Quantification of low-level human cytomegalovirus and Epstein-Barr virus DNAemia by digital PCR.

BACKGROUND: Digital PCR (dPCR) can quantify cell-free viral DNA (DNAemia), a biomarker of active viral infection. To accelerate epidemiologic investigation into low-level viral reactivation in chronic disease, we have evaluated the performance of dPCR to detect cytomegalovirus (CMV) and Epstein-Barr virus (EBV) DNAemia across platforms and blood matrices. METHODS: The droplet-based (BioRad) dPCR platform performance was compared to chip-based (BioMark), and assay validation followed dMIQE guidelines. CMV and EBV DNA reference materials were spiked into known negative plasma and serum samples. In addition, two independent cohorts of ovarian cancer patients were evaluated for viral DNAemia (n = 65 serum and 79 plasma samples). RESULTS: The limit of quantification (LOQ) was at or slightly above 100 copies/mL for both instruments: 105-135 copies/mL for droplet-based detection and 100 copies/mL for chip-based detection. DNAemia in serum had a slightly lower LOQ (105-110 copies/mL) compared to plasma (LOQ; 115-135 copies/mL). The variation (CV) coefficients for each assay and machine were less than 5 %. In patient samples, CVs ranged from 4.5 - 7.4 % and were similar for cell-free DNA derived from serum or plasma. There was good correlation between DNAemia measurements in patient samples across dPCR platforms (r > 0.90 for each assay and matrix). CONCLUSION: dPCR can quantify low-level herpes virus DNAemia with CVs below 8 %. Our results indicate that using serum-derived cell-free DNA and droplet-based dPCR is optimal for quantitating low-level viral DNAemia; however, plasma and chip-based approaches are acceptable alternatives and suitable for epidemiologic investigation.

Prevalence of active cytomegalovirus infection at diagnosis of ovarian cancer and during chemotherapy and subsequent changes in cognitive functioning.

PURPOSE: One of the most frequently reported effects of cancer and its treatments is cancer-related cognitive impairment (CRCI). Viral infections may affect inflammation and immune function and therefore may influence patient symptoms, including CRCI. The goal of this study was to describe the prevalence of cytomegalovirus (CMV) infections at diagnosis, during, and after chemotherapy in individuals with ovarian cancer and explore CMV infection at diagnosis with cancer-related cognitive impairment (CRCI) following chemotherapy. METHODS: We recruited adults newly diagnosed with ovarian, primary peritoneal or fallopian tube cancer at a single academic cancer center into two prospective studies. In Study 1 (N = 71), participants provided blood samples at diagnosis. In Study 2 (N = 18), participants provided blood samples and completed symptom surveys before, during and after front-line adjuvant chemotherapy. Serum CMV DNA levels were assessed using digital PCR; >100 copies/mL of serum was considered positive for active CMV infection (CMV+). CRCI was measured using the Functional Assessment of Cancer Therapy - Cognitive Function (FACT-Cog) questionnaire. Changes in FACT-Cog scores were compared by CMV status at diagnosis using t-tests at each time point. RESULTS: At diagnosis, 29.2% were CMV+ (28.2% in Study 1, 33.3% in Study 2). Following three cycles of chemotherapy (Study 2), CMV positivity rose to 60.0% and then back down to 31.3% after chemotherapy. We observed significant differences in CRCI following chemotherapy by CMV status at diagnosis. CONCLUSION: Our data suggest that active CMV infection is common among patients undergoing treatment for ovarian cancer and may contribute to symptoms of CRCI.

Aging measures and cancer: Findings from the Health and Retirement Study.

Background: Compared to cancer-free persons, cancer survivors of the same chronological age (CA) have increased physiological dysfunction, i.e., higher biological age (BA), which may lead to higher morbidity and mortality. We estimated BA using eight aging metrics: BA computed by Klemera Doubal method (KDM-BA), phenotypic age (PhenoAge), five epigenetic clocks (ECs, Horvath, Hannum, Levine, GrimAge, and pace of aging (POA)), and subjective age (SA). We tested if aging constructs were associated with total cancer prevalence and all-cause mortality in cancer survivors and controls, i.e., cancer-free persons, in the Health and Retirement Study (HRS), a large population-based study. Methods: In 2016, data on BA-KDM, PhenoAge, and SA were available for 946 cancer survivors and 4,555 controls; data for the five ECs were available for 582 cancer survivors and 2,805 controls. Weighted logistic regression was used to estimate the association between each aging construct and cancer prevalence (odds ratio, OR, 95%CI). Weighted Cox proportional hazards regression was used to estimate the associations between each aging construct and cancer incidence as well as all-cause mortality (hazard ratio, HR, 95%CI). To study all BA metrics (except for POA) independent of CA, we estimated age acceleration as residuals of BA regressed on CA. Results: Age acceleration for each aging construct and POA were higher in cancer survivors than controls. In a multivariable-adjusted model, five aging constructs (age acceleration for Hannum, Horvath, Levine, GrimAge, and SA) were associated with cancer prevalence. Among all cancer survivors, age acceleration for PhenoAge and four ECs (Hannum, Horvath, Levine, and GrimAge), was associated with higher all-cause mortality over 4 years of follow-up. PhenoAge, Hannum, and GrimAge were also associated with all-cause mortality in controls. The highest HR was observed for GrimAge acceleration in cancer survivors: 2.03 (95% CI, 1.58-2.60). In contrast, acceleration for KDM-BA and POA was significantly associated with mortality in controls but not in cancer survivors. When all eight aging constructs were included in the same model, two of them (Levine and GrimAge) were significantly associated with mortality among cancers survivors. None of the aging constructs were associated with cancer incidence. Conclusion: Variations in the associations between aging constructs and mortality in cancer survivors and controls suggests that aging constructs may capture different aspects of aging and that cancer survivors may be experiencing age-related physiologic dysfunctions differently than controls. Future work should evaluate how these aging constructs predict mortality for specific cancer types.

Associations between MICA and MICB Genetic Variants, Protein Levels, and Colorectal Cancer: Atherosclerosis Risk in Communities (ARIC).

BACKGROUND: The MHC class I chain-related protein A (MICA) and protein B (MICB) participate in tumor immunosurveillance and may be important in colorectal cancer, but have not been examined in colorectal cancer development. METHODS: sMICA and sMICB blood levels were measured by SomaScan in Visit 2 (1990-92, baseline) and Visit 3 (1993-95) samples in cancer-free participants in the Atherosclerosis Risk in Communities Study. We selected rs1051792, rs1063635, rs2516448, rs3763288, rs1131896, rs2596542, and rs2395029 that were located in or in the vicinity of MICA or MICB and were associated with cancer or autoimmune diseases in published studies. SNPs were genotyped by the Affymetrix Genome-Wide Human SNP Array. We applied linear and Cox proportional hazards regressions to examine the associations of preselected SNPs with sMICA and sMICB levels and colorectal cancer risk (236 colorectal cancers, 8,609 participants) and of sMICA and sMICB levels with colorectal cancer risk (312 colorectal cancers, 10,834 participants). In genetic analyses, estimates adjusted for ancestry markers were meta-analyzed. RESULTS: Rs1051792-A, rs1063635-A, rs2516448-C, rs3763288-A, rs2596542-T, and rs2395029-G were significantly associated with decreased sMICA levels. Rs2395029-G, in the vicinity of MICA and MICB, was also associated with increased sMICB levels. Rs2596542-T was significantly associated with decreased colorectal cancer risk. Lower sMICA levels were associated with lower colorectal cancer risk in males (HR = 0.68; 95% confidence interval, 0.49-0.96) but not in females (Pinteraction = 0.08). CONCLUSIONS: Rs2596542-T associated with lower sMICA levels was associated with decreased colorectal cancer risk. Lower sMICA levels were associated with lower colorectal cancer risk in males. IMPACT: These findings support an importance of immunosurveillance in colorectal cancer.

Evaluation of the Association Between Congenital Cytomegalovirus Infection and Pediatric Acute Lymphoblastic Leukemia.

Importance: Acute lymphoblastic leukemia (ALL) is the most common form of pediatric cancer, and a leading cause of death in children. Understanding the causes of pediatric ALL is necessary to enable early detection and prevention; congenital cytomegalovirus (cCMV) has recently been identified as a potential moderate-to-strong factor associated with risk for ALL. Objective: To compare the prevalence of cCMV infection between ALL cases and matched controls. Design, Setting, and Participants: In this population-based case-control study of ALL cases and matched controls, cases consisted of children aged 0 to 14 years between 1987 and 2014 with an ALL diagnosis identified through the Michigan Cancer Surveillance Program and born in Michigan on or after October 1, 1987. Cancer-free controls were identified by the Michigan BioTrust for Health and matched on age, sex, and mother's race and ethnicity. Data were analyzed from November to May 2022. Exposures: cCMV infection measured by quantitative polymerase chain reaction in newborn dried blood spots. Main Outcomes and Measures: ALL diagnosed in children aged 0 to 14 years. Results: A total of 1189 ALL cases and 4756 matched controls were included in the study. Bloodspots were collected from participants at birth, and 3425 (57.6%) participants were male. cCMV was detected in 6 ALL cases (0.5%) and 21 controls (0.4%). There was no difference in the odds of cCMV infection comparing ALL cases with controls (odds ratio, 1.30; 95% CI, 0.52-3.24). Immunophenotype was available for 536 cases (45.1%) and cytogenetic data for 127 (27%). When stratified by subtype characteristics, hyperdiploid ALL (74 cases) was associated with 6.26 times greater odds of cCMV infection compared with unmatched controls (95% CI, 1.44-27.19). Conclusions and Relevance: In this case-control study of cCMV and pediatric ALL, cCMV was associated with increased risk of hyperdiploid ALL. These findings encourage continued research.

Impact of Genetic Variants in the Nicotine Metabolism Pathway on Nicotine Metabolite Levels in Smokers.

BACKGROUND: Nicotine metabolism is a major factor in nicotine dependence, with approximately 70% to 80% of nicotine metabolized to cotinine in Caucasians. Cotinine formation is catalyzed primarily by CYP2A6, which also converts cotinine to trans-3'-hydroxycotinine (3HC). The goal of the present study was to examine the effects of CYP2A6 deficiency on nicotine metabolism profiles in vivo and the importance of genetic variants in nicotine-metabolizing enzyme genes on urinary nicotine metabolites levels. METHODS: Urine samples from 722 smokers who participated in the Singapore Chinese Health Study were analyzed using UPLC-MS/MS to detect nicotine and eight of its urinary metabolites, and a total of 58 variants in 12 genes involved in nicotine metabolism were investigated in 475 of these subjects with informative genotyping data. RESULTS: Urine samples stratified by the ratio of 3HC/cotinine exhibited a 7-fold increase in nicotine-N'-oxide, a 6-fold increase in nicotine-Glucuronide (Gluc), and a 5-fold decrease in 3HC-Gluc when comparing the lower versus upper 3HC/cotinine ventiles. Significant (P < 0.0001) associations were observed between functional metabolizing enzyme genotypes and levels of various urinary nicotine metabolites, including CYP2A6 genotype and levels of nicotine, nicotine-Gluc, nicotine-N'-oxide and 3HC, UGT2B10 genotype and levels of cotinine, nicotine-Gluc and cotinine-Gluc, UGT2B17 genotype and levels of 3HC-Gluc, FMO3 genotype and levels of nicotine-N'-oxide, and CYP2B6 genotype and levels of nicotine-N'-oxide and 4-hydroxy-4-(3-pyridyl)-butanoic acid. CONCLUSIONS: These data suggest that several pathways are important in nicotine metabolism. IMPACT: Genotype differences in several nicotine-metabolizing enzyme pathways may potentially lead to differences in nicotine dependence and smoking behavior and cessation.

Is hypermethylation of SOX1 gene an independent prognostic marker in surgically resected non-small cell lung cancer?

Background: Promoter hypermethylation of tumor suppressor genes presents promising markers for lung cancer diagnosis and prognosis. The purpose of this study was to determine the association between the promoter hypermethylation of multiple genes and 5-year survival rate in patients with Non-small cell lung cancer (NSCLC). Materials and Methods: Primary tumor samples (n = 65), corresponding nonmalignant lung tissues (n = 65), and circulating blood were obtained from NSCLC patients who underwent curative surgery. Promoter methylation status in seven genes (RASSF1A, CDH13, MGMT, ESR1, DAPK, SOX1, and HOXA9) was quantified by using bisulfite pyrosequencing. Five-year survival data were obtained by a clinician. Cox proportional hazards models were used to analyze the associations between gene methylation status and overall patient survival. Results: The 5-year survival of the patients with SOX1 aberrant tumor methylation was found to be statistically significantly shorter than for those patients without aberrant tumor methylation (P = 0.01). This effect was independent of TNM stage. No significant survival differences were associated with aberrant methylation in other genes tested in either of the two tissue types. Conclusion: Our study shows that SOX1 promoter hypermethylation in NSCLC tumors is significantly associated with inferior survival, showing promise as a useful prognostic biomarker in patients with NSCLC.

Human cytomegalovirus alters immune cell profile with potential implications for patient survival in head and neck cancer.

Cytomegalovirus (CMV) is a highly prevalent human herpes virus that exerts a strong influence on immune repertoire which may influence cancer risk. We have tested whether CMV immunoglobulin G (IgG) serostatus is associated with immune cell proportions (n = 132 population controls), human papillomavirus (HPV) co-infection and head and neck cancer risk (n = 184 cancer cases and 188 controls) and patient survival. CMV status was not associated with the proportion of Natural Killer cells, B cells or the neutrophil-to-lymphocyte ratio. However, CD8+ T cells increased with increasing categories of IgG titers (P =1.7 × 10-10), and titers were inversely associated with the CD4:CD8 ratio (P = 5.6 × 10-5). Despite these differences in T cell proportions, CMV was not associated with HPV16 co-infection. CMV seropositivity was similar in cases (52%) and controls (47%) and was not associated with patient survival (hazard ratio [HR] 1.14, 95% confidence interval [CI]: 0.70 to 1.86). However, those patients with the highest titers had the worst survival (HR 1.91, 95% CI: 1.13 to 3.23). Tumor-based data from The Cancer Genome Atlas demonstrated that the presence of CMV transcripts was associated with worse patient survival (HR 1.79, 95% CI: 0.96 to 2.78). These findings confirm that a history of CMV infection alters T cell proportions, but this does not translate to HPV16 co-infection or head and neck cancer risk. Our data suggest that high titers and active CMV virus in the tumor environment may confer worse survival.

High prevalence of asymptomatic CMV shedding in healthy children attending the minnesota state fair.

BACKGROUND: Young children in the household are a known risk factor for maternal CMV infection and consequently, congenital infection in infants. However, little is known about viral shedding in pre-school aged children. OBJECTIVES: To estimate the prevalence of CMV DNA shedding and CMV antibodies among healthy children and their mothers. STUDY DESIGN: A study of children ages 0 through 5 years was undertaken at the 2019 Minnesota State Fair. Children and their mothers were assessed for CMV shedding by procurement of a saliva swab for CMV PCR testing. An optional finger-stick for capillary blood was used to assess CMV antibodies. RESULTS: A total of 109 children and 85 mothers were enrolled. The prevalence of CMV saliva shedding among children (mean age 3.1 years, SE=0.16) and their mothers was 12/109 (11.0%) and 1/85 (1.2%), respectively. The prevalence of CMV DNA among children peaked at 3 years of age (26%) while the mean viral load was greatest at one year of age (236,693 IU/mL). CMV IgG antibodies among those who agreed to a finger-stick were detected in 16/35 mothers (45.7%) and 0/7 children (0%). Mothers of children aged 5 years or greater had the highest seroprevalence (61.5%). CONCLUSIONS: The prevalence of CMV salivary shedding in this unselected sample of young children was approximately 11.0%. The overall maternal seroprevalence in our sample was <50%, suggesting these women are at risk for acquisition of a primary CMV infection in subsequent pregnancies.

DNA methylation-derived systemic inflammation indices and their association with oropharyngeal cancer risk and survival.

BACKGROUND: Head and neck squamous cell carcinomas are associated with systemic inflammation (SI). We evaluated whether DNA methylation-derived SI (mdSI) indices are associated with oropharyngeal cancer risk and survival. METHODS: Ninety-four oropharyngeal squamous cell carcinoma (OPSCC) cases and 57 controls with DNA methylation data were included. Logistic regression analysis and survival analysis were performed to test the association of mdSI indices with OPSCC risk and survival. RESULTS: Higher methylation-derived neutrophil-to-lymphocyte ratio (mdNLR) was associated with increased risk of OPSCC (OR = 1.21, 95%CI: 1.11-1.40) while no association was found with methylation-derived lymphocyte-to-monocyte ratio (mdLMR). For 5-year overall survival, higher mdLMR was significantly associated with decreased risk of death (HR = 0.25, 95%CI: 0.10-0.64) while the converse was observed for mdNLR (HR = 2.48, 95%CI: 1.04-5.92). CONCLUSION: We observed an association between mdSI indices and OPSCC risk and 5-year overall survival. It is possible to use mdLMR as an independent prognostic factor for OPSCC.

Cytomegalovirus infection in malignant pleural mesothelioma.

Human cytomegalovirus (HCMV) is a highly prevalent herpes virus which persists as a latent infection and has been detected in several different tumor types. HCMV disease is rare but may occur in high-risk settings, often manifesting as a pulmonary infection. To date HCMV has not been investigated in malignant pleural mesothelioma (MPM). In a consecutive case series of 144 MPM patients we evaluated two biomarkers of HCMV: IgG serostatus (defined as positive and negative) and DNAemia (>100 copies/mL of cell free HCMV DNA in serum). Approximately half of the MPM patient population was HCMV IgG seropositive (51%). HCMV DNAemia was highly prevalent (79%) in MPM and independent of IgG serostatus. DNAemia levels consistent with high level current infection (>1000 copies/mL serum) were present in 41% of patients. Neither IgG serostatus nor DNAemia were associated with patient survival. In tissues, we observed that HCMV DNA was present in 48% of tumors (n = 40) and only 29% of normal pleural tissue obtained from individuals without malignancy (n = 21). Our results suggest nearly half of MPM patients have a high level current HCMV infection at the time of treatment and that pleural tissue may be a reservoir for latent HCMV infection. These findings warrant further investigation to determine the full spectrum of pulmonary infections in MPM patients, and whether treatment for high level current HCMV infection may improve patient outcomes.

The Prenatal Origin of Childhood Leukemia: Potential Applications for Epidemiology and Newborn Screening.

Childhood leukemias are heterogeneous diseases with widely differing incident rates worldwide. As circulating tumors, childhood acute leukemias are uniquely accessible, and their natural history has been described in greater detail than for solid tumors. For several decades, it has been apparent that most cases of childhood acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) initiate in utero. Circumstantial evidence in support of this contention includes the young age of onset and high rate of concordance among identical twins. "Backtracking" of leukemic somatic mutations, particularly gene translocations, to cord blood and dried blood spots collected during the perinatal period has provided molecular proof of prenatal leukemogenesis. Detection of a patient's leukemia translocation in easily accessible birth samples, such as dried blood spots, is straightforward with the knowledge of their idiosyncratic breakpoints. However, to translate these findings into population-based screening and leukemia prevention requires novel methods able to detect translocations at all possible breakpoints when present in a low frequency of cells. Several studies have attempted to screen for leukemic translocations, mainly the common ETV6-RUNX1 translocation, in cord blood samples from healthy children. Most studies have reported finding translocations in healthy children, but estimates of prevalence have varied widely and greatly exceed the incidence of leukemia, leading to concerns that technical artifact or contamination produced an artificially inflated estimate of translocation prevalence at birth. New generation techniques that capture the presence of these translocations at birth have the potential to vastly increase our understanding of the epidemiology of acute leukemias. For instance, if leukemic translocations are present at birth in a far higher proportion of children than eventually develop acute leukemia, what are the exposures and somatic molecular events that lead to disease? And could children with translocations present at birth be targeted for prevention of disease? These questions must be answered before large-scale newborn screening for leukemia can occur as a public health initiative. Here, we review the literature regarding backtracking of acute leukemias and the prevalence of leukemic translocations at birth. We further suggest an agenda for epidemiologic research using new tools for population screening of leukemic translocations.

Cytomegalovirus and systemic inflammation at time of surgery is associated with worse outcomes in serous ovarian cancer.

OBJECTIVES: Cytomegalovirus (CMV) is a common infection that establishes latency in healthy people. CMV has been associated with alterations of the immune compartment leading to improved responses, while inflammation has been shown to adversely impact outcomes. We investigated whether CMV serostatus predicts outcomes in ovarian cancer in the presence or absence of inflammation. METHODS: A total of 106 patients with serous ovarian cancer from 2006 to 2009 were analyzed. CMV and systemic inflammation was measured using CMV immunoglobulin G (IgG) and C-reactive protein (CRP), respectively, in serum collected prior to cytoreduction. Patients were stratified by CMV IgG (non-reactive, reactive/borderline) and CRP (≤10, >10 mg/L) status. Overall survival (OS) and recurrence-free survival (RFS) were compared by group using log-rank tests and Cox proportional hazards regression models adjusting for age at surgery. RESULTS: Of 106 eligible patients, 40 (37.7%) were CMV+/CRP+, 24 (22.6%) CMV+/CRP-, 19 (17.9%) CMV-/CRP+, and 23 (21.7%) CMV-/CRP-. CRP+ had higher CA-125 levels (P = 0.05) and higher rates of suboptimal debulking (P = 0.03). There were no other significant differences in demographic, surgical, or pathologic factors between groups. CMV+/CRP+ patients median RFS and OS were 16.9 months (95% CI: 9.0-21.1) and 31.7 months (95% CI: 25.0-48.7), respectively, with a significantly worse RFS (aHR: 1.85, 95% CI: 1.05-3.24, P = 0.03) and OS (aHR: 2.12, 95% CI: 1.17-3.82, P = 0.01) compared to CMV-/CRP- (RFS = 31.2 months (95% CI: 16.0-56.4) and OS = 63.8 months (95% CI: 50.7-87.0)). CMV+/CRP- group displayed the longest OS (89.3 months). CONCLUSIONS: Previous exposure to CMV and high CRP at surgery portended worse RFS and OS compared to women who tested negative. The CMV+/CRP- group had the longest OS, indicating that CMV status alone, in the absence of inflammation, may be protective.

Perspectives of cancer patients and their health during the COVID-19 pandemic.

INTRODUCTION: The immunosuppressive nature of some cancers and many cancer-directed treatments may increase the risk of infection with and severe sequelae from Coronavirus Disease 2019 (COVID-19). The objective of this study was to compare concerns about COVID-19 among individuals undergoing cancer treatment to those with a history of cancer not currently receiving therapy and to those without a cancer history. METHODS: We conducted a cross-sectional anonymous online survey study of adults currently residing in the United States. Participants were recruited over a one-week period (April 3-11, 2020) using promoted advertisements on Facebook and Twitter. Groups were compared using chi-squared tests, Fisher's exact tests, and t-tests. RESULTS: 543 respondents from 47 states provided information on their cancer history and were included in analyses. Participants receiving active treatment reported greater concern about infection from the SARS-CoV-2 coronavirus (p<0.001), higher levels of family distress caused by the COVID-19 pandemic (p = 0.004), and greater concern that the general public does not adequately understand the seriousness of COVID-19 (p = 0.04). Those with metastatic disease were more likely to indicate that COVID-19 had negatively affected their cancer care compared to patients with non-metastatic cancer (50.8% vs. 31.0%; p = 0.02). The most commonly reported treatment modifications included chemotherapy delays. CONCLUSIONS: Patients undergoing active treatment for cancer were most concerned about the short-term effects of the COVID-19 pandemic on the logistics as well as potential efficacy of ongoing cancer treatment, longer term effects, and overarching societal concerns that the population at large is not as concerned about the public health implications of SARS-CoV-2 infection.

Perspectives of Cancer Patients and Their Health during the COVID-19 Pandemic.

Introduction The immunosuppressive nature of some cancers and many cancer-directed treatments may increase the risk of infection with and severe sequelae from Coronavirus Disease 2019 (COVID-19). The objective of this study was to compare concerns about COVID-19 among individuals undergoing cancer treatment to those with a history of cancer not currently receiving therapy and to those without a cancer history. Methods We conducted a cross-sectional anonymous online survey study of adults currently residing in the United States. Participants were recruited over a one-week period (April 3-11, 2020) using promoted advertisements on Facebook and Twitter. Groups were compared using chi-squared tests, Fisher's exact tests, and t-tests. Results 543 respondents from 47 states provided information on their cancer history and were included in analyses. Participants receiving active treatment reported greater concern about coronavirus infection (p<0.0001), higher levels of family distress caused by the COVID-19 pandemic (p=0.004), and greater concern that the general public does not adequately understand the seriousness of COVID-19 (p=0.04). Those with metastatic disease were more likely to indicate that COVID-19 had negatively affected their cancer care compared to patients with non-metastatic cancer (50.8% vs. 31.0%; p=0.02). The most commonly reported treatment modifications included chemotherapy delays. Conclusions Patients undergoing active treatment for cancer were most concerned about the short-term effects of the COVID-19 pandemic on the logistics as well as potential efficacy of ongoing cancer treatment, longer term effects, and overarching societal concerns that the population at large is not as concerned about the public health implications of the coronavirus.

Cytomegalovirus and cancer-related mortality in the national health and nutritional examination survey.

PURPOSE: Cytomegalovirus (HCMV) is a common viral infection that shapes lifelong immunity. A history of infection with HCMV has been associated with many chronic diseases, including cancer. In addition, prospective cohort studies have established that HCMV is associated with all-cause mortality. However, there are limited data regarding HCMV and cancer mortality. METHODS: Data were obtained from the National Health and Nutrition Examination Survey (NHANES) III study (1988-1994): subjects aged 18 to 98, who had HCMV serology results, did not report having cancer at baseline, and were eligible for mortality follow-up (n = 14,498). Mortality was ascertained until December 2011 using National Death Index (NDI) linkage. RESULTS: The unadjusted risk of all-cancer mortality was higher in HCMV seropositive individuals (HR 2.74, 95% CI 2.05-3.64). This association was attenuated after adjusting for age (HR 1.39, 95% CI 1.02-1.92), and other covariates (age, sex, race/ethnicity, smoking status, BMI, education, and C-reactive protein (CRP); HR 1.21, 95% CI 0.91-1.81). There was a statistically significant interaction between HCMV and sex (p = 0.01): HCMV seropositivity was associated with increased cancer mortality in men (HR 1.65, 95% CI 0.99-2.73) but not in women (HR 0.95, 95% CI 0.59-1.54). CONCLUSION(S): Consistent with prior reports, HCMV seropositivity may be associated with an increased risk of cancer-related mortality but the association is partially driven by socioeconomic status and other risk factors. Future research is needed to determine whether HCMV is a risk factor for cancer, as well as identify the specific cancer types where HCMV increases mortality.

Field Application of Digital Technologies for Health Assessment in the 10,000 Families Study.

BACKGROUND: We field tested new-to-market portable, digital applications to assess hearing, pulmonary, and cognitive function to determine the feasibility of implementing these applications across a range of age groups in the pilot phase of the 10,000 Families Study (10KFS), a new Minnesota family-based prospective cohort study. METHODS: We followed manufacturer recommended protocols for audiometry (SHOEBOX Inc), spirometry (NuvoAir), and the digital clock drawing test (dCDT; Digital Cognition Technologies Inc). RESULTS: These digital devices were low cost and readily implemented in a 2.5-hour health fair visit with minimal training (2-3 hours) of study staff. To date, we have performed these measurements on 197 eligible 10KFS participants during an in-person clinic visit. A total of 37 children (age 4-17 years), 107 adults (18-64 years), and 53 seniors (≥65 years) were eligible to undergo hearing and pulmonary assessments. Children were less likely to successfully complete the hearing test (76%) compared with adults (86%) and seniors (89%). However, successful completion of the pulmonary assessment was high across all groups: 100% of children and seniors and 98% of adults. The dCDT was performed among those over the age of 40, and completion rates were 92% for those aged 41-64 and 94% for those ≥65 years. CONCLUSIONS: Our field testing indicates these digital applications are easy and cost-effective to implement in epidemiologic studies. IMPACT: Digital applications provide exciting opportunities to collect data in population studies. Issues related to data privacy, data access, and reproducibility of measurements need to be addressed before deploying digital applications in epidemiologic studies.See all articles in this CEBP Focus section, "Modernizing Population Science."

Chrysotile fibers in tissue adjacent to laryngeal squamous cell carcinoma in cases with a history of occupational asbestos exposure.

Asbestos describes a group of naturally occurring fibrous silicate mineral compounds that have been associated with a number of respiratory maladies, including mesothelioma and lung cancer. In addition, based primarily on epidemiologic studies, asbestos has been implicated as a risk factor for laryngeal and pharyngeal squamous cell carcinoma (SCC). The main objective of this work was to strengthen existing evidence via empirical demonstration of persistent asbestos fibers embedded in the tissue surrounding laryngeal and pharyngeal SCC, thus providing a more definitive biological link between exposure and disease. Six human papillomavirus (HPV)-negative laryngeal (n = 4) and pharyngeal (n = 2) SCC cases with a history working in an asbestos-exposed occupation were selected from a large population-based case-control study of head and neck cancer. A laryngeal SCC case with no history of occupational asbestos exposure was included as a control. Tissue cores were obtained from adjacent nonneoplastic tissue in tumor blocks from the initial primary tumor resection, and mineral fiber analysis was performed using a scanning electron microscope equipped with an energy dispersive X-ray analyzer (EDXA). Chrysotile asbestos fiber bundles were identified in 3/6 of evaluated cases with a history of occupational asbestos exposure. All three cases had tumors originating in the larynx. In addition, a wollastonite fiber of unclear significance was identified one of the HPV-negative pharyngeal SCC cases. No mineral fibers were identified in adjacent tissue of the case without occupational exposure. The presence of asbestos fibers in the epithelial tissue surrounding laryngeal SCC in cases with a history of occupational asbestos exposure adds a key line of physical evidence implicating asbestos as an etiologic factor.

Association between MICA polymorphisms, s-MICA levels, and pancreatic cancer risk in a population-based case-control study.

BACKGROUND: Pancreatic tumor cells may avoid immune surveillance by releasing the transmembrane major histocompatibility complex class I chain-related A (MICA) protein in soluble form (s-MICA). We hypothesized that the presence of the A5.1 polymorphism in the MICA gene, which encodes a truncated MICA protein, is associated with higher s-MICA levels and increased pancreatic cancer risk. METHODS: MICA alleles and s-MICA levels were measured in 121 pancreatic cancer cases and 419 controls. General linear regression with a log transformation assessed geometric means of s-MICA levels across MICA alleles. Unconditional logistic regression was used to calculate the odds ratio (OR) and 95% confidence intervals (CI) for pancreatic cancer associated with MICA alleles. RESULTS: After multivariate adjustment, participants with at least one copy of the A5.1 allele versus no A5.1 allele had 1.35 (95% CI: 1.05-1.74) times greater s-MICA levels (1.65 times higher for cases and 1.28, for controls) and increased risk of pancreatic cancer (OR = 1.91, 95% CI: 1.05-3.48). CONCLUSIONS: Our study suggests higher risk of pancreatic cancer among those with the MICA A5.1 polymorphism, which may be explained by an increase in s-MICA secretion and impaired immune response. IMPACT: These findings provide further evidence at the genetic and molecular level of the important role of MICA in pancreatic cancer development, and may have important implications with regards to pancreatic cancer screening.