Posttransplant lymphoproliferative disorders in liver transplantation: a 20-year experience

OBJECTIVE: To evaluate the incidence of posttransplant lymphoproliferative disease (PTLD) and the risk factors and the impact of this complication on survival outcomes in a large cohort of liver transplant recipients at a single institution. SUMMARY BACKGROUND DATA: Liver transplantation has been accepted as a therapeutic option for patients with end-stage liver disease since 1983, in large part due to the availability and reliance on the use of nonspecifically directed immunosuppression. However, as predicted and subsequently verified in 1968, an increased incidence of certain de novo malignancies has been observed, particularly with regards to lymphoid neoplasms. While many reports have confirmed and clarified the nature of PTLD, the literature is fraught with conflicting experience and outcomes with PTLD. METHODS: Four thousand consecutive patients who underwent liver transplants between February 1981 and April 1998 were included in this analysis and were followed to November 2001. The effect of recipient age at the time of transplant, recipient gender, diagnosis, baseline immunosuppression, grading of PTLD, and association with Epstein-Barr virus were compared. The causes of death were also examined. Treatment for PTLD varied over the 20-year period, but all included massive reduction or elimination of baseline immunosuppression. RESULTS: The 1-year patient survival for liver transplant patients with PTLD was 85%, while the overall patient survival for the entire cohort was 53%. The actuarial 20-year survival was estimated at 45%. The overall median time to PTLD presentation was 10 months, and children had an incidence of PTLD that was threefold higher than adults. Patient survival was better in children, in patients transplanted in the era of tacrolimus immunosuppression, in patients with polymorphic PTLD, and in those with limited disease. Interestingly, neither the presence or absence of Epstein-Barr virus nor the timing of PTLD presentation appeared to influence overall patient survival. Patients transplanted for alcohol-related liver disease had a similar incidence of PTLD but had a higher risk of mortality. CONCLUSIONS: While PTLD continues to pose problems in patients receiving liver transplants, improvements in patient survival have been observed over time. While it is too early to assess the impact of new advances in prophylaxis, diagnosis, and treatment, such approaches are based on an increased knowledge of the pathophysiology of PTLD.     

Sex ratios of children of Russian pesticide producers exposed to dioxin

We investigated the sex ratio of children of pesticide workers who produced the biocide trichlorophenol and the herbicide 2,4,5-trichlorophenoxy acetic acid from 1961 to 1988 in the city of Ufa, Bashkortostan, Russia. We measured exposure of the two related cohorts to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and other dioxins by analyzing 84 blood samples, which produced median TCDD toxic equivalents blood lipid values of 240 ng/kg, which are more than 30 times higher than background or normal exposure from the region. The sex ratio (fraction male) of the combined cohort of 227 children from 150 male and 48 female workers was 0.40, significantly lower (z-test for proportions = 3.21; p < 0.001) than those for the city of Ufa (0.512) and elsewhere worldwide. When we analyzed the sex ratio of the children according to maternal or paternal exposure, we observed a decrease in the number of boys (ratio 0.38) for fathers and a normal number (ratio 0.51) for the mothers. Human exposure of these pesticide producers to high levels of dioxins is associated with the birth of more girls, but only for paternal exposures.     

Conantokin-L,a new NMDA receptor antagonist: determinants for anticonvulsant potency

Conantokins are N-methyl-D-aspartate receptor antagonist peptides found in the venoms of marine cone snails. Current intense interest in this peptide family stems from the discovery of their therapeutic potential as anticonvulsants. It was recently reported that conantokin-R is a highly potent anticonvulsant compound, with a protective index of 17.5 when tested in the audiogenic mouse model of epilepsy. Conantokin-L was characterized from Conus lynceus and found to have extensive homology with conantokin-R, except For the C-terminal amino acids. Although conantokin-L appears almost as potent as conantokin-R in standard in vivo assays for conantokins and NMDA receptor binding assays, it is far less potent as an anticonvulsant, with a protective index of 1.2 in the audiogenic mouse model. The results suggest that the C-terminal sequences of conantokin-R and conantokin-L are a major determinant of their anticonvulsant potency.     

Improving the consistency in cervical esophageal target volume definition by special training

PURPOSE: Three-dimensional conformal radiation therapy requires the precise definition of the target volume. Its potential benefits could be offset by the inconsistency in target definition by radiation oncologists. In a previous survey of radiation oncologists, a large degree of variation in target volume definition of cervical esophageal cancer was noted for the boost phase of radiotherapy. The present study evaluated whether special training could improve the consistency in target volume definitions. METHODS AND MATERIALS: A pre-training survey was performed to establish baseline values. This was followed by a special one-on-one training session on treatment planning based on the RTOG 94-05 protocol to 12 radiation oncologists. Target volumes were redrawn immediately and at 1-2 months later. Post-training vs. pre-training target volumes were compared. RESULTS: There was less variability in the longitudinal positions of the target volumes post-training compared to pre-training (p < 0.05 in 5 of 6 comparisons). One case had more variability due to the lack of a visible gross tumor on CT scans. Transverse contours of target volumes did not show any significant difference pre- or post-training. CONCLUSION: For cervical esophageal cancer, this study suggests that special training on protocol guidelines may improve consistency in target volume definition. Explicit protocol directions are required for situations where the gross tumor is not easily visible on CT scans. This may be particularly important for multicenter clinical trials, to reduce the occurrences of protocol violations.     

Same-day pegfilgrastim and chemotherapy

Pegylated filgrastim is a new formulation of a neutrophil colony-stimulating factor that has a long circulating half-life, permitting a single dose of filgrastim per cycle of chemotherapy. The pegylated filgrastim is recommended to be administered not less than 24 hours following chemotherapy and not less than 14 days prior to chemotherapy based on the theoretic concern that marrow suppression would be accentuated. This schedule of usage for pegylated filgrastim may compromise its application for weekly chemotherapy schedules. We have treated 80 patients with pegylated filgrastim administered on the same day as chemotherapy; the latter delivered on a weekly schedule. Twenty-four patients had non-small cell lung cancer (NSCLC) and were treated with one of two weekly chemotherapy regimens alternating triplets [AT] taxane, cisplatin, irinotecan alternating with gemcitabine, cisplatin, vinorelbine or alternating doublets [AD] taxane, cisplatin alternating with gemcitabine, vinorelbine; four of these patients also received weekly taxane and carboplatin with concomitant thoracic radiation. A consistent pattern emerged in which leukocytosis was observed at Day 8; median WBC 15,800/uL (range 7,200 to 35,000/uL); at Day 14, the median WBC was 9,300/uL (range 1,100 to 17,400/uL). Pegylated filgrastim can be given safely simultaneously with chemotherapy in weekly chemotherapy schedules. The pegfilgrastim can be administered on an every two week (fortnightly) schedule to maintain a weekly chemotherapy schedule.     

Bioassessment of an Appalachian Headwater Stream Influenced by an Abandoned Arsenic Mine

Recent debate concerning the modification of safe drinking water standards for arsenic (As) has led to increased awareness of the risks As poses to both humans and the environment. However, few studies have examined the effects of As on the diversity and composition of aquatic assemblages in streams. Benthic macroinvertebrate surveys, chemical analysis of water column and sediment, and laboratory toxicity tests were conducted to assess effects of an abandoned As mine on a headwater stream, and to determine the primary component of toxicity. The average 48-hr LC50 value for Daphnia magna was 4316 μg As/L, and the average 96-hr LC50 value for Lepidostoma spp. was 2138 μg As/L. Reproduction was significantly reduced for D. magna at concentrations ≥312 μg As/L in water column laboratory bioassays, and for treatments in bioassays with sediments containing elevated As (≥2630 mg/kg). These results support the findings of the in-stream benthic macroinvertebrate survey as the density and percent Ephemeroptera + Plecoptera, + Trichoptera (EPT) were substantially lower at sites downstream of the mine compared to upstream reference sites. Results of bioassays comparing the toxicity of As-contaminated site water and upstream reference water spiked with As salts suggest that As is the primary component of toxicity impacting the stream. Measured As concentrations at downstream sites were above the recommended Criterion Maximum Concentration of 340 μg As/L and Criterion Continuous Concentration of 150 μg As/L for protection of aquatic life published by the United States Environmental Protection Agency. At the study site, elevated As concentrations likely prevent recruitment of benthic macroinvertebrates and recovery of the perturbed headwater stream.     

Immunization Needs of Chronic Liver Disease Patients Seen in Primary Care Versus Specialist Settings

Chronic liver disease patients may benefit from certain vaccines, but their immunization coverage levels have not been widely studied. We examined the serologic and vaccination status of 693 chronic liver disease patients from 37 primary care and specialist centers. Patients in primary care had more often received influenza (47 versus 32%; P < .001) and pneumococcal (39 versus 19%; P < .001) vaccines. Among patients without documented prior exposure, those seeing specialists had more often completed hepatitis A (28 versus 5%; P < .001) and hepatitis B (29 versus 14%; P < .001) vaccination. Coverage was higher in centers with a policy of vaccinating on-site, among non-Hispanic whites, and among patients with hepatitis C and cirrhosis. In summary, most patients were unprotected against one or more vaccine preventable diseases. The higher coverage rates evident in centers vaccinating on-site suggests a breakdown may occur when patients are referred to alternative vaccination venues.