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Biomedical subjects

J L Wagner

Publications and source records attributed to J L Wagner.

At least 19 recordsLinked to original sources
PubMed2001

Pharmacogenetics of methotrexate: toxicity among marrow transplantation patients varies with the methylenetetrahydrofolate reductase C677T polymorphism.

This study investigated whether a polymorphism in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene (C677T) modifies responses to methotrexate (MTX) in patients undergoing bone marrow transplantation. About 10% to 12% of the population carry the MTHFR TT genotype (enzyme activity, 30% of wild type [CC]). Patients (n = 220) with chronic myelogenous leukemia underwent marrow allografts and were given a short course of MTX. MTX toxicity measures included the oral mucositis index (OMI), speed of engraftment (platelet and granulocyte counts), and bilirubin. Patients with lower MTHFR activity (TT genotype) had 36% higher mean OMI during days 1 to 18 (+5.7, P =.046) and 20% higher OMI between days 6 and 12 (+3.8, P =.27). Platelet counts recovered more slowly among patients with the TT genotype compared to wild type (24% slower recovery to 10 000 platelets/microL, P =.23; 34% slower to 20 000/microL, P =.08). Patients with decreased MTHFR activity appear at risk of higher MTX toxicity. Because of the high prevalence of the TT genotype, these results may have implications for MTX dosage.

Adult↗
PubMed2001

Hematopoietic cell transplantation in older patients with hematologic malignancies: replacing high-dose cytotoxic therapy with graft-versus-tumor effects.

Toxicities have limited the use of allogeneic hematopoietic cell transplantation (HCT) to younger, medically fit patients. In a canine HCT model, a combination of postgrafting mycophenolate mofetil (MMF) and cyclosporine (CSP) allowed stable allogeneic engraftment after minimally toxic conditioning with low-dose (200 cGy) total-body irradiation (TBI). These findings, together with the known antitumor effects of donor leukocyte infusions (DLIs), led to the design of this trial. Forty-five patients (median age 56 years) with hematologic malignancies, HLA-identical sibling donors, and relative contraindications to conventional HCT were treated. Immunosuppression involved TBI of 200 cGy before and CSP/MMF after HCT. DLIs were given after HCT for persistent malignancy, mixed chimerism, or both. Regimen toxicities and myelosuppression were mild, allowing 53% of eligible patients to have entirely outpatient transplantations. Nonfatal graft rejection occurred in 20% of patients. Grades II to III acute graft-versus-host disease (GVHD) occurred in 47% of patients with sustained engraftment. With median follow-up of 417 days, survival was 66.7%, nonrelapse mortality 6.7%, and relapse mortality 26.7%. Fifty-three percent of patients with sustained engraftment were in complete remission, including 8 with molecular remissions. This novel allografting approach, based on the use of postgrafting immunosuppression to control graft rejection and GVHD, has dramatically reduced the acute toxicities of allografting. HCT with the induction of potent graft-versus-tumor effects can be performed in previously ineligible patients, largely in an outpatient setting. Future protocol modifications should reduce rejection and GVHD, thereby facilitating studies of allogeneic immunotherapy for a variety of malignancies. (Blood. 2001;97:3390-3400)

Adult↗
PubMed2001

Is rheumatoid arthritis care more costly when provided by rheumatologists compared with generalists?

OBJECTIVE: Controversy surrounds the cost-effectiveness of rheumatologist care compared with generalist care for patients with rheumatoid arthritis (RA). Rheumatologists can provide 2 distinct types of care for RA patients: primary care and specialist care. We sought to examine the relationship between cost and type of care in a population-based cohort of patients with RA. METHODS: Data regarding specialty of care and use of health services (i.e., total direct medical costs, surgeries, radiographs, laboratory tests, hospital days) were collected from a community sample of 249 patients with RA (defined using the 1987 American College of Rheumatology diagnostic criteria) among Rochester, Minnesota residents > or =35 years of age. In a randomly selected subset of 99 of these RA patients, detailed information on all physician encounters was collected and categorized according to whether or not the care received constituted "primary care" according to the Institute of Medicine definition. Using these data, we evaluated the influence of type of care as well as specialty of provider on utilization. For these analyses, total direct costs included all inpatient and outpatient health care costs incurred by all local providers (excluding outpatient prescription drugs). RESULTS: The 249 patients with RA (mean age 64 years, 75% women) were followed up for a median of 5.4 years, while the subset of 99 RA patients (mean age 64 years, 77% women) were followed up for a median of 4.7 years. The overall median direct medical costs per person per year were $2,749 and $2,929 for the total cohort and for the subset of 99 patients, respectively. Generalized linear regression analyses (considering all visits of the 249 RA patients) revealed that after adjusting for demographics and disease characteristics, rheumatologist care (compared with nonrheumatologist care) was not associated with higher total direct medical costs (P = 0.85) or more hospital days (P = 0.35), but was associated with slightly more radiographs (P = 0.037) and significantly more laboratory tests (P < 0.0001). When considering only primary care, such care by rheumatologists was, again, not associated with higher total direct medical costs (P = 0.11) or more hospital days (P = 0.69) or more laboratory tests (P = 0.54), but was associated with slightly more radiographs (P = 0.035). CONCLUSION: Rheumatologist care is not more costly than generalist care for patients with RA. Important differences (especially in the use of laboratory tests) become apparent when the type of care provided as well as the specialty of the provider are considered in the analyses.

Adult↗
PubMed2001

Utility of additional slides from residual Preservcyt material in difficult ThinPrep gynecologic specimens: a prospective study of 58 cases.

ThinPrep purportedly increases the sensitivity of cervicovaginal cytology for detecting abnormal squamous and glandular cells. The value of additional slides from residual Preservcyt material to characterize difficult lesions is unknown. Fifty-eight cases were studied to determine the utility of additional slides for diagnosis and to assess cellular uniformity. In 32 (55%), repeat slides helped make a definitive diagnosis, including 18 atypical squamous cells of uncertain significance (ASCUS) reclassified as low-grade squamous intraepithelial lesion (LGSIL) (13), high-grade squamous intraepithelial lesion (HGSIL) (4), or endometrial adenocarcinoma (1); 5 LGSIL reclassified as HGSIL; 3 atypical glandular cells of uncertain significance (AGUS) reclassified as LGSIL (1) or HGSIL (2); 2 LGSIL?HGSIL classified as LGSIL; and 4 cases confirmed as LGSIL (2) or HGSIL (2). Results were compared to follow-up clinical information, including subsequent cervicovaginal samples and biopsies. The number of abnormal cells was similar between slides in most cases. We conclude that, while ThinPreps prepared from the same vial have similar numbers of abnormal cells, additional slides can be helpful for diagnosis in select cases.

Female↗
PubMed2001

Economic analysis of lung volume reduction surgery as part of the National Emphysema Treatment Trial. NETT Research Group.

BACKGROUND: In today's cost-conscious health care environment, obtaining timely and accurate economic information regarding new medical technologies has become extremely important. The National Emphysema Treatment Trial, a multicenter, randomized controlled trial of lung volume reduction surgery (LVRS) plus medical therapy, versus medical therapy for patients with severe emphysema, includes a parallel cost-effectiveness analysis. METHODS: The analysis is designed to determine the cost-effectiveness of LVRS versus medical therapy for those who are eligible for the procedure. After describing theoretical foundations of cost-effectiveness analysis as they apply to this study, we describe the economic and quality of life data that are being collected alongside the clinical trial, methods of analysis, and approach to presenting the results. RESULTS: The cost-effectiveness of LVRS relative to medical therapy will be presented as costs per quality-adjusted life years gained. CONCLUSIONS: This analysis will provide timely economic data that can be considered alongside the clinical results of the National Emphysema Treatment Trial. As one of the largest clinical trials to include a parallel, prospective cost-effectiveness analyses, this study will also provide valuable practical information about conducting an economic analysis alongside a multicenter clinical trial.

Cost-Benefit Analysis↗
PubMed2001

Nomenclature for factors of the dog major histocompatibility system (DLA), 2000: second report of the ISAG DLA Nomenclature Committee.

The International Society for Animal Genetics (ISAG) Dog Leukocyte Antigen (DLA) Nomenclature Committee met during the "Comparative Evolution of the Mammalian major Histocompatibility Complex (MHC)" meeting in Manchester, UK on 10 September 2000. The main points discussed were the naming of class I genes and alleles, and the inclusion of alleles from other canidae.

Alleles↗
PubMed2001

Racial and ethnic colorectal cancer patterns affect the cost-effectiveness of colorectal cancer screening in the United States.

BACKGROUND & AIMS: Colorectal cancer screening beginning at age 50 is recommended for all Americans considered at "average" risk for the development of colorectal cancer. METHODS: We used 1988-1995 California Cancer Registry data to compare the cost-effectiveness of two 35-year colorectal cancer screening interventions among Asians, blacks, Latinos, and Whites. RESULTS: Average annual age-specific colorectal cancer incidence rates were highest in blacks and lowest in Latinos. Screening beginning at age 50 was most cost-effective in blacks and least cost-effective in Latinos (measured as dollars spent per year of life saved), using annual fecal occult blood testing (FOBT) combined with flexible sigmoidoscopy every 5 years and using colonoscopy every 10 years. A 35-year screening program beginning in blacks at age 42, whites at age 44, or Asians at age 46 was more cost-effective than screening Latinos beginning at age 50. CONCLUSIONS: Colorectal cancer screening programs beginning at age 50, using either FOBT and flexible sigmoidoscopy or colonoscopy in each racial or ethnic group, are within the $40,000-$60,000 per year of life saved upper cost limit considered acceptable for preventive strategies. Screening is most cost-effective in blacks because of high age-specific colorectal cancer incidence rates.

Adult↗
PubMed2000

Exfoliative cytology of primary poorly differentiated (small-cell) neuroendocrine carcinoma of the uterine cervix in ThinPrep material: a case report.

Poorly differentiated neuroendocrine (small-cell) carcinoma of cervical origin is a rare neoplasm that frequently metastasizes. Although the cytologic features have been described for conventional cervical smears, we know of no reports of its appearance in ThinPrep (TP) material. Therefore, we present a TP case of primary, small-cell carcinoma arising in a 46-yr-old female, confirmed by histologic and immunohistochemical analysis. Similar to conventional smears, the neoplastic cells occurred either individually or in small clusters. The cells were relatively monomorphic, with stippled chromatin and minimal amounts of cytoplasm. Unlike conventional smears, nuclear molding was not prominent (although overlap was observed), and nuclear smearing was not identified. The features are compared to TP cases of squamous-cell carcinoma, small-cell type, and endometrioid adenocarcinoma, which are close mimics of small-cell carcinoma. We conclude that correct diagnosis of small-cell carcinoma in TP is difficult, requiring a high degree of suspicion and immunohistochemical confirmation.

Carcinoma, Small Cell↗
PubMed2000

De novo chronic graft-versus-host disease in marrow graft recipients given methotrexate and cyclosporine: risk factors and survival.

A retrospective study was performed to determine risk factors for the development of de novo chronic graft-versus-host disease (GVHD) in patients given marrow grafts from HLA-identical sibling donors (85%), HLA-nonidentical family members (3%), or HLA-matched unrelated donors (12%) and for postgrafting immunosuppression with methotrexate and cyclosporine. We also examined the impact of chronic GVHD on survival and identified patients at low risk for chronic GVHD in whom immunosuppression might be stopped safely early after transplantation. Among 489 patients with either grade 0 or I acute GVHD, 33% developed chronic GVHD. Overall survival was 70%, and relapse-free survival was 63% at 8 years. Risk factors for chronic GVHD were found to include donor buffy coat infusions among patients given transplants for aplastic anemia (relative risk [RR] = 2.9, P = .05), patient-donor sex/parity combination (likelihood ratio test, P < .001), grade I acute GVHD (RR = 1.6, P = .003), and active cytomegalovirus infection (RR = 1.5, P = .05) before day 60. Among 45 patients aged <19 years who had male donors, only 1 developed chronic GVHD. This group had an overall survival rate of 65% and a relapse-free survival rate of 54% at 8 years post-transplantation-a result not better than that among the entire cohort. The lack of improvement in survival in the low-risk group was related to a high rate of relapse of the underlying diseases. Therefore, the development of de novo chronic GVHD does not have a negative impact on patient survival; the adverse effect from increased transplantation-related complications is offset by a lower relapse rate, the result of an allogeneic graft-versus-tumor effect.

Adolescent↗
PubMed2000

Dog class I gene DLA-88 histocompatibility typing by PCR-SSCP and sequencing.

The dog has been an important model for solid organ and hematopoietic stem cell transplantation, as well as for studying autoimmune diseases, the growth of malignant tumors and the immunology of vaccines. Fundamental to the continuing usage of the canine model for research is the development of molecular-based histocompatibility typing. Previous histocompatibility methods have focused on class II genes. This study was undertaken to develop a molecular-based histocompatibility typing method for the most polymorphic class I gene, DLA-88. In this study, polymerase chain reaction single-stranded conformational polymorphism was used to separate alleles, thereby allowing sequenced-based typing.

Alleles↗
PubMed2000

DLA-DQB1 alleles and bone marrow transplantation experiments in narcoleptic dogs.

Human narcolepsy is a neurological disorder known to be tightly associated with HLA-DQB1*0602. A clinically similar disorder has been described in various dog breeds. The canine form of the disease is inherited as an autosomal recessive disorder in Labrador retrievers and Doberman pinschers (canarc-1) but occurs sporadically in other breeds, most typically dachshunds and poodles. In this study, we have examined if there is a relationship between the development of narcolepsy and specific dog leukocyte antigen (DLA)-DQB1 alleles. Ninety-nine dogs were typed for DLA-DQB1-31 with narcolepsy and 68 control animals. Recent studies have linked the development of autosomal recessive canine narcolepsy to a disruption of the hypocretin receptor 2 (Hcrtr2) gene on the same chromosome as the canine MHC region (CFA12), but not close to the DLA. Four Hcrtr2-positive families (two Doberman pinscher families, one Labrador retriever family, one dachshund family) were analyzed at the DLA-DQ level. No relationship was found between narcolepsy and DLA in Hcrtr2-mediated narcolepsy but loose genetic linkage was observed (Zmax=2.3 at theta=25%, m= 40). Bone marrow transplantation between two DLA identical affected (Hcrtr2-/-) and unaffected (Hcrtr2+/-) siblings was also performed and found not to be successful neither in transmitting narcolepsy nor in relieving the symptoms in Doberman pinschers. DLA-DQB1 was next studied in 11 dogs with sporadic (non-familial) narcolepsy and in unrelated control animals of the same and different breeds. The allelic and carrier frequencies of various DLA-DQB1 alleles were analyzed. There was no strong positive or negative correlation between the development of narcolepsy and specific DLA-DQB1 alleles. These results do not support the involvement of DLA-DQ in canine narcolepsy, whether of sporadic or familial origin.

Animals↗
PubMed2000

Nomenclature for factors of the dog major histocompatibility system (DLA), 1998: first report of the ISAG DLA Nomenclature Committee.

A Nomenclature committee for Factors of the Dog Major Histocompatibility System or Dog Leukocyte Antigen (DLA) has been convened under the auspices of the International Society for Animal Genetics (ISAG) to define a sequence based nomenclature for the genes of the DLA system. The remit of this committee includes: assignment of gene names rules for naming alleles assignment of names to published alleles assignment of names to new alleles rules for acceptance of new alleles DLA Nomenclature Committee, rules for acceptance, DLA genes and alleles, sequence based nomenclature.

Alleles↗
PubMed2000

Epistaxis associated with elevation of INR in a patient switched to generic warfarin.

A 61-year-old man with atrial fibrillation receiving Coumadin brand warfarin was switched to Barr brand warfarin without his knowledge as a result of a retail pharmacy dispensing error. The patient took the same dosage for 6-7 days and experienced severe epistaxis that required two visits to the emergency room. Previously, his coagulation values were within therapeutic range, but when tested at the emergency room the international normalized ratio was elevated. The patient denied changes in therapy compliance, diet, alcohol ingestion, or use of other drugs. His only other drug, taken periodically, was sildenafil for erectile dysfunction. Clinicians should be aware of differences between branded and generic compounds.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed1999

Stable mixed hematopoietic chimerism in dogs given donor antigen, CTLA4Ig, and 100 cGy total body irradiation before and pharmacologic immunosuppression after marrow transplant.

Stable mixed chimerism can be established in dogs given a sublethal dose of 200 cGy total body irradiation (TBI) before and immunosuppression with mycophenolate mofetil (MMF) and cyclosporine (CSP) for 28 and 35 days, respectively, after dog leukocyte antigen-identical marrow transplantation. Most likely, the role of pretransplant TBI was to provide host immunosuppression, since stable mixed chimerism was also achieved in MMF/CSP-treated dogs when 450 cGy irradiation, targeted to cervical, thoracic, and upper abdominal lymph nodes, was substituted for TBI. When TBI was reduced from 200 to 100 cGy, all grafts were rejected within 3 to 12 weeks. Here, we asked whether stable engraftment after 100 cGy TBI could be accomplished by first reducing the intensity of host immune responsiveness with help of the fusion peptide CTLA4Ig, which blocks T-cell costimulation through the B7-CD28 signal pathway. Accordingly, recipient T cells were activated with intravenous (IV) injections of 10(6) donor peripheral blood mononuclear cells (PBMC)/kg per day on days -7 to -1 before 100 cGy TBI, with concurrent administration of CTLA4Ig 4 mg/kg/d IV. All 7 dogs so treated showed initial mixed chimerism. Two rejected their allografts after 8 and 20 weeks, respectively, and survived with autologous marrow recovery; 1 mixed chimera was unevaluable because of death at 3 weeks from intussusception; and 4 showed persisting mixed chimerism, including unirradiated marrow and lymph node spaces, for now more than 46 to 70 weeks after transplant. Data support the hypothesis that stable marrow allografts can be established by combining nonmyeloablative pretransplant host immunosuppression with posttransplant host and donor cell immunosuppression using MMF/CSP.

Abatacept↗
PubMed1999

Stable mixed hematopoietic chimerism in dog leukocyte antigen-identical littermate dogs given lymph node irradiation before and pharmacologic immunosuppression after marrow transplantation.

Stable mixed donor/host hematopoietic chimerism can be accomplished in dog leukocyte antigen (DLA)-identical littermate dogs given sublethal (200 cGy) total-body irradiation (TBI) before and immunosuppression with mycophenolate mofetil (MMF) and cyclosporine (CSP) after transplant (Blood 89:3048, 1997). Studies were based on the hypothesis that drugs that prevent graft-versus-host disease (GVHD) after transplant also suppress host-versus-graft (HVG) reactions and thereby enhance engraftment. Here, we asked whether pretransplant TBI provided marrow space for the graft to home or caused host immunosuppression. To address the questions, recipients were given pretransplant irradiation to cervical, thoracic, and abdominal lymph nodes (except pelvis), DLA-identical littermate marrow grafts, and MMF/CSP posttransplant. Six dogs that received 450 cGy irradiation showed initial engraftment. Two rejected their grafts after 8 and 18 weeks, 1 died with GVHD and engraftment, and 3 are alive as mixed chimeras after 57 to 97 weeks. Four dogs given 200 cGy irradiation also showed initial engraftment, but rejected their grafts after 10 to 18 weeks. Mixed chimerism was present in nonirradiated marrow and lymph node spaces and involved granulocytes, T cells, and monocytes. While other explanations are possible, results seem consistent with the hypothesis that pretransplant radiation provides host immunosuppression, and grafts can create their own marrow space. These data set the stage for the development of novel transplant regimens that substitute immunosuppressive for cytotoxic agents.

Animals↗
PubMed1999

Long-term survival and function of intrahepatic islet allografts in rhesus monkeys treated with humanized anti-CD154.

Reported effects of anti-CD154 treatment on autoimmunity, alloreactivity, and inflammatory events mediated by macrophages and endothelial cells indicated that it might be an ideal agent for the prevention of intrahepatic islet allograft failure. This hypothesis was tested in MHC-mismatched rhesus monkeys. Transplantation of an adequate number of viable islets resulted in engraftment and insulin independence in six of six recipients treated with anti-CD154 (hu5c8) induction plus monthly maintenance therapy (post-operative day >125, >246, >266, >405, >419, >476). Anti-CD154 (hu5c8) displayed no inhibitory effect on islet cell function. For monkeys followed for >100 days, continued improvement in graft function, as determined by first phase insulin release in response to intravenous glucose, was observed after the first 100 days post-transplant. No evidence of toxicity or infectious complications has been observed. All recipients treated with anti-CD154 became specifically nonresponsive to donor cells in mixed lymphocyte reactions. Furthermore, three monkeys are now off therapy (>113, >67, and >54 days off anti-CD154), with continued insulin independence and donor-specific mixed lymphocyte reaction hyporeactivity. In striking contrast to all previously tested strategies, transplantation of an adequate number of functional islets under the cover of anti-CD154 (hu5c8) monotherapy consistently allows for allogeneic islet engraftment and long-term insulin independence in this highly relevant preclinical model.

Animals↗