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Aberrant DNA methylation patterns have been used for cancer detection. However, DNA hemi-methylation, present at about 10% CpG dinucleotides, has been less well studied. Here we show that a majority of differentially hemi-methylated regions (DHMRs) in liver tumor DNA or plasma cells free (cf) DNA do not overlap with differentially methylated regions (DMRs) of the same samples, indicating that DHMRs could serve as independent biomarkers. Furthermore, we analyzed the cfDNA methylomes of 215 samples from individuals with liver or brain cancer and individuals without cancer (controls), and trained machine learning models using DMRs, DHMRs or both. The models incorporated with both DMRs and DHMRs show a superior performance compared to models trained with DMRs or DHMRs, with AUROC being 0.978, 0.990, and 0.983 in distinguishing control, liver and brain cancer, respectively, in a validation cohort. This study supports the potential of utilizing both DMRs and DHMRs for multi-cancer detection. Alterations in DNA methylation patterns are known as predictors of cancer diagnosis. Here, the authors develop a method to analyze both symmetric- and hemi-methylated regions in plasma cell free DNA and show its utility in detecting both liver and brain cancer.

Background The association between body mass index (BMI) and risk of breast cancer depends on time of life, but it is unknown whether this association depends on a woman’s familial risk. Methods We conducted a prospective study of a cohort enriched for familial risk consisting of 16,035 women from 6701 families in the Breast Cancer Family Registry and the Kathleen Cunningham Foundation Consortium for Research into Familial Breast Cancer followed for up to 20 years (mean 10.5 years). There were 896 incident breast cancers (mean age at diagnosis 55.7 years). We used Cox regression to model BMI risk associations as a function of menopausal status, age, and underlying familial risk based on pedigree data using the Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA), all measured at baseline. Results The strength and direction of the BMI risk association depended on baseline menopausal status ( P  < 0.001); after adjusting for menopausal status, the association did not depend on age at baseline ( P  = 0.6). In terms of absolute risk, the negative association with BMI for premenopausal women has a much smaller influence than the positive association with BMI for postmenopausal women. Women at higher familial risk have a much larger difference in absolute risk depending on their BMI than women at lower familial risk. Conclusions The greater a woman’s familial risk, the greater the influence of BMI on her absolute postmenopausal breast cancer risk. Given that age-adjusted BMI is correlated across adulthood, maintaining a healthy weight throughout adult life is particularly important for women with a family history of breast cancer.

Background Alcohol consumption and cigarette smoking are associated with an increased risk of breast cancer (BC), but it is unclear whether these associations vary by a woman’s familial BC risk. Methods Using the Prospective Family Study Cohort, we evaluated associations between alcohol consumption, cigarette smoking, and BC risk. We used multivariable Cox proportional hazard models to estimate hazard ratios (HR) and 95% confidence intervals (CI). We examined whether associations were modified by familial risk profile (FRP), defined as the 1-year incidence of BC predicted by Breast Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA), a pedigree-based algorithm. Results We observed 1009 incident BC cases in 17,435 women during a median follow-up of 10.4 years. We found no overall association of smoking or alcohol consumption with BC risk (current smokers compared with never smokers HR 1.02, 95% CI 0.85–1.23; consuming ≥ 7 drinks/week compared with non-regular drinkers HR 1.10, 95% CI 0.92–1.32), but we did observe differences in associations based on FRP and by estrogen receptor (ER) status. Women with lower FRP had an increased risk of ER-positive BC associated with consuming ≥ 7 drinks/week (compared to non-regular drinkers), whereas there was no association for women with higher FRP. For example, women at the 10th percentile of FRP (5-year BOADICEA = 0.15%) had an estimated HR of 1.46 (95% CI 1.07–1.99), whereas there was no association for women at the 90th percentile (5-year BOADICEA = 4.2%) (HR 1.07, 95% CI 0.80–1.44). While the associations with smoking were not modified by FRP, we observed a positive multiplicative interaction by FRP ( p interaction  = 0.01) for smoking status in women who also consumed alcohol, but not in women who were non-regular drinkers. Conclusions Moderate alcohol intake was associated with increased BC risk, particularly for women with ER-positive BC, but only for those at lower predicted familial BC risk (5-year BOADICEA < 1.25). For women with a high FRP (5-year BOADICEA ≥ 6.5%) who also consumed alcohol, being a current smoker was associated with increased BC risk.

While immunotherapy tends to be ineffective against pancreatic ductal adenocarcinoma (PDAC), this cancer type often elicits B-cell immunity. However, the exact antigens responsible for these spontaneous immune responses are still unclear. This study used a unique high-dimensional ELISA to analyze IgG responses to 93 post-translational modifications and other chemical determinants in PDAC patients at the time of diagnosis and before therapy. Results identified 13 specific targets of serum IgG that distinguished PDAC patients from healthy donors. Phosphorylated-serine, -threonine, and -tyrosine emerged as the primary targets, with most patients showing high-titer IgG, predominantly of the IgG1 and IgG3 subclasses. Moreover, serum reactivity to these phosphorylated residues was higher in patients with metastatic disease, suggesting a relation between B cell immunity and tumor burden. Lastly, immunofluorescence staining and phosphoproteomic analysis provided evidence of the accumulation of phosphorylated amino acids in PDAC cells and identified a series of consensus abnormal phosphosites. Overall, our findings reveal for the first time the development of robust antibody responses targeting phosphorylated residues in PDAC.

Metronidazole is the most commonly used drug for the treatment of giardiasis in humans. In spite of its therapeutic efficacy for giardiasis, low patient compliance, especially in children, side effects, and the emergence of metronidazole-resistant strains may restrict its use. Albendazole has been used to treat Giardia duodenalis infections in recent years. However, efficacy studies in vivo and in vitro have produced diverse results as to its effectiveness. A moderately benign side effect profile, combined with established efficacy against many helminths, renders it promising for treatment of giardiasis in humans. We performed a search in the PubMed, Scopus, EMBASE, the ISI Web of Science, LILIACS, and Cochrane Controlled Trials Register for trials published before February 2010 as well as in references of relevant research and review articles. Eight randomized clinical trials (including 900 patients) comparing the effectiveness of albendazole with that of metronidazole were included in meta-analysis. After extracting and validating the data, the pooled risk ratio (RR) was calculated using an inverse-variance random-effects model. Albendazole was found to be equally as effective as metronidazole in the treatment of giardiasis in humans (RR 0.97; 95% CI, 0.93, 1.01). In addition, safety analysis suggested that patients treated with albendazole had a lower risk of adverse effects compared with those who received metronidazole (RR 0.36; 95% CI, 0.10, 1.34), but limitations of the sample size precluded a definite conclusion. The effectiveness of albendazole, when given as a single dose of 400 mg/day for 5 days, was comparable to that of metronidazole. Patients treated with albendazole tended to have fewer side effects compared with those who took metronidazole. Given the safety, effectiveness, and low costs of albendazole, this drug could be potentially used as an alternative and/or a replacement for the existing metronidazole therapy protocols in the treatment of giardiasis in humans.

Background Adults in the United States (U.S) can be simultaneously exposed to more than one social risk factor over their lifetime. However, cancer epidemiology tends to focus on single social risk factors at a time. We examined the prospective association between cumulative social risk exposure and deaths from cancer in a nationally representative sample of U.S. adults. Methods The study included 8745 adults (aged ≥ 40 years) in the NHANES Survey III Mortality Study over a median follow-up of 13.5 years (1988-1994 enrollment dates and 1988 through 2006 for mortality data). Social risk factors (low family income, low education level, minority race, and single-living status) were summed to create a cumulative social risk score (0 to ≥3). We used Cox proportional hazard models to estimate age- and sex-adjusted hazard ratios (HRs) and 95 % confidence intervals (95 % CI) for the association between cumulative social risk with deaths from all-cancers combined, tobacco-related cancers, and screening-detectable cancers. Results Deaths from all-cancers combined ( P for trend = 0.001), tobacco-related cancers ( P for trend = <0.001), and lung cancer ( P for trend = 0.01) increased with an increasing number of social risk factors. As compared with adults with no social risk factors, those exposed to ≥3 social risk factors were at increased risk of deaths from all-cancers combined (HR = 1.8, 95 % CI = 1.3-2.4), tobacco-related cancers (HR = 2.6, 95 % CI: 1.6-4.0), and lung cancer (HR = 2.3, 95 % CI = 1.3-4.1). Conclusions U.S. adults confronted by higher amounts of cumulative social risk appear to have increased mortality from all-cancers combined, tobacco-related cancers, and lung cancer. An enhanced understanding of the cumulative effect of social risk factors may be important for targeting interventions to address social disparities in cancer mortality.

The authors review the key studies on the association between meat intake and cancer risk, including a new prospective cohort study by Amanda Cross and colleagues published inPLoS Medicine.

ObjectivePancreatic ductal adenocarcinoma (PDA) has among the highest stromal fractions of any cancer and this has complicated attempts at expression-based molecular classification. The goal of this work is to profile purified samples of human PDA epithelium and stroma and examine their respective contributions to gene expression in bulk PDA samples.DesignWe used laser capture microdissection (LCM) and RNA sequencing to profile the expression of 60 matched pairs of human PDA malignant epithelium and stroma samples. We then used these data to train a computational model that allowed us to infer tissue composition and generate virtual compartment-specific expression profiles from bulk gene expression cohorts.ResultsOur analysis found significant variation in the tissue composition of pancreatic tumours from different public cohorts. Computational removal of stromal gene expression resulted in the reclassification of some tumours, reconciling functional differences between different cohorts. Furthermore, we established a novel classification signature from a total of 110 purified human PDA stroma samples, finding two groups that differ in the extracellular matrix-associated and immune-associated processes. Lastly, a systematic evaluation of cross-compartment subtypes spanning four patient cohorts indicated partial dependence between epithelial and stromal molecular subtypes.ConclusionOur findings add clarity to the nature and number of molecular subtypes in PDA, expand our understanding of global transcriptional programmes in the stroma and harmonise the results of molecular subtyping efforts across independent cohorts.

Purpose: Tea is one of the most commonly consumed beverages worldwide. To date, observational data from prospective cohort studies investigating the relationship between green and black tea intake and prostate cancer risk are sparse and equivocal. In a population-based, prospective cohort study of Chinese men in Singapore, we investigated the relationship between green and black tea intake and prostate cancer risk. Methods: Tea consumption data for 27,293 men were collected at baseline (between 1993 and 1998) using a validated food frequency questionnaire. After an average of 11.2 years of follow-up, 298 men had developed prostate cancer. Proportional hazards regression methods were used to assess the associations between tea intake and prostate cancer risk. Results: There was no association between daily green tea intake and prostate cancer risk, compared with no green tea intake [hazard ratio (HR) = 1.08; 95 % confidence interval (CI) 0.79, 1.47]. For black tea, a statistically significant positive association and trend were observed for daily intake compared with no black tea intake (HR = 1.41, 95 % CI 1.03, 1.92; p for trend <0.01) Conclusions: Few prospective data are available from populations that have both a high level and wide range of black and green tea intake; this study represents a unique opportunity to evaluate their individual effects on prostate cancer risk. Our findings support the notion that green tea intake does not protect against prostate cancer and that black tea intake may increase prostate cancer risk.

Background We sought to determine whether the differences in short-term outcomes between patients undergoing robot-assisted radical prostatectomy (RARP) and those treated with open radical prostatectomy (ORP) differ by race and ethnicity. Methods This observational study used New York State Cancer Registry data linked to discharge records and included patients undergoing radical prostatectomy for localized prostate cancer during 2008–2018. We used logistic regression to examine the association between race and ethnicity (non-Hispanic White [NHW], non-Hispanic Black [NHB], Hispanic), surgical approach (RARP, ORP), and postoperative outcomes (major events, prolonged length of stay [pLOS], 30-day re-admission). We tested interaction between race and ethnicity and surgical approach on multiplicative and additive scales. Results The analytical cohort included 18,926 patients (NHW 14,215 [75.1%], NHB 3195 [16.9%], Hispanic 1516 [8.0%]). The average age was 60.4 years (standard deviation 7.1). NHB and Hispanic patients had lower utilization of RARP and higher risks of postoperative adverse events than NHW patients. NHW, NHB, and Hispanic patients all had reduced risks of adverse events when undergoing RARP versus ORP. The absolute reductions in the risks of major events and pLOS following RARP versus ORP were larger among NHB {relative excess risk due to interaction (RERI): major events −0.32 [95% confidence interval (CI) −0.71 to −0.03]; pLOS −0.63 [95% CI −0.98 to −0.35]) and Hispanic (RERI major events −0.27 [95% CI −0.77 to 0.09]; pLOS −0.93 [95% CI −1.46 to −0.51]) patients than among NHW patients. The interaction was absent on the multiplicative scale. Conclusions RARP use has not penetrated and benefited all racial and ethnic groups equally. Increasing utilization of RARP among NHB and Hispanic patients may help reduce disparities in patient outcomes after radical prostatectomy.