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To facilitate the development of new therapies for Prader-Willi syndrome (PWS), we sought to develop a reliable and valid assessment of anxiousness and distress, common characteristics that have a significant negative impact on individuals with PWS and their families.The PWS Anxiousness and Distress Behaviors Questionnaire (PADQ) was developed with extensive input from clinical experts, as well as caregivers of individuals with PWS, who participated in iterative sets of qualitative interviews. The psychometric properties of the PADQ were subsequently demonstrated in a cross-sectional evaluation using data from the Global PWS Registry provided by400 caregivers and confirmed using data from a phase 3 clinical trial of an oxytocin analogue (intranasal carbetocin, LV-101).Qualitative interview participants consistently endorsed the content of the PADQ and were confident they could accurately respond to each item based on their observations of their child's behavior. Analysis of cross-sectional data supported the computation of a total PADQ score, as well as the reliability and validity of the measure. The results of analyses using longitudinal clinical trial data confirmed these properties and provided evidence for the responsiveness of the PADQ, further supporting its appropriateness for the evaluation of new treatments targeting anxiousness and distress in PWS.The current body of evidence supports the conclusion that the PADQ measures observable behaviors that are meaningful to patients and their families and provides a valid and reliable method to assess beneficial treatment effects for some of the most challenging behaviors associated with PWS.

Purpose: Cytology-based screening has limited sensitivity to detect prevalent cervical precancers. Human papilloma virus (HPV) DNA testing is highly sensitive and provides a high, long-term reassurance of low risk of cervical cancer. However, the specificity of HPV DNA testing is limited, requiring additional, more disease-specific markers for efficient screening approaches.Experimental Design: Liquid-based cytology samples were collected from 625 women referred to colposcopy. A slide was stained using the CINtec plus cytology assay. Pap cytology and HPV genotyping were conducted from the same vial. Clinical performance characteristics were calculated for all women, stratified by age, and for women referred with a low-grade squamous intraepithelial lesion (LSIL) Pap.Results: p16/Ki-67 positivity increased with histologic severity, from 26.8% in normal histology, 46.5% in CIN1, 82.8% in CIN2 to 92.8% in CIN3. Among women with CIN3, p16/Ki-67 positivity increased from 77.8% for women younger than 30 years without HPV16 to 100% for women 30 years and older with HPV16. The sensitivity and specificity to detect CIN3+ were 93.2% and 46.1%, respectively, and increased to 97.2% and 60.0% among women 30 years and older. In women with high-risk (HR)-HPV–positive atypical squamous cells of undetermined significance (ASC-US) and LSIL, sensitivity and specificity for detection of CIN3 were 90.6% and 48.6%, respectively.Conclusions: p16/Ki-67 testing could reduce referral to colposcopy by almost half while detecting the most severe cases of CIN3. The high sensitivity of p16/Ki-67 with significantly improved specificity compared with HPV testing makes p16/Ki-67 a viable option for LSIL triage. Further studies are required to evaluate p16/Ki-67 as triage marker in HPV-based screening strategies. Clin Cancer Res; 18(15); 4154–62. ©2012 AACR.

How, in the aftermath of National Socialism and World War II, was the memory landscape of Munich and Bavaria denazified under the Office of the Military Government of the United States? Supplementing existing cultural approaches and scholarship on denazification in Bavaria, this article considers the execution of Allied Control Council Directive Number 30 by the American occupation government (omgus) in Bavaria, in conjunction with appropriated native Bavarian bureaucracies and bureaucrats, to inventory and assess the built environment in order to register militaristic or Nazi monuments and prioritize their removal or modification. The limitations of the project to renew or restore the monument landscape confront in turn the limitations on the “bureaucratic manufacture of memory” in the modification of individual memory.

Introduction: The presence of sarcomatoid features in localized renal cell carcinoma (RCC) is associated with worse outcomes. We sought to use a national database to evaluate the outcomes and prognosis of metastatic RCC (mRCC) with sarcomatoid features treated with cytoreductive nephrectomy (CN) and targeted therapy (TT). Methods: The National Cancer Database (2010-2013) was used to identify patients with mRCC at diagnosis. Only patients who underwent CN followed by TT were included. Kaplan-Meier curves, log-rank test, and multivariate Cox regression analysis were used to compare overall survival (OS) between mRCC with and without sarcomatoid features. Subgroup analysis in patients with clear cell RCC (ccRCC) was performed. Results: A total of 1,427 patients with mRCC treated with CN followed by TT were included of which 364 (26%) had mRCC with sarcomatoid features. mRCC with sarcomatoid features were more likely to have Fuhrman grade 4 cancer. mRCC with sarcomatoid features had worse OS than mRCC without sarcomatoid features (24.6 vs 12.0 months, P < 0.001). For the clear cell cohort, mRCC with sarcomatoid features had worse OS than mRCC without sarcomatoid features (26.2 vs 14.0 months, P < 0.001). Multivariate Cox regression showed sarcomatoid features was significantly associated with worse OS in the overall cohort (hazard ratio [HR] =1.63, 95% confidence interval [CI] =1.38-1.91, P < 0.001) and the ccRCC subcohort (HR=1.53, 95% CI=1.23-1.90, P < 0.001). Discussion/Conclusion: mRCC with sarcomatoid features treated with CN and TT has a very poor and drastically different prognosis compared with mRCC without sarcomatoid features. With the expansion of systemic RCC therapies, investigation is needed to optimize treatment in this high-risk cohort.

Most succinate dehydrogenase (SDH)-deficient renal cell carcinomas (RCCs) demonstrate stereotypical morphology characterized by bland eosinophilic cells with frequent intracytoplasmic inclusions. However, variant morphologic features have been increasingly recognized. We therefore sought to investigate the incidence and characteristics of SDH-deficient RCC with variant morphologies. We studied a multi-institutional cohort of 62 new SDH-deficient RCCs from 59 patients. The median age at presentation was 39 years (range 19-80), with a slight male predominance (M:F = 1.6:1). A relevant family history was reported in 9 patients (15%). Multifocal or bilateral tumors were identified radiologically in 5 patients (8%). Typical morphology was present at least focally in 59 tumors (95%). Variant morphologies were seen in 13 (21%) and included high-grade nuclear features and various combinations of papillary, solid, and tubular architecture. Necrosis was present in 13 tumors, 7 of which showed variant morphology. All 62 tumors demonstrated loss of SDHB expression by immunohistochemistry. None showed loss of SDHA expression. Germline SDH mutations were reported in all 18 patients for whom the results of testing were known. Among patients for whom follow-up data was available, metastatic disease was reported in 9 cases, 8 of whom had necrosis and/or variant morphology in their primary tumor. Three patients died of disease. In conclusion, variant morphologies and high-grade nuclear features occur in a subset of SDH-deficient RCCs and are associated with more aggressive behavior. We therefore recommend grading all SDH-deficient RCCs and emphasize the need for a low threshold for performing SDHB immunohistochemistry in any difficult to classify renal tumor, particularly if occurring at a younger age.

Alveolar soft-part sarcoma (ASPS) is a rare soft tissue tumor that primarily involves the extremities. We report a case of a 30-year-old never-smoker man who presented with hematuria, dysuria, and constipation at an outside hospital. He was diagnosed with and treated for multiple episodes of urinary tract infection. However, he continued to have voiding symptoms for which a cystoscopy was performed and revealed a bladder neck mass. He underwent transurethral resection of a bladder tumor and was diagnosed with muscle-invasive urothelial carcinoma, nested variant, at an outside hospital. Subsequent to this diagnosis he transferred his care to our center. In-house imaging revealed a large vascular mass involving the prostate and pushing against the bladder base. Prostate needle biopsies were performed and revealed an epithelioid neoplasm with a nested growth pattern composed of cells with a moderate amount of eosinophilic cytoplasm, mildly pleomorphic nuclei, and occasional prominent nucleoli. Since the findings were not classic for urothelial carcinoma or for prostate cancer, we included a wider differential of poorly differentiated carcinoma, sarcoma, and paraganglioma. A wide panel of keratin stains was negative, ETS (erythroblast transformation-specific)-related gene highlighted an extensive vascular network and neuroendocrine stains were all negative. A transcription factor E3 fluorescent in-situ hybridization was positive and subsequently, an ASPSCR1 gene rearrangement was demonstrated. The outside hospital transurethral resection of bladder tumor was obtained for review and the tumor was morphologically similar to that seen on the in-house prostate needle biopsies. Based on the above findings a final diagnosis of primary ASPS of the prostate with involvement of the bladder was made. The patient was later diagnosed with bilateral lung metastases. He was treated with pazopanib, radiation therapy, and cystoprostatectomy and is symptom-free on a 15-month follow-up.

Background: Disease often depends on how a host interacts with his or her environment. This interaction is important for respiratory infectious diseases, where built environments may promote transmission. To learn about time use, or the amount of time people spend in a day doing various activities, in sub-Saharan Africa may be difficult because of low literacy and different cultural perceptions of time. We developed a culturally appropriate survey tool to measure time use called the mweso game. Method: Three cross-sectional studies were performed among adults in Kampala, Uganda, to evaluate criterion and construct validity and to assess reliability of the mweso game. The mweso game was compared to actual elapsed time, a detailed 24-hr recall survey, and between three different recall periods. In all analyses, the mean number of beads, or hours, was calculated; Pearson correlation coefficients and Cronbach’s α were estimated. Results: Criterion validity for the use of beads to measure time was fair; mean values tended to be accurate, but there was variability in estimates of time across participants. When comparing the mweso game to the 24-hr recall survey, construct validity was very good. For most of the settings, the difference between measurements was less than one hour; there was good to excellent correlation for most settings. Reliability and internal consistency were best for time use at home and work. Conclusions: We have developed the mweso game as an instrument to measure time use in the context of low literacy and different cultural perceptions of time. The mweso game was valid and reliable, especially for measuring time use at home and work. With further validation, it may prove useful in measuring time use and in studying its relation to transmission of respiratory infectious diseases.

BACKGROUND Natural language processing (NLP) offers significantly faster variable extraction compared to traditional human extraction but cannot interpret complicated notes as well as humans can. Thus, we hypothesized that an “NLP-assisted” extraction system, which uses humans for complicated notes and NLP for uncomplicated notes, could produce faster extraction without compromising accuracy. OBJECTIVE The aim of this study was to develop and pilot an NLP-assisted extraction system to leverage the strengths of both human and NLP extraction of prostate cancer Gleason scores. METHODS We collected all available clinical and pathology notes for prostate cancer patients in an unselected academic biobank cohort. We developed an NLP system to extract prostate cancer Gleason scores from both clinical and pathology notes. Next, we designed and implemented the NLP-assisted extraction system algorithm to categorize notes into “uncomplicated” and “complicated” notes. Uncomplicated notes were assigned to NLP extraction and complicated notes were assigned to human extraction. We randomly reviewed 200 patients to assess the accuracy and speed of our NLP-assisted extraction system and compared it to NLP extraction alone and human extraction alone. RESULTS Of the 2051 patients in our cohort, the NLP system extracted a prostate surgery Gleason score from 1147 (55.92%) patients and a prostate biopsy Gleason score from 1624 (79.18%) patients. Our NLP-assisted extraction system had an overall accuracy rate of 98.7%, which was similar to the accuracy of human extraction alone (97.5%; P=.17) and significantly higher than the accuracy of NLP extraction alone (95.3%; P CONCLUSIONS We demonstrated that an NLP-assisted extraction system was able to achieve much faster Gleason score extraction compared to traditional human extraction without sacrificing accuracy.

5030 Background: We performed the first clinical trial to evaluate expression of PARP-1, the target of PARP-inhibitors (PARPi), in prostate cancer (PC) using 18F-FluorThanatrace (18F-FTT), a novel radiopharmaceutical that selectively measures PARP-1 expression with PET/CT. Approvals for PARPi in metastatic castrate resistant prostate cancer (mCRPC) have improved clinical outcomes in men with homologous recombination deficient (HRD) associated PC. Patient selection using genetic biomarkers such as HRD and PARP-1 IHC are insufficient PARPi biomarkers. We report the first trial of assessment of PARP-1 expression in men with prostate cancer. Methods: Men with localized PC with planned prostatectomy were included. Patients were required to have 2+ biopsy cores with > 50% involvement, OR > 1cm dominant prostate lesion on MRI. Men received a single pre-operative [18F]FTT scan. [18F]FTT is. Patients received a single injection of 8-12 mCi [18F]FTT and underwent 60 minutes dynamic scanning and static scan at 90 minutes post-injection. Ex vivo IHC, autoradiography, and germline/somatic genomic testing was performed after surgical removal. The study was approved by the University of Pennsylvania IRB (UPCC #13817, ClinicalTrials.gov, NCT03334500). Results: 30 men consented for participation (29 with presurgical MRI) from 6/2019 to 12/2020. Mean PSA was 9.8 ng/mL (range 2.35 – 60). Gleason Grade (GG) groups included: GG 1 (n = 1), GG 2 (n = 10), GG 3 (n = 5), GG 4 (n = 7), and GG 5 (n = 7). Stages included: pT2 (n = 12), pT3a (n = 10), pT3b (n = 8). Two patients had pN1 disease (cN0 by MRI). Mean injected dose was 10.32 mCi (range 7.52 – 11.62). There were no serious adverse events noted for any patient. Of patients with presurgical MRI, a range of uptake on the PET/CT correlated to the dominant lesion on MRI. The mean and median SUVMax of all lesions was 3.52 and 3.46, respectively (range 1.03 – 6.56). Both patients cN0 on MRI, had those nodes identified on the [18F]FTT scan. SUVMax was significantly associated with increasing Gleason Grade group Rs = 0.37298, p (2-tailed) = 0.04. SUVMax was significantly associated with Decipher scores (GenomeDx Biosciences, San Diego, CA) Rs = 0.63077, p (2-tailed) = 0.02. Ex vivo IHC showed PARP1 localization to the dominant region on the MRI. Ex vivo autoradiography using [I125]KX1, a FTT analogue, and correlation to genomic HRD (DDR aberrations and HRD scores) is underway. Conclusions: [18F]FTT detects in vivo PARP-1 expression in prostate cancer and SUVMax is associated with higher Gleason Grade groups and Decipher scores, This tracer may be used as an imaging biomarker for PARP-1 expression in men with prostate cancer, the target of PARPi. A follow-up study to assess change in [18F]FTT uptake before and after administration of PARPi in men with mCRPC is underway to test [18F]FTT as a biomarker PARPi (UPCC #08821). Clinical trial information: NCT03334500.

Funder: Foundation for Prader-Willi Research; doi: http://dx.doi.org/10.13039/100002889, Prader-Willi syndrome (PWS) is a rare neurodevelopmental genetic disorder associated with a characteristic behavioral phenotype that includes severe hyperphagia and a variety of other behavioral challenges such as temper outbursts and anxiety. These behaviors have a significant and dramatic impact on the daily functioning and quality of life for the person with PWS and their families. To date, effective therapies addressing these behavioral challenges have proven elusive, but several potential treatments are on the horizon. However, a limiting factor for treatment studies in PWS is the lack of consensus in the field regarding how to best define and measure the complex and interrelated behavioral features of this syndrome. The International PWS Clinical Trials Consortium (PWS-CTC, www.pwsctc.org) includes expert PWS scientists, clinicians, and patient advocacy organization representatives focused on facilitating clinical trials in this rare disease. To address the above gap in the field, members of the PWS-CTC “Behavior Outcomes Working Group” sought to develop a unified understanding of the key behavioral features in PWS and build a consensus regarding their definition and description. The primary focus of this paper is to present consensus definitions and descriptions of key phenotypic PWS behaviors including hyperphagia, temper outbursts, anxiety, obsessive–compulsive behaviors, rigidity, and social cognition deficits. Patient vignettes are provided to illustrate the interrelatedness and impact of these behaviors. We also review some available assessment tools as well as new instruments in development which may be useful in measuring these behavioral features in PWS.

Objectives To develop key messages for methadone and buprenorphine safety education material based on an analysis of calls to the NYC Poison Control Center (NYC PCC) and designed for distribution to caregivers of young children. Methods Retrospective review of all calls for children 5 years of age and younger involving methadone or buprenorphine from January 1, 2000, to June 15, 2014. A data abstraction form was completed for each case to capture patient demographics, exposure and caller sites, caller relation to patient, qualitative information regarding the exposure scenario, the product information, if naloxone was given, and the medical outcome of the case. Results A total of 123 cases were identified. The ages of the children ranged from 4 days to 5 years; 55% were boys. All exposures occurred in a home environment. The majority of the calls were made to the NYC PCC by the doctor (74%) or nurse (2%) at a health care facility. Approximately one-fourth of the calls came from the home and were made by the parent (22%) or grandparent (2%). More than one-half of the exposures involved methadone (64%). Naloxone was administered in 28% of cases. Approximately one-fourth of the children did not experience any effect after the reported exposure, one-half (51%) experienced some effect (minor, moderate, or major), and there was 1 death (1%). More than one-half of the children were admitted to the hospital, with 40% admitted to critical care and 13% to noncritical care. Approximately 23% were treated and released from the hospital, and 20% were lost to follow-up or never arrived to the hospital. The remaining 4% were managed on site without a visit to the hospital. Conclusion Exposures to methadone and buprenorphine are dangerous with some leading to serious health effects. Safe storage and disposal instructions are needed for homes where children may be present.

Context: Short messaging service (SMS or text messaging) allows for the exchange of electronic text messages. Online chatting refers to Internet-based transmission of messages for real-time convers...

Objective Caring for children with developmental and epileptic encephalopathies (DEEs) places substantial demands on the entire family unit, including siblings. The Sibling Voices Survey assesses parental and sibling responses to questions designed to assess how children adapt to growing up with siblings with DEE. Methods Participants responded to 1 of 4 online, age- and role-specific surveys (9–12, 13–17, and ≥ 18-year-old [adult] siblings; parents responded with perceptions of their unaffected child's/children's feelings). Survey questions used visual analog scales, categorical responses, and free-form responses. Results Survey submissions (n = 248) included 128 parents and 120 siblings (9- to 12-year-olds, n = 24; 13- to 17-year-olds, n = 17; adults, n = 79). All groups identified home life as the most substantially affected area of their lives (71%–84%), compared with interactions at school (21%–32%) or with friends (28%–42%). The most difficult aspect across all sibling groups was “feeling worried/scared when their sibling has seizures” (58%–70%). Feeling “overly responsible” for the sibling was reported by most adult siblings (63%), 41% of 13- to 17-year-old siblings, and 34% of parents. Siblings reported more symptoms of depressed mood (e.g., “down/unhappy,” 47%–62%) than their parents perceived them feeling (25%). Most sibling groups (29%–49%) reported more symptoms of anxious mood (e.g., “nightmares/bad dreams”) than parents perceived (15%). Identification of potential helpful coping mechanisms varied by age group. Most respondents (68%–76%) reported positive aspects, including greater maturity and compassion. Significance The Sibling Voices Survey provided important insights into how DEE impacts siblings psychologically and socially. This study highlights the need for increased awareness among parents and healthcare providers to monitor siblings for potential signs of depressed or anxious mood, to provide proper support, and to decrease potential for negative long-term consequences.

Background: Hepatocellular carcinoma (HCC) occurs less commonly among women than men in almost all regions of the world. The disparity in risk is particularly notable prior to menopause suggesting that hormonal exposures during reproductive life may be protective. Exogenous oestrogenic exposures such as oral contraceptives (OCs), however, have been reported to increase risk, suggesting that estrogens may be hepatocarcinogenic. To examine the effects of reproductive factors and exogenous hormones on risk, we conducted a prospective analysis among a large group of US women. Methods: In the Liver Cancer Pooling Project, a consortium of US-based cohort studies, data from 799 500 women in 11 cohorts were pooled and harmonised. Cox proportional hazards regression models were used to generate hazard ratios (HRs) and 95% confidence intervals (CIs) for the associations of reproductive factors and exogenous hormones with HCC (n=248). Results: Bilateral oophorectomy was associated with a significantly increased risk of HCC (HR=2.67, 95% CI=1.22–5.85), which did not appear to be related to a shorter duration of exposure to endogenous hormones or to menopausal hormone therapy use. There was no association between OC use and HCC (HR=1.12, 95% CI=0.82–1.55). Nor were there associations with parity, age at first birth, age at natural menopause, or duration of fertility. Conclusions: The current study suggests that bilateral oophorectomy increases the risk of HCC but the explanation for the association is unclear. There was no association between OC use and HCC risk. Examination of endogenous hormone levels in relation to HCC may help to clarify the findings of the current study.

Background: Excessive alcohol consumption is a well-established risk factor for liver disease and hepatocellular carcinoma (HCC). Previous studies have found that increased alcohol consumption can lead to lower absorption of folate. Conversely, higher folate intake has been inversely associated with liver damage and HCC. In the current study, we investigate the effect of alcohol consumption and folate intake on HCC incidence and liver disease mortality in the NIH–American Association of Retired Persons Diet and Health Study. Methods: The study population included 494,743 participants who reported at baseline their dietary intake for the previous year. Alcohol and folate were analyzed with hazards ratios (HR) and 95% confidence intervals (CI) using multivariate Cox proportional hazards regression models adjusted for age, sex, race, education, smoking, body mass index, and diabetes. HCC incidence (n = 435) was determined through 2006 via linkage with cancer registries, and liver disease mortality (n = 789) was determined through 2008 via linkage to the U.S. Social Security Administration Death Master File and the National Death Index Plus by the National Center for Health Statistics. Results: Consumption of more than three drinks per day was positively associated with both HCC incidence (HR: 1.92; 95%CI: 1.42–2.60) and liver disease mortality (HR: 5.84; 95%CI: 4.81–7.10), whereas folate intake was associated with neither outcome. Folate, however, modified the relationship between alcohol and HCC incidence (Pinteraction = 0.03), but had no effect on the relationship between alcohol and liver disease mortality (Pinteraction = 0.54). Conclusions: These results suggest that higher folate intake may ameliorate the effect of alcohol consumption on the development of HCC. Impact: Folate intake may be beneficial in the prevention of alcohol-associated HCC. Cancer Epidemiol Biomarkers Prev; 22(3); 415–21. ©2013 AACR.

This paper reports on the ‘Prader-Willi Syndrome (PWS) Mental Health Research Strategy Workshop’ that took place in March 2015. PWS is characterized by a complex phenotype affecting multiple systems with a high prevalence of maladaptive behaviours, and neuropsychiatric illness. Prader Willi syndrome results from the absence of paternally derived alleles located at the imprinted chromosomal locus, 15q11–13. The goal of the workshop was to highlight the state of the science of the mental health of people with this rare neurodevelopmental disorder. Mental ill health and maladaptive behaviors significantly impact quality of life for persons with PWS and their caregivers. Effective treatments and further research into this area are critically needed. Methods A multidisciplinary group of scientists and health care professionals were brought together to discuss the mental health and behavioral needs of people with PWS. The workshop strategy was to integrate established work on PWS with other relevant areas of study. The meeting also focused on two neurobiological systems that research had suggested were relevant to understanding the broader mental health aspects of PWS: the autonomic nervous system and oxytocin/vasopressin pathways. Other relevant topics were considered and recommendations made. Results The workshop presentations and working group discussions revealed that no one approach was sufficient to fully conceptualize the mental health challenges in PWS. Workshop discussions pointed to the need for theoretically informed studies focused on clinical characterization, measurement, and the probing of specific neurobiological systems through pharmaceutical or other interventions. Future studies in this area should explore the use of advanced neuroimaging protocols, as well as molecular studies using iPS cells in order to create more informed theories. Conclusions Within this framework, workshop participants identified and prioritized key research questions, and highlighted current opportunities. Recommendations were made with respect to the development of specific resources and tools for furthering mental health research such as The Global PWS Registry, the development of effective endpoints, the use of animal models and iPS cells to aid understanding of the neurobiological underpinnings. Additionally, collaborative opportunities across disciplines and syndromes were highlighted and targeted research initiatives focused on psychological/behavioral interventions modified for use in PWS were recommended.

Purpose: Cytology-based screening has limited sensitivity to detect prevalent cervical precancers. Human papilloma virus (HPV) DNA testing is highly sensitive and provides a high, long-term reassurance of low risk of cervical cancer. However, the specificity of HPV DNA testing is limited, requiring additional, more disease-specific markers for efficient screening approaches. Experimental Design: Liquid-based cytology samples were collected from 625 women referred to colposcopy. A slide was stained using the CINtec plus cytology assay. Pap cytology and HPV genotyping were conducted from the same vial. Clinical performance characteristics were calculated for all women, stratified by age, and for women referred with a low-grade squamous intraepithelial lesion (LSIL) Pap. Results: p16/Ki-67 positivity increased with histologic severity, from 26.8% in normal histology, 46.5% in CIN1, 82.8% in CIN2 to 92.8% in CIN3. Among women with CIN3, p16/Ki-67 positivity increased from 77.8% for women younger than 30 years without HPV16 to 100% for women 30 years and older with HPV16. The sensitivity and specificity to detect CIN3+ were 93.2% and 46.1%, respectively, and increased to 97.2% and 60.0% among women 30 years and older. In women with high-risk (HR)-HPV–positive atypical squamous cells of undetermined significance (ASC-US) and LSIL, sensitivity and specificity for detection of CIN3 were 90.6% and 48.6%, respectively. Conclusions: p16/Ki-67 testing could reduce referral to colposcopy by almost half while detecting the most severe cases of CIN3. The high sensitivity of p16/Ki-67 with significantly improved specificity compared with HPV testing makes p16/Ki-67 a viable option for LSIL triage. Further studies are required to evaluate p16/Ki-67 as triage marker in HPV-based screening strategies. Clin Cancer Res; 18(15); 4154–62. ©2012 AACR.

BACKGROUND: The majority of anal cancers are caused by persistent infections with carcinogenic human papillomaviruses (HPV). Similar to cervical carcinogenesis, the progression from HPV infection to anal cancer occurs through precancerous lesions that can be treated to prevent invasion. In analogy to cervical cytology, anal cytology has been proposed as a screening tool for anal cancer precursors in high-risk populations. METHODS: The authors analyzed the interobserver reproducibility of anal cytology in a population of 363 human immunodeficiency virus (HIV)-infected men who have sex with men (MSM). Liquid-based cytology (LBC) specimens were collected in the anal dysplasia clinic before the performance of high-resolution anoscopy on all patients. Papanicolaou-stained LBC slides were evaluated by 2 cytopathologists, each of whom was blinded to the clinical outcome and the other pathologist's results, using the revised Bethesda terminology. RESULTS: Overall agreement between the 2 observers was 66% (kappa, 0.54; linear-weighted kappa, 0.69). Using dichotomizing cytology results (atypical squamous cells of undetermined significance [ASC-US] or worse vs less than ASC-US), the agreement increased to 86% (kappa, 0.69). An increasing likelihood of testing positive for markers associated with HPV-related transformation, p16/Ki-67, and HPV oncogene messenger RNA was observed, with increasing severity of cytology results noted both for individual cytologists and for consensus cytology interpretation (P value for trend [ptrend] < .0001 for all). CONCLUSIONS: Moderate to good agreement was observed between 2 cytopathologists evaluating anal cytology samples collected from HIV-positive MSM. A higher severity of anal cytology was associated with biomarkers of anal precancerous lesions. Anal cytology may be used for anal cancer screening in high-risk populations, and biomarkers of HPV-related transformation can serve as quality control for anal cytology. Cancer (Cancer Cytopathol) 2013. Published 2012 by the American Cancer Society.

Objectives Prader-Willi syndrome (PWS) is a rare genetic neurodevelopmental disorder that is characterized by hyperphagia, developmental delay, incomplete sexual development, mild-to-moderate intellectual disability, and a variety of challenging behavioral and psychiatric symptoms. The characteristics of PWS can be difficult for caregivers to cope with and are likely to cause significant and long- term caregiver burden. The current study examined burden in 142 caregivers of children and adults with PWS living in the US using the Zarit Burden Interview (ZBI). The study aimed to measure the level of burden in caregivers of individuals with PWS, to explore the impact of PWS on caregiver quality of life, and to assess ZBI as an indicator of that impact. Results Caregivers participating in this study were predominantly mothers, 30-59 years old, non-Hispanic Whites, married or in a relationship, with an annual household income slightly distributed towards higher income. Nearly 90% of the caregiver`s children with PWS lived at home. Caregivers experienced high caregiver burden with an average ZBI score of 44.4 ± 15.4. ZBI scores were highest for caregivers of teenage and young adult individuals with PWS (49.2 ± 14.6 and 49.2 ± 14.1, respectively), while those caring for older adults (>30) and the youngest age group had lower scores (38.6 ±10.5 and 34.8 ±12.5, respectively). Caregivers reported that caring for a person with PWS negatively impacted their romantic relationship, ability to work, sleep, and mood. Whereas we did not find strong correlations between family income or level of help the caregiver receives and ZBI scores, the results showed significant correlations and a linear relationship between ZBI scores and caregiver depressed mood, feelings of anxiety, negative romantic relationship impact, as well as sleep and work disruption. Conclusions Our study reveals that PWS incurs high caregiver burden and impacts many aspects of the lives of caregiver. We identified the ZBI as a good predictor of that impact. Our findings draw attention to the critical unmet need for support for caregivers of individuals with PWS.

Preface The leadership of Women in Neurosurgery (WINS) has been asked by the Board of Directors of the American Association of Neurological Surgeons (AANS) to compose a white paper on the recruitment and retention of female neurosurgical residents and practitioners. Introduction Neurosurgery must attract the best and the brightest. Women now constitute a larger percentage of medical school classes than men, representing approximately 60% of each graduating medical school class. Neurosurgery is facing a potential crisis in the US workforce pipeline, with the number of neurosurgeons in the US (per capita) decreasing. Women in the Neurosurgery Workforce The number of women entering neurosurgery training programs and the number of board-certified female neurosurgeons is not increasing. Personal anecdotes demonstrating gender inequity abound among female neurosurgeons at every level of training and career development. Gender inequity exists in neurosurgery training programs, in the neurosurgery workplace, and within organized neurosurgery. Obstacles The consistently low numbers of women in neurosurgery training programs and in the workplace results in a dearth of female role models for the mentoring of residents and junior faculty/practitioners. This lack of guidance contributes to perpetuation of barriers to women considering careers in neurosurgery, and to the lack of professional advancement experienced by women already in the field. There is ample evidence that mentors and role models play a critical role in the training and retention of women faculty within academic medicine. The absence of a critical mass of female neurosurgeons in academic medicine may serve as a deterrent to female medical students deciding whether or not to pursue careers in neurosurgery. There is limited exposure to neurosurgery during medical school. Medical students have concerns regarding gender inequities (acceptance into residency, salaries, promotion, and achieving leadership positions). Gender inequity in academic medicine is not unique to neurosurgery; nonetheless, promotion to full professor, to neurosurgery department chair, or to a national leadership position is exceedingly rare within neurosurgery. Bright, competent, committed female neurosurgeons exist in the workforce, yet they are not being promoted in numbers comparable to their male counterparts. No female neurosurgeon has ever been president of the AANS, Congress of Neurological Surgeons, or Society of Neurological Surgeons (SNS), or chair of the American Board of Neurological Surgery (ABNS). No female neurosurgeon has even been on the ABNS or the Neurological Surgery Residency Review Committee and, until this year, no more than 2 women have simultaneously been members of the SNS. Gender inequity serves as a barrier to the advancement of women within both academic and community-based neurosurgery. Strategic Approach to Address Issues Identified. To overcome the issues identified above, the authors recommend that the AANS join WINS in implementing a strategic plan, as follows: 1) Characterize the barriers. 2) Identify and eliminate discriminatory practices in the recruitment of medical students, in the training of residents, and in the hiring and advancement of neurosurgeons. 3) Promote women into leadership positions within organized neurosurgery. 4) Foster the development of female neurosurgeon role models by the training and promotion of competent, enthusiastic, female trainees and surgeons.

An essential component of quality care for limited English proficient (LEP) patients is language access. Linguistically accessible medication instructions are particularly important, given the serious consequences of error and patient responsibility for managing often complex medication regimens on their own. Approximately 21 million people in the U.S. were LEP at the time of the 2000 census, representing a 50% increase since 1990. Little information is available on their access to comprehensible medication instructions. In an effort to address this knowledge gap, we conducted a telephone survey of 200 randomly selected NYC pharmacies. The primary focus of the survey was translation need, capacity, and practice. The majority of pharmacists reported that they had LEP patients daily (88.0%) and had the capacity to translate prescription labels (79.5%). Among pharmacies serving LEP patients on a daily basis, just 38.6% translated labels daily; 22.7% never translated. In multivariate analysis, pharmacy type (OR = 4.08, 95%CI = 1.55-10.74, independent versus chain pharmacies) and proportion of Spanish-speaking LEP persons in the pharmacy's census tract (OR = 1.09, 95%CI = 1.05-1.13 for each 1% increase in Spanish LEP population) were associated with increased label translation. Although 88.5% of the pharmacies had bilingual staff, less than half were pharmacists or pharmacy interns and thus qualified to provide medication counseling. More than 80% of the pharmacies surveyed lacked systematic methods for identifying linguistic needs and for informing patients of translation capabilities. Consistent with efforts to improve language access in other health care settings, the critical gap in language appropriate pharmacy services must be addressed to meet the needs of the nation's large and ever-growing immigrant communities. Pharmacists may require supplemental training on the need and resources for meeting the verbal and written language requirements of their LEP patients. Dispensing software with accurate translation capability and telephonic interpretation services should be utilized in pharmacies serving LEP patients. Pharmacists should post signs and make other efforts to inform patients about the language resources available to them.

Objective. To examine the association between pain-coping strategies and adjustment to cerebral palsy (CP)-related pain. Design. Longitudinal study of 48 adults with CP-related chronic pain. Study participants were interviewed on two occasions, separated by 6 months, to assess pain-coping strategies used and two domains of adjustment to chronic pain: depression and pain interference. Results. Changes in coping strategy use were associated with changes in functioning. Specifically, decreased use of catastrophizing and rest, and increased use of task persistence were associated with decreases in depression over a 6-month period. Increased use of task persistence was also associated with decreases in pain interference. Conclusion. Changes in pain-coping strategies over time are associated with changes in functioning in persons with CP-related pain, consistent with biopsychosocial models of chronic pain. Some coping strategies (e.g., catastrophizing, task persistence), however, appear to be more closely linked to functioning than others. These results provide preliminary empiric guidance for the coping strategies that may be most fruitfully targeted in the treatment of CP-related pain.

Operant behavioral models of chronic pain posit that the pain behaviors and disability of patients with chronic pain can be influenced by social contingencies, such as significant others’ responses to pain and well behaviors. The aim of the present study was to develop and evaluate a comprehensive measure of spouse responses to patient pain and well behaviors, the Spouse Response Inventory (SRI). One hundred four patients with chronic pain and their spouses completed a battery of questionnaires, including the SRI. The final analysis yielded a 39-item inventory divided into 4 scales that assess spouse solicitous and negative responses to patient pain behaviors and spouse encouraging and negative responses to patient well behaviors. Analyses yielded results that were consistent with previous research demonstrating an association between spouse solicitous and negative responses to patient pain behaviors and measures of patient functioning, providing preliminary support for the validity of the SRI scales. The results are discussed in terms of implications for further research and the clinical applicability of the SRI. Perspective This article presents the psychometric properties of a new measure of spouse responses to patient chronic pain and well behavior. This measure could potentially be helpful to clinicians seeking to assess the extent to which spouse responses may contribute to patient pain and disability and also to researchers who wish to test hypotheses derived from operant theory as applied to chronic pain.

Objectives To determine if cerebral palsy-related pain and frequency of use of pain treatments change over time and to examine the association between use of pain treatments and changes in pain intensity. Design Longitudinal study of 50 adults with cerebral palsy-related chronic pain, interviewed five times during the course of 2 yrs (6 mos between each interview). Subjects ranged in age from 18 to 76 yrs old and included 25 women and 25 men. Results Pain intensity did not change significantly during the time period of the study (2 yrs), although there was a substantial increase in the frequency of use of several pain treatments from the initial to the second interview. Participants reported that many pain treatments were at least moderately helpful, but only three of the treatments (whirlpool, ultrasound, and transcutaneous electrical nerve stimulation) seemed to be associated with a decrease in pain among those who started using these treatments during the study. Conclusion Pain does not seem to become systematically better or worse during the course of a 2-yr time period in adults with cerebral palsy-related pain. Although several pain treatments are reported to provide pain relief, many of these were rarely used by (or provided to) the study participants. There is a need for more research to determine which pain treatments are most helpful for cerebral palsy-related pain and to increase patient accessibility to effective pain treatments.

Slit ventricle syndrome is a rare condition whereby brain compliance is reduced and can be associated with intermittent intracranial hypertension. A 19-year-old male with a ventriculoperitoneal shunt for congenital hydrocephalus presented with a 1-day history of headache and drowsiness-symptoms from which he suffered in many recurrent episodes over the past 5 years. The improvement of headaches without surgical intervention led to the diagnosis of migraine. During this hospitalization, episodes of intermittent intracranial hypertension were documented along with the remission and relapse of the symptoms. While the patient’s intracranial pressure was within normal range in over 90% of his monitoring period, which postponed shunting, replacement of his ventriculoperitoneal shut eventually resolved his symptoms. Slit ventricle syndrome with reduced ventricular compliances should be considered in patients with clinical evidence of intermittent intracranial hypertension and small ventricular size. The authors advocate shunt replacement as an appropriate treatment for this condition.

PURPOSE: There is now substantial data that poly (ADP-ribose) polymerase-1 (PARP) inhibitors have activity in tumors with defects in homologous recombination, in particular BRCA-related cancers. One of the challenges, however, is identifying patients that may best respond to these class of drugs. 18F-FTT (fluorthanotrace) is a novel PET imaging tracer that can quantify PARP enzyme activity in vivo. We report results on an initial pilot study of 18F-FTT imaging in patients with ovarian carcinoma. METHODS: Eight patients with newly diagnosed or recurrent ovarian, primary peritoneal, or fallopian tube carcinoma and measurable disease underwent both 18F-FDG PET/CT and 18F-FTT PET/CT imaging within 30 days of each other. Patients who were undergoing surgery or had disease amenable to biopsy underwent dynamic imaging of the abdomen/pelvis and static skull base to mid-thigh imaging following injection of approximately 10mCi of 18F-FTT. Patients with no biopsy accessible disease underwent a series of whole body PET/CT scans over 4 hours following injection of 18F-FTT to evaluate the biodistribution and dosimetry of 18F-FTT. Standardized uptake value (SUV) was calculated for primary and/or metastatic implants on all patients with quantifiable tumor on both PET/CT scans. Quantitative assessment of the 18F-FTT PET/CT was performed first using the 18F-FDG PET/CT to identify and match lesions. Regions of interest were then drawn over the tumor implant using multiple planar view. Up to three lesions were quantified on each dataset (primary and metastases if present). Ex vivo autoradiography with [ 125I]-KX (a novel radio-iodinated PARP radiotracer that can quantitatively assess PARP-1 enzyme expression in vitro), immunohistochemical staining with γh2ax, CD45, and keratin was performed on tumor samples. RESULTS: Active regions of disease was noted for 7/8 patients on 18F-FDG PET/CT imaging and 18F-FTT PET/CT imaging. Maximum SUV of primary or metastases on 18F-FDG PET/CT ranged from 1.97-14.54 and on 18F-FTT PET/CT ranged from 3.04-12.13. We acquired tumor tissue on four patients for analysis. SUV on 18F-FTT PET/CT correlated with average counts/area on [ 125I]-KX autoradiography (R=0.70) and gammh2ax immunohistochemistry staining on tumor specimens. Low SUV FTT:FDG ratio was noted in 4/4 patients with platinum resistant disease and/or low PARP-1 expression on [ 125I]-KX autoradiography and high FTT:FDG ratio was noted in 2/3 patients with platinum sensitivity and/or high binding on [ 125I] KX auto-radiography. CONCLUSION: Our initial preliminary studies demonstrate that 18F-FTT localizes to known areas of tumor and may distinguish between tumors with low level expression of PARP and platinum resistance vs high levels of PARP and platinum sensitivity and may be a promising biomarker for PARP inhibitor and platinum sensitivity. Citation Format: Lilie Lin MD, Mehran Makvandi PharmD, Austin Pantel MD, Robert Doot PhD, Lauren Schwartz MD, Fiona Simpkins MD, David Mankoff MD PHD, Robert Mach PhD. A PILOT STUDY OF A POLY (ADP–RIBOSE) POLYMERASE–1 (PARP) TARGETED NOVEL PET TRACER (18F–FLUOURTHANOTRACE) IN PATIENTS WITH OVARIAN CARCINOMA [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr AP20.

Objective: Warfarin is a high-risk medication whose safe use may be greatly improved by patient education. This study evaluate evaluated patients’ understanding of warfarin instructions, medication management, the Food and Drug Administration’s (FDA) warfarin medication guide content, and patient information recommendations. Methods: Interviews conducted at 2 hospital-based outpatient primary care sites with patients initiated on warfarin therapy within the last year. Results: Interviews were conducted with 49 patients. Seventy percent were between 36 and 64 years old and reported taking between 1 and 18 different medications daily. Many (76%) received information about warfarin when first prescribed to them, 65% written and 60% verbal (answers reflect more than one response). Patients found content in the medication guide difficult to understand; 18% were unable to identify information about diet and 21% were unable to locate information about when to call their provider. Analysis showed that 19% had trouble with numeracy issues related to warfarin. Patients’ suggestions of ways to convey warfarin information included more graphics, in-person counseling, and multilingual translations. Conclusion: This study demonstrates gaps in patients’ understanding of warfarin therapy. Relying solely on the information in the FDA medication guide is insufficient to guarantee adequate understanding. Utilizing the suggestions from patients’ feedback on other ways to deliver information should help future patients with different learning abilities and styles.

Pain is a serious secondary problem for many persons with cerebral palsy (CP). Cognitive-behavioral models of pain hypothesize that how patients cope with painful episodes plays an important role in their adjustment to chronic pain. The utility of this model, however, has never been tested in persons with CP-related pain. Fifty adults with CP and chronic pain were interviewed to assess pain experience, the interference of pain on activities (BPI), depressive symptoms (CES-D), and coping strategies used for the pain (CSQ and CPCI). The results indicated that pain-contingent rest and catastrophizing were both significantly associated with pain interference and depressive symptoms even when controlling for pain severity. These findings support a cognitive-behavioral model of chronic pain as it might be applied to persons with CP. The results also support the need for research to determine if, and to what extent, cognitive-behavioral interventions that provide training in specific coping responses reduce depressive symptoms and pain interference in persons with CP.

Research in the area of family issues and multiple sclerosis has mainly focused on the impact of multiple sclerosis on the spouse. The aim of the current study was to examine the relationship between patients' ratings of their spouses' responses to multiple sclerosis patient disability behaviors and the impact on patient psychological and physical functioning. Multiple sclerosis patients were interviewed over the telephone using standardized questionnaires to assess patient physical and psychological functioning, spouse responses to patient disability and well behaviors (i.e., how does the spouse respond when you're having difficulties related to multiple sclerosis ?), and family environment factors. The study was set in a large university-based Multiple Sclerosis Clinical Center. Forty-four of 64 patients approached with definite multiple sclerosis participated in the study. Physical functioning was assessed by the Kurtzke-EDSS, SIP, SF-36, and psychological functioning was assessed by the CES-D and SF-36. Scores on the SF-36 were generally lower compared with a normative sample of individuals with major medical problems; however, mean Kurtzke scores of 5.60 reflected moderate to severe impairment. Exploring spouse responses to disability, correlation analyses revealed that solicitous spouse responses to patient disability behaviors were significantly associated with greater multiple sclerosis-related physical disability. This relationship was stronger for patients who were more depressed. Spouse negative responses to patient disability behaviors were associated with poorer mental health, whereas spouses' encouragement of patient well behaviors was associated with lower emotional distress. Poorer psychological functioning was found in patients with families who were reported to have higher conflict and/or who were more controlling. Higher levels of independence in families were associated with better psychological and physical functioning in the patients. These preliminary findings suggest that patients' perceptions of their families' responses to disability and family environment factors may be important areas for further research. The findings may also provide potential targets for clinical intervention in the future.

Objective: To examine the nature and scope of pain in persons with cerebral palsy (CP). Design: Standardized interviews to assess demographics, pain experiences, and the impact of pain on activities. Subjects: Ninety-three adults with CP recruited from medical clinics at the University of Washington and local residential and community housing for persons with developmental disabilities. Main Outcome Measures: Weekly and 3-month pain intensities, chronic pain grade, interference in daily activities caused by pain, and pain-exacerbating and pain-relieving factors. Results: Sixty-two subjects (67%) reported one or more areas of pain of ≥3 months' duration. Lower extremity pain and back pain were the most common complaints. Fifty-six percent of the subjects reporting pain indicated it occurred daily. Mean average pain intensity, graded on a scale of 0 (no pain) to 10 (pain as bad as could be), was 3.16 (SD = 2.45) in the preceding week and 4.45 (SD = 2.34) in the previous 3 months. Approximately 53% of subjects reporting pain indicated their average pain was of moderate to severe intensity (average pain rated as ≥5). Using Von Korff's Chronic Pain Grade classification system, the majority of subjects who reported pain fell into either grade II(low disability, low pain intensity; 51%) or grade II (low disability, high pain intensity; 39%). Subjects reported many factors that exacerbate pain (eg, stress or weather) or decrease it (eg, exercise or rest). Conclusions: The data suggest that pain is common in adults with CP. In many subjects, pain levels were moderate to intense

Complex regional pain syndrome (CRPS) remains a poorly understood chronic pain disorder. Little data has been published assessing the epidemiology of CRPS (and reflex sympathetic dystrophy, RSD). This study assessed epidemiological variables in 134 CRPS patients evaluated at a tertiary chronic pain clinic in the US, including demographic, health care utilization and legal/workman's compensation measures. In addition, the frequency of physician-imposed immobilization of the CRPS limb was assessed, as was physical examination evidence of myofascial dysfunction. This study found that these patients had seen on average 4.8 different physicians before referral to the pain center and had received an average of five different kinds of treatments both prior to and during pain clinic treatment. The mean duration of CRPS symptoms prior to pain center evaluation was 30 months. Seventeen percent had a lawsuit and 54% had a worker compensation claim related to the CRPS. Fifty-one patients received a bone scan, but only 53% of which were interpreted as consistent with the diagnosis of RSD/CRPS. Forty-seven percent had a history of physician-imposed immobilization, and 56% had a myofascial component present at evaluation. The duration of CRPS symptoms and the involvement of the upper extremity was significantly associated with the presence of myofascial dysfunction. Thus, this study found that most CRPS patients are referred to a pain specialty clinic after several years of symptoms and many failed therapies. The data also suggest the lack of utility of a diagnostic bone scan and highlight the prominence of myofascial dysfunction in a majority of CRPS patients.

The thermodynamic functions that describe the complexation of a series of four carboxylic acid guests and two related quaternary ammonium derivatives with β-cyclodextrin were measured using flow calorimetry at 298 K in aqueous media in the presence and in the absence of large concentrations of urea. The relative differences of the thermodynamic parameters of complexation revealed the existence of specific interactions between urea and the aromatic surfaces of some of the nonpolar guests. As expected, the relative changes in the complex stability constants upon addition of urea have been found to depend on the balance of opposing enthalpic and entropic contributions. The interpretation as well as the magnitude of the interaction between urea and aromatic surfaces are in line with previous experimental and computational studies. The experimental evidence presented in this work provides insight into the mechanism by which large amounts of urea denature globular proteins in aqueous media.

Anal cancer is relatively uncommon in the United States, with an expected 6000 new cases in 2012 and an overall annual incidence rate of 2/100 000 [1, 2]. Most anal cancers are caused by human papillomavirus (HPV) infection [3]. Certain populations, such as human immunodeficiency virus (HIV)–infected and other immunosuppressed individuals, appear to have an increased risk of both HPV infection and anal cancer. A recent worldwide metaanalysis showed that HIV-infected men who have sex with men (MSM) have an estimated 46/100 000 incident anal cancer cases per year compared with HIV-negative MSM who have 5/100 000 incident cases per year [4]. Since the advent of highly active antiretroviral therapy (HAART), the life expectancy for HIV-infected individuals has significantly increased. This may have allowed time for progression of carcinogenic HPV infections to anal cancer and possibly explains an increase in anal cancer incidence in the United States [5–8]. Anal cancer natural history presumably follows the same steps as cervical cancer natural history: HPV acquisition, HPV persistence, progression of persistent HPV infections to high-grade anal intraepithelial neoplasia (AIN), and invasion to anal cancer [5]. Studies have identified risk factors for each stage in the progression from cervical HPV infection to cervical cancer [9–11], and we are beginning to find similar risk factors in anal cancer natural history. Risk factors for anal HPV infection are related to sexual behavior, such as lifetime number of sexual partners, as well as low CD4 count in HIV-infected populations [12–15]. Smoking history has been shown to be associated with anal HPV persistence [16, 17] and anal cancer [18, 19], but it is unclear at what stage smoking influences the natural history. To add to our understanding of risk factors that influence the natural history of HPV and anal cancer, we conducted a study of lifestyle characteristics and clinical parameters for HIV-infected MSM undergoing routine anal cancer screening at Kaiser Permanente Northern California (KPNC) Health Maintenance Organization.

Background Excess alcohol consumption adversely affects one-carbon metabolism and increases the risk of liver disease and liver cancer. Conversely, higher folate levels have been inversely associated with liver damage. The current study investigated the effects of alcohol and one-carbon metabolite intake on liver cancer incidence and liver disease mortality within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study. Methods Cox proportional hazards modeling was used to calculate hazard ratios and 95% confidence intervals (CIs) in a population of 27,086 Finnish males with 194 incident liver cancers and 213 liver disease deaths. In a nested case-control subset (95 liver cancers, 103 controls), logistic regression was used to calculate odds ratios and 95% CIs for serum one-carbon metabolites in relation to liver cancer risk. Results Daily alcohol consumption of more than 20.44 g was associated with an increased risk of both liver cancer incidence (Hazard Ratio (HR) 1.52, 95%CI 1.06–2.18) and liver disease mortality (HR 6.68, 95%CI 4.16–10.71). These risks were unaffected by one-carbon metabolite intake. Similarly, in the case-control study, none of the serum one-carbon metabolites were associated with liver cancer. Conclusions The current study provided no convincing evidence for a protective association of one-carbon metabolite intake or serum level on the risk of liver cancer or liver disease mortality.