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Screening for oral leukoplakia, an oral cavity cancer (OCC) precursor, could lead to earlier detection of OCC. However, the progression rate from leukoplakia to OCC and the benefits of leukoplakia screening for improving OCC outcomes are currently unclear. We conducted a case–cohort study of U.S. adults ages ≥65 years in the Surveillance, Epidemiology, and End Results (SEER)-Medicare linkage. We identified leukoplakia diagnoses through Medicare claims, and OCC diagnoses through SEER cancer registries. Weighted Cox regression was used to estimate leukoplakia associations with OCC incidence, and the absolute OCC risk following leukoplakia diagnosis was calculated. Among OCC cases, we compared OCC stage and OCC survival between cases with a prior leukoplakia diagnosis versus those without prior leukoplakia. Among 470,266 individuals in the SEER-Medicare subcohort, 1,526 (0.3%) had a leukoplakia diagnosis. Among people with leukoplakia, the cumulative OCC incidence was 0.7% at 3 months and 2.5% at 5 years. OCC risk was most increased N = 8,927), those with prior leukoplakia were less likely to be diagnosed at regional/distant stage (OR, 0.36; 95% CI, 0.30–0.43), and had lower mortality (HR, 0.74; 95% CI, 0.65–0.84) when compared with OCC cases without a prior leukoplakia. Individuals with leukoplakia have substantially elevated risk of OCC. Lower stage and better survival after OCC diagnosis suggest that leukoplakia identification can lead to earlier OCC detection and reduced mortality. Cancer Prev Res; 8(9); 857–63. ©2015 AACR.

Supplementary Tables 1 & 2. Table 1: Comparison of American Joint Committee on Cancer (AJCC) stage to SEER historic stage within the SEER database. Table 2: Primary treatment for oral cavity cancer cases.

The contribution of the host immune system to the efficacy of new anti-hepatitis C virus (HCV) drugs is unclear. We undertook a longitudinal prospective study of 33 individuals with chronic HCV treated with combination pegylated IFN-α, ribavirin, and telaprevir/boceprevir. We characterized innate and adaptive immune cells to determine whether kinetics of the host response could predict sustained virologic response (SVR). We show that characteristics of the host immune system present before treatment were correlated with successful therapy. Augmentation of adaptive immune responses during therapy was more impressive among those achieving SVR. Most importantly, active memory T cell proliferation before therapy predicted SVR and was associated with the magnitude of the HCV-specific responses at week 12 after treatment start. After therapy initiation, the most important correlate of success was minimal monocyte activation, as predicted by previous in vitro work. In addition, subjects achieving SVR had increasing expression of the transcription factor T-bet, a driver of Th1 differentiation and cytotoxic effector cell maturation. These results show that host immune features present before treatment initiation predict SVR and eventual development of a higher frequency of functional virus-specific cells in blood. Such host characteristics may also be required for successful vaccine-mediated protection.

Screening for oral leukoplakia, an oral cavity cancer (OCC) precursor, could lead to earlier detection of OCC. However, the progression rate from leukoplakia to OCC and the benefits of leukoplakia screening for improving OCC outcomes are currently unclear. We conducted a case–cohort study of U.S. adults ages ≥65 years in the Surveillance, Epidemiology, and End Results (SEER)-Medicare linkage. We identified leukoplakia diagnoses through Medicare claims, and OCC diagnoses through SEER cancer registries. Weighted Cox regression was used to estimate leukoplakia associations with OCC incidence, and the absolute OCC risk following leukoplakia diagnosis was calculated. Among OCC cases, we compared OCC stage and OCC survival between cases with a prior leukoplakia diagnosis versus those without prior leukoplakia. Among 470,266 individuals in the SEER-Medicare subcohort, 1,526 (0.3%) had a leukoplakia diagnosis. Among people with leukoplakia, the cumulative OCC incidence was 0.7% at 3 months and 2.5% at 5 years. OCC risk was most increased

Few population-based studies have described characteristics and management of patients with chronic hepatitis B (CHB) in the USA.We retrospectively studied adults with CHB in the Northern California Kaiser Permanente Medical Care Program (KPNC) from July 2009 to December 2010 (n = 12,016). Laboratory tests, treatment patterns, and hepatocellular carcinoma (HCC) surveillance were ascertained during a "recent" 18-month study window (July 2009-December 2010), or as "ever" based on records dating to 1995.The mean age was 49 years; 51 % were men, 83 % Asian, and 87 % KPNC members5 years. Overall, 51 % had ≥ 1 liver-related visit, 14 % with gastroenterology or infectious disease specialists, and 37 % with primary care providers (PCP) only. Less than 40 % of patients had both hepatitis B virus (HBV) DNA and ALT testing conducted recently, while 56 % of eligible patients had received HCC surveillance. Recent laboratory testing and HCC surveillance were more frequent in patients seen by a specialist versus PCP only (90 vs. 47 % and 92 vs. 73 %, respectively, p values0.001). During the study period, 1,649 (14 %) received HBV treatment, while 5 % of untreated patients had evidence of treatment eligibility. Among 599 patients newly initiated on HBV therapy, 76 % had guideline-based indications for treatment.Most patients initiated on HBV treatment met eligibility, and very few patients with evidence of needing treatment were left untreated. However, monitoring of ALT and HBV DNA levels, as well as HCC surveillance, were not frequent, underestimating the proportion of patients that warranted HBV therapy. Viral monitoring and cancer surveillance are therefore important targets for improving the scope of CHB care in the community setting.

Hepatitis C virus (HCV) antiviral therapy entails a long treatment course, as well as significant side effects that can lead to medication non-adherence and premature termination of treatment. Few large studies have comprehensively examined patient perspectives on the treatment experience, particularly the social and personal effects. We sought to understand how a diverse group of patients’ lives were affected during HCV treatment, and to obtain suggestions about how to better support patients during treatment. On average, 13 months after therapy we interviewed by telephone a consecutive sample of 200 patients treated for hepatitis C with ribavirin and pegylated interferon in a comprehensive, integrated health plan in the years 2008–2010. Mixed (quantitative and qualitative) survey methods were used. The response rate was 68.9 %. Mean age at treatment was 51 years; 63.0 % were men; and Black, Hispanic, Asian, and White non-Hispanic racial/ethnic groups were similarly represented. Patients whose treatment was managed by nurses or clinical pharmacists (vs. physicians) were more likely to report their providers as being part of their support system (83.5 % vs. 58.9 %; p

Hepatitis C virus (HCV) genotypes influence response to therapy, and recently approved direct-acting antivirals are genotype-specific. Genotype distribution information can help to guide antiviral development and elucidate infection patterns. HCV genotype distributions were studied in a diverse cross-section of patients in the Northern California Kaiser Permanente health plan. Associations between genotype and race/ethnicity, age, and sex were assessed with multivariate logistic regression models. The 10,256 patients studied were median age 56 years, 62% male, 55% White non-Hispanic. Overall, 70% were genotype 1, 16% genotype 2, 12% genotype 3, 1% genotype 4

Obesity appears to be a risk factor for hepatic steatosis, which has been implicated in the development of hepatic fibrosis in patients with hepatitis C virus infection. We conducted the current study to examine whether obesity is associated with hepatic steatosis among patients with chronic hepatitis C identified from a population-based cohort. Study participants were persons with chronic hepatitis C who had had a liver biopsy, identified from a population-based study of persons with newly identified chronic liver disease conducted in gastroenterology practices. Data were collected through patient interviews, medical record abstraction, and review of previously performed liver biopsies. The outcome variable of interest was significant steatosis, defined as steatosis grade > or =2 determined from liver biopsy samples. Univariate and multivariate analyses were performed using logistic regression techniques. The analysis included 450 patients with chronic hepatitis C with available liver biopsy slides. Overall, only 15.8% of subjects had significant hepatic steatosis (grade > or =2), while 35.9% of obese subjects had significant steatosis. In multivariate analysis, significant fibrosis (defined as > or = grade 2) (odds ratio [OR], 3.43; 95% confidence interval [CI], 1.59-7.37), obesity (OR, 3.32; 95% CI, 1.84-5.98), genotype 3 (OR, 2.5; 95% CI, 1.09-5.75), and the presence of multiple metabolic comorbidities (OR, 1.91; 95% CI, 0.88-4.11) were independently associated with steatosis. In this unique United States cohort of patients with newly diagnosed chronic liver disease due to hepatitis C, obesity was independently associated with hepatic steatosis. The results of this study provide additional evidence that obesity worsens liver damage in patients with chronic hepatitis C, and suggest a role for weight loss as a treatment modality in these patients.

Chronic liver disease (CLD) is an important cause of morbidity and mortality, but the epidemiology is not well described. We conducted prospective population-based surveillance to estimate newly diagnosed CLD incidence, characterize etiology distribution, and determine disease stage.We identified cases of CLD newly diagnosed during 1999-2001 among adult county residents seen in any gastroenterology practice in New Haven County, Connecticut; Multnomah County, Oregon; and Northern California Kaiser Permanente Medical Care Program (KPMCP, Oakland, California [total population 1.48 million]). We defined CLD as abnormal liver tests of at least 6 months' duration or pathologic, clinical, or radiologic evidence of CLD. Consenting patients were interviewed, a blood specimen obtained, and the medical record reviewed.We identified 2,353 patients with newly diagnosed CLD (63.9 cases/100,000 population), including 1,225 hepatitis C patients (33.2 cases/100,000). Men aged 45-54 yr had the highest hepatitis C incidence rate (111.3/100,000). Among 1,040 enrolled patients, the median age was 48 yr (range 19-86 yr). Hepatitis C, either alone (442 [42%]) or in combination with alcohol-related liver disease (ALD) (228 [22%]), accounted for two-thirds of the cases. Other etiologies included nonalcoholic fatty liver disease (NAFLD, 95 [9%]), ALD (82 [8%]), and hepatitis B (36 [3%]). Other identified etiologies each accounted for3% of the cases. A total of 184 patients (18%) presented with cirrhosis, including 44% of patients with ALD.Extrapolating from this population-based surveillance network to the adult U.S. population, approximately 150,000 patients with CLD were diagnosed in gastroenterology practices each year during 1999-2001. Most patients had hepatitis C; heavy alcohol consumption among these patients was common. Almost 20% of patients, an estimated 30,000 per year, had cirrhosis at presentation. These results provide population-level baseline data to evaluate trends in identification of patients with CLD in gastroenterology practices.

Although hepatitis C virus (HCV) infection has been shown to be associated with development of non-Hodgkin's lymphoma (NHL), few studies have investigated the association between chronic HBV infection and NHL. The purpose of this study was to compare the incidence of NHL between patients with and without chronic hepatitis B virus (HBV) infection. Using automated laboratory result and clinical data from two United States health systems, we identified individuals with chronic HBV infection from January 1, 1995 through December 31, 2001. Using each health system's population-based tumor registry, we identified all cases of NHL diagnosed through December 31, 2002. We excluded any individual with a history of NHL or human immunodeficiency virus (HIV). We fit Cox proportional hazards models to calculate hazard ratios comparing the incidence of NHL between chronic HBV-infected patients (N = 3,888) and patients without HBV (N = 205,203) drawn from the source populations. We identified 8 NHL cases in the chronic HBV infection cohort and 111 cases in the comparison cohort. Patients with chronic HBV infection were 2.8 times more likely to develop NHL than matched comparison patients (adjusted hazard ratio = 2.80, 95% confidence interval = 1.16-6.75), after controlling for age, race, sex, income, Charlson comorbidity index, study site, and HCV infection. Conclusion: chronic HBV-infected patients were nearly 3 times more likely to develop NHL than comparison patients. (HEPATOLOGY 2007.)

Objective High-risk HPV (hrHPV) and cytology co-testing is utilized for primary cervical cancer screening and for enhanced follow-up of women who are hrHPV-positive, cytology negative. However, data are lacking on the utility of this method to detect pre-cancer or cancer in community-based clinical practice. This study describes cytology and hrHPV results preceding high-grade cervical intraepithelial neoplasia, adenocarcinoma in situ, or cervical cancer (i.e., CIN2+) in an integrated health system employing routine co-testing among women aged 30 years and older. Methods We conducted a cross-sectional analysis of adult female members of Kaiser Permanente Northern California (KPNC) with incident CIN2+ between July 2008 and June 2009. The primary outcome was the proportions of cytologic diagnoses and hrHPV co-test results preceding a diagnosis of CIN2+. Cervical cytology and hrHPV testing results were abstracted from electronic medical records. Results Of 1283 CIN2+ cases among adult women, 880 (68.5%) were among women aged 30 years and older and 145/880 (16.5%, 95% CI 14.1–19.1) had only normal cytology during the 12 months prior to diagnosis. Furthermore, 133/880 (15.1%, 95% 12.9–17.7) were preceded by only normal cytology and persistent hrHPV infection (at least 2 positive hrHPV tests) during the 6–36 months preceding CIN2+ diagnosis. Conclusions Incident CIN2+ is frequently preceded by normal cytology and persistent hrHPV infection among women aged 30 years and older; screening strategies that employ HPV testing and cytology may improve the detection of CIN2+ compared with cytology alone.

BackgroundIn 2011, the FDA approved telaprevir (TVR) and boceprevir (BOC) for use with pegylated interferon and ribavirin to treat hepatitis C virus (HCV) genotype 1. We aimed to evaluate the real-world application, tolerability, and effectiveness of TVR- and BOC-based HCV treatment in a large integrated care setting.MethodsWe utilized Northern California Kaiser Permanente Medical Care Program (KPNC) electronic databases and medical records to study the experience of all KPNC patients who initiated TVR or BOC from June 2011 to March 2012.ResultsCompared with the pool of 5,194 treatment-eligible patients, the 352 treatment initiators were more likely to be cirrhotic (24 vs. 10%, p < 0.001) and treatment-experienced (44 vs. 22%, p < 0.001). Among the treatment initiators, 211 received TVR and 141 BOC. Overall, 31% discontinued treatment prematurely; 16% of patients stopped treatment early because of side effects. One patient with cirrhosis died of sepsis during treatment. Premature discontinuation was highest among TVR-treated cirrhotic patients (58%). Sustained virologic response (SVR) was achieved in 55% overall and was similar comparing the TVR (56%)- and BOC (53%)-treated groups. The only independent predictors of treatment failure were cirrhosis at baseline [odds ratio (OR) for SVR 0.44, p = 0.004] and prior partial or null response (OR for SVR 0.57, p = 0.02).ConclusionsIn the initial application of TVR and BOC, patients with cirrhosis and prior treatment failure were prioritized for treatment. In this real-world experience, most patients successfully completed a full treatment course. However, side effect-related premature discontinuations were common, and SVR rates were lower than reported in clinical trials.

Background: Opportunities to prevent late-stage breast cancer within the course of usual care are needed. We evaluate whether clinical encounters offer such opportunities. Methods: Within seven health care plans, we identifi ed 1298 women aged more than 50 years with early (

When using patient self-report of processes of care as part of measuring quality performance, validity and reliability are important considerations. In this study, the congruence of patient report of recommendations of screening follow-up care was compared with record audit data. Survey data were collected from a random sample of patients with abnormal breast (n = 230) or cervical (n = 219) cancer screening tests from four health centers. With patient consent, record audits were conducted to validate self-report. Measures of congruence for recommendations for follow-up were calculated along with sensitivity and specificity for procedure-specific recommendations. Overall congruence was higher in the mammography sample (81%) as compared to the Pap sample (61%). Predictors of overall congruence for the abnormal Pap test sample included health plan, self-reported health status, and test result. There were no significant predictors of congruence for the abnormal mammogram test sample from the potential variables collected. Raw agreement rates support using patient self-report in assessing abnormal test follow-up recommendations.

Background Invasive cervical cancer is highly preventable, yet it continues to occur, even among women who have access to cancer screening and treatment services. To reduce cervical cancer among such women, reasons for its occurrence must be better understood. We examined factors associated with the diagnosis of cervical cancer among women enrolled in health plans. Methods We identified all cases of invasive cervical cancer (n = 833) diagnosed from January 1, 1995, through December 31, 2000, among women who were long-term members of seven prepaid comprehensive health plans and reviewed each woman's medical records for the 3 years prior to her cancer diagnosis. Women were classified into one of three categories based on Pap test histories 4-36 months before diagnosis: failure to screen with a Pap test, failure in detection by a Pap test, or failure in follow-up of an abnormal test result. Results The majority of cases (n = 464; 56%) were in women who had no Pap tests during the period 4-36 months prior to diagnosis. Of the remaining cases, 263 (32%) were attributed to Pap test detection failure and 106 (13%) to follow-up failure. Being older (odds ratio [OR] = 6.48, 95% confidence interval [CI] = 3.89 to 10.79) or living in an area of higher poverty (OR = 1.72, 95% CI = 1.11 to 2.67) or having a lower education level (OR= 1.52; 95% CI = 1.07 to 2.16) was associated with the likelihood of being assigned to the failure to screen category versus either of the other two categories. A total of 375 (81%) of the 464 patients who had not had Pap screening had had at least one outpatient visit 4-36 months prior to cancer diagnosis. The cancer diagnostic process was triggered by a routine screening examination in 44% of patients, whereas 53% of the patients presented with symptoms consistent with cervical cancer; the remaining 3% were identified fortuitously during the course of receiving noncervical care. Conclusions To reduce the incidence of invasive cervical cancer among women with access to screening and treatment, Pap screening adherence should be increased. In addition, strategies to improve the accuracy of Pap screening could afford earlier detection of cervical cancer.

Five panelists independently reviewed 135 consecutive conventional cervical smears (CPs) originally classified as atypical glandular cells of undetermined significance (AGUS). A thin-layer slide (TP), prepared from the residual material, also was reviewed in each case. All patients underwent colposcopy that yielded at least 1 histologic specimen. Three or more of 5 reviewers retained the AGUS interpretation for 29% of CPs and 12% of the corresponding TPs. Interobserver variability infrequency of use of AGUS was marked, and interobserver agreement was poor. Agreement was improved for cases cytologically interpreted as a high-grade lesion, especially in TPs. Four of 5 reviewers retained the AGUS classification in CPs for all 7 biopsy-proven neoplastic glandular lesions. Of 95 CP interpretations made by 5 reviewers in the 19 histologically diagnosed high-grade lesions, 8 were "negative/reactive" and 6 were AGUS "favor reactive." AGUS is a poorly reproducible cytologic interpretation. Although most neoplastic glandular lesions may be distinguished by cytopathologists experienced in this area from mimics originally considered AGUS, attempts to increase the diagnostic specificity of AGUS may diminish sensitivity for an underlying high-grade precursor. Interobserver agreement was better for TPs than for the corresponding CPs. However, the split-sample TP slides may not have been fully comparable to the CPs.

Background. Interferon α (IFN-α) and ribavirin can induce a sustained virologic response (SVR) in some but not all hepatitis C virus (HCV)-infected patients. The mechanism of effective treatment is unclear. One possibility is that IFN-α differentially improves the functional capacity of classic myeloid dendritic cells (mDCs) by altering expression of surface molecules or cytokines. Others have proposed that antigen-presenting cell activation could be paradoxically detrimental during HCV infection because of the production by monocytes of substances inhibitory or toxic to plasmacytoid dendritic cells. Methods. We examined responses to in vitro IFN-α treatment of peripheral blood leukocyte samples from a retrospective treatment cohort of nearly 200 HCV-seropositive patients who had undergone antiviral therapy with ribavirin and pegylated IFN.We analyzed the variable responses of antigen-presenting cell subsets to drug. Results. We found that patients achieving SVR were no more likely to have robust mDC activation in response to IFN-α than those who did not achieve SVR. Rather, patients achieving SVR were distinguished by restrained monocyte activation in the presence of IFN-α, a factor that was second in importance only to IL28B genotype in its association with SVR. Conclusions. These results suggest that interindividual variability in the response of monocytes to IFN-α is an important determinant of treatment success with IFN-α-based regimens. © 2013 The Author.

Summary Background Risks and benefits of protease inhibitor (PI) (telaprevir or boceprevir) triple therapy in hepatitis C virus (HCV)-infected patients with mildly decompensated cirrhosis, including those wait-listed for liver transplantation (LT), are incompletely known. Aim To assess virological responses and safety of PI triple therapy in patients with mildly decompensated Child-Pugh (CP) CP ≥6 vs. compensated (CP = 5) cirrhosis. Methods Multicentre cohort of 160 adults with cirrhosis treated with peginterferon/ribavirin (peg-IFN/RBV) plus telaprevir (69%) or boceprevir (31%), comparing outcomes between those with CP = 5 and CP ≥6. Results Patients, 47% with CP ≥6 cirrhosis (CP range 6–10), received PI triple therapy for a targeted duration of 48 weeks. The cohort was median age 59 years, 32% female, 59% genotype 1a, 35% previous null/partial responders. Sustained virological response at 12 weeks (SVR12) was achieved by 35% of patients with CP ≥6 vs. 54% of those with CP = 5 (P = 0.02). CP = 5, achievement of rapid virological response and genotype 1b/other, independently predicted SVR12. Compared to those with CP = 5, patients with CP ≥6 had more peg-IFN dose reductions, eltrombopag use, transfusions and hospitalisations to manage adverse events (all P

Objectives. We compared chronic liver disease (CLD) mortality from 1999 to 2009 between American Indians and Alaska Natives (AI/ANs) and Whites in the United States after improving CLD case ascertainment and AI/AN race classification. Methods. We defined CLD deaths and causes by comprehensive death certificate-based diagnostic codes. To improve race classification, we linked US mortality data to Indian Health Service enrollment records, and we restricted analyses to Contract Health Service Delivery Areas and to non-Hispanic populations. We calculated CLD death rates (per 100 000) in 6 geographic regions. We then described trends using linear modeling. Results. CLD mortality increased from 1999 to 2009 in AI/AN persons and Whites. Overall, the CLD death rate ratio (RR) of AI/AN individuals to Whites was 3.7 and varied by region. The RR was higher in women (4.7), those aged 25 to 44 years (7.4), persons residing in the Northern Plains (6.4), and persons dying of cirrhosis (4.0) versus hepatocellular carcinoma (2.5), particularly those aged 25 to 44 years (7.7). Conclusions. AI/AN persons had greater CLD mortality, particularly from premature cirrhosis, than Whites, with variable mortality by region. Comprehensive prevention and care strategies are urgently needed to stem the CLD epidemic among AI/AN individuals.

Human papillomavirus (HPV)-16 causes about half the cases of cervical cancer worldwide and is the focus of HPV vaccine development efforts. Systematic data are lacking as to whether the prevention of HPV-16 could affect the equilibrium of infection with other HPV types and thus alter the predicted impact of vaccination on the occurrence of cervical neoplasia. Therefore, the associations of HPV-16 detection with subsequent acquisition of other HPV types and with the persistence of concomitantly detected HPV types were examined prospectively among 1124 initially cytologically normal women. Preexisting HPV-16 was generally associated with an increased risk for subsequent acquisition of other types. HPV-16 did not affect the persistence of concomitant infections, regardless of type. These findings suggest that the prevention or removal of HPV-16 is not likely to promote the risk of infection with other types, a theoretical concern with current vaccination efforts.

%Objective: To characterize the relative contributions of the different abnormal Papanicolaou smear cytologic diagnoses in the Bethesda System to the subsequent histologic diagnosis of high-grade cervical neoplasia. Methods: A total of 46,009 nonpregnant female members of the Kaiser Permanente Health Plan, Northern California Region, were studied prospectively. The main outcome measures included routine Papanicolaou smear diagnoses and subsequent histologic diagnosis of colposcopically directed cervical tissue specimens. Results: Atypical squamous cells of undetermined significance (ASCUS) was the most common abnormal Papanicolaou diagnosis, representing 3.6% of the total number of smears. Of the total number of cases of histologically confirmed high-grade cervical neoplasia present in the population, the largest proportion (38.8%) was in women with smears showing ASCUS. Minimal abnormalities combined (ASCUS, atypical glandular cells of undetermined significance, and low-grade squamous intraepithelial lesion) were coincident with 68.6% of the cases of histologic high-grade cervical neoplasia diagnosed in this routine screening population. Conclusion: Recognition of the importance of equivocal and mild Papanicolaou test abnormalities in the subsequent diagnosis of high-grade cervical neoplasia emphasizes the need for accurate and cost-effective triage of the large population of women with minimally abnormal Papanicolaou diagnoses.

Several earlier case-control studies reported inverse associations of cervical squamous intraepithelial lesions (SIL) with high dietary or biomarker levels of carotenoids, folate, and vitamins C and E. However, most studies did not measure the primary causal factor, cancer-associated genital human papillomaviruses (HPV), now detected by sensitive viral DNA tests. This nested case-control study assessed whether high dietary intakes of these nutrients, plus zinc and vitamin A, reduced SIL risk in cancer-associated HPV DNA-positive women. Using a 60-item food-frequency questionnaire, nutrient estimates were obtained for 33 incident cases with high-grade lesions, 121 with low-grade lesions, 97 with equivocal SIL, and 806 cytologically normal controls sampled from a large prospective cohort study. Baseline cervicovaginal lavages were tested for HPV DNA by the polymerase chain reaction. Among DNA-positive cases (n = 68) and controls (n = 69), age-adjusted odds ratios (ORs) of SIL in the highest vs. the lowest nutrient quartiles were 1.4 [95% confidence interval (CI) = 0.5-4.2] for vitamin A, 0.6 (CI = 0.2-2.0) for beta-carotene, 1.3 (CI = 0.4-3.6) for vitamin C, 1.0 (CI = 0.4-3.6) for vitamin E, 0.7 (CI = 0.3-2.1) for folate, and 0.8 (CI = 0.3-2.2) for zinc. ORs in HPV DNA-negative women approximated 1.0, with the exception of vitamin E (OR = 0.5, CI = 0.3-0.9). These results do not support a protective role for the above nutrients against low-grade or equivocal SIL, which constituted the majority of diagnoses in this study.

The strong association of human papillomavirus (HPV) and cervical cancer makes it important to study HPV detection methods that may play a role in cervical cancer screening. We compared two DNA methods that are commonly used for HPV research in the United States: the MY09/MY11 L1 consensus primer PCR-based test and the first-generation Hybrid Capture tube method (HCT). Laboratory assays by each method were performed with 596 cervicovaginal specimens collected from participants in a large cohort study conducted in Portland, Oreg. Included were 499 specimens from women whose cytology was normal and 97 specimens from women with squamous intraepithelial lesions (SILs). The overall HPV DNA positivity for known types was 22.5% by PCR compared to 13.6% by HCT. When the analysis was restricted to the 14 HPV types detectable by both methods, the sensitivity of HCT, with PCR used as the standard for HPV status, was higher for specimens from women with concurrent SILs (81.0%) than for specimens from women with normal cytology (46.7%). Among specimens testing positive by both methods, 97.2% of the time the two methods agreed on whether specimens were positive for cancer-associated HPV types. Both of these HPV test methods provide information that supplements the information provided by the Pap smear. The PCR method has higher analytic sensitivity than HCT in detecting HPV, but HCT may be helpful in identifying women with concurrent SILs.

The epidemiologic determinants of seroreactivity to human papillomavirus (HPV) type 16 L1/L2 virus-like particles (VLPs) were assessed separately in HPV-16 DNA-positive and -negative women participating in a nested case-control study of incident cervical neoplasia. Seventy-four women with cervical HPV-16 DNA and 656 cytologically normal HPV-16 DNA-negative subjects were interviewed and tested at two time points for viral DNA and once (at the later time) for VLP seroreactivity. Among subjects who were currently HPV-16 DNA-negative, seroreactivity odds ratios increased from 2.9 for 2-5 male sex partners (vs. 0 or 1) to 5.4 for 6-9 partners and 14.0 for > or = 10. Thus, prior cervical infection may be a major determinant of seroreactivity in HPV-16 DNA-negative women. This trend was not observed in HPV-16 DNA-positive subjects. Seroreactivity was independently associated with oral contraceptive use, particularly in HPV-16 DNA-negative subjects with use for > or = 10 years. Consequently, a possible role for virus-steroid hormone interactions in seroconversion is suggested.

An ELISA to detect serum IgG antibody response to human papillomavirus (HPV) type 16 virus-like particles (VLPs) was evaluated in a case-control study of cervical neoplasia, nested within a prospective cohort study. Subjects included 688 controls with continued normal cytology and 152 cases with confirmed incident squamous intraepithelial lesions who were tested for DNA of a broad spectrum of HPV types at cohort enrollment and follow-up. Of controls, 16.6% were seropositive compared with 30.8% and 52.4% of cases with low- and high-grade lesions, respectively. Of HPV-16 DNA-negative subjects, 16.5% were seropositive. Seropositivity increased from 22.2% in subjects who were HPV-16 DNA-positive by polymerase chain reaction once only (enrollment or follow-up) to 83.3% in those who were HPV-16 DNA-positive at both time points. These data imply that serum antibody to HPV-16 VLPs is a relatively sensitive indicator of persisting cervical HPV-16 infection.

As part of a large-scale, community-based cervical neoplastic screening project in rural Taiwan, a case-control study was undertaken to evaluate the etiologic role of human papillomavirus (HPV) infection in this mainly monogamous (2% reported having multiple sexual partners) female population. A total of 88 biopsy-confirmed cases and 261 cytologically normal controls were selected for the study. The case group included 40 cases of cervical intraepithelial neoplasia (CIN) 1, 9 of CIN 2, 36 of CIN 3 and 3 cases of invasive cancer. Cervical swabs collected at screening from study subjects were tested for HPV DNA by an LI consensus primer polymerase chain reaction (PCR)-based technique. HPV DNA was found in 92% of high-grade cases (CIN 2-3 and invasive cancer); 54% of low-grade cases (CIN I); and 9% of controls. HPV was significantly associated with both high-grade and low-grade cervical neoplasia. As reported in Western countries, HPV 16 was the predominant type among HPV-positive high-grade cases. However, HPVs 52 and/or 58 combined were the most common types among HPV-positive low-grade cases and controls. Among women without any high-risk HPV infection (types 16, 18, 31 or 45), those with multiple-type HPV infection had a higher risk for high-grade cervical neoplasia than those with single-type infection. Overall, 91% of high-grade cases and 50% of low-grade cases could be attributed to HPV infection. Our results show that, even in this monogamous population, HPV is the major risk factor for high-grade cervical neoplasia. © 1995 Wiley-Liss, Inc.

Epidemiologists and clinicians wishing to introduce human papillomavirus (HPV) testing into cervical cancer prevention programs need standardized, reliable, and accurate HPV DNA tests that can detect the full spectrum of pathogenic HPV types. The Hybrid Capture System assay from Digene (hybrid capture assay) is a nonradioactive kit designed to detect 14 HPV types in two groups: a mix of 9 high-risk types associated with anogenital cancer (HPV types 16, 18, 31, 33, 35, 45, 51, 52, and 56) and another group of 5 low-risk types associated with condyloma acuminatum (HPV types 6, 11, 42, 43, and 44). The assay yields quantitative data meant to reflect viral concentration. In a study of 199 cervical specimens from women with concurrent Pap smears, we assessed the reliability of the new assay by comparing the hybrid capture assay results from three laboratories. We assessed the accuracy of the hybrid capture assay in comparison with a reference standard of HPV DNA content (multiple testing by several methods in two reference laboratories). We also compared the hybrid capture assay results with the concurrent cytologic diagnoses on the basis of an independent review of each smear by five pathologists. Pairwise interlaboratory agreement rates on HPV positivity for either high-risk or low-risk types ranged from 87 to 94%, and kappa values ranged from 0.61 to 0.83. Among specimens positive for high-risk types (the most important clinical outcome), the interlaboratory correlations of the quantitative data ranged from 0.60 to 0.90. Test results from all three laboratories were strongly associated with those of the HPV DNA reference standard and with the concurrent cytopathologic diagnoses. The most common errors were sporadic, apparently false-positive results.

The identification and taxonomy of papillomaviruses has become increasingly complex, as approximately 70 human papillomavirus (HPV) types have been described and novel HPV genomes continue to be identified. Methods and corresponding DNA sequence data bases were designed for the reliable identification of mucosal HPV genomes from clinical specimens. HPVs are identified by the amplification of a fragment of the L1 region by consensus primer polymerase chain reaction (PCR) and subsequent hybridization or restriction fragment length polymorphism analysis. L1 PCR fragments may be further characterized by nucleotide sequencing. Conservation of 30 (of 151) predicted amino acids identifies HPV genomic fragments, and nucleotide sequence alignments allow calculation of their phylogenetic relatedness. Sequence differences > 10% from any known HPV type suggest a novel HPV type. Phylogenetic relationships with known HPV types may permit predictions of biology. With these criteria, 10 PCR fragments were identified that would qualify as new genital HPV types after complete genomic isolation.

Polymerase chain reaction (PCR)-based genital human papillomavirus (HPV) detection methods that use consensus primers have enabled the broad-spectrum detection of most characterized HPV types. In addition, these techniques have allowed the identification of potentially novel viral sequences in clinical specimens. These methods were used to determine the partial L1 nucleotide sequence (the region generated by L1 consensus primers MY09 and MY11) of four novel viruses. The prevalence of these viruses in cytologically normal and dysplastic cervical specimens and in invasive cervical cancer was also determined. The partial DNA sequences of W13B (MM4), PAP291 (MM7), PAP155 (MM8), and PAP238a (MM9) are most similar to HPV-51, -61, -61, and -34, respectively. Prevalence studies suggest that W13B and PAP238a are cancer-associated, while PAP155 and PAP291 appear to be lower-risk viruses.

Using The Bethesda System, five pathologists independently diagnosed 200 smears that originally had been classified as “atypical,” and the results were correlated with concurrent detection of human papillomavirus (HPV) DNA by Southern analysis and by polymerase chain reaction amplification. The smears were reclassified as benign reactive changes (negative), atypical squamous cells of undetermined significance, or squamous intraepithelial lesion (S1L). Exact five-way cytologic agreement was achieved in only 29% of smears, and no slide was diagnosed as atypical squamous cells of undetermined significance by all reviewers. The detection of high-risk types of HPV correlated strongly with the likelihood of a diagnosis of squamous intraepithelial lesion. High-risk HPV types were detected in approximately 60% of smears reclassified as squamous intraepithelial lesion compared with 30% of those reclasssified as atypical squamous cells of undetermined significance and 10% of negative smears ( P < .001). Every smear unanimously diagnosed by the panel as squamous intraepithelial lesion was associated with detectable HPV DNA, mainly of high-risk types. Low-risk HPV DNA types were found with similar frequency in all diagnostic categories assigned by the reviewers. Based on the consistent relation between high-risk HPV detection and diagnoses according to the Bethesda System, the authors conclude that HPV testing may have an important role in quality assurance in cervical cytopathology.

The seroepidemiology of genital human papillomavirus (HPV) and incident cervical squamous intraepithelial lesions (SIL) was studied in subjects selected from a large cohort monitored for the development of SIL. Serum IgG and IgA responses to 10 epitopes derived from HPV were measured in 21 incident cases of SIL and 56 matched controls. Cases showed elevated antibody (i.e., IgG and/or IgA) seroprevalence to 245:16, a peptide antigen derived from the E2 open reading frame of HPV 16 (OR = 5.76; 95% CI: 1.24, 26.81). The type of HPV DNA detected in cervical lavage specimens had no effect on this relationship. Multivariate analysis also showed that IgG to 245:6, an analogous peptide derived from HPV 6, was negatively associated with SIL (OR = 0.12; 95% CI: 0.02, 0.77). No other antibody responses tested were associated with SIL. Furthermore, no antibody responses were positively associated with detection of HPV DNA in women without SIL. We conclude that incident SIL is positively associated with antibody to an epitope derived from the E2 region of HPV 16, and negatively associated with antibody to an analogous peptide derived from HPV 6. The seroepidemiology of incident SIL appears different from that of cervical HPV infection in the absence of SIL.

Objectives To confirm the risk factors for genital human papillomavirus (HPV) infection. Goal of this study To investigate risk factors for HPV detection independent of the correlated risk factors for cervical neoplasia, in a high-risk population. Study design We investigated 404 cytologically normal women attending medical assistance clinics in the Washington, D.C. area. Risk factor information was obtained and a cervicovaginal lavage was collected and used for HPV detection and typing by a PCR-based technique. Results The point prevalence of HPV was 33.7%. This contrasts with the 17.7% and 44.3% observed in the companion reports published in this issue of the journal. HPV prevalence decreased with age and increased with greater numbers of sexual partners. Moreover, more recent sexual behavior was a better predictor of current HPV detection than lifetime number of sexual partners. Numbers of pregnancies and current pregnancy were positively associated with HPV prevalence and there was an indication that current oral contraceptive users had a higher prevalence of HPV compared to never users. Smoking was not associated with increased HPV prevalence. Conclusion Findings support the sexual route of transmission of HPV and confirm the association of HPV detection with age, suggesting the host's ability to clear infection or the virus' ability to become latent.

OBJECTIVES To confirm the risk factors for genital human papillomavirus (HPV) infection. GOAL OF THIS STUDY To investigate risk factors for HPV detection independent of the correlated risk factors for cervical neoplasia in a low-risk population. STUDY DESIGN HPV DNA was assessed among 483 cytologically normal women with no known history of cervical neoplasia. A cervicovaginal lavage was collected for HPV detection and typing using a PCR-based DNA amplification system. Information on risk factors of subjects was obtained through a questionnaire. RESULTS HPV DNA was found in 17.7% of study women. On univariate analysis, factors associated with increasing HPV prevalence included younger age, fewer years of education, lower income, higher lifetime number of sex partners, lower age at first intercourse, nulliparity, oral contraceptive use, and current smoking. After statistical adjustment, we found younger age and higher number of sex partners were strongly and independently associated with higher HPV prevalence. We also observed increased HPV prevalence among women with lower levels of education and lower incomes. CONCLUSION These findings and corroborative data from the companion reports in this issue of the journal support the sexual route of transmission of the virus.

Objectives To confirm the risk factors for genital human papillomavirus (HPV) infection. Goal of this study To investigate risk factors for HPV detection apart from the correlated risk factors for cervical neoplasia. Study design Cervical human papillomavirus (HPV) DNA was assessed in 357 cytologically normal women attending the University of New Mexico student health center. Cervical swab samples were obtained for HPV DNA detection and typing using a PCR-based DNA amplification system. Possible determinants of cervical HPV were examined including age, ethnicity, history of sexually transmitted disease, oral contraceptive use, smoking, age at first intercourse, lifetime number of sex partners, marital status, and history of pregnancy. Results A 44.3% overall prevalence of cervical HPV was observed. On univariate analysis, factors associated with increasing HPV prevalence included higher lifetime number of sex partners and single marital status. After adjustment for potential confounding variables, we found that HPV prevalence increased with higher lifetime number of sexual partners. Conclusion These findings, along with those from the companion reports in this issue of the journal, support the sexual route of transmission of the virus.

Given improvements in human papillomavirus (HPV) testing that have revealed a strong link between sexual activity history and cervical HPV infection the authors conducted a large case-control study of HPV and cervical intraepithelial neoplasia (CIN) to evaluate whether sexual behavior and the other established risk factors for CIN influence risk primarily via HPV infection. The authors studied 500 women with CIN and 500 control subjects receiving cytologic screening at Kaiser Permanente a large prepaid health plan in Portland Oregon. The established epidemiologic risk factors for CIN were assessed by telephone interview. The authors performed HPV testing of cervicovaginal lavage specimens by gene amplification using polymerase chain reaction with a consensus primer to target the L1 gene region of HPV. Unconditional logistic regression analysis was used to estimate relative risk of CIN and to adjust the epidemiologic associations for HPV test results to demonstrate whether the associations were mediated by HPV. The case subjects demonstrated the typical epidemiologic profile of CIN: they had more sex partners more cigarette smoking earlier ages at first sexual intercourse and lower socioeconomic status. Statistical adjustment for HPV infection substantially reduced the size of each of these case-control differences. 76% of cases could be attributed to HPV infection; the results of cytologic review suggested that the true percentage was even higher. Once HPV infection was taken into account an association of parity with risk of CIN was observed in both HPV-negative and HPV-positive women. The data show that the great majority of all grades of CIN can be attributed to HPV infection particularly with the cancer-associated types of HPV. In light of this conclusion the investigation of the natural history of HPV has preventive as well as etiologic importance. (authors)

Background. The occurrence of multiple Bowen's disease (bd) in skin away from the anogenital area is rare. In contrast, multiple lesions of bd involving the anogenital skin (bowenoid papulosis) are not so rare and have been found to associated with human papilloma virus (hpv) usually type 16. We encountered a patient with multiple BD of the fingers and endeavored to detect hpv in his lesions. Methods. Separate bd lesions from 3 fingers of the patient were investigated for the presence of hpv by means of the polymerase chain reaction, followed by dot blot hybridization. Other cases of bd with coexistent HPV infection excluding the anogenital area were collected from the literature for comparative study. Resultshpv type 16 was detected in each of the three finger lesions of bd. Twenty cases of hpv related bd involving sites other than the anogenital area were found in the literature. Three of these cases had multiple lesions. Conclusions. Review of the 4 cases with multiple hpv related nonanogenital bd and the 17 others with solitary lesions reveals predilection for the hands and feet (90%) and affinity for type 16 infection (81%). The lesions usually present as verrucous plaques.

To the Editor: Although congenital toxoplasmosis occurs throughout the United States, little information is available about the rates of diagnosed illness in most of the nation, including California. Infection usually occurs by ingestion of undercooked meat and unwashed fruits and vegetables or exposure to soil or water contaminated with cat feces. Congenital transmission can occur when a woman is infected with Toxoplasma gondii during, or just before, pregnancy. Approximately 91% of women of childbearing age in the United States are susceptible to T. gondii infection (1). The United States has a low prevalence of T. gondii infection compared with many areas of the world (2). Severe congenital toxoplasmosis can result in hydrocephalus, retinochoroiditis that affects vision, microcephalus, seizures, hepatosplenomegaly, icterus, psychomotor retardation, and other sequelae (3). Infants with congenital toxoplasmosis are most often asymptomatic at birth; however, when severe symptoms occur, they are usually recognized and the condition diagnosed by the time the child is 2 years of age (3). Our goal was to determine the rate of clinically identified cases of congenital toxoplasmosis in children from birth to 2 years of age within the Northern California Kaiser Permanente Medical Care Program (KPNC) during a 15-year period. KPNC is a group health plan that provides care for >3.2 million residents of northern California. The KPNC membership represents ≈30% of the insured population in the region and is demographically similar to the residents of the counties served except that the very poor and very wealthy are underrepresented (4). We studied live births and infants during 1998–2012, the most recent 15-year period for which records were available and considered complete. We identified potential cases from KPNC electronic medical record databases and confirmed them by reviewing electronic and paper records. The system documents outside services, identified by the corresponding diagnostic codes or laboratory test codes. Eligible case-patients were infants, defined as 1 of 23 specific KPNC laboratory codes for related serologic and PCR tests. We considered clinically confirmed case-patients to be infants with positive T. gondii IgM and/or IgA tests at 12 months of age, PCR–positive results for T. gondii, or diagnosis and care of toxoplasmosis-related conditions. To calculate 95% confidence intervals for rates, we used the exact binomial method. During the 15-year study period, there were 521,655 live births at KPNC facilities and 2,010 infants received >1 test for toxoplasmosis. Ten infants met the potential case criteria of diagnostic codes; no additional patients met any of the case criteria by age 2 years. After electronic and paper charts were reviewed, 2 cases of congenital toxoplasmosis were confirmed. One case was diagnosed in 2003, the other in 2011. Both case-patients were girls: 1 was of Hispanic ethnicity and the other was of mixed Filipino-White heritage; both had IgG persistently detected beyond 12 months of age and were monitored clinically for retinochoroiditis. Their charts contained no information regarding maternal exposure or risk factors. During the 15-year period, the rate of diagnosed congenital toxoplasmosis was 3.8 (95% CI 1.5–9.2) per million live births. There were no infant deaths for which congenital toxoplasmosis was recorded as a cause. We were unable to study fetal deaths because the corresponding cause-of-death codes were not readily available. Historically, the lowest prevalence of T. gondii infection has been recorded in the western United States (5). The rate of clinically apparent congenital toxoplasmosis in this study was lower than that found during the late 1980s through early 1990s in the New England Newborn Screening Program initially after birth (2 per 521,555 live births [3.8 per million] versus 5 per 635,000 live births [7.9 per million], respectively) (6). However, the prevalence of T. gondii infection has decreased in the United States since the 1990s (1). Our study is subject to several limitations. Our approach would only detect clinically apparent cases, and the results should be considered a minimal estimate of congenital infection. Some cases may not have been recorded in the electronic system, but this omission is not likely for severe illness, repeated hospital or clinic visits, or outside consultation. The small number of cases makes the rate of diagnosed congenital toxoplasmosis somewhat imprecise; a few missed cases would increase the rate considerably. In addition, we were not able to evaluate fetal deaths; however, stillbirth is reportedly a rare complication of congenital toxoplasmosis (7). Although we found a low rate of diagnosed congenital toxoplasmosis in northern California, population-based studies to evaluate rates of the disease in other geographic areas would be beneficial.

To examine a wide range of sociodemographic and clinical characteristics as potential predictors of complementary and alternative medicine (CAM) use among chronic liver disease (CLD) patients, with a focus on CAM therapies with the greatest potential for hepatotoxicity and interactions with conventional treatments.There is some evidence that patients with CLD commonly use CAM to address general and CLD-specific health concerns.Patients enrolled in a population-based surveillance study of persons newly diagnosed with CLD between 1999 and 2001 were asked about current use of CAM specifically for CLD. Sociodemographic and clinical information was obtained from interviews and medical records. Predictors of CAM use were examined using univariate and multivariate logistic regression analysis.Of the 1040 participants, 284 (27.3%) reported current use of at least 1 of 3 CAM therapies of interest. Vitamins or other dietary supplements were the most commonly used therapy, reported by 188 (18.1%) patients. This was followed by herbal medicine (175 patients, 16.8%) and homeopathy (16 patients, 1.5%). Several characteristics were found to be independent correlates of CAM use: higher education and family income, certain CLD etiologies (alcohol, hepatitis C, hepatitis C and alcohol, and hepatitis B), and prior hospitalization for CLD.Use of CAM therapies that have the potential to interact with conventional treatments for CLD was quite common among this population-based sample of patients with CLD. There is a need for patient and practitioner education and communication regarding CAM use in the context of CLD.

Carcinoma of the cervix has several well-established epidemiologic risk factors, including multiple sexual partners and early age at first intercourse. Human papillomavirus (HPV) infection appears to have an etiologic role in the development of cervical neoplasia, but evidence linking HPV infection to known risk factors for cervical cancer has been inconsistent. The lack of expected correlations may be due to the inaccuracy of HPV assays previously used. A polymerase chain reaction DNA amplification method for the detection of HPV was used to investigate the determinants of genital HPV infection in a cross-sectional sample of 467 women attending a university health service. In contrast to studies using less accurate detection methods, the risk factors for HPV infection found here were consistent with those for cervical neoplasia. The risk of HPV infection was strongly and independently associated with increasing numbers of sexual partners in a lifetime, use of oral contraceptives, younger age, and black race. Age at first intercourse, smoking, and history of a prior sexually transmitted disease were correlated with, but not independently predictive of, HPV infection. These results demonstrate that the key risk factors for cervical carcinoma are strongly associated with genital HPV infection. This correlation suggests that HPV has an etiologic role in cervical neoplasia and reaffirms the sexual route of HPV transmission.

Background: Little is known about the potential adverse hepatic effects of HMG-CoA reductase inhibitors (‘statins’) in patients with existing liver disease; therefore, we examined the risk of liver toxicity with lovastatin exposure in these patients. Methods: A retrospective cohort study was performed using data from a large integrated health plan in Northern California, USA. Patients with laboratory or clinical evidence of liver disease were identified and their exposure to lovastatin was determined. The primary outcome was a pattern of liver-test abnormalities associated with a poor prognosis among patients with drug-induced liver disease, based on Hy’s Rule. Secondary outcomes included liver injury (defined as moderate or severe, depending on the degree of ALT level elevations) or the development of either clinical cirrhosis or liver failure. Incidence rate ratios (IRRs) were calculated and multivariate analyses conducted using extended Cox models. Results: A total of 93 106 patients met the entry criteria. Lovastatin exposure was associated with a lower incidence of all endpoints, including the primary outcome (IRR = 0.28, 95% CI 0.12, 0.55), moderate liver injury (IRR = 0.56, 95% CI 0.47, 0.65), severe liver injury (IRR = 0.50, 95% CI 0.29, 0.81) and the occurrence of either cirrhosis or liver failure (IRR = 0.29, 95% CI 0.21, 0.38); adjustment for age and sex resulted in some attenuation of this reduction in incidence. The observed effects were generally consistent across a range of baseline liver-disease diagnoses and greater cumulative lovastatin exposure was associated with fewer outcome events for some endpoints. Conclusions: In this retrospective analysis, exposure to lovastatin was not associated with an increased risk of adverse hepatic outcomes. These results do not support concern regarding lovastatin-related hepatotoxicity in patients with existing liver disease.

Standard death certificate–based methods for ascertaining deaths due to chronic liver disease (CLD), such as the U.S. vital statistics approach, rely on a limited set of diagnostic codes to define CLD. These codes do not include viral hepatitis or consider hepatocellular carcinoma (HCC) deaths, and thus, underestimate the true burden of CLD mortality. Deaths associated with CLD may be further misunderstood because of the inherent limitations of death record information. Using a comprehensive list of CLD-related codes to search death records, we investigated the CLD mortality rate and associated etiologies (derived from medical records) in a large managed care health plan. From the 16,970 deaths among health plan members in 2000, we confirmed 355 (2.1%) as CLD related, including 75 with HCC. The age-adjusted CLD mortality rate using the comprehensive codes was 11.9 per 100,000 compared with 6.3 per 100,000 using only conventional codes. Based on medical records, the underlying CLD was attributed to alcoholic liver disease (ALD) in 44% of deaths, HCV infection with ALD in 16%, HCV without ALD in 18%, and chronic HBV infection in 7%. Only 64% of HCV-associated, 48% of HBV-associated, and 64% of ALD-associated deaths ascertained by medical record had that specific etiology mentioned on the death certificate. Conclusion: CLD mortality burden was almost doubled by using a comprehensive list of mortality codes and considering HCC deaths as CLD related. Furthermore, the contributions of viral hepatitis and ALD to CLD mortality may be underestimated if based solely on death records. (HEPATOLOGY 2008.)

• Clinical specimens from nine patients with papillomatosis of the vocal cords and three patients with vocal cord polyps were evaluated for the presence of human papillomavirus (HPV) DNA using two complementary molecular hybridization techniques. In one method, involving polymerase chain reaction (PCR) amplification, HPV DNA sequences were replicated in vitro from tissue DNA extracted from paraffin sections prior to hybridization. Polymerase chain reaction amplification was compared with the standard method of Southern blot hybridization. Results of the two techniques for all nine laryngeal papillomas agreed completely: five patients harbored HPV type 6 and four HPV type 11. Both PCR amplification and Southern blot hybridization found two of the three polyps to be free of HPV infection, while PCR detected HPV type 18 in one polyp specimen that was reported negative by Southern blot hybridization, suggesting a greater sensitivity of PCR. Our results demonstrate that PCR amplification is as reliable and at least as sensitive as Southern blot hybridization. Moreover the PCR technique opens the way to the undertaking of a whole variety of retrospective studies using formaldehyde-fixed paraffinembedded tissues. (Arch Otolaryngol Head Neck Surg. 1990;116:844-848)

The purpose of this study was to develop an algorithm for identifying patients with chronic hepatitis B virus (HBV) using automated data sources from two US health systems and evaluate the algorithm's performance by quantifying the incidence of hepatocellular carcinoma (HCC) among chronic HBV patients. To allow comparisons with estimates from automated databases that may not contain all data elements used in this algorithm, we created three definitions of chronic HBV infection and used these definitions to create three overlapping cohorts. We compared the incidence of HCC in each cohort with the incidence of HCC in a matched general population comparison cohort with no evidence of HBV. Patients who met the most stringent criteria for chronic HBV infection (based on the standard definition of 6 months of infection using repeat laboratory tests and record review) were 146 times more likely to develop HCC than matched comparison patients (adjusted hazard ratio = 146.5, 95% CI: 74.0-289.8). Those not meeting the stringent criteria, but who met the criterion of at least one positive hepatitis B surface antigen test were 30 times more likely to develop HCC than comparison patients (adjusted hazard ratio = 29.8, 95% CI: 16.5-53.6). Finally, patients who met the criterion based on at least one HBV diagnosis were 38 times more likely to develop HCC than matched comparison patients (adjusted hazard ratio = 37.8, 95% CI: 25.9-55.1). The magnitude of the relative increase in HCC risk seen using different criteria used to define HBV infection indicate that these automated data algorithms can identify patients with chronic HBV infection.

Objective To determine the incidence of abnormal laboratory test results among isotretinoin users. Design Retrospective cohort. Setting Comprehensive managed care health plan in Northern California. Participants The study population comprised 13 772 patients aged 13 to 50 years with acne, undergoing oral isotretinoin therapy between March 1995 and September 2002. Main Outcome Measures Laboratory values for serum triglyceride, total cholesterol, and liver transaminase levels; white blood cell count, hemoglobin level, and platelet count; and frequency of abnormal laboratory results by severity grade as defined by the National Cancer Institute Common Terminology Criteria for Adverse Events v3.0. Results Substantial increases in the cumulative incidence of abnormalities were seen in serum lipid and transaminase levels, but not in hematologic parameters, during isotretinoin treatment compared with the baseline period. The cumulative incidence of new abnormalities in patients with normal values at baseline was 44% for triglyceride level, 31% for total cholesterol level, and 11% for transaminase level. Moderate to severe abnormalities in lipid and transaminase levels were generally transient and reversible. New abnormalities in hematological test results were uncommon. Conclusions The incidence of abnormally high serum lipid levels during isotretinoin treatment may be greater than previously estimated. Elevations in transaminase level are generally mild. Normal baseline values of serum lipid and transaminase levels do not preclude the development of new abnormalities during isotretinoin treatment. Routine monitoring of white blood cell count, hemoglobin level, and platelet count during isotretinoin therapy may be of little utility without clinical suspicion of an abnormality. The clinical significance of laboratory abnormalities during isotretinoin therapy remains to be determined.

We performed a cross-sectional study of newly diagnosed cases of nonalcoholic fatty liver disease (NAFLD) identified between December 1998 and December 2000 in the Chronic Liver Disease Surveillance Study. We compared the demographic and clinical features of NAFLD in a racially diverse representative U.S. population (Alameda County, CA). Diagnostic criteria for probable NAFLD were persistent unexplained elevation of serum aminotransferase levels, radiology (ultrasound or computed tomography scan) consistent with fatty liver, and/or two or more of the following: (i) body mass index of 28 kg/m2 or more, (ii) type 2 diabetes, or (iii) hyperlipidemia, in the absence of significant alcohol use. Definite NAFLD cases required histological confirmation. Of the 742 persons with newly diagnosed chronic liver disease, 159 (21.4%) had definite or probable NAFLD. The majority were nonwhite: Hispanics (28%), Asians (18%), African Americans (3%), and other race(s) (6%). African Americans with NAFLD were significantly older than other racial or ethnic groups (P < .001), and in Asians, NAFLD was 3.5 times more common in males than in females (P = .016). Clinical correlates of NAFLD (obesity, hyperlipidemia, diabetes) were similar among racial and ethnic groups, except that body mass index was lower in Asians compared with other groups (P < .001). Compared with the base population (Kaiser Permanente members), Hispanics with NAFLD were overrepresented (28% vs. 10%) and whites were underrepresented (45% vs. 59%). In conclusion, these racial and gender variations may reflect differences in genetic susceptibility to visceral adiposity, including hepatic involvement, and may have implications for the evaluation of persons with the metabolic syndrome. Clinicians need to be aware of the variable presentations of NAFLD in different racial and ethnic groups. (HEPATOLOGY 2005;41:372–379.)

Mammography screening increases the detection of early-stage breast cancers. Therefore, implementing screening should reduce the percentage of women who are diagnosed with late-stage disease. However, despite high national mammography screening rates, late-stage breast cancers still occur, possibly because of failures in screening implementation.Using data from seven health care plans that included 1.5 million women aged 50 years or older, we conducted retrospective reviews of chart and automated data for 3 years before 1995-1999 diagnoses of late-stage (metastatic and/or tumor sizeor =3 cm; case subjects, n = 1347) and early-stage breast cancers (control subjects, n = 1347). We categorized the earliest screening mammogram during the period 13-36 months before diagnosis as none (absence of screening), negative (absence of detection), or positive (potential breakdown in follow-up). We compared the proportion of case and control subjects in each category of screening implementation and estimated the likelihood (odds ratio [OR] with 95% confidence intervals [CIs]) of late-stage breast cancer. We also evaluated demographic characteristics associated with absence of screening in women with late-stage disease. All statistical tests were two-sided.Absence of screening, absence of detection, and potential breakdown in follow-up were distributed differently among case (52.1%, 39.5%, and 8.4%, respectively) and control subjects (34.4%, 56.9%, and 8.8%, respectively) (P = .03). Among all women, the odds of having late-stage cancer were higher among women with an absence of screening (OR = 2.17, 95% CI = 1.84 to 2.56; P.001). Among case patients, women were more likely to be in the absence-of-screening group if they were aged 75 years or older (OR = 2.77, 95% CI = 2.10 to 3.65), unmarried (OR = 1.78, 95% CI = 1.41 to 2.24), or without a family history of breast cancer (OR = 1.84, 95% CI = 1.45 to 2.34). A higher proportion of women from census blocks with less education (58.5% versus 49.4%; P = .003) or lower median annual income (54.4% versus 42.9%; P = .004) were in the absence-of-screening category compared with the proportion for the other two categories combined.To reduce late-stage breast cancer occurrence, reaching unscreened women, including elderly, unmarried, low-income, and less educated women, should be made a top priority for screening implementation.

Background . Given limited research, we investigated patient reports of processes of care related to screening follow-up, timing of result notification, communication issues, and adherence following an abnormal mammogram or Pap test. Methods . Women age 50 and over with an abnormal screening mammogram and women age 18 and above with an abnormal Pap test result completed surveys. The mammogram and Pap survey instruments had similar items except pertaining to measures specific to mammography or Pap tests. Bivariate associations between processes of care variables (test results, result receipt, recommendation adherence, receipt of confusing/conflicting information) and global satisfaction were explored using chi-square contingency table analysis. Multivariable logistic regression modeling was conducted. Results . One thousand one hundred thirty-four women (79.1%) completed the mammogram survey and 1087 women (69.7%) completed the Pap survey. The majority of women received test results quickly. High compliance was reported with recommendations for short-term follow-up. Conflicting/confusing information was reported by a minority of women, but was significantly and positively related to reporting that “care could be better”. Patient's lack of understanding about equivocal findings was evident. Conclusions . This study confirms that patients need clear messages about recommendations, especially when findings are equivocal and where multiple providers are involved in the process of making clinical decisions.