Anti-prion drugs do not improve survival in novel knock-in models of inherited prion disease.

Prion diseases uniquely manifest in three distinct forms: inherited, sporadic, and infectious. Wild-type prions are responsible for the sporadic and infectious versions, while mutant prions cause inherited variants like fatal familial insomnia (FFI) and familial Creutzfeldt-Jakob disease (fCJD). Although some drugs can prolong prion incubation times up to four-fold in rodent models of infectious prion diseases, no effective treatments for FFI and fCJD have been found. In this study, we evaluated the efficacy of various anti-prion drugs on newly-developed knock-in mouse models for FFI and fCJD. These models express bank vole prion protein (PrP) with the pathogenic D178N and E200K mutations. We applied various drug regimens known to be highly effective against wild-type prions in vivo as well as a brain-penetrant compound that inhibits mutant PrPSc propagation in vitro. None of the regimens tested (Anle138b, IND24, Anle138b + IND24, cellulose ether, and PSCMA) significantly extended disease-free survival or prevented mutant PrPSc accumulation in either knock-in mouse model, despite their ability to induce strain adaptation of mutant prions. Our results show that anti-prion drugs originally developed to treat infectious prion diseases do not necessarily work for inherited prion diseases, and that the recombinant sPMCA is not a reliable platform for identifying compounds that target mutant prions. This work underscores the need to develop therapies and validate screening assays specifically for mutant prions, as well as anti-prion strategies that are not strain-dependent.

Patient-Reported Outcome Measures Following Hyperbaric Oxygen Therapy for Radiation Cystitis: Early Results From the Multicenter Registry for Hyperbaric Oxygen Therapy.

PURPOSE: Our purpose was to determine changes in patient-reported hematuria and urinary symptoms after hyperbaric oxygen (HBO2) treatment for radiation cystitis (RC). MATERIALS AND METHODS: We analyzed prospectively collected data from the Multicenter Registry for Hyperbaric Oxygen Therapy Consortium accumulated within a week of beginning and ending HBO2. Measures included the modified Radiation Therapy Oncology Group (RTOG) Hematuria Scale, Urinary Distress Inventory Short Form, and EuroQol Five Dimension Five Level instrument. RTOG hematuria and Urinary Distress Inventory Short Form scores were compared using the sign test. Logistic regression was used to evaluate characteristics associated with hematuria improvement. RESULTS: A total of 470 registry patients had RC. The median age, number of HBO2 sessions, and years after radiation were 73 (IQR 12) years, 39 (IQR 10) sessions, and 5 (IQR 8) years, respectively. Eighty-four percent of patients (393/470) had prostate cancer‒related radiation. EuroQol Five Dimension Five Level scores improved from 0.83 (IQR 0.14) to 0.85 (IQR 0.22; P < .001. Three hundred seventy patients had complete RTOG hematuria scores that improved from 2 (IQR 2) to 0 (IQR 2; P < .001. Two hundred forty-six patients had complete Urinary Distress Inventory Short Form ratings that decreased from 33.3 (IQR 44) to 22.2 (IQR 33; P < .001). Regression analysis of those with visible hematuria before HBO2 showed lower improvement odds associated with higher HBO2 hematuria scores (odds ratio [OR] 0.44, 95% CI 0.26-0.73; P < .01), a smoking history (OR 0.44, 95% CI 0.21-0.92; P = .03), or a nonprostate cancer history (OR 0.32, 95% CI 0.10-0.99; P = .05). CONCLUSIONS: HBO2 for RC improved reported hematuria, urinary function, and quality of life. Higher baseline hematuria scores, smoking, and nonprostate cancer history were associated with lower odds of hematuria improvement.

A population-based survey of self-reported delays in breast, cervical, colorectal and lung cancer screening.

The early COVID-19 pandemic was associated with cessation of screening services, but the prevalence of ongoing delays in cancer screening into the third year of the pandemic are not well-characterized. In February/March 2022, a population-based survey assessed cancer needs in New Hampshire and Vermont. The associations between cancer screening delays (breast, cervical, colorectal or lung cancer) and social determinants of health, health care access, and cancer attitudes and beliefs were tested. Distributions and Rao-Scott chi-square tests were used for hypothesis testing and weighted to represent state populations. Of 1717 participants, 55% resided in rural areas, 96% identified as White race, 50% were women, 36% had high school or less education. Screening delays were reported for breast cancer (28%), cervical cancer (30%), colorectal cancer (24%), and lung cancer (30%). Delays were associated with having higher educational attainment (lung), urban living (colorectal), and having Medicaid insurance (breast, cervical). Low confidence in ability to obtain information about cancer was associated with screening delays across screening types. The most common reason for delay was the perception that the screening test was not urgent (31% breast, 30% cervical, 28% colorectal). Cost was the most common reason for delayed lung cancer screening (36%). COVID-19 was indicated as a delay reason in 15-29% of respondents; 12-20% reported health system capacity during the pandemic as a reason for delay, depending on screening type. Interventions that address sub-populations and reasons for screening delays are needed to mitigate the impact of the COVID-19 pandemic on cancer burden and mortality.

International Multicenter Registry for Hyperbaric Oxygen Therapy: Results through June 2021.

Introduction: The International Multicenter Registry for Hyperbaric Oxygen Therapy (International Report Registered Identifier DERR1-10.2196/18857) was established in 2011 to capture outcomes and complications data for both Undersea and Hyperbaric Medical Society (UHMS) approved and selected unapproved hyperbaric oxygen (HBO2) therapy indications. Methods: A Research Electronic Data Capture (REDCap) template was designed and distributed to all participating centers for prospective data collection. Centers contributed de-identified demographic, treatment, complications, and outcome data. This report provides summary data on sites and enrollment, as well as pre- and post-treatment data on quality of life (EQ-5D-5L questionnaire), head and neck radiationoutcomes, non-healing wounds (Strauss score), and idiopathic sudden sensorineural hearing loss. Data were analyzed mainly using the Wilcoxon signed-rank test. Results: Twenty-two centers contributed data for 2,880 patients. The most common UHMS-approved indication was delayed radiation injury, followed by enhancement of wound healing, and carbon monoxide poisoning. One hundred and twenty-five patients were treated for non-UHMS approved indications. Quality of life, head and neck radiation symptoms, Strauss wound scores, and hearing were significantly improved after HBO2. Complication rates were low and comparable to previous reports. The registry also offered the ability to analyze factors that affect outcomes, such as smoking and severity of hearing loss. Discussion: The registry accrues prospective data on defined outcomes from multiple centers and allows for analysis of factors affecting outcomes. This registry does not have a control group, which is a limitation. Nevertheless, the registry provides a unique, comprehensive dataset on HBO2 outcomes from multiple centers internationally.

Alternating anti-prion regimens reduce combination drug resistance but do not further extend survival in scrapie-infected mice.

Prion diseases are fatal and infectious neurodegenerative diseases in humans and other mammals caused by templated misfolding of the endogenous prion protein (PrP). Although there is currently no vaccine or therapy against prion disease, several classes of small-molecule compounds have been shown to increase disease-free incubation time in prion-infected mice. An apparent obstacle to effective anti-prion therapy is the emergence of drug-resistant strains during static therapy with either single compounds or multi-drug combination regimens. Here, we treated scrapie-infected mice with dynamic regimens that alternate between different classes of anti-prion drugs. The results show that alternating regimens containing various combinations of Anle138b, IND24 and IND116135 reduce the incidence of combination drug resistance, but do not significantly increase long-term disease-free survival compared to monotherapy. Furthermore, the alternating regimens induced regional vacuolation profiles resembling those generated by a single component of the alternating regimen, suggesting the emergence of strain dominance.

Risk of melanoma following keratinocyte malignancies.

Patients diagnosed with keratinocyte cancer experience heightened risk for melanoma, yet patients who go on to develop this malignancy have not been well-characterized. We followed a population-based cohort of 2243 participants with histologically confirmed KC identified from dermatology and pathology practices who did not have a history of internal malignancy (1363 BCC, 880 SCC). A total of 77 participants went on to develop melanoma. Individual-level data were collected via personal interviews including demographic information and skin cancer risk factors, as well as KC tumor characteristics such as anatomic site and histologic subtype. Using adjusted Cox proportionate hazards models, older patients (age 61 or older vs 60 or younger) were at twofold increased risk for developing melanoma following KC (age 61-65 HR = 2.5; 95% CI = 1.3-4.6) (age > 65 HR = 2.0; 95% CI = 1.2-3.4) and women were at reduced risk compared to men (HR = 0.5; 95% CI = 0.3-0.8). Among patients with BCC, those with tumors on the trunk/limbs compared to the head/neck were at greater risk for subsequent melanoma (HR = 2.7; 95% CI = 1.3-5.7). Subsequent risk of melanoma also related to established risk factors including blond/red vs dark hair (HR = 1.9; 95% CI = 1.1-3.4), tendency to burn rather than tan (HR = 1.7; 95% CI = 1.0-2.7), ≥1 nevi on their back compared to no nevi (HR = 2.2; 95% CI = 1.2-3.8) and a history of ≥1 painful childhood sunburns vs none (HR = 2.1; 95% CI = 1.2-3.6). Thus, in addition to pigmentary traits, ultraviolet radiation (UVR)-related factors and clinical features of KC such as anatomic site may be useful in identifying patients at increased risk for melanoma after KC.

Patient and physician factors associated with Oncotype DX and adjuvant chemotherapy utilization for breast cancer patients in New Hampshire, 2010-2016.

BACKGROUND: Oncotype DX® (ODX) is used to assess risk of disease recurrence in hormone receptor positive, HER2-negative breast cancer and to guide decisions regarding adjuvant chemotherapy. Little is known about how physician factors impact treatment decisions. The purpose of this study was to examine patient and physician factors associated with ODX testing and adjuvant chemotherapy for breast cancer patients in New Hampshire. METHODS: We examined New Hampshire State Cancer Registry data on 5630 female breast cancer patients diagnosed from 2010 to 2016. We performed unadjusted and adjusted hierarchical logistic regression to identify factors associated with a patient's receipt of ODX, being recommended and receiving chemotherapy, and refusing chemotherapy. We calculated intraclass correlation coefficients (ICCs) to examine the proportion of variance in clinical decisions explained by between-physician and between-hospital variation. RESULTS: Over the study period, 1512 breast cancer patients received ODX. After adjustment for patient and tumor characteristics, we found that patients seen by a male medical oncologist were less likely to be recommended chemotherapy following ODX (OR = 0.50 (95% CI = 0.34-0.74), p < 0.01). Medical oncologists with more clinical experience (reference: less than 10 years) were more likely to recommend chemotherapy (20-29 years: OR = 4.05 (95% CI = 1.57-10.43), p < 0.01; > 29 years: OR = 4.48 (95% CI = 1.68-11.95), p < 0.01). A substantial amount of the variation in receiving chemotherapy was due to variation between physicians, particularly among low risk patients (ICC = 0.33). CONCLUSIONS: In addition to patient clinicopathologic characteristics, physician gender and clinical experience were associated with chemotherapy treatment following ODX testing. The significant variation between physicians indicates the potential for interventions to reduce variation in care.

Body mass index, calcium supplementation and risk of colorectal adenomas.

Calcium supplementation (1,200 mg/day) did not significantly reduce colorectal adenomas in our recent randomized, controlled trial (Vitamin D/Calcium Polyp Prevention Study, VCPPS, 2004-2013) in contrast to our previous trial (Calcium Polyp Prevention Study, CPPS, 1988-1996). To reconcile these findings, we identified participant characteristics that differed between the study populations and modified the effect of calcium supplementation on adenomas or high-risk findings (advanced or multiple adenomas). Compared to the CPPS, more participants in the VCPPS were obese (body mass index (BMI) ≥30 kg/m2 ; 37.5% vs. 24.4%) and fewer had normal BMI (BMI <25 kg/m2 ; 18.5% vs. 31%). BMI appeared to modify the effect of calcium supplementation on adenomas and especially on high risk-findings: in the VCPPS, there was a 44% reduction in high-risk findings among individuals whose BMI was normal (RR = 0.56, 95% CI = 0.26-1.23), but not among overweight (RR = 1.09, 95% CI = 0.62-1.91) or obese (RR = 1.54, 95% CI = 0.92-2.57) individuals (pinteraction = 0.03). Similarly, in the CPPS, there was a 56% reduction in high-risk findings among individuals whose BMI was normal (RR = 0.44, 95% CI = 0.26-0.74), but not among overweight (RR = 0.87, 95% CI = 0.55-1.39) or obese (RR = 1.02, 95% CI = 0.57-1.82) individuals (pinteraction = 0.02). Standardization of each trial's findings to the BMI distribution in the other attenuated calcium's protective effect on adenomas in the CPPS but enhanced it in the VCPPS. In conclusion, 1,200 mg/day calcium supplementation may reduce risk of colorectal adenomas among those with normal BMI but not in overweight or obese individuals; and differences in BMI distribution partially account for the apparent difference in calcium efficacy between the two trials.

Capture of tobacco use among population-based registries: Findings from 10 National Program of Cancer Registries states.

BACKGROUND: Tobacco use data are important when the epidemiology and prognosis of tobacco-associated cancers are being defined. Central cancer registries in 10 National Program of Cancer Registries states pilot-tested the collection of standardized tobacco use variables. This study evaluated the capture of tobacco use data and examined smoking prevalence among cancer patients. METHODS: Participating registries collected data about the use of tobacco-cigarettes, other smoked tobacco, and smokeless tobacco-for cases diagnosed during 2011-2013. The percentage of cases with known tobacco variable values was calculated, and the prevalence of tobacco use was analyzed by the primary cancer site and state. RESULTS: Among 1,646,505 incident cancer cases, 51% had known cigarette use data: 18% were current users, 31% were former users, and 51% reported never using. The percentage of cases with a known status for both other smoked tobacco and smokeless tobacco was 43%, with 97% and 98% coded as never users, respectively. The percent known for cigarette use ranged from 27% to 81% by state and improved from 47% in 2011 to 59% in 2013 for all 10 states combined. The percent known for cigarette use and the prevalence of ever smoking cigarettes were highest for laryngeal cancer and tracheal, lung, and bronchus cancer. CONCLUSIONS: Cancer registrars ascertained cigarette use for slightly more than half of all new cancer cases, but other tobacco-related fields were less complete. Studies to evaluate the validity of specific tobacco-related variables and the ability of cancer registries to capture this information from the medical record are needed to gauge the usefulness of collecting these variables through cancer surveillance systems. Cancer 2018;124:2381-9. © 2018 American Cancer Society.

A Trial of Calcium and Vitamin D for the Prevention of Colorectal Adenomas.

BACKGROUND: Epidemiologic and preclinical data suggest that higher intake and serum levels of vitamin D and higher intake of calcium reduce the risk of colorectal neoplasia. To further study the chemopreventive potential of these nutrients, we conducted a randomized, double-blind, placebo-controlled trial of supplementation with vitamin D, calcium, or both for the prevention of colorectal adenomas. METHODS: We recruited patients with recently diagnosed adenomas and no known colorectal polyps remaining after complete colonoscopy. We randomly assigned 2259 participants to receive daily vitamin D3 (1000 IU), calcium as carbonate (1200 mg), both, or neither in a partial 2×2 factorial design. Women could elect to receive calcium plus random assignment to vitamin D or placebo. Follow-up colonoscopy was anticipated to be performed 3 or 5 years after the baseline examinations, according to the endoscopist's recommendation. The primary end point was adenomas diagnosed in the interval from randomization through the anticipated surveillance colonoscopy. RESULTS: Participants who were randomly assigned to receive vitamin D had a mean net increase in serum 25-hydroxyvitamin D levels of 7.83 ng per milliliter, relative to participants given placebo. Overall, 43% of participants had one or more adenomas diagnosed during follow-up. The adjusted risk ratios for recurrent adenomas were 0.99 (95% confidence interval [CI], 0.89 to 1.09) with vitamin D versus no vitamin D, 0.95 (95% CI, 0.85 to 1.06) with calcium versus no calcium, and 0.93 (95% CI, 0.80 to 1.08) with both agents versus neither agent. The findings for advanced adenomas were similar. There were few serious adverse events. CONCLUSIONS: Daily supplementation with vitamin D3 (1000 IU), calcium (1200 mg), or both after removal of colorectal adenomas did not significantly reduce the risk of recurrent colorectal adenomas over a period of 3 to 5 years. (Funded by the National Cancer Institute; ClinicalTrials.gov number, NCT00153816.).

Risk Factors for Diagnosis of Colorectal Cancer at a Late Stage: a Population-Based Study.

BACKGROUND: Late-stage colorectal cancer (CRC) is associated with significantly less effective treatment and poorer survival than early-stage colorectal cancer. OBJECTIVE: Identify and assess patient characteristics, demographic factors, and lifestyle factors that are associated with late-stage colorectal cancer at diagnosis. APPROACH: We linked two longstanding statewide, population-based registry databases: the New Hampshire Colonoscopy Registry and the New Hampshire State Cancer Registry, to assess the associations between patient characteristics and late-stage CRC diagnoses. The State Cancer Registry provided information on cancer stage and the Colonoscopy Registry provided detailed information on patient characteristics and lifestyle factors, allowing these factors to be analyzed in relation to colorectal cancer stage. KEY RESULTS: The risk of late-stage CRC diagnosis was highest among those diagnosed at a young age (< 50 years old) (OR 1.81, 95% CI 1.27-2.58). Those with Medicaid were also at increased risk, particularly < 65 years of age (OR 2.32, 95% CI 1.05-5.26). A family or personal history of polyps and/or CRC was associated with early stage at diagnosis (p = 0.014). CONCLUSIONS: Public health outreach and screening efforts should focused on patients at risk of late-stage CRC to encourage earlier diagnosis and prevention. Underserved patients have a lower rate of CRC screening and an increased risk of late-stage CRC, emphasizing the critical need to reach these populations. Further investigation of susceptibility characteristics and the effectiveness of non-invasive early screening techniques is warranted to address the late-stage CRC diagnoses in young individuals.

Capture and coding of industry and occupation measures: Findings from eight National Program of Cancer Registries states.

BACKGROUND: Although data on industry and occupation (I&O) are important for understanding cancer risks, obtaining standardized data is challenging. This study describes the capture of specific I&O text and the ability of a web-based tool to translate text into standardized codes. METHODS: Data on 62 525 cancers cases received from eight National Program of Cancer Registries (NPCR) states were submitted to a web-based coding tool developed by the National Institute for Occupational Safety and Health for translation into standardized I&O codes. We determined the percentage of sufficiently analyzable codes generated by the tool. RESULTS: Using the web-based coding tool on data obtained from chart abstraction, the NPCR cancer registries achieved between 48% and 75% autocoding, but only 12-57% sufficiently analyzable codes. CONCLUSIONS: The ability to explore associations between work-related exposures and cancer is limited by current capture and coding of I&O data. Increased training of providers and registrars, as well as software enhancements, will improve the utility of I&O data.

Lifestyle and Other Factors Explain One-Half of the Variability in the Serum 25-Hydroxyvitamin D Response to Cholecalciferol Supplementation in Healthy Adults.

BACKGROUND: Many factors have been associated with serum 25-hydroxyvitamin D [25(OH)D] concentrations in observational studies, with variable consistency. However, less information is available on factors affecting the magnitude of changes in serum 25(OH)D resulting from vitamin D supplementation. OBJECTIVE: This study aimed to identify factors associated with the serum 25(OH)D response to supplementation with 1000 IU cholecalciferol/d during the first year of a large, multicenter, randomized, placebo-controlled colorectal adenoma chemoprevention trial. METHODS: Eligible older adults who were not vitamin D-deficient [serum 25(OH)D ≥12 ng/mL] were randomly assigned in a modified 2 × 2 factorial design to 1 of 4 groups: daily 1000 IU cholecalciferol, 1200 mg Ca as carbonate, both, or placebo. Women could elect 2-group (calcium ± cholecalciferol) random assignment. In secondary analyses, we used multivariable models to assess factors associated with serum 25(OH)D concentrations in all enrollees (n = 2753) and with relative changes in serum 25(OH)D after 1 y cholecalciferol supplementation among those randomly assigned (n = 2187). RESULTS: In multivariable models, 8 factors accounted for 50% of the variability of proportional change in serum 25(OH)D after cholecalciferol supplementation. Larger increases were associated with being female (34.5% compared with 20.5%; P < 0.001) and with lower baseline serum 25(OH)D (P < 0.0001), optimal adherence to study pill intake (P = 0.0002), wearing long pants and sleeves during sun exposure (P = 0.0002), moderate activity level (P = 0.01), use of extra vitamin D-containing supplements during the trial (P = 0.03), and seasons of blood draw (P ≤ 0.002). Several genetic polymorphisms were associated with baseline serum 25(OH)D and/or serum response, but these did not substantially increase the models' R2 values. Other factors, including body mass index, were associated with serum 25(OH)D at baseline but not with its response to supplemental cholecalciferol. CONCLUSIONS: The factors that most affected changes in serum 25(OH)D concentrations in response to cholecalciferol supplementation included sex, baseline serum 25(OH)D, supplement intake adherence, skin-covering clothes, physical activity, and season. Genetic factors did not play a major role. This trial was registered at www.clinicaltrials.gov as NCT00153816.

Survival after squamous cell and basal cell carcinoma of the skin: A retrospective cohort analysis.

A retrospective cohort analysis of survival after keratinocyte cancer (KC) was conducted using data from a large, population-based case-control study of KC in New Hampshire. The original study collected detailed information during personal interviews between 1993 and 2002 from individuals with squamous (SCC) and basal (BCC) cell carcinoma, and controls identified through the Department of Transportation, frequency-matched on age and sex. Participants without a history of non-skin cancer at enrolment were followed as a retrospective cohort to assess survival after either SCC or BCC, or a reference date for controls. Through 2009, cancers were identified from the New Hampshire State Cancer Registry and self-report; death information was obtained from state death certificate files and the National Death Index. There were significant differences in survival between those with SCC, BCC and controls (p = 0.040), with significantly greater risk of mortality after SCC compared to controls (adjusted hazard ratio [HR] 1.25; 95% confidence interval 1.01-1.54). Mortality after BCC was not significantly altered (HR 0.96; 95% CI 0.77-1.19). The excess mortality after SCC persisted after adjustment for numerous personal risk factors including time-varying non-skin cancer occurrence, age, sex and smoking. Survival from the date of the intervening cancer, however, did not vary (HR for SCC 0.98; 95% CI 0.70-1.38). Mortality also remained elevated when individuals with subsequent melanoma were excluded (HR for SCC 1.30; 95% CI 1.05-1.61). Increased mortality after SCC cannot be explained by the occurrence of intervening cancers, but may reflect a more general predisposition to life threatening illness that merits further investigation.

Trends in initial management of prostate cancer in New Hampshire.

PURPOSE: Prostate cancer management strategies are evolving with increased understanding of the disease. Specifically, there is emerging evidence that "low-risk" cancer is best treated with observation, while localized "high-risk" cancer requires aggressive curative therapy. In this study, we evaluated trends in management of prostate cancer in New Hampshire to determine adherence to evidence-based practice. METHODS: From the New Hampshire State Cancer Registry, cases of clinically localized prostate cancer diagnosed in 2004-2011 were identified and classified according to D'Amico criteria. Initial treatment modality was recorded as surgery, radiation therapy, expectant management, or hormone therapy. Temporal trends were assessed by Chi-square for trend. RESULTS: Of 6,203 clinically localized prostate cancers meeting inclusion criteria, 34, 30, and 28% were low-, intermediate-, and high-risk disease, respectively. For low-risk disease, use of expectant management (17-42%, p < 0.001) and surgery (29-39%, p < 0.001) increased, while use of radiation therapy decreased (49-19 %, p < 0.001). For intermediate-risk disease, use of surgery increased (24-50%, p < 0.001), while radiation decreased (58-34%, p < 0.001). Hormonal therapy alone was rarely used for low- and intermediate-risk disease. For high-risk patients, surgery increased (38-47%, p = 0.003) and radiation decreased (41-38%, p = 0.026), while hormonal therapy and expectant management remained stable. DISCUSSION: There are encouraging trends in the management of clinically localized prostate cancer in New Hampshire, including less aggressive treatment of low-risk cancer and increasing surgical treatment of high-risk disease.

Risk of death from cardiovascular disease associated with low-level arsenic exposure among long-term smokers in a US population-based study.

High levels of arsenic exposure have been associated with increases in cardiovascular disease risk. However, studies of arsenic's effects at lower exposure levels are limited and few prospective studies exist in the United States using long-term arsenic exposure biomarkers. We conducted a prospective analysis of the association between toenail arsenic and cardiovascular disease mortality using longitudinal data collected on 3939 participants in the New Hampshire Skin Cancer Study. Using Cox proportional hazard models adjusted for potential confounders, we estimated hazard ratios and 95% confidence intervals associated with the risk of death from any cardiovascular disease, ischemic heart disease, and stroke, in relation to natural-log transformed toenail arsenic concentrations. In this US population, although we observed no overall association, arsenic exposure measured from toenail clipping samples was related to an increased risk of ischemic heart disease mortality among long-term smokers (as reported at baseline), with increased hazard ratios among individuals with ≥ 31 total smoking years (HR: 1.52, 95% CI: 1.02, 2.27), ≥ 30 pack-years (HR: 1.66, 95% CI: 1.12, 2.45), and among current smokers (HR: 1.69, 95% CI: 1.04, 2.75). These results are consistent with evidence from more highly exposed populations suggesting a synergistic relationship between arsenic exposure and smoking on health outcomes and support a role for lower-level arsenic exposure in ischemic heart disease mortality.

Cofactor molecules maintain infectious conformation and restrict strain properties in purified prions.

Prions containing misfolded prion protein (PrP(Sc)) can be formed with cofactor molecules using the technique of serial protein misfolding cyclic amplification. However, it remains unknown whether cofactors materially participate in maintaining prion conformation and infectious properties. Here we show that withdrawal of cofactor molecules during serial propagation of purified recombinant prions caused adaptation of PrP(Sc) structure accompanied by a reduction in specific infectivity of >10(5)-fold, to undetectable levels, despite the ability of adapted "protein-only" PrP(Sc) molecules to self-propagate in vitro. We also report that changing only the cofactor component of a minimal reaction substrate mixture during serial propagation induced major changes in the strain properties of an infectious recombinant prion. Moreover, propagation with only one functional cofactor (phosphatidylethanolamine) induced the conversion of three distinct strains into a single strain with unique infectious properties and PrP(Sc) structure. Taken together, these results indicate that cofactor molecules can regulate the defining features of mammalian prions: PrP(Sc) conformation, infectivity, and strain properties. These findings suggest that cofactor molecules likely are integral components of infectious prions.

Body mass and smoking are modifiable risk factors for recurrent bladder cancer.

BACKGROUND: In the Western world, bladder cancer is the fourth most common cancer in men and the eighth most common in women. Recurrences frequently occur, and continued surveillance is necessary to identify and treat recurrent tumors. Efforts to identify risk factors that are potentially modifiable to reduce the rate of recurrence are needed. METHODS: Cigarette smoking behavior and body mass index were investigated at diagnosis for associations with bladder cancer recurrence in a population-based study of 726 patients with bladder cancer in New Hampshire, United States. Patients diagnosed with non-muscle invasive urothelial cell carcinoma were followed to ascertain long-term prognosis. Analysis of time to recurrence was performed using multivariate Cox regression models. RESULTS: Smokers experienced shorter time to recurrence (continuing smoker hazard ratio [HR] = 1.51, 95% confidence interval [CI] = 1.08-2.13). Although being overweight (body mass index > 24.9 kg/m(2) ) at diagnosis was not a strong independent factor (HR = 1.33, 95% CI = 0.94-1.89), among continuing smokers, being overweight more than doubled the risk of recurrence compared to smokers of normal weight (HR = 2.67, 95% CI = 1.14-6.28). CONCLUSIONS: These observational results suggest that adiposity is a risk factor for bladder cancer recurrence, particularly among tobacco users. Future intervention studies are warranted to evaluate whether both smoking cessation and weight reduction strategies reduce bladder tumor recurrences.

New malignancies after squamous cell carcinoma and melanomas: a population-based study from Norway.

BACKGROUND: Skin cancer survivors experience an increased risk for subsequent malignancies but the associated risk factors are poorly understood. This study examined the risk of a new primary cancer following an initial skin cancer and assessed risk factors associated with second primary cancers. METHODS: All invasive cutaneous malignant melanomas (CMM, N = 28 069) and squamous cell carcinomas (SCC, N = 24 620) diagnosed in Norway during 1955-2008 were included. Rates of new primary cancers in skin cancer survivors were compared to rates of primary malignancies in the general population using standardized incidence ratios (SIR). Discrete-time logistic regression models were applied to individual-level data to estimate cancer risk among those with and without a prior skin cancer, accounting for residential region, education, income, parenthood, marital status and parental cancer status, using a 20% random sample of the entire Norwegian population as reference. Further analyses of the skin cancer cohort were undertaken to determine risk factors related to subsequent cancers. RESULTS: During follow-up, 9608 new primary cancers occurred after an initial skin cancer. SIR analyses showed 50% and 90% increased risks for any cancer after CMM and SCC, respectively (p < 0.01). The logistic regression model suggested even stronger increase after SCC (130%). The highest risk was seen for subsequent skin cancers, but several non-skin cancers were also diagnosed in excess: oral, lung, colon, breast, prostate, thyroid, leukemia, lymphoma and central nervous system. Factors that were associated with increased risk of subsequent cancers include male sex, older age, lower residential latitude, being married and low education and income. Parental cancer did not increase the risk of a subsequent cancer after SCC, but was a significant predictor among younger CMM survivors. CONCLUSIONS: Our results provide information on shared environmental and genetic risk factors for first and later cancers and may help to identify individuals at high risk for subsequent cancers, which will be important as skin cancer incidence continues to rise.