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Current approaches to staging chronic liver diseases have limited utility for predicting liver cancer risk. Here, we employed single-nucleus RNA sequencing (snRNA-seq) to characterize the cellular microenvironment of healthy and pre-malignant livers using two distinct mouse models. Downstream analyses unraveled a previously uncharacterized disease-associated hepatocyte (daHep) transcriptional state. These cells were absent in healthy livers but increasingly prevalent as chronic liver disease progressed. Copy number variation (CNV) analysis of microdissected tissue demonstrated that daHep-enriched regions are riddled with structural variants, suggesting these cells represent a pre-malignant intermediary. Integrated analysis of three recent human snRNA-seq datasets confirmed the presence of a similar phenotype in human chronic liver disease and further supported its enhanced mutational burden. Importantly, we show that high daHep levels precede carcinogenesis and predict a higher risk of hepatocellular carcinoma development. These findings may change the way chronic liver disease patients are staged, surveilled, and risk stratified.

PurposeCancer survivors diagnosed at an early age remain at risk for cancer recurrence and other chronic diseases. This study assessed engagement in surveillance for recurrence, cancer screening, and other recommended preventive health services among breast and colorectal cancer survivors with early-onset disease (≤ 50 years) who were diagnosed in California.MethodsBreast and colorectal cancer survivors diagnosed with early-onset cancer between 1999 and 2009 were identified through the California Cancer Registry, the state-based cancer registry, and surveyed. Multivariable regression analyses were used to assess correlates of receipt of cancer surveillance, cancer screening, and other preventive health services.ResultsOf the 497 survivors that were invited to participate in the study, 156 completed the survey for a response rate of 31%. The sample was 50 years of age on average (range 32-69 years) with a mean time since diagnosis of 9 years. The majority of the sample (71%) was a racial/ethnic minority (24% Latino, 15% African American, 29% Asian). Overall, 80% received appropriate surveillance for recurrence, and 72% received recommended screening for early detection of other cancers (breast, cervical, colorectal). Increasing age was associated with lower likelihood of early detection screening (adjusted odds ratio (aOR) 0.28, 95% confidence interval (CI) 0.11-0.69), and higher income was associated with a greater likelihood (aOR 4.89, 95% CI 1.62-14.81). Screening rates were highest for blood pressure (96%), cholesterol (86%), and diabetes (81%), followed by dental visits (64%) and flu vaccination (35%). Greater use of recommended preventive health services was associated with increasing age, female sex, higher education level, and having health insurance.ConclusionsAlthough the majority of survivors received appropriate surveillance for recurrence, engagement in other preventive health services varied substantially.Implications for cancer surv

PurposeCancer survivors diagnosed at an early age remain at risk for cancer recurrence and other chronic diseases. This study assessed engagement in surveillance for recurrence, cancer screening, and other recommended preventive health services among breast and colorectal cancer survivors with early-onset disease (≤ 50 years) who were diagnosed in California.MethodsBreast and colorectal cancer survivors diagnosed with early-onset cancer between 1999 and 2009 were identified through the California Cancer Registry, the state-based cancer registry, and surveyed. Multivariable regression analyses were used to assess correlates of receipt of cancer surveillance, cancer screening, and other preventive health services.ResultsOf the 497 survivors that were invited to participate in the study, 156 completed the survey for a response rate of 31%. The sample was 50 years of age on average (range 32-69 years) with a mean time since diagnosis of 9 years. The majority of the sample (71%) was a racial/ethnic minority (24% Latino, 15% African American, 29% Asian). Overall, 80% received appropriate surveillance for recurrence, and 72% received recommended screening for early detection of other cancers (breast, cervical, colorectal). Increasing age was associated with lower likelihood of early detection screening (adjusted odds ratio (aOR) 0.28, 95% confidence interval (CI) 0.11-0.69), and higher income was associated with a greater likelihood (aOR 4.89, 95% CI 1.62-14.81). Screening rates were highest for blood pressure (96%), cholesterol (86%), and diabetes (81%), followed by dental visits (64%) and flu vaccination (35%). Greater use of recommended preventive health services was associated with increasing age, female sex, higher education level, and having health insurance.ConclusionsAlthough the majority of survivors received appropriate surveillance for recurrence, engagement in other preventive health services varied substantially.Implications for cancer surv

Rhabdoid tumors are rare aggressive malignancies in infants and young children with a poor prognosis. The most common anatomic localizations are the central nervous system, the kidneys, and other soft tissues. Rhabdoid tumors share germline and somatic mutations in SMARCB1 or, more rarely, SMARCA4, members of the SWI/SNF chromatin-remodeling complex. Rhabdoid tumor predisposition syndrome (RTPS) is a condition characterized by a high risk of developing rhabdoid tumors, among other features. RTPS1 is characterized by pathogenic variants in the SMARCB1 gene, while RTPS2 has variants in SMARCA4. Interestingly, germline variants of SMARCB1 and SMARCA4 have been identified also in patients with Coffin-Siris syndrome. Children with RTPS typically present with tumors before 1 year of age and in a high percentage of cases develop synchronous or multifocal tumors with aggressive clinical features. The diagnosis of RTPS should be considered in patients with rhabdoid tumors, especially if they have multiple primary tumors and/or in individuals with a family history. Because germline mutations result in an increased risk of carriers developing rhabdoid tumors, genetic counseling, and surveillance for all family members with this condition is recommended.

Early detection of cancer and the monitoring of cancer recurrence in treated patients are significant challenges in esophageal squamous cell carcinoma (ESCC). Liquid biopsy is the identification of tumor biomarkers from minimally invasive samples of biological fluids, including urine, blood, stool, saliva, or cerebrospinal fluid. Liquid biopsy offers a potential solution to the problems of detection and surveillance as DNA shed from cancer cells as cell-free DNA or in exosomes can be detected in body fluids. By detecting these DNAs, we can identify the presence of cancer-associated mutations for basic detection, as well as to obtain information on the recurrence and evolution of disease following initial treatment. These sources of information have the potential to significantly improve the management of patients with ESCC. In this chapter, we detail a method for the isolation of cell-free DNA from blood plasma and DNA associated with exosomes in blood from patients with esophageal squamous cell carcinomas.

BackgroundCirculating tumor DNA (ctDNA) is a promising technology for treatment selection, prognostication, and surveillance after definitive therapy. Its use in the perioperative setting for patients with metastatic disease has not been well studied. We characterize perioperative plasma ctDNA and its association with progression-free survival (PFS) in patients undergoing surgery for peritoneal metastases.Patients and methodsWe recruited 71 patients undergoing surgery for peritoneal metastases and evaluated their plasma with a targeted 73-gene ctDNA next-generation sequencing test before and after surgery. The association between perioperative ctDNA, as well as other patient factors, and PFS was evaluated by Cox regression.ResultsctDNA was detectable in 28 patients (39.4%) preoperatively and in 37 patients (52.1%) postoperatively. Patients with high ctDNA [maximum somatic variant allele fraction (MSVAF) > 0.25%] had worse PFS than those with low MSVAF (< 0.25%) in both the pre- and postoperative settings (median 4.8 vs. 19.3 months, p < 0.001, and 9.2 vs.15.0 months, p = 0.049, respectively; log-rank test). On multivariate analysis, high-grade histology [hazard ratio (HR) 3.42, p = 0.001], incomplete resection (HR 2.35, p = 0.010), and high preoperative MSVAF (HR 3.04, p = 0.001) were associated with worse PFS. Patients with new postoperative alterations in the context of preoperative alteration(s) also had a significantly shorter PFS compared with other groups (HR 4.28, p < 0.001).ConclusionsHigh levels of perioperative ctDNA and new postoperative ctDNA alterations in the context of preoperative alterations predict worse outcomes in patients undergoing resection for peritoneal metastases. This may highlight a role for longitudinal ctDNA surveillance in this population.

BackgroundNational patterns of breast imaging in women with a personal history of breast cancer (PHBC) are unknown making evaluation of annual surveillance recommendations a challenge.ObjectiveTo describe variation in use of mammography and breast magnetic resonance imaging (MRI) examinations beginning 6 months after diagnosis among women with PHBC in US community practice. We report on the breast imaging indication, imaging intervals, and time since breast cancer diagnosis by examination type.DesignLongitudinal study using cross-sectional data.SettingBreast Cancer Surveillance Consortium breast imaging facilities.Participants19,955 women diagnosed between 2005 and 2012 with AJCC stage 0-III incident breast cancer who had 69,386 mammograms and 3,553 breast MRI examinations from January 2005 to September 2013; median follow-up of 37.6 months (interquartile range, 22.1-60.7).Main measuresBreast imaging indication, imaging intervals, and time since breast cancer diagnosis by examination type.Key resultsAmong women with a PHBC who received breast imaging, 89.4% underwent mammography alone, 0.8% MRI alone, and 10.3% had both mammography and MRI. About half of mammograms and MRIs were indicated for surveillance vs. diagnostic, with an increase in the proportion of surveillance exams as time from diagnosis increased (mammograms, 45.7% at 1 year to 72.2% after 5 years; MRIs, 54.8% at 1 year to 78.6% after 5 years). In the first post-diagnosis period, 32.8% of women had > 2 breast imaging examinations and of these, 65.8% were less than 6 months apart. During the first 5-year post-diagnosis, the frequency of examinations per year decreased and the interval between examinations shifted towards annual examinations.ConclusionIn women with a PHBC who received post-diagnosis imaging, a third underwent multiple breast imaging examinations per year during the first 2-year post-diagnosis despite recommendations for annual exams. As time since dia

Liquid biopsy of cancers is an area of increasing interest in medical practice for the surveillance, management, and potential detection of malignant cells, using minimally invasive collection of body fluids. A liquid biopsy is particularly useful for metastatic cancers, which may be difficult to be sampled by core biopsy, due to difficulty of access or an occult location. Access to DNA shed from esophageal adenocarcinoma can enable the detection of mutations confirming the presence of malignant cells or the evolution of clonal lines with altered treatment response profiles. In this chapter, we detail a method for the isolation of cell-free DNA from blood plasma and DNA associated with exosomes in blood from patients with esophageal adenocarcinoma.

A large proportion of memory T cells disseminated throughout the body are non- recirculating cells whose maintenance and function is regulated by tissue- specific environmental cues. These sessile cells are referred to as tissue- resident memory T (TRM) cells and similar populations of non- recirculating cells also exist among uncon-ventional T cells and innate lymphocyte cells. The pool of TRM cells is highly diverse with respect to anatomical positioning, phenotype, molecular regulation and effector function. Nevertheless, certain transcriptional programs are shared and appear as important unifying features for the overall population of TRM cells and tissue- resident lymphocytes. It is now widely appreciated that TRM cells are a critical component of our immune defense by acting as peripheral sentinels capable of rapidly mobilizing protective tissue immunity upon pathogen recognition. This function is of particular importance in anatomical sites that are not effectively surveilled by blood- borne memory T cells in absence of inflammation, such as neuronal tissues or epithelial compartments in skin and mucosae. Focusing on the well- characterized subtype of CD8+ CD69+ CD103+ TRM cells, we will review current concepts on the generation, persistence and function of TRM cells and will summarize commonly used tools to study these cells. Furthermore, we will discuss accumulating data that emphasize localized TRM responses as an important determinant of tissue homeostasis and im-mune defense in the context of microbiota- immune interactions, persistent infec-tions and cancer surveillance.

Background We examined the methodological quality of guidelines on syndromes conferring genetic susceptibility to breast cancer. Methods PubMed, EMBASE, and Google were searched for guidelines published up to October 2010. All guidelines in English were included. The Appraisal of Guidelines, Research and Evaluation (AGREE) instrument was used to assess the quality of the guidelines, and their reported evidence base was evaluated. Results Thirteen guidelines were deemed eligible: seven had been developed by independent associations, and the other six had national/state endorsements. Four guidelines performed satisfactorily, achieving a score of greater than 50% in all six AGREE domains. Mean ± SD standardized scores for the six AGREE domains were: 90 ± 9% for 'scope and purpose', 51 ± 18% for 'stakeholder involvement', 55 ± 27% for 'rigour of development', 80 ± 11% for 'clarity and presentation', 37 ± 32% for 'applicability', and 47 ± 38% for 'editorial independence'. Ten of the thirteen guidelines were found to be based on research evidence. Conclusions Given the ethical implications and the high costs of genetic testing for hereditary breast cancer, guidelines on this topic should provide clear and evidence-based recommendations. Our analysis shows that there is scope for improving many aspects of the methodological quality of current guidelines. The AGREE instrument is a useful tool, and could be used profitably by guidelines developers to improve the quality of recommendations.

Cervical cancer is the second most common cancer among women world-wide. Objective: Evaluation of cervical cancer risks, frequency and screening uptake in women with learning disability (LD). Method: Review of the literature. Results: Few data are available on the risks of cervical cancer among women with LD, but those available suggest a lower incidence and the presence of fewer risk factors. Uptake of screening in this group is as low as 7%. A number of factors contribute to low uptake, including ineligibility based on comprehension and physical disabilities, as well as a general perception that women with LD are sexually inactive and therefore not at risk. Conclusion: More data are needed to evaluate the incidence of cervical cancer among women with LD, preferably disaggregated by sexual activity. The subgroup who are sexually active should be actively recruited into screening programmes. Further research is also needed on the consequences of a positive screening result and how women with LD cope with a diagnosis of cancer.