Faculty Bibliography

OBJECTIVE:African-Americans have been underrepresented in most large Crohn's disease (CD) trials. This study was undertaken to assess the course and character of CD in African-Americans in comparison with whites. METHODS:We retrospectively compared the course and character of CD in African-American and white patients at 3 Atlanta hospitals. Ninety-nine patients (55 African-American, 44 whites) were enrolled. Telephone interviews and chart reviews were used to identify disease location, presence of fistulae and perirectal disease, surgical history, and medication use. Patients with ulcerative colitis or indeterminant colitis, and all non-African-Americans or whites, were excluded. RESULTS:The numbers of male and female patients were similar (50 and 49). Overall, men comprised 54% of white patients and 47% of African-American patients. There were no significant differences in the setting in which CD were diagnosed, number of flares per year, or duration of symptoms before diagnosis. White patients were more likely to seek care for their CD in a clinic setting, both their primary care physicians (1.31 versus 0.21 visits/yr, P < 0.001) and their gastroenterologists (3.2 versus 2.3 visits/yr, P = 0.03). Small bowel (SB) disease was present more frequently in white patients, 84% versus 65% (P = 0.03), and SB resection was more common in this group, 59% versus 16% (P < 0.01). Colonic disease was more common in African-American patients, 89% versus 63% (P = 0.002). Perirectal fistulae were more frequent in African-American patients, 58% versus 22% (P < 0.001) white patients were more likely to report complete compliance with medical therapy, 77% versus 49% (P = 0.004). African-American patients more frequently discontinued medical therapy because they "felt better" (27% versus 9%, P = 0.02). Medication usage, including immunosuppressants, was similar in both groups, except that white patients were more likely to receive multiple doses of infliximab (34% versus 11%, P = 0.005). Both groups felt equally informed about CD, but white patients felt that their disease was under good control a greater percentage of the time, 71% versus 58% (P = 0.04). CONCLUSIONS:These data lend credence to the suggestion that the nature of CD may be different in African-Americans compared with whites. However, despite this apparent difference in disease manifestation, the contribution of socioeconomic factors, access to health care, and understanding of the disease likely play a role as well.

OBJECTIVES/OBJECTIVE:Synthesize evidence of the natural history of chronic hepatitis B (CHB) and effects and harms of antiviral drugs on clinical, virological, histological, and biochemical outcomes. DATA SOURCES/METHODS:MEDLINE, electronic databases, and manual searches of systematic reviews. REVIEW METHODS/METHODS:We included original observational studies to assess natural history and randomized controlled trials (RCTs) of adults with CHB published in English to assess treatment effects and harms if they reported mortality, incidence of hepato-cellular carcinoma (HCC), cirrhosis or failure, HBeAg or HBsAg, viral load (HBV DNA), alanine aminotransferase (ALT) levels, histological necroinflammatory and fibrosis scores, and adverse events after interferon alfa-2b, pegylated interferon alfa 2-a, lamivudine, adefovir, entecavir, tenovir or telbivudine. We excluded pregnant women, transplant patients, and individuals undergoing cancer chemotherapy. We calculated relative risk or absolute risk differences at end of treatment and post-treatment. RESULTS:Observational studies (41 publications) suggested that male gender, coinfection with hepatitis C, D, or HIV, increased HBV DNA, and cirrhosis were associated with increased risk of HCC and death. Drugs did not reduce death, liver failure, or HCC in 16 RCTs not designed to test long-term clinical outcomes. Evidence from 93 publications of 60 RCTs suggested drug effects on viral load or replication, liver enzymes, and histology at end of treatment and lasting from 3 to 6 months off treatment. No one treatment improved all outcomes and there was limited evidence on comparative effects. Two RCTs suggested interferon alfa-2b increased CHB solution versus placebo. Interferon alfa-2b or lamivudine improved off treatment HBV DNA and HBeAg clearance and seroconversion and ALT normalization. Adefovir improved off treatment ALT normalization and HBV DNA clearance. Pegylated interferon alfa 2-a versus lamivudine improved off-treatment HBV DNA and HBeAg clearance and seroconversion, ALT normalization and liver histology. Lamivudine combined with interferon alfa-2b versus lamivudine improved off treatment HBV DNA clearance and HBeAg seroconversion and reduced HBV DNA mutations. Pegylated interferon alfa 2-a plus lamivudine improved off treatment HBV DNA and HBeAg clearance and seroconversion and ALT normalization compared to lamivudine but not pegylated interferon alfa 2-a monotherapy. Adverse events were common but generally mild and did not result in increased treatment discontinuation. Longer hepatitis duration, male gender, baseline viral load and genotype, HBeAg, and histological status may modify treatment effect on intermediate outcomes. Adefovir and pegylated interferon alfa 2-a with lamivudine improved off treatment viral clearance in HBeAg negative patients. There was insufficient evidence to determine if biochemical, viral, or histological measures are valid surrogates of treatment effect on mortality, liver failure, or cancer. CONCLUSION/CONCLUSIONS:Adults with CHB have an increased risk of death, hepatic decompensation, and HCC. Mono or combined drug therapy improves selected virological, biochemical, and histological markers with no consistent effects on all examined outcomes. Patient and disease characteristics may modify treatment-induced intermediate outcomes. Evidence was insufficient to assess treatment effect on clinical outcomes, predict individualized patient response, or determine if intermediate measures are reliable surrogates. Future research should assess long-term drug effects on clinical outcomes and among patient subpopulations.

Human sporadic colorectal cancer is the result of a lengthy somatic evolutionary process facilitated by various forms of genomic instability. Such instability arises endogenously from mutations in genes whose role is to preserve genomic integrity, and exogenously from environmental agents that generate genomic damage. We have found that cigarette smoking shifts the genomic profiles and genomic instability patterns of colorectal carcinomas. The genomic profiles of 57 consecutive cancers were examined; 31 cases were current or former smokers and 26 were nonsmokers. Genome-wide allelotypes of 348 markers were examined, along with comparative genomic hybridization (CGH) on ordered BAC microarrays, microsatellite instability, and inter-(simple sequence repeat) polymerase chain reaction instability. Tumors from nonsmokers exhibited losses of heterozygosity, particularly on chromosomes 14 and 18, whereas tumors from smokers exhibited a more diffuse pattern of allelic losses. Tumors from smokers exhibited higher overall rates of loss of heterozygosity, but showed lower rates of background microsatellite instability (MSI-L). On BAC array CGH, higher levels of generalized amplifications and deletions were observed in tumors from smokers, differentially affecting male smokers. In the transforming growth factor-beta signaling pathway, MADH4 mutations were more common in tumors from smokers, whereas transforming growth factor-beta RII mutations were more common among nonsmokers.

Invasive mould infections are a major cause of morbidity and mortality in hematopoietic stem cell transplant recipients (HSCT). Allogeneic HSCT recipients are at substantially higher risk than autologous HSCT recipients. Although neutropenia following the conditioning regimen remains an important risk factor for opportunistic fungal infections, most cases of invasive mould infection in allogeneic HSCT recipients occur after neutrophil recovery in the setting of potent immunosuppressive therapy for graft-versus-host disease. Invasive aspergillosis is the most common mould infection. However, there has been an increased incidence of less common non-Aspergillus moulds that include zygomycetes, Fusarium sp., and Scedosporium sp. Reflecting a key need, important advances have been made in the antifungal armamentarium. Voriconazole has become a new standard of care as primary therapy for invasive aspergillosis based on superiority over amphotericin B. There is significant interest in combination therapy for invasive aspergillosis pairing voriconazole or an amphotericin B formulation with an echinocandin. There have also been advances in novel diagnostic methods that facilitate early detection of invasive fungal infections that include galactomannan and beta-glucan antigen detection and PCR using fungal specific primers. We review the epidemiology, diagnosis, and management of invasive mould infection in HSCT, with a focus on allogeneic recipients. We also discuss options for prevention and early treatment of invasive mould infections.

OBJECTIVE:Breastfeeding reduces the risk of asthma and respiratory infections in infants. Since respiratory infections are associated with reduced pulmonary function in adolescents, pulmonary function impairment may be carried into adulthood. Our aim was to determine whether a history of having been breastfed as an infant is a determinant of adult pulmonary function. METHODS:We analyzed data from a general population sample of residents of Erie and Niagara Counties between September 1995 and December 1999. We calculated forced expiratory volume in one second (FEV(1)) and forced vital capacity (FVC) prediction equations and used multiple linear regression models to study the association between having been breastfed as an infant and percentage predicted FEV(1) (FEV(1)%) and percentage predicted FVC (FVC%) after adjustment for covariates. RESULTS:Of 2305 subjects, 62% reported having been breastfed. After controlling for age, gender, weight, smoking status, pack-years of smoking, eosinophil counts and dietary factors, there was no association between having been breastfed (yes/no) and FEV(1)% or FVC% (regression coefficients 0.0049, p = 0.46 and 0.0055, p = 0.43, respectively). CONCLUSIONS:We did not find a strong or consistent association between having been breastfed as an infant and pulmonary function in adulthood.

INTRODUCTION/BACKGROUND:: Epstein-Barr virus (EBV) infection frequently involves the liver, presenting as elevations in transaminases. EBV infection associated hepatitis, presenting with hyperbilirubinemia is rare. We describe a case of infectious mononucleosis that presented with cholestatasis, and summarize 23 cases from the literature to categorize this increasingly recognized clinical spectrum of EBV infection induced cholestatic hepatitis. METHODS:: We conducted an extensive literature review of all cases of EBV in pediatric and adult literature with cholestatasis using MEDLINE and EMBASE. We also included information on one case from our institution. RESULTS:: We identified 24 cases. Median age was 20 years (range 1-72 years), with 14 (58%) females. On presentation, fever (72%), jaundice (67%) and splenomegaly (62%) were the most common signs. Laboratory data revealed the median asparate aminotransferase (AST), or alanine aminotransferase (ALT) level was 179IU/L (range 56-2518IU/L), median serum bilirubin level 12.6mg/dL (range 2.2-47.5mg/dL) and median alkaline phosphatase level 749IU/L (range 31-3105IU/L). Diagnosis was confirmed using EBV viral capsid antigen IgM in 20 (83%) patients. HIV testing was done in 7 (29%) of the cases, and was negative. One patient died from the illness, while full recovery was reported in all other cases, with median follow-up of 30 days (range 5-180 days). CONCLUSIONS:: Cholestatasis is associated with EBV infection, and should be part of the differential diagnosis in all age groups, presenting with hyperbilirubinemia.

The use of computed tomography scan (CT) of the abdomen and pelvis for surveillance of colorectal cancer (CRC) after primary curative therapy (PCT) remains controversial. Surveillance guidelines at Roswell Park Cancer Institute have included annual CT for the first 2 years after PCT. Isolated metastases from CRC may be amenable to surgical resection, potentially leading to a survival advantage. To assess this, a retrospective chart review of all 203 patients diagnosed with stage II or III CRC between January 1, 1990, and December 31, 1995, was conducted. First-year surveillance CT (CT-1) was performed for 146 of 203 patients and 81 of 146 patients had second-year surveillance CT (CT-2). CT was considered "directed" when at least 1 of the following prompted evaluation: suspicious symptoms or signs, rising carcinoembryonic antigen, findings from colonoscopies, chest x-rays, or laboratory tests. Otherwise, CT was considered "nondirected." Of 121 of 146 CT-1 and 63 of 81 CT-2 with nondirected CT, 7 of 121(5.8%) and 4 of 63 (6.4%) had proven recurrence, respectively. During 2 years of follow up, the estimated lower bound for detection of recurrence by nondirected CT was 11 of 121(9.1%). There were no apparent differences between the 2 groups in demographics, clinical presentation, surgical margins, treatment, tumor site, grade, or TNM stage. Surgical resectability of the metastases for directed and nondirected groups was 10 of 28 (36%) and 6 of 11 (54%), respectively. The median survival for the patients with recurrence in the directed and nondirected groups was 35 and 50 months, respectively. In conclusion, this retrospective study generates the hypothesis that CT surveillance may be of value. A prospective study, properly sized for power, is needed to answer this question.