Nancy J. Petersen

The Continuing Increase in the Incidence of Hepatocellular Carcinoma in the United States: An Update

Context Incidence rates of hepatocellular carcinoma have been increasing in the United States. Contribution This large, retrospective, population-based cohort study confirmed an almost 2-fold increase in the incidence of hepatocellular carcinoma from 1975 to 1998. Increases were seen in all ethnic groups and in most age groups after 40 years of age. Although black people and older people remained most at risk, the largest recent increase in rates (from 1995 to 1998) occurred in white men 45 to 54 years of age. Implications The incidence of hepatocellular carcinoma continues to increase rapidly in the United States, especially in white, middle-aged men. The Editors We previously reported an increase in the incidence and mortality rates of hepatocellular carcinoma in the United States (1). Studies among U.S. hospitalized veterans, as well as those conducted in large single centers, indicated that approximately half of the observed increase was attributable to hepatitis C virus (HCV) infection, whereas the incidence of hepatocellular carcinoma related to hepatitis B virus (HBV), alcoholic liver disease, or idiopathic cirrhosis remained relatively stable (2, 3). If HCV were indeed responsible for the increasing rates of hepatocellular carcinoma, this increase would be expected to continue for at least several more years since 2 to 4 decades of chronic HCV infection is required to develop cirrhosis and subsequent hepatocellular carcinoma (4). On the other hand, if the increased rates of hepatocellular carcinoma were related to better detection due to technologically improved diagnostic testing, such an effect would be expected to plateau at some point in the future. The observed increase in hepatocellular carcinoma could have other explanations. Changes in the demographic structure (age, sex, ethnicity, and geography) of the underlying population may have resulted in an increasing number of persons at high risk for hepatocellular carcinoma (older age and increased number of ethnic and racial minorities). Hepatocellular carcinoma is an age-dependent cancer that peaks in incidence between 75 and 79 years of age, and direct standardization methods may not have been sufficient to control for the effect of aging in the underlying population (5). The observed increase could also have resulted from an increase in high-risk sex or racial or ethnic groups or the population residing in 1 or a few high-risk geographic regions (6). For example, rates of hepatocellular carcinoma were severalfold higher in Asian Americans than in white people, and African Americans had rates between those of the other 2 groups (1). The current study was designed to update the recent trends in hepatocellular carcinoma incidence by using data from the National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) registries and to examine the temporal trends in hepatocellular carcinoma through adjustments for potential changes in several influential factors. Methods Data Sources: SEER Beginning in 1973, the SEER registry program was established to identify all new cancer cases diagnosed in 7 geographic areas. By 1975, SEER included 9 geographic regions, 5 states (Connecticut, Hawaii, Iowa, New Mexico, and Utah) and 4 metropolitan areas (San FranciscoOakland in California; SeattlePuget Sound in Washington; Detroit, Michigan; and Atlanta, Georgia). In 1992, the Los Angeles County and San JoseMonterey areas in California joined the SEER program, expanding the representation to approximately 14% of the U.S. population. Overall, the SEER population is similar to the general U.S. population, particularly in measures of poverty and education. However, SEER regions are more urban and have a higher proportion of foreign-born persons than the general U.S. population. Data for this study were obtained from SEER*STAT public-use data files (National Cancer Institute, Bethesda, Maryland), available on CD-ROM from the National Cancer Institute (7). Data from the SEER public-use CD-ROM were converted into SAS datasets for further analyses (SAS software, version 8.2, SAS Institute, Inc., Cary, North Carolina). Demographic and cancer-related information included in this database are obtained by medical record review. Studies are conducted annually at each SEER registry site to verify that data are being collected accurately and that case ascertainment is at least 98%. Types of cancer are coded according to the International Classification of Disease for Oncology (ICD-O) (8). There are several categories of race or ethnicity, including Hispanic white, non-Hispanic white, Chinese, Japanese, Filipino, Pacific Islander, and American Indian. However, accurate information on the underlying population in the areas covered by the SEER program is available only on race classified as white (which includes Hispanic), black, or other (which includes all other ethnic groups listed). As a result, valid incidence rates can be calculated for only these 3 broad racial or ethnic groups (white, black, and other). Study Sample Patients eligible for inclusion in this study were all individuals with hepatocellular carcinoma (ICD-O code 8170) identified from 9 SEER registries between 1975 and 1998. Patients younger than 20 years of age were excluded to avoid including those with hepatoblastoma (<1% of total cases). Cases in which the patients race or ethnicity was unknown (<1% of total cases) also were excluded. To examine the potential role of diagnostic bias, we calculated the proportion of cases with microscopic confirmation, which is defined by SEER as the presence of a confirmatory histologic or cytologic evidence of hepatocellular carcinoma. Statistical Analysis The age-adjusted incidence rates for hepatocellular carcinoma were calculated for 3-year periods between 1975 and 1998. Sex- and ethnicity-specific, age-adjusted incidence rates and their 95% CIs were calculated. Adjustment was made to the 1990 U.S. population. Age-specific incidence rates were calculated for all patients and for each of the 3 broad categories of race or ethnicity (white, black, and other). Among patients with hepatocellular carcinoma, we calculated the proportions of cases belonging to the following racial or ethnic groups: Hispanic white, non-Hispanic white, Asian (Chinese, Japanese, Filipino, or Pacific Islander), and others. We also calculated the proportion of patients with liver cancer who had microscopic confirmation for each time period. These calculations were made by using the SEER*STAT statistical software (7). The temporal trends of the incidence of hepatocellular carcinoma were examined in linear Poisson multivariate regression models. We used SAS PROC GENMOD for this task. The model was used to analyze the effect of the period of diagnosis (independent variable) on the incidence of hepatocellular carcinoma (dependent variable), while controlling for several other independent variables including age (20 to 49, 50 to 64, 65 to 74, or 75 years), sex, race or ethnicity (white, black, or other), and differences in the geographic regions (9 SEER registries). Similar categories were assembled for the underlying population and were included as an offset variable in the model. Risk estimates (incidence rates and incidence rate ratios) and 95% CIs were calculated for all the independent variables in the final model. The model was tested for interactions between time of diagnosis and each variable of age, sex, and race or ethnicity. Role of the Funding Source The funding source had no role in the design, conduct, or reporting of the study or in the decision to submit the manuscript for publication. Results Between 1975 and 1998, there were 11 547 cases of hepatocellular carcinoma. The overall age-adjusted incidence rates of hepatocellular carcinoma started to increase in the early 1980s, from 1.3 per 100 000 persons in 1981 to 1983 to 3.0 per 100 000 persons in 1996 to 1998 (Figure 1). This is equivalent to a 114% overall increase throughout the study period. There was a 25% increase during the last 3 years of the study (1996 to 1998) compared with the previous 3 years (1993 to 1995). The proportions of patients with liver cancer who underwent microscopic confirmation were relatively stable during the study period: 86%, 86%, 84%, 82%, 78%, and 80% in consecutive 3-year periods between 1981 and 1998, respectively. All hepatocellular carcinoma cases were included in subsequent analyses regardless of microscopic confirmation. Figure 1. The overall age-adjusted incidence rates for hepatocellular carcinoma for consecutive 3-year periods between 1975 and 1998. In addition to the variable of more recent time period, age, sex, race or ethnicity, and geographic region were statistically significant determinants of the incidence of hepatocellular carcinoma. Hepatocellular carcinoma was rare among individuals younger than 40 years of age, and the incidence peaked at 75 to 79 years of age. Concomitant with the increase in incidence, the age distribution of patients with hepatocellular carcinoma progressively shifted toward relatively younger persons. Figure 2 shows the temporal changes in the age distribution of new cases of hepatocellular carcinoma in men, with age-specific incidence rates for consecutive 3-year periods from 1975 to 1998. The incidence has increased in most age groups older than 40 years; the greatest increase occurred in patients 45 to 55 years of age. For example, in the 1990s, the incidence rates increased 110% among white men 45 to 49 years of age and 60% among white men 50 to 54 years of age (Figure 3). Similar trends were seen for women (data not shown); the greatest increase in incidence occurred in women 60 to 69 years of age. Figure 2. Age-adjusted incidence rates for hepatocellular carcinoma broken down by sex and race or ethnicity for consecutive 3-year periods between 1975 and 1998. Figure 3. Temporal trends in the age distribution of hepatocellular carcinoma. Throughout

Cytokines and Cytokine Receptors in Advanced Heart Failure

Background—Previous reports have shown that elevated circulating levels of cytokines and/or cytokine receptors predict adverse outcomes in patients with heart failure. However, these studies were limited by small numbers of patients and/or they were performed in a single center. In addition, these studies did not have sufficient size to address the influence of age, race, sex, and cause of heart failure on the circulating levels of these inflammatory mediators in patients with heart failure. Methods and Results—We analyzed circulating levels of cytokines (tumor necrosis factor [TNF] and interleukin-6) and their cognate receptors in 1200 consecutive patients who were enrolled in a multicenter clinical trial of patients with advanced heart failure. This analysis constitutes the largest analysis of cytokines and cytokine receptors to date. Analysis of the patients receiving placebo showed that increasing circulating levels of TNF, interleukin-6, and the soluble TNF receptors were associated with increased mo...

Long-term outcomes of patients receiving percutaneous endoscopic gastrostomy tubes

OBJECTIVE: Percutaneous endoscopic gastrostomy (PEG) tube placement is the preferred method for long-term enteral feeding of patients who are unable to take food by mouth. Despite the widespread acceptance of the procedure, no large-scale study of the long-term outcomes of patients receiving PEG tubes has been reported. The objective of this study was to determine the survival of patients in whom PEG tubes are placed.DESIGN: Retrospective cohort study using data obtained from two computerized databases.SETTING: Department of Veterans Affairs hospitals.PATIENTS: Seven thousand three hundred sixty-nine patients who received a PEG tube in fiscal years 1990 through 1992.RESULTS: For the 7,369 patients, the mean age was 68.1 years and 98.6% were men. PEG tubes were most commonly placed in patients with cerebrovascular disease (18.9%), other organic neurologic disease (28.6%), or head and neck cancer (15.7%). Although the complication rate of the procedure itself was low (4%), because of the severity of their underlying disease, 1,732 patients (23.5%) died during the hospitalization in which the PEG tube was placed. The median survival of the full cohort was 7.5 months.CONCLUSIONS: This study documents the widespread placement of PEG tubes in severely ill patients, half of whom are in the terminal phase of their illness. Further study is needed to determine whether these patients benefit from PEG tube placement in terms of their quality of life and survival.OBJECTIVE: Percutaneous endoscopic gastrostomy (PEG) tube placement is the preferred method for long-term enteral feeding of patients who are unable to take food by mouth. Despite the widespread acceptance of the procedure, no large-scale study of the long-term outcomes of patients receiving PEG tubes has been reported. The objective of this study was to determine the survival of patients in whom PEG tubes are placed. DESIGN: Retrospective cohort study using data obtained from two computerized databases. SETTING: Department of Veterans Affairs hospitals. PATIENTS: Seven thousand three hundred sixty-nine patients who received a PEG tube in fiscal years 1990 through 1992. RESULTS: For the 7,369 patients, the mean age was 68.1 years and 98.6% were men. PEG tubes were most commonly placed in patients with cerebrovascular disease (18.9%), other organic neurologic disease (28.6%), or head and neck cancer (15.7%). Although the complication rate of the procedure itself was low (4%), because of the severity of their underlying disease, 1,732 patients (23.5%) died during the hospitalization in which the PEG tube was placed. The median survival of the full cohort was 7.5 months. CONCLUSIONS: This study documents the widespread placement of PEG tubes in severely ill patients, half of whom are in the terminal phase of their illness. Further study is needed to determine whether these patients benefit from PEG tube placement in terms of their quality of life and survival.

Geographic Variations in Utilization Rates in Veterans Affairs Hospitals and Clinics

BACKGROUND In the United States, geographic variation in hospital use is common. It is uncertain whether there are similar geographic variations in the health care system of the Department of Veterans Affairs (VA), which differs from the private sector because it predominantly serves men with annual incomes below

Diffusion Tensor Imaging of Mild to Moderate Blast-Related Traumatic Brain Injury and Its Sequelae

20,000, has a central system of administration, and uses salaried physicians. Thus, it might be less likely to have geographic variations. METHODS We used VA data bases to obtain information on patients treated for eight diseases (chronic obstructive pulmonary disease, pneumonia, congestive heart failure, angina, diabetes, chronic renal failure, bipolar disorder, and major depression). We analyzed their use of hospital and outpatient services by assessing the risk-adjusted numbers of hospital days (the average number of days a patient spent in the hospital per 12 months of follow-up, regardless of the number of hospital stays), hospital-discharge rates, and clinic-visit rates from 1991 through 1995 for the entire system and within the 22 geographically based health care networks. RESULTS We found substantial geographic variation in hospital use for all eight cohorts of patients and all the years studied. Variations in the numbers of hospital days per person-year among the networks were greatest among patients with chronic obstructive pulmonary disease (ranging from a factor of 2.7 to a factor of 3.1) during a given year and smallest among patients with angina (ranging from a factor of 1.5 to a factor of 2.1). Levels of hospital use were highest in the Northeast and lowest in the West. The variation in the rates of clinic visits for principal medical care among the networks ranged from a factor of approximately 1.6 to a factor of 4.0; variations in the rates were greatest among patients with chronic renal failure and smallest among patients with chronic obstructive pulmonary disease. There was no clear geographic pattern in the rates of outpatient-clinic use. CONCLUSIONS There are significant geographic variations in the use of hospital and outpatient services in the VA health care system. Because VA physicians are unable to increase their income by changing their patterns of practice, our findings suggest that their practice styles are similar to those of other physicians in their geographic regions.

Variation in hemodialysis patient compliance according to demographic characteristics

To evaluate the effects of mild to moderate blast-related traumatic brain injury (TBI) on the microstructure of brain white matter (WM) and neurobehavioral outcomes, we studied 37 veterans and service members (mean age 31.5 years, SD = 7.2; post-injury interval 871.5 days; SD = 343.1), whose report of acute neurological status was consistent with sustaining mild to moderate TBI due to blast while serving in Iraq or Afghanistan. Fifteen veterans without a history of TBI or exposure to blast (mean age 31.4 years, SD = 5.4) served as a comparison group, including seven subjects with extracranial injury (post-injury interval 919.5 days, SD = 455.1), and eight who were uninjured. Magnetic resonance imaging disclosed focal lesions in five TBI participants. Post-concussion symptoms (Neurobehavioral Symptom Inventory), post-traumatic stress disorder (PTSD) symptoms (PTSD Checklist-Civilian), and global distress and depression (Brief Symptom Inventory) were worse in the TBI participants than the comparison group, but no group differences were found in perceived physical or mental functioning (SF-12). Verbal memory (Selective Reminding) was less efficient in the TBI group, but there were no group differences in nonverbal memory (Selective Reminding) or decision making (Iowa Gambling Task). Verbal memory in the TBI group was unrelated to PTSD severity. Diffusion tensor imaging (DTI) using tractography, standard single-slice region-of-interest measurement, and voxel-based analysis disclosed no group differences in fractional anisotropy (FA) and apparent diffusion coefficient (ADC). However, FA of the left and right posterior internal capsule and left corticospinal tract was positively correlated with total words consistently recalled, whereas ADC for the left and right uncinate fasciculi and left posterior internal capsule was negatively correlated with this measure of verbal memory. Correlations of DTI variables with symptom measures were non-significant and inconsistent. Our data do not show WM injury in mild to moderate blast-related TBI in veterans despite their residual symptoms and difficulty in verbal memory. Limitations of the study and implications for future research are also discussed.

Prescription Errors and Outcomes Related to Inconsistent Information Transmitted through Computerized Order-Entry: A Prospective Study

Patient noncompliance with treatment regime undermines the effectiveness of medical care, resulting in an unpredictable progression of the primary disease and a greater likelihood of complications. Hemodialysis patients are well suited for studying noncompliance because their treatment is prolonged and intensive, and medical regimens are clear cut and easily determined with objective measures. Moreover, noncompliant behavior by these patients not only endangers their life in the long run, but also results in negative effects within a day or two. Despite severe consequences, noncompliance with their medical regimen is the norm for dialysis patients rather than the exception. A large-scale study of chronic, outpatient hemodialysis patients (N = 1230 patients, response rate = 96%) treated in a variety of facility types (N = 29 facilities) was conducted to investigate prevalence and associated demographic characteristics of noncompliance with four treatment regimens--protein and potassium restrictions in the diet, medication regimen, and fluid restrictions. Few patients were noncompliant with diet regimens (9% with protein and 2% with potassium restrictions) but half were noncompliant with medication taking (50.2%) and fluid restrictions (49.5%). The prevalence of noncompliance with medication and fluid regimens was consistent with previous studies of dialysis patients but the prevalence of noncompliance with diet was much lower than that reported elsewhere. Prevalence of noncompliant patients varied between studies according to the cut-point used to establish compliance criteria, where more stringent cut-points inflated the percentage and more lenient cut-points reduced the percentage. Thus, there is a need to establish uniform criteria in order to test real differences in compliance between patient groups vs simply differences in measurement.(ABSTRACT TRUNCATED AT 250 WORDS)

Greater Prevalence and Incidence of Dementia in Older Veterans with Posttraumatic Stress Disorder

BACKGROUND Although several types of computerized provider order entry (CPOE)-related errors may occur, errors related to inconsistent information within the same prescription (ie, mismatch between the structured template and the associated free-text field) have not been described, to our knowledge. We determined the nature and frequency of such errors and identified their potential predictive variables. METHODS In this prospective study, we enrolled pharmacists to report prescriptions containing inconsistent communication over a 4-month period at a tertiary care facility. We also electronically retrieved all prescriptions written during the study period containing any comments in the free-text field and then randomly selected 500 for manual review to determine inconsistencies between free-text and structured fields. Of these, prescriptions without inconsistencies were categorized as controls. Data on potentially predictive variables from reported and unreported errors and controls were collected. For all inconsistencies, we determined their nature (eg, drug dosage or administration schedule) and potential harm and used multivariate logistic regression models to identify factors associated with errors and harm. RESULTS Of 55 992 new prescriptions, 532 (0.95%) were reported to contain inconsistent communication, a rate comparable to that obtained from the unreported group. Drug dosage was the most common inconsistent element among both groups. Certain medications were more likely associated with errors, as was the inpatient setting (odds ratio, 3.30; 95% confidence interval, 2.18-5.00) and surgical subspecialty (odds ratio, 2.45; 95% confidence interval, 1.57-3.82). About 20% of errors could have resulted in moderate to severe harm, for which significant independent predictors were found. CONCLUSIONS Despite standardization of data entry, inconsistent communication in CPOE poses a significant risk to safety. Improving the usability of the CPOE interface and integrating it with workflow may reduce this risk.

Healthy IDEAS: A Depression Intervention Delivered by Community-Based Case Managers Serving Older Adults

To explore the association between posttraumatic stress disorder (PTSD) and dementia in older veterans.

Information Overload and Missed Test Results in Electronic Health Record–Based Settings

This study evaluated an evidence-based intervention for depression delivered by case managers in three community-based service agencies to high-risk, diverse older adults. Case managers were trained to provide screening and assessment, education, referral and linkage, and behavioral activation. Outcomes addressed depression, general health status, social and physical activation, and mental health services use at baseline and 6 months. Participants (n = 94) were predominantly women (79%) and Hispanic (44%), with a mean age of 72 years. Mean Geriatric Depression Scale—15 scores differed significantly between baseline and 6 months (9.0 versus 5.5). At 6 months, significantly more participants knew how to get help for depression (68% versus 93%), reported that increasing activity helped them feel better (72% versus 89%), and reported reduced pain (16% versus 45 %). The authors conclude that nonspecialty providers can be trained to successfully implement an evidence-based self-management intervention for depression with frail, high-risk, and diverse older adults.