will be used to explain the outcomes. Finally, based on findings gathered, IPT will be refined to highlight how to improve the NUHS-RHS by detailing what works (outcome), as well as how (mechanisms) and under what conditions (context).

Ethics and dissemination

The National Healthcare Group, Singapore, Domain Specific Review Board reviewed and approved this study protocol. Study results will be published in international peer-reviewed journals and presented at conferences and internally to NUHS-RHS and Ministry of Health, Singapore.

http://ift.tt/2Fg864c

Negotiating acceptable termination of pregnancy for non-lethal fetal anomaly: a qualitative study of professional perspectives

Objective

This study aims to explore the perspectives of professionals around the issue of termination of pregnancy for non-lethal fetal anomaly (TOPFA).

Methods

Semi-structured interviews were undertaken with medical professionals (14 consultants in fetal medicine, obstetrics, neonatology and paediatrics) and social care professionals (nine individuals with roles supporting people living with impairment) from the Northeast of England. Analysis adopted an inductive thematic approach facilitated by NVivo.

Results

The overarching theme to emerge from the interview data was of professionals, medical and social care, wanting to present an acceptable self-image of their views on TOPFA. Professionals' values on 'fixing', pain and 'normality' influenced what aspects of moral acceptability they gave priority to in terms of their standpoint and, in turn, their conceptualisations of acceptable TOPFA. Thus, if a termination could be defended morally, including negotiation of several key issues (including 'fixing', perceptions of pain and normality), then participants conceptualised TOPFA as an acceptable pregnancy outcome.

Conclusion

Despite different professional experiences, these professional groups were able to negotiate their way through difficult terrain to conceptualise TOPFA as a morally acceptable principle. While professionals have different moral thresholds, no one argued for a restriction of the current legislation. The data suggest that social care professionals also look at the wider social context of a person with an impairment when discussing their views regarding TOPFA. Medical professionals focus more on the individual impairment when discussing their views on TOPFA.

http://ift.tt/2GVMkjj

Combination therapy of anabolic agents and bisphosphonates on bone mineral density in patients with osteoporosis: a meta-analysis of randomised controlled trials

Objective

We aimed to determine whether the concomitant combination therapy of anabolic agents and bisphosphonates produces more effects on bone mineral density (BMD) than anabolic agents alone in patients with osteoporosis.

Methods

We searched MEDLINE, EMBASE and the Cochrane Library for publications from 1 January 1980 to 1 August 2016 to identify all the randomised controlled trials (RCTs) and quasi-RCTs. The primary outcome was the mean per cent changes in BMD at the lumbar spine, the total hip and the femoral neck with an optimal period of treatment (6 to 12 months). The secondary outcome was the mean per cent changes in BMD at the same sites with the full period of recommendation (18 to 24 months). A random-effects model was used to estimate the standardised mean differences (SMDs) and the 95% CIs.

Results

Seven studies, with 747 patients, were included. With the optimal period, the concomitant combination therapy demonstrated a significant advantage over a monotherapy in BMD improvement at the total hip (SMD 0.42; 95% CI 0.26 to 0.58) and the femoral neck (SMD 0.30; 95% CI 0.14 to 0.46), but not for the spine BMD (SMD 0.13; 95% CI –0.17 to 0.43). With the full period, the concomitant combination therapy did not improve the BMD at the lumbar spine (SMD –0.06; 95% CI –0.71 to 0.59), the total hip (SMD 0.05; 95% CI –0.71 to 0.82) and the femoral neck (SMD –0.32; 95% CI –1.15 to 0.50).

Conclusions

Compared with anabolic monotherapy, the concomitant combination therapy of anabolic agents and bisphosphonates significantly improved the BMD at the total hip and femoral neck with a shorter term (6 to 12 months) and produced similar benefits on BMD for the longer term (18 to 24 months). Also, the effect of concomitant combination therapy might be affected by the dose of anabolic agents.

PROSPERO registration number

CRD42016041335.

http://ift.tt/2oAfygS

Increased Single fiber jitter level is associated with reduction in motor function with aging

ABSTRACTObjectiveAge-associated skeletal muscle weakness is a major contributing factor to an increased late life mortality and morbidity, but its neurobiology is poorly understood. Previously, we provided histological evidence of dying-back axonal degeneration of motor neurons and denervation of neuromuscular junctions (NMJ) in age-associated muscle weakness. Given this, we aim to evaluate the relation between impaired neuromuscular transmission and various aspects of age-associated muscle weakness.DesignWe compared two electrophysiological measures, single fiber jitter and compound motor action potential (CMAP) in mice of different age groups, and correlated them with various physical performance measures, such as grip strength, standing and walking time and treadmill performance.ResultsConsistent with our previous histological data, single fiber jitter, a measure of NMJ transmission, was significantly increased in older animals, while CMAP shows no difference between young and old age groups. Neither jitter nor CMAP correlated with any of physical performance measures, except for jitter and standing activity.ConclusionImpaired neuromuscular transmission – represented as increase in SFEMG jitter level – reflects decline in motor function with aging. Objective Age-associated skeletal muscle weakness is a major contributing factor to an increased late life mortality and morbidity, but its neurobiology is poorly understood. Previously, we provided histological evidence of dying-back axonal degeneration of motor neurons and denervation of neuromuscular junctions (NMJ) in age-associated muscle weakness. Given this, we aim to evaluate the relation between impaired neuromuscular transmission and various aspects of age-associated muscle weakness. Design We compared two electrophysiological measures, single fiber jitter and compound motor action potential (CMAP) in mice of different age groups, and correlated them with various physical performance measures, such as grip strength, standing and walking time and treadmill performance. Results Consistent with our previous histological data, single fiber jitter, a measure of NMJ transmission, was significantly increased in older animals, while CMAP shows no difference between young and old age groups. Neither jitter nor CMAP correlated with any of physical performance measures, except for jitter and standing activity. Conclusion Impaired neuromuscular transmission – represented as increase in SFEMG jitter level – reflects decline in motor function with aging. Acknowledgement This work was supported by RMSTP K12 grant (5K12HD001097-19), the Dr. Miriam and Sheldon G Adelson Medical Research Foundation, the National Institutes on Aging (NIA) (R21-AG025143) and the Johns Hopkins Older Americans Independence Center (P30-AG021334). Correspondence: Tae Chung, MD, Johns Hopkins School of Medicine, Department of Physical Medicine and Rehabilitation, 4940 Eastern Avenue/Asthma Allergy bldg. 1A44, Baltimore MD 21224, Email: tchung7@jhmi.edu Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

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Advancing Cancer Screening with Liquid Biopsies [News in Brief]

A new liquid biopsy technique, CancerSEEK, that evaluates tumor mutations and cancer-linked proteins can detect 70% of cancers in patients who have one of eight tumor types. The technique can pinpoint the location of a tumor in 68% of cases. However, its sensitivity drops off at earlier disease stages.

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Deconstruction of a Metastatic Tumor Microenvironment Reveals a Common Matrix Response in Human Cancers [Research Articles]

We have profiled, for the first time, an evolving human metastatic microenvironment by measuring gene expression, matrisome proteomics, cytokine and chemokine levels, cellularity, extracellular matrix organization, and biomechanical properties, all on the same sample. Using biopsies of high-grade serous ovarian cancer metastases that ranged from minimal to extensive disease, we show how nonmalignant cell densities and cytokine networks evolve with disease progression. Multivariate integration of the different components allowed us to define, for the first time, gene and protein profiles that predict extent of disease and tissue stiffness, while also revealing the complexity and dynamic nature of matrisome remodeling during development of metastases. Although we studied a single metastatic site from one human malignancy, a pattern of expression of 22 matrisome genes distinguished patients with a shorter overall survival in ovarian and 12 other primary solid cancers, suggesting that there may be a common matrix response to human cancer.

Significance: Conducting multilevel analysis with data integration on biopsies with a range of disease involvement identifies important features of the evolving tumor microenvironment. The data suggest that despite the large spectrum of genomic alterations, some human malignancies may have a common and potentially targetable matrix response that influences the course of disease. Cancer Discov; 8(3); 304–19. ©2017 AACR.

This article is highlighted in the In This Issue feature, p. 253

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CD10+GPR77+ Cancer-Associated Fibroblasts Promote Chemoresistance [Stem Cells]

CD10 and GPR77 define a cancer-associated fibroblast (CAF) subset that sustains cancer stemness.

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E-cigarette Report Reveals Research Gaps [News in Brief]

In a comprehensive analysis of existing studies, the U.S. National Academies of Sciences, Engineering, and Medicine concluded that electronic cigarettes are addictive, though less toxic than conventional cigarettes. The report also identified key areas for future research, including smoking cessation, adolescent use, and long-term health effects.

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Dimerization Is Critical for the Functions of Wild-type and Mutant KRAS [Lung Cancer]

Wild-type KRAS increases survival and resistance to MEK inhibitors in KRAS-mutant lung cancer cells.

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CNS Metastases Needn't Rule Out Trial Inclusion [News in Brief]

New guidelines from an expert working group describe when to include or exclude patients with brain metastases from clinical trials. In the past, these patients have often been inappropriately excluded from trials, resulting in a dearth of information on the efficacy of cancer drugs in the central nervous system.

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Digital Circulating Tumor Cell Analyses for Prostate Cancer Precision Oncology [In the Spotlight]

Summary: In this issue of Cancer Discovery, Miyamoto and colleagues adapted their microfluidic CTC-iChip isolation platform with a digital RNA-PCR readout for eight prostate-specific transcripts and two assays for the androgen receptor mRNA splice variant ARV7 and the TMPRSS2–ERG translocation transcript. In patients with metastatic castrate-resistant prostate cancer at initiating abiraterone therapy in a first-line setting, the resulting RNA-based digital circulating tumor cell signatures identified patients with a shorter overall survival, and in patients with clinically localized disease, the signatures identified those with seminal vesicle invasion and pelvic lymph node involvement. Cancer Discov; 8(3); 269–71. ©2018 AACR.

See related article by Miyamoto et al., p. 288.

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First Comprehensive Companion Diagnostic OK'd [News in Brief]

The FDA has approved F1CDx, a comprehensive companion diagnostic test that can detect genetic alterations and two genomic signatures in any type of solid tumor. Patients with five common types of advanced cancer can be matched to one of 17 targeted therapies with this single test.

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Chromatin-Remodeling Genes Promote Immunotherapy Resistance [News in Brief]

Two studies show that genes that encode a chromatin-remodeling complex foster resistance to checkpoint inhibitors. One study identified the proteins by using CRISPR/Cas9 to knock out genes in mouse melanoma cells. The other study converged on the same result by identifying mutations in patients with clear cell renal cell carcinoma who responded to PD-1 inhibitors.

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Venetoclax Data Prompt Rethink of CLL Therapy [News in Depth]

The BCL2 inhibitor venetoclax is approved in the United States for only a subset of patients with refractory chronic lymphocytic leukemia. However, in light of data presented at the American Society of Hematology 2017 Annual Meeting, clinicians are thinking ahead to administering the drug more broadly—in combinations and as a first-line therapy—for other patients with the disease.

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Nivolumab plus Ipilimumab Achieves Responses in dMMR/MSI-H Tumors [Clinical Trials]

Nivolumab plus ipilimumab achieves higher response rates than previously reported for nivolumab alone.

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Patients with Desmoplastic Melanoma May Respond to PD-1 Blockade [Immunotherapy]

PD-1 blockade achieved responses in 70% of patients with desmoplastic melanoma in a retrospective analysis.

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KRASG12D Gene Dosage Drives Pancreatic Tumor Evolution and Progression [Pancreatic Cancer]

Allelic imbalance with increased Kras^G12D gene dosage drives key PDAC characteristics.

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Chromosomal Instability Drives Metastasis Independent of Aneuploidy [Metastasis]

Chromosomal instability (CIN) promotes metastasis with little effect on primary tumor growth.

http://ift.tt/2t8dvFz

Autophagy Sustains Pancreatic Cancer Growth through Both Cell-Autonomous and Nonautonomous Mechanisms [Research Brief]

Autophagy has been shown to be elevated in pancreatic ductal adenocarcinoma (PDAC), and its role in promoting established tumor growth has made it a promising therapeutic target. However, due to limitations of prior mouse models as well as the lack of potent and selective autophagy inhibitors, the ability to fully assess the mechanistic basis of how autophagy supports pancreatic cancer has been limited. To test the feasibility of treating PDAC using autophagy inhibition and further our understanding of the mechanisms of protumor effects of autophagy, we developed a mouse model that allowed the acute and reversible inhibition of autophagy. We observed that autophagy inhibition causes significant tumor regression in an autochthonous mouse model of PDAC. A detailed analysis of these effects indicated that the tumor regression was likely multifactorial, involving both tumor cell–intrinsic and host effects. Thus, our study supports that autophagy inhibition in PDAC may have future utility in the treatment of pancreatic cancer and illustrates the importance of assessing complex biological processes in relevant autochthonous models.

Significance: This work demonstrates that autophagy is critical pancreatic tumor maintenance through tumor cell–intrinsic and –extrinsic mechanisms. These results have direct clinical relevance to ongoing clinical trials as well as drug-development initiatives. Cancer Discov; 8(3); 276–87. ©2018 AACR.

See related commentary by Noguera-Ortega and Amaravadi, p. 266.

This article is highlighted in the In This Issue feature, p. 253

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In This Issue [In This Issue]

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Expressed Gene Fusions as Frequent Drivers of Poor Outcomes in Hormone Receptor-Positive Breast Cancer [Research Articles]

We sought to uncover genetic drivers of hormone receptor–positive (HR⁺) breast cancer, using a targeted next-generation sequencing approach for detecting expressed gene rearrangements without prior knowledge of the fusion partners. We identified intergenic fusions involving driver genes, including PIK3CA, AKT3, RAF1, and ESR1, in 14% (24/173) of unselected patients with advanced HR⁺ breast cancer. FISH confirmed the corresponding chromosomal rearrangements in both primary and metastatic tumors. Expression of novel kinase fusions in nontransformed cells deregulates phosphoprotein signaling, cell proliferation, and survival in three-dimensional culture, whereas expression in HR⁺ breast cancer models modulates estrogen-dependent growth and confers hormonal therapy resistance in vitro and in vivo. Strikingly, shorter overall survival was observed in patients with rearrangement-positive versus rearrangement-negative tumors. Correspondingly, fusions were uncommon (<5%) among 300 patients presenting with primary HR⁺ breast cancer. Collectively, our findings identify expressed gene fusions as frequent and potentially actionable drivers in HR⁺ breast cancer.

Significance: By using a powerful clinical molecular diagnostic assay, we identified expressed intergenic fusions as frequent contributors to treatment resistance and poor survival in advanced HR⁺ breast cancer. The prevalence and biological and prognostic significance of these alterations suggests that their detection may alter clinical management and bring to light new therapeutic opportunities. Cancer Discov; 8(3); 336–53. ©2017 AACR.

See related commentary by Natrajan et al., p. 272.

See related article by Liu et al., p. 354.

This article is highlighted in the In This Issue feature, p. 253

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People [News in Brief]

Chi Van Dang, MD, PhD, and Elizabeth Barrett, MBA, are featured.

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Enhancer-Driven Gene Expression Changes Facilitate Metastasis [Osteosarcoma]

Altered enhancer activity allows for dynamic gene expression to promote osteosarcoma metastasis.

http://ift.tt/2FK5EAZ

LXR Agonism Depletes MDSCs to Promote Antitumor Immunity [Immunology]

LXR activation reduces immunosuppressive MDSCs to activate antitumor cytotoxic T cells.

http://ift.tt/2FK5mtT

How to do a simple laparoscopic jejunostomy

http://ift.tt/2HYFR8y

Accuracy of digital radiography: regional scaling factors for trauma

Background

Surgical planning in trauma is essential for optimal patient care and best patient outcomes. Digital radiography has improved the availability, convenience and access to radiographs worldwide as used in every trauma centre in Australia. One shortcoming, however, is the variability in magnification error associated with different anatomic regions. Accurate assessment of radiographs is paramount to proper surgical planning.

Methods

A retrospective review of 513 post-operative trauma radiographs of implants at a single centre, collected from January 2015 to August 2016, was measured by the four individual investigators. A comparison of the digital calliper reading with the known implant size, taken from operation reports and company implant data, was conducted. Magnification scales were created for different anatomic regions: femur, tibia, humerus, elbow, wrist and hand, foot and ankle.

Results

Precise regional scaling factors increase accuracy of digital radiography. Average magnification for hand, wrist, ankle and forearm is 5% (1–16%). Average magnification for foot, knee, tibia and elbow is 8% (3–11%). Humerus magnification is 10.3% (3–17%) and shoulder and femur approximately 15% (12–18%). Inter-rater Pearson's R reliability testing is 0.985–0.995 and intra-observer reliability is 0.998.

Discussion

Applying regional scaling factors improves accuracy of digital imaging, therefore improving clinical decision-making regarding fractures, distance from bony landmarks, component sizing and reduction assessment. Femoral and tibial fracture measurements with appropriate scaling factors allow the accurate estimation of nail diameter required for fixation and screw diameter for fragment fixation.

http://ift.tt/2oLspfx

Gene Transfer of ZMapp Antibodies Mediated by Recombinant Adeno-Associated Virus Protects Against Ebola Infections

Human Gene Therapy , Vol. 0, No. 0.


http://ift.tt/2FJiY8u

Adeno-Associated Virus Serotype 2 Vector–Mediated Reintroduction of microRNA-19b Attenuates Hepatic Fibrosis

Human Gene Therapy , Vol. 0, No. 0.


http://ift.tt/2F6u1Yt

The distinct roles of mesenchymal stem cells in the initial and progressive stage of hepatocarcinoma

The distinct roles of mesenchymal stem cells in the initial and progressive stage of hepatocarcinoma

The distinct roles of mesenchymal stem cells in the initial and progressive stage of hepatocarcinoma, Published online: 01 March 2018; doi:10.1038/s41419-018-0366-7

The distinct roles of mesenchymal stem cells in the initial and progressive stage of hepatocarcinoma

http://ift.tt/2FjcTBQ

Vangl2 regulates spermatid planar cell polarity through microtubule (MT)-based cytoskeleton in the rat testis

Vangl2 regulates spermatid planar cell polarity through microtubule (MT)-based cytoskeleton in the rat testis

Vangl2 regulates spermatid planar cell polarity through microtubule (MT)-based cytoskeleton in the rat testis, Published online: 01 March 2018; doi:10.1038/s41419-018-0339-x

Vangl2 regulates spermatid planar cell polarity through microtubule (MT)-based cytoskeleton in the rat testis

http://ift.tt/2CSARP2

Proteasome inhibition blocks necroptosis by attenuating death complex aggregation

Proteasome inhibition blocks necroptosis by attenuating death complex aggregation

Proteasome inhibition blocks necroptosis by attenuating death complex aggregation, Published online: 01 March 2018; doi:10.1038/s41419-018-0371-x

Proteasome inhibition blocks necroptosis by attenuating death complex aggregation

http://ift.tt/2F4nUIf

Ischemic preconditioning attenuates ischemia/reperfusion-induced kidney injury by activating autophagy via the SGK1 signaling pathway

Ischemic preconditioning attenuates ischemia/reperfusion-induced kidney injury by activating autophagy via the SGK1 signaling pathway

Ischemic preconditioning attenuates ischemia/reperfusion-induced kidney injury by activating autophagy via the SGK1 signaling pathway, Published online: 01 March 2018; doi:10.1038/s41419-018-0358-7

Ischemic preconditioning attenuates ischemia/reperfusion-induced kidney injury by activating autophagy via the SGK1 signaling pathway

http://ift.tt/2CSAtQA

ER–mitochondria signaling in Parkinson’s disease

ER–mitochondria signaling in Parkinson's disease

ER–mitochondria signaling in Parkinson's disease, Published online: 01 March 2018; doi:10.1038/s41419-017-0079-3

ER–mitochondria signaling in Parkinson's disease

http://ift.tt/2FgIc0o

DAX1 promotes cervical cancer cell growth and tumorigenicity through activation of Wnt/β-catenin pathway via GSK3β

DAX1 promotes cervical cancer cell growth and tumorigenicity through activation of Wnt/β-catenin pathway via GSK3β

DAX1 promotes cervical cancer cell growth and tumorigenicity through activation of Wnt/β-catenin pathway via GSK3β, Published online: 01 March 2018; doi:10.1038/s41419-018-0359-6

DAX1 promotes cervical cancer cell growth and tumorigenicity through activation of Wnt/β-catenin pathway via GSK3β

http://ift.tt/2CSuwTU

Sei-1 promotes double minute chromosomes formation through activation of the PI3K/Akt/BRCA1-Abraxas pathway and induces double-strand breaks in NIH-3T3 fibroblasts

Sei-1 promotes double minute chromosomes formation through activation of the PI3K/Akt/BRCA1-Abraxas pathway and induces double-strand breaks in NIH-3T3 fibroblasts

Sei-1 promotes double minute chromosomes formation through activation of the PI3K/Akt/BRCA1-Abraxas pathway and induces double-strand breaks in NIH-3T3 fibroblasts, Published online: 01 March 2018; doi:10.1038/s41419-018-0362-y

Sei-1 promotes double minute chromosomes formation through activation of the PI3K/Akt/BRCA1-Abraxas pathway and induces double-strand breaks in NIH-3T3 fibroblasts

http://ift.tt/2FgI29i

Podocyte-specific Rac1 deficiency ameliorates podocyte damage and proteinuria in STZ-induced diabetic nephropathy in mice

Podocyte-specific Rac1 deficiency ameliorates podocyte damage and proteinuria in STZ-induced diabetic nephropathy in mice

Podocyte-specific Rac1 deficiency ameliorates podocyte damage and proteinuria in STZ-induced diabetic nephropathy in mice, Published online: 01 March 2018; doi:10.1038/s41419-018-0353-z

Podocyte-specific Rac1 deficiency ameliorates podocyte damage and proteinuria in STZ-induced diabetic nephropathy in mice

http://ift.tt/2CSArrW

Loci That Control Nonlinear, Interdependent Responses to Combinations of Drought and Nitrogen Limitation

Crop improvement must accelerate to feed an increasing human population in the face of environmental changes. Including anticipated climatic changes with genetic architecture in breeding programs could better optimize improvement strategies. Combinations of drought and nitrogen limitation already occur world-wide. We therefore analyzed the genetic architecture underlying the response of Zea mays to combinations of water and nitrogen stresses. Recombinant inbreds were subjected to nine combinations of the two stresses using an optimized response surface design, and their growth was measured. Three-dimensional response surfaces were fit globally and to each polymorphic allele to determine which genetic markers were associated with different response surfaces. Three quantitative trait loci that produced nonlinear surfaces were mapped. To better understand the physiology of the response, we developed a model that reproduced the shapes of the surfaces, their most characteristic feature. The model contains two components that each combine the nitrogen and water inputs. The relative weighting of the two components and the inputs is governed by five parameters, and each QTL affects all five parameters. We estimated the model's parameter values for the experimental surfaces using a mesh of points that covered the surfaces' most distinctive regions. Surfaces computed using these values reproduced the experimental surfaces well, as judged by three different criteria at the mesh points. The modeling and shape comparison techniques used here can be extended to other complex, high-dimensional, nonlinear phenotypes. We encourage the application of our findings and methods to experiments that mix crop protection measures, stresses, or both, on elite and landrace germplasm.

http://ift.tt/2GUl2dk

Genomic Locus Modulating IOP in the BXD RI Mouse Strains

Intraocular pressure (IOP) is the primary risk factor for developing glaucoma, yet little is known about the contribution of genomic background to IOP regulation. The present study leverages an array of systems genetics tools to study genomic factors modulating normal IOP in the mouse. The BXD recombinant inbred (RI) strain set was used to identify genomic loci modulating IOP. We measured the IOP in a total of 506 eyes from 38 different strains. Strain averages were subjected to conventional quantitative trait analysis by means of composite interval mapping. Candidate genes were defined, and immunohistochemistry and quantitative PCR (qPCR) were used for validation. Of the 38 BXD strains examined the mean IOP ranged from a low of 13.2mmHg to a high of 17.1mmHg. The means for each strain were used to calculate a genome wide interval map. One significant quantitative trait locus (QTL) was found on Chr.8 (96 to 103 Mb). Within this 7 Mb region only 4 annotated genes were found: Gm15679, Cdh8, Cdh11 and Gm8730. Only two genes (Cdh8 and Cdh11) were candidates for modulating IOP based on the presence of non-synonymous SNPs. Further examination using SIFT (Sorting Intolerant From Tolerant) analysis revealed that the SNPs in Cdh8 (Cadherin 8) were predicted to not change protein function; while the SNPs in Cdh11 (Cadherin 11) would not be tolerated, affecting protein function. Furthermore, immunohistochemistry demonstrated that CDH11 is expressed in the trabecular meshwork of the mouse. We have examined the genomic regulation of IOP in the BXD RI strain set and found one significant QTL on Chr. 8. Within this QTL, there is one good candidate gene, Cdh11.

http://ift.tt/2F61nuz

In vivo E2F reporting reveals efficacious schedules of MEK1/2-CDK4/6 targeting and mTOR-S6 resistance mechanisms [Research Articles]

Targeting cyclin-dependent kinases 4/6 (CDK4/6) represents a therapeutic option in combination with BRAF inhibitor and/or MEK inhibitor (MEKi) in melanoma; however, continuous dosing elicits toxicities in patients. Using quantitative and temporal in vivo reporting, we show that continuous MEKi with intermittent CDK4/6 inhibitor (CDK4/6i) led to more complete tumor responses versus other combination schedules. Nevertheless, some tumors acquired resistance that was associated with enhanced phosphorylation of ribosomal S6 protein. These data were supported by phospho S6 staining of melanoma biopsies from patients treated with CDK4/6i plus targeted inhibitors. Enhanced phospho S6 in resistant tumors provided a therapeutic window for the mTORC1/2 inhibitor, AZD2014. Mechanistically, upregulation or mutation of NRAS was associated with resistance in in vivo models and patient samples, respectively, and mutant NRAS was sufficient to enhance resistance. This study utilizes an in vivo reporter model to optimize schedules and supports targeting mTORC1/2 to overcome MEKi plus CDK4/6i resistance.

http://ift.tt/2oDTSAH

HOXA9 cooperates with activated JAK/STAT signaling to drive leukemia development. [Research Articles]

Leukemia is caused by the accumulation of multiple genomic lesions in hematopoietic precursor cells. However, how these events cooperate during oncogenic transformation remains poorly understood. We studied the cooperation between activated JAK3/STAT5 signaling and HOXA9 overexpression, two events identified as significantly co-occurring in T-cell acute lymphoblastic leukemia. Expression of mutant JAK3 and HOXA9 led to a rapid development of leukemia originating from multipotent or lymphoid-committed progenitors, with a significant decrease in disease latency compared to JAK3 or HOXA9 alone. Integrated RNA-seq, ChIP-seq and ATAC-seq revealed that STAT5 and HOXA9 have co-occupancy across the genome resulting in enhanced STAT5 transcriptional activity and ectopic activation of Fos/Jun (AP-1). Our data suggest that oncogenic transcription factors such as HOXA9 provide a fertile ground for specific signaling pathways to thrive, explaining why JAK/STAT pathway mutations accumulate in HOXA9 expressing cells.

http://ift.tt/2GUqKvE

A pre-existing rare PIK3CAE545K subpopulation confers clinical resistance to MEK plus CDK4/6 inhibition in NRAS melanoma and is dependent on S6K1 signaling [Research Articles]

Combined MEK and CDK4/6 inhibition (MEKi+CDK4i) has shown promising clinical outcomes in NRAS mutant melanoma patients. Here, we interrogated longitudinal biopsies from a patient who initially responded to MEKi+CDK4i therapy but subsequently developed resistance. Whole exome sequencing and functional validation identified an acquired PIK3CAE545K mutation as conferring drug resistance. We demonstrate that PIK3CAE545K pre-existed in a rare subpopulation that was missed by both clinical and research testing, but was revealed upon multi-region sampling due to PIK3CAE545K being non-uniformly distributed. This resistant population rapidly expanded after the initiation of MEKi+CDK4i therapy and persisted in all successive samples even after immune checkpoint therapy and distant metastasis. Functional studies identified activated S6K1 as both a key marker and specific therapeutic vulnerability downstream of PIK3CAE545K-induced resistance. These results demonstrate that difficult-to-detect pre-existing resistance mutations may exist more often than previously appreciated and also posit S6K1 as a common downstream therapeutic nexus for the MAPK, CDK4/6, and PI3K pathways.

http://ift.tt/2FhD4Jc

The RNA-binding protein MEX3B mediates resistance to cancer immunotherapy by downregulating HLA-A expression

Purpose: Cancer immunotherapy has shown promising clinical outcomes in many patients. However, some patients still fail to respond, and new strategies are needed to overcome resistance. The purpose of this study was to identify novel genes and understand the mechanisms that confer resistance to cancer immunotherapy. Experimental Design: To identify genes mediating resistance to T cell killing, we performed an open reading frame (ORF) screen of a kinome library to study whether overexpression of a gene in patient-derived melanoma cells could inhibit their susceptibility to killing by autologous Tumor-Infiltrating Lymphocytes (TILs). Results: The RNA-binding protein MEX3B was identified as a top candidate that decreased the susceptibility of melanoma cells to killing by TILs. Further analyses of anti-PD-1-treated melanoma patient tumor samples suggested that higher MEX3B expression is associated with resistance to PD-1 blockade. In addition, significantly decreased levels of IFN were secreted from TILs incubated with MEX3B-overexpressing tumor cells. Interestingly, this phenotype was rescued upon overexpression of exogenous HLA-A2. Consistent with this, we observed decreased HLA-A expression in MEX3B-overexpressing tumor cells. Finally, luciferase reporter assays and RNA-binding protein immunoprecipitation assays suggest that this is due to MEX3B binding to the 3' UTR of HLA-A to destabilize the mRNA. Conclusions: MEX3B mediates resistance to cancer immunotherapy by binding to the 3' UTR of HLA-A to destabilize the HLA-A mRNA and thus downregulate HLA-A expression on the surface of tumor cells, thereby making the tumor cells unable to be recognized and killed by T cells.

http://ift.tt/2CTpIh3

Impact of 68 Ga-PSMA-PET imaging on target volume definition and guidelines in radiation oncology - a patterns of failure analysis in patients with primary diagnosis of prostate cancer

Abstract

Background

⁶⁸Ga-PSMA-PET-imaging has proven to be a highly sensitive and specific diagnostic element for patients with prostate cancer (PC). Does the standard clinical target volume (CTV) cover the majority of ⁶⁸Ga-PSMA-PET detected lymph nodes (LNs) in a primary setting?

Methods

25 out of 159 patients with primary PC who underwent ⁶⁸Ga-PSMA-PET-imaging were analyzed in the process of this study. These 25 high-risk patients had a total of 126 LNs with positive ⁶⁸Ga-PSMA-ligand uptake. A standard CTV according to the 'Radiation Therapy Oncology Group' consensus was delineated and LNs were judged whether they were in- or outside of this target volume. With a Pearson correlation we additionally evaluated whether the Gleason score, the prostate-specific antigen (PSA) value or the risk according to the Roach formula correlate with a higher chance of LNs being outside of the CTV in uncommon LN locations.

Results

81 (64.3%) of 126 LNs were covered by the CTV with a complete coverage of all positive LNs inside the respective radiation volume in 11 of 25 patients (44%). LNs that were not covered by the CTV included (para-aortic,) common-iliac, pre-sacral, obturatoric, para-rectal, para-vesical and pre-acetabular locations. In a statistical analysis neither the Gleason score, nor the PSA value, nor the calculated risk with the Roach formula correlated with LNs being inside or outside of the CTV in this patient group.

Conclusion

⁶⁸Ga-PSMA-PET-imaging proves to be a valuable asset for patients and physicians for primary diagnosis and treatment planning. In our study, trusting the RTOG consensus for CTV delineation would have led to up to 35.7% of all LNs not to be included in the clinical radiation volume, which might have resulted in insufficient radiation dose coverage.

http://ift.tt/2F5OuAH

The breakdown of the Simon effect in cross-modal contexts: EEG evidence

Abstract

In everyday life we often must coordinate information across spatial locations and different senses for action. It is well known, for example, that reactions are faster when an imperative stimulus and its required response are congruent than when they are not, even if stimulus location itself is completely irrelevant for the task (the so-called Simon effect). However, because these effects have been frequently investigated in single modality scenarios, the consequences of spatial congruence when more than one sensory modality is at play are less well known. Interestingly, at a behavioural level, the visual Simon effect vanishes in mixed (visual and tactile) modality scenarios, suggesting that irrelevant spatial information ceases to exert influence on vision. In order to shed some light on this surprising result, here we address the expression of irrelevant spatial information in EEG markers typical of the visual Simon effect (P300, theta power modulation, LRP) in mixed modality contexts. Our results show no evidence for the visual spatial information to affect performance at behavioural and neurophysiological levels. The absence of evidence of the neural markers of visual S-R conflict in the mixed modality scenario implies that some aspects of spatial representations that are strongly expressed in single modality scenarios might be bypassed.

This article is protected by copyright. All rights reserved.

http://ift.tt/2FKg9UC

Calcium and vitamin D supplementation and increased risk of serrated polyps: results from a randomised clinical trial

Objective

Serrated lesions such as sessile serrated adenomas or polyps (SSA/Ps) are important colorectal cancer precursors, but aetiological factors for these lesions are largely unknown. We aimed to determine the effects of calcium and vitamin D supplementation on the incidence of serrated polyps (SPs) in general and hyperplastic polyps and SSA/Ps specifically.

Design

Participants with one or more adenoma at baseline were randomised to receive 1200 mg/day of elemental calcium, 1000 IU/day of vitamin D₃, both or neither agent. Treatment continued for 3 or 5 years, when risk of polyps was determined from surveillance colonoscopy (treatment phase). Outcomes after treatment ceased were also assessed (observational phase). Adjusted risk ratios (aRRs) of SPs were determined via multivariable generalised linear models.

Results

SPs were diagnosed in 565 of 2058 (27.5%) participants during the treatment phase and 329/1108 (29.7%) during the observational phase. In total, 211 SSA/Ps were identified during follow-up. In the treatment phase, there was no effect of either calcium or vitamin D on incidence of SSA/Ps. However, during the later observational phase, we observed elevated risks of SSA/Ps associated with calcium alone and calcium+vitamin D treatment (aRR (95% CI): 2.65 (1.43 to 4.91) and 3.81 (1.25 to 11.64), respectively).

Conclusion

In a large multicentre chemoprevention study, we found evidence that calcium and vitamin D supplementation increased the risk of SSA/Ps. This appeared to be a late effect: 6–10 years after supplementation began. These possible risks must be weighed against the benefits of calcium and vitamin D supplementation.

Trial registration number

NCT00153816; Results.

http://ift.tt/2FKctSO

CC Nerd-The Case of the Unbalanced Solution

The use of 0.9% saline has undergone a degree of scrutiny in recent years. Detractors claim high chloride content, leads to acidosis and kidney injury. But clinical evidence supporting the clinically deleterious effects is lacking. The SPLIT Trial published in JAMA in 2015 by Young et (1) al failed to find any difference in outcomes […]

EMCrit Project by Rory Spiegel.

http://ift.tt/2HYtuts

Not a Hydrocele!

An 11-month-old boy presented with a painless right scrotal swelling that was gradually increasing in size since birth. On examination, the swelling was scrotal, cystic, and transilluminant (Figure 1). There was no change in size of swelling on crying. An ultrasound showed a cystic mass 10 × 8 cm with multiple septae and lobulations suggestive of a lymphangioma. On excision, the lymphangioma appeared to be associated with the gubernaculum of the right testis, although the body of the testis was characteristically uninvolved.

http://ift.tt/2oLAmRQ

Value-based care: the preference of outcome over prediction

Anderson et al report that "structural evaluation of brain magnetic resonance imaging (MRI) at term equivalent is predictive of outcome at 7 years of age, independent of clinical and social factors."1 The same volume of The Journal featured a commentary from Fisher,2 which acknowledged the need for prospective studies that demonstrate effective interventions for at-risk infants and questioned the Choosing Wisely campaign's recommendation to "avoid routine screening term equivalent or discharge brain MRIs in preterm infants."3

http://ift.tt/2HVpqKr

The prognostic value of a novel magnetic resonance imaging/magnetic resonance spectroscopy score after hypoxic ischemic encephalopathy: methodological concerns

In regard to the prognostic accuracy study by Weeke et al testing a novel magnetic resonance imaging/magnetic resonance spectroscopy score to predict outcome after hypoxic-ischemic encephalopathy, the multifaceted score and the predicted probability graph for outcome up to school age are key strengths.1 However, to appraise critically the design, analysis, and results of this study, some aspects require clarification or additional information.

http://ift.tt/2oILQG1

Clinical Predictors of Residual Sleep Apnea after Weight Loss Therapy in Obese Adolescents

To investigate clinical factors that could predict residual sleep-disordered breathing (SDB) after weight loss.

http://ift.tt/2HTmwFY

Internal Mammary Lymph Node Biopsy During Free-Flap Breast Reconstruction: Optimizing Adjuvant Breast Cancer Treatment Through Comprehensive Staging

Abstract

Background

Accurate breast cancer staging is essential for optimal management of adjuvant therapies. While breast lymphatic drainage involves both axillary and internal mammary (IM) lymph node (LN) basins, IM LN sampling is not routinely advocated. The current study analyzes the incidence of IM LN metastases sampled during free flap breast reconstruction and subsequent changes in adjuvant treatment.

Methods

A retrospective analysis of patients with positive IM LN biopsies during free flap breast reconstruction was performed. Pre-reconstruction surgical and adjuvant therapies as well as staging and prognostic data were recorded. Change in adjuvant therapies based solely on IM LN positivity was determined.

Results

IM LN metastases were found on 28 (1.3%) out of 2057 patients and comprised the study population. Mean age was 49 years with pre-reconstruction chemotherapy or radiation administered in 50 or 54% of cases, respectively. Five (18%) patients had previously undergone lumpectomy with axillary sampling. Mean tumor size was 3.1 cm with tumor location evenly distributed among all four quadrants. Ten (36%) patients had isolated IM LN metastases Patients with both axillary and IM disease had larger lesions, increased prevalence of pre-reconstruction chemotherapy and radiation. Based exclusively on positive IM LN disease, 17 (63%) patients had a change in adjuvant therapy.

Conclusion

Despite the low incidence of IM LN metastases, IM LN biopsy during free flap breast reconstruction is recommended. In 36% of cases, nodal metastases were isolated to the IM nodes. Identification of IM metastases influenced adjuvant therapies in a majority of cases.

http://ift.tt/2CQFrgP

Prediction of Overall Survival and Novel Classification of Patients with Gastric Cancer Using the Survival Recurrent Network

Abstract

Background

Artificial neural networks (ANNs) have been applied to many prediction and classification problems, and could also be used to develop a prediction model of survival outcomes for cancer patients.

Objective

The aim of this study is to develop a prediction model of survival outcomes for patients with gastric cancer using an ANN.

Methods

This study enrolled 1243 patients with stage IIA–IV gastric cancer who underwent D2 gastrectomy from January 2007 to June 2010. We used a recurrent neural network (RNN) to make the survival recurrent network (SRN), and patients were randomly sorted into a training set (80%) and a test set (20%). Fivefold cross-validation was performed with the training set, and the optimized model was evaluated with the test set. Receiver operating characteristic (ROC) curves and area under the curves (AUCs) were evaluated, and we compared the survival curves of the American Joint Committee on Cancer (AJCC) 8th stage groups with those of the groups classified by the SRN-predicted survival probability.

Results

The test data showed that the ROC AUC of the SRN was 0.81 at the fifth year. The SRN-predicted survival corresponded closely with the actual survival in the calibration curve, and the survival outcome could be more discriminately classified by using the SRN than by using the AJCC staging system.

Conclusion

SRN was a more powerful tool for predicting the survival rates of gastric cancer patients than conventional TNM staging, and may also provide a more flexible and expandable method when compared with fixed prediction models such as nomograms.

http://ift.tt/2oMijLJ

Corticocortical projections to area 1 in squirrel monkeys (Saimiri sciureus)

Abstract

Cortical area 1 is a non-primary somatosensory area in the primate anterior parietal cortex that is critical to tactile discrimination. The corticocortical projections to area 1 in squirrel monkeys were determined by placing multiple injections of anatomical tracers into separate body part representations defined by multiunit microelectrode mapping in area 1. The pattern of labeled cells in the cortex indicated that area 1 has strong intrinsic connections within each body part representation, and has inputs from somatotopically matched regions of areas 3b, 3a, 2, and 5. Somatosensory areas in the lateral sulcus, including the second somatosensory area (S2), the parietal ventral area (PV), and the presumptive parietal rostral (PR) and ventral somatosensory (VS) areas also project to area 1. Topographically organized projections to area 1 also came from the primary motor cortex (M1), the dorsal and ventral premotor areas (PMd and PMv), and the supplementary motor area (SMA). Labeled cells were also found in cingulate motor and sensory areas on the medial wall of the hemisphere. Previous studies revealed a similar pattern of projections to area 1 in Old World macaque monkeys, suggesting a pattern of cortical inputs to area 1 that is common across anthropoid primates.

This article is protected by copyright. All rights reserved.

http://ift.tt/2t8QKRV

A Convenient Method for Extraction and Analysis with High-Pressure Liquid Chromatography of Catecholamine Neurotransmitters and Their Metabolites

We present a convenient solid-phase extraction coupled to high-pressure liquid chromatography (HPLC) with electrochemical detection (ECD) for simultaneous determination of three monoamine neurotransmitters and two of their metabolites in infants' urine. We also identify the metabolite MHPG as a potential biomarker for the early diagnosis of brain damage for infants.

http://ift.tt/2F4FMyh

Pharmacokinetics and pharmacodynamics of dexmedetomidine-induced vasoconstriction in healthy volunteers

Abstract

Aims

Alpha-2 agonists are direct peripheral vasoconstrictors by activation of vascular smooth muscle alpha-2 adrenoceptors. The impact of this response during dexmedetomidine infusion remains poorly quantified. Our goal was to investigate the pharmacokinetic (PK) and pharmacodynamic (PD, vasoconstriction) effects of a computer controlled dexmedetomidine infusion in healthy volunteers.

Methods

After local ethics committee approval, we studied 10 healthy volunteers. To study the peripheral vasoconstrictive effect of dexmedetomidine without concurrent sympatholytic effects, sympathetic fibers were blocked with a brachial plexus block. Volunteers received dexmedetomidine target controlled infusion for 15 min to a target concentration of 0.3 ng/ml. Arterial blood samples were collected during and for 60 min after dexmedetomidine infusion for pharmacokinetic analysis. Peripheral vasoconstriction (PD) was assessed using finger photoelectric plethysmography. PK/PD analysis was done using nonlinear mixed effect models.

Results

We found that the computer-controlled infusion pump delivered mean concentrations greater than 0.3 ng/ml over the 15 min infusion duration. The peripheral vasoconstrictive effect correlated with dexmedetomidine plasma concentrations during and after the infusion. This verifies that dexmedetomidine induced vasoconstriction is concentration dependent over time. A 3-compartment model provided a better fit to the data than a 2-compartment model.

Conclusions

We found that dexmedetomidine induced vasoconstriction is concentration dependent over time. Dexmedetomidine pharmacokinetics were best estimated by a 3-compartment model with allometric scaling. Our results will contribute to future modeling of dexmedetomidine induced hemodynamic effects.

http://ift.tt/2F8ubhX