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John R Wingard

Publications and source records attributed to John R Wingard.

At least 37 records · Page 2Linked to original sources
PubMed2005

Caspofungin versus amphotericin B for candidemia: a pharmacoeconomic analysis.

BACKGROUND: In a randomized, comparative, clinical trial, caspofungin was found to be as effective as amphotericin B deoxycholate (ampho B) for treating candidemia (favorable outcomes in 71.7% and 62.8% of patients, respectively) and exhibited a generally better safety profile, particularly with respect to impaired renal function (IRF) (P = 0.02). OBJECTIVE: The goal of this study was to examine whether cost savings generated from the reduced rates of IRF observed in the clinical trial would be enough to offset the higher acquisition cost of caspofungin relative to ampho B. METHODS: We developed an economic model in which 100 hypothetical patients with candidemia were treated with caspofungin or ampho B. Rates of IRF and duration of drug therapy were taken from the clinical trial. Information on the cost of treating IRF was obtained through a search of MEDLINE using the terms amphotericin and cost, amphotericin and resource, amphotericin and hospital, and amphotericin and toxicity; and the medical subject headings kidney failure, acute/drug therapy; kidney failure, acute/epidemiology; kidney failure, acute/etiology; kidney/drug effects; cost of illness; costs and cost analysis; kidney failure, acute, and economics; and kidney failure, acute/economics. In addition, the Web site was searched for relevant references, and the Merck publication alert system was used. Antifungal drug costs were estimated using data from IMS Health. Costs were reported in year-2003 US dollars. RESULTS: In the base case, the model projected that using caspofungin instead of ampho B would result in substantially lower treatment costs for IRF, which would more than offset the higher drug acquisition cost (cost-offset percentage, 122%), leading to a net mean savings of 758.60 US dollars per patient. These results were not very sensitive to the difference in daily drug cost, but were sensitive to the mean cost attributable to treating IRF. As that varied, the cost-offset percentage varied from 61% (substantial cost offset) to 183% (cost savings). CONCLUSIONS: The results of this economic model suggest that, based only on differences in drug acquisition cost and renal toxicity, the use of caspofungin instead of ampho B in patients with candidemia may be a cost-saving strategy from the perspective of a hospital.

Amphotericin B↗
PubMed2005

The changing face of invasive fungal infections in hematopoietic cell transplant recipients.

PURPOSE OF REVIEW: To review recent observations that describe changes in the likelihood of invasive fungal infections, shifts in types of fungal pathogens, and altered manifestations of fungal syndromes after hematopoietic cell transplantation and explore how changes in transplant practices are influencing these epidemiologic shifts. RECENT FINDINGS: Shifts in invasive fungal infections are occurring as a consequence of changes in transplant practices, including the intensity of conditioning regimens, new immunosuppressive therapies, new antineoplastic therapies administered before hematopoietic cell transplantation, and possibly use of mold-active agents as prophylaxis. Non-fumigatus Aspergillus species and other mold pathogens, such as Fusarium and zygomycosis, are assuming greater prominence and may be increasing. SUMMARY: Epidemiologic shifts in invasive fungal infections are likely co-travelers with advances in transplant practices. Thus, ongoing studies of epidemiologic shifts in invasive fungal infections are important.

Fusarium↗
PubMed2005

Developmental differences in megakaryocyte maturation are determined by the microenvironment.

Historically, physicians have attributed delayed platelet engraftment following umbilical cord blood transplant to decreased numbers of stem cells in cord blood compared with adult bone marrow. However, recent studies suggest that delayed platelet engraftment may be caused by an intrinsic inability of neonatal stem cells to produce mature, polyploid megakaryocytes. We tested this hypothesis by transplanting adult bone marrow and newborn liver hematopoietic stem and progenitor cells from transgenic mice expressing green fluorescent protein into myeloablated wild-type recipients and comparing the size and ploidy levels of megakaryocytes that developed in adult transplant recipients. Transplanted stem and progenitor cells, regardless of their source, gave rise to megakaryocytes that were larger than normal adult megakaryocytes as early as 7 days post-transplant. However, megakaryocytes that developed after transplant of neonatal stem and progenitor cells were significantly smaller than those derived from adult stem and progenitor cells. Furthermore, megakaryocytes derived from neonatal cells had lower ploidy values than megakaryocytes derived from adult cells at 18 days post-transplant, when ploidy could first be reliably measured in the bone marrow. These differences in size and ploidy disappeared by 1 month post-transplant. The largest megakaryocytes developed in the spleen. These results suggest that, in the mouse, the microenvironment is responsible for some of the maturational differences in size and ploidy between neonatal and adult megakaryocytes. Furthermore, neonatal and adult megakaryocyte progenitors also have cell-intrinsic differences in the way they engraft and respond to thrombocytopenic stress. These differences may contribute to the delay in platelet engraftment that frequently complicates cord blood transplants.

Age Factors↗
PubMed2004

The design of clinical trials that evaluate antifungal prophylaxis and combination therapy: introduction and overview.

On 8 February 2003, the second in a series of meetings in honor of John E. Bennett, M.D., was convened in New York City. A report from the previous meeting was published in 2003. The goal of this second meeting was to discuss the design of clinical trials in prophylaxis and combination therapy. This supplement presents 12 articles by leading clinicians who are currently active in trials in this area and presents a current view of the unmet needs and challenges.

Antifungal Agents↗
PubMed2004

Design issues in a prospective randomized double-blinded trial of prophylaxis with fluconazole versus voriconazole after allogeneic hematopoietic cell transplantation.

BACKGROUND: Aspergillus infections pose the toughest infectious challenges to the clinician caring for hematopoietic cell transplant recipients. About 15% of patients become infected, with a case fatality rate of approximately 65%. To date, no effective prophylactic strategies have been developed. METHODS: Voriconazole, a recently licensed extended-spectrum azole, with demonstrated efficacy against aspergillus, is currently being tested as a potential prophylactic agent against aspergillus and other invasive fungal infections. Logistic issues--such as patient selection, choice of comparator, blinding of study drugs, duration of study drug administration, and how to handle empirical amphotericin B for possible invasive fungal infections--and analytic concerns, including choice and definition of the primary end point and the potential confounding effect of informative censoring (as a result of noninfectious events), were considered in the design of the clinical trial. RESULTS: The trial is now under way, with a projected 3-year enrollment period. CONCLUSIONS: Each design decision shaped the trial in a way that permitted certain questions to be answered while not allowing others to be addressed. Once completed, the trial's results must be interpreted in light of these design details.

Antifungal Agents↗
PubMed2004

Empirical antifungal therapy in treating febrile neutropenic patients.

Persistent or recurrent unexplained fever in neutropenic patients receiving antibiotics can be caused by invasive fungal infections, which are often difficult to diagnose. Early trials of empirical antifungal therapy with amphotericin B deoxycholate (AmB) documented reductions in the frequency of and the morbidity and mortality associated with invasive fungal infections. Because of AmB's infusional and renal toxicities, subsequent trials used newer, less toxic agents, such as the lipid formulations of AmB, the extended-spectrum azoles, and, more recently, the echinocandins. To date, alternatives to AmB have shown less toxicity, but improved efficacy has been less clear. Overall, empirical antifungal therapy can help prevent the morbidity associated with many fungal infections, eliminate concerns about diagnostic pitfalls, and prevent breakthrough undetected infections. However, its potential shortcomings are overtreatment, toxicity, and increased treatment-related costs when treatment is given to persons not needing it. Newer diagnostic tools are needed to target those most in need of antifungal therapy.

Amphotericin B↗
PubMed2004

Physicians' attitudes about quality-of-life issues in hematopoietic stem cell transplantation.

Studies investigating quality of life (QOL) after hematopoietic stem cell transplantation demonstrate the spectrum of QOL outcomes awaiting survivors. Nevertheless, how transplantation physicians interpret and apply QOL information to clinical practice is poorly understood. We conducted a cross-sectional survey of transplantation physicians to address these issues and received 180 (24%) responses from physicians in 29 countries. Seventy-two percent reported that their patients are willing to accept poor QOL for a small chance of cure. Only 28% said that QOL considerations "often" or "almost all the time" enter into patients' decisions about transplantation. This contrasted with physicians' reported attention to QOL in their discussions with patients. Although 53% of physicians reported using QOL results to modify practice, 55% would be more likely to use these data if they were more understandable. To ensure generalizability of the results, a validation sample was randomly selected, and these 85 physicians (response rate, 76%) confirmed the findings of the original survey. Given the extensive data regarding posttransplantation QOL, resources should be devoted to exploring how patients and physicians use these data in clinical care and in devising methods to ensure that QOL results are interpretable and relevant to patients and physicians.

Adaptation, Psychological↗
PubMed2004

Bone marrow transdifferentiation in brain after transplantation: a retrospective study.

BACKGROUND: End-organ repair by adult haemopoietic stem cells is under great scrutiny with investigators challenging the notion of these cells' plasticity. Some investigations of animals and short-term human bone marrow transplants suggest that bone marrow can repair brain. We looked for evidence of clinically relevant marrow-derived restorative neurogenesis: long-term, multilineage, neural engraftment that is not the result of cell-fusion events. METHODS: We examined autopsy brain specimens from three sex-mismatched female bone-marrow-transplantation patients, a female control, and a male control. We did immunohistochemistry, fluorescence in-situ hybridisation, and tissue analysis to look for multilineage, donor-derived neurogenesis. FINDINGS: Hippocampal cells containing a Y chromosome were present up to 6 years post-transplant in all three patients. Transgender neurons accounted for 1% of all neurons; there was no evidence of fusion events since only one X chromosome was present. Moreover, transgender astrocytes and microglia made up 1-2% of all glial cells. INTERPRETATION: Postnatal human neuropoiesis happens, and human haemopoietic cells can transdifferentiate into neurons, astrocytes, and microglia in a long-term setting without fusing. Transplantable human haemopoietic cells could serve as a therapeutic source for long-term regenerative neuropoiesis.

Adult↗
PubMed2004

Low dendritic cell count after allogeneic hematopoietic stem cell transplantation predicts relapse, death, and acute graft-versus-host disease.

Dendritic cells (DCs) are key antigen-presenting cells with a potential role in tumor vaccines. We investigated the hypothesis that early reconstitution of DCs after allogeneic hematopoietic stem cell transplantation (SCT) improves survival. We also correlated DC reconstitution with complications of relapse and acute graft-versus-host disease (aGVHD). Fifty patients underwent transplantation between February 2000 and March 2003, with a median follow-up of 501 days (range, 136-1263 days). Most (92%) received blood stem cells, and the remainder received bone marrow from HLA-matched sibling donors for predominantly high-risk hematologic malignancies. Around the time of engraftment, peripheral blood underwent flow cytometry analysis for DCs, and the cells were divided as DC1 and DC2. Using Kaplan-Meier analysis, patients with lower DC counts (< 4.97 cells/microL) were found to have significantly worse survival (P =.002), increased incidence of relapse (P =.002), higher incidence of aGVHD onset (P =.0005), and a composite end point of relapse or death (P =.0017). A Cox proportional hazards multivariate model adjusted for important covariates confirmed that low DC count is independently associated with death (hazard ratio [HR], 3.8; P =.02), time to relapse (HR, 11.6; P =.001), and aGVHD (HR, 3.3; P =.04). Sensitivity and specificity rates for low DC count in predicting death or relapse are 73% and 75%, respectively. Low numbers of circulating DCs significantly increase the risk for relapse and acute GVHD and predict death after allogeneic SCT.

Acute Disease↗
PubMed2004

A new era of antifungal therapy.

Invasive fungal infections pose major management problems for clinicians caring for hematopoietic cell transplant patients. Two major fungal genera, Candida and Aspergillus, account for most fungal infections. Rates of systemic Candida infection range from 15% to 25%, mostly in the pre-engraftment period. Prophylaxis by fluconazole has dramatically reduced the frequency of early Candida infections. Caspofungin has recently been shown to offer an excellent alternative to amphotericin B (with less toxicity) or fluconazole (with a broader spectrum) for therapy of systemic Candida infections. Aspergillus infections occur in 15% to 20% of allogeneic hematopoietic cell transplant patients, most frequently in the post-engraftment period; they are associated with a severe diminution of cell-mediated immune responses by graft-versus-host disease and prolonged corticosteroid use. Voriconazole, a recently introduced broad-spectrum azole, has excellent activity against Aspergillus and is generally well tolerated. Voriconazole currently offers the best prospect for success and tolerance as a first-line treatment for aspergillosis. Second-line therapies include lipid formulations of amphotericin B, caspofungin, or intravenous itraconazole. Unfortunately, early initiation of therapy for aspergillosis is frequently not possible because of inaccurate diagnostics. One new diagnostic, the galactomannan assay, has recently been approved, and others are in development; these offer promise for earlier diagnosis without the need for invasive procedures. It is hoped that these new therapies and new diagnostics will usher in a new era of antifungal therapy.

Antifungal Agents↗
PubMed2004

Dose modification protocol using intravenous busulfan (Busulfex) and cyclophosphamide followed by autologous or allogeneic peripheral blood stem cell transplantation in patients with hematologic malignancies.

We evaluated the safety and toxicity through a 5-cohort dose-modification model of once-daily administration of IV busulfan (Bu) in combination with high-dose cyclophosphamide (Cy) as preparative therapy for stem cell transplantation. Twenty-one adult patients with hematologic malignancies were evaluated. Eleven patients underwent autologous and 10 patients underwent HLA-matched sibling allogeneic transplantation. Patients were sequentially enrolled into 5 cohorts. Cohort 1 received intravenous (IV) Bu 1.6 mg/kg every 12 hours for 2 doses and then 0.8 mg/kg every 6 hours for 12 doses; cohort 2 received IV Bu 1.6 mg/kg every 12 hours for 4 doses and then 0.8 mg/kg every 6 hours for 8 doses; cohort 3 received IV Bu 3.2 mg/kg for 1 dose and then 1.6 mg/kg every 12 hours for 2 doses and 0.8 mg/kg every 6 hours for 8 doses; cohort 4 received IV Bu 3.2 mg/kg every 24 hours for 2 doses and then 0.8 mg/kg every 6 hours for 8 doses; and cohort 5 received IV Bu 3.2 mg/kg every 24 hours for 4 doses. In all groups, Bu was administered on day -7 through day -4 and was followed at least 6 hours after the last Bu dose by Cy 60 mg/kg daily for 2 doses on days -3 and -2. Blood samples were collected for pharmacokinetic analysis on the first and last day of IV Bu administration. All patients were alive and had engrafted at day 30. Five patients developed grade 3 or 4 toxicities. Four patients developed hepatic abnormalities, and 3 exhibited evidence of veno-occlusive disease. Two of 3 patients in cohort 5 with a Bu area under the curve >6000 micromol/min developed autopsy-confirmed veno-occlusive disease. Interpatient variability in AUCs was observed in patients within and between cohorts, but no statistically significant interpatient differences were observed in Bu half-life, volume of distribution, clearance, or dose-adjusted area under the curve. Further, minimal variability in Bu pharmacokinetics was observed between the 2 evaluations performed in each patient, thus reflecting the stability of Bu disposition within individual patients. On the basis of the dosing guidelines and schedule outlined in this study, our data suggest that administration of IV Bu 3.2 mg/kg IV every 24 hours for 4 doses in combination with Cy may result in excessive toxicity.

Adolescent↗
PubMed2004

A phase III, randomized, double-blind, placebo-controlled, study of iseganan for the reduction of stomatitis in patients receiving stomatotoxic chemotherapy.

The invasion and colonization of oral cavity mucosal tissues by microflora may contribute to the pathophysiology of ulcerative oral mucositis (UOM). Iseganan is an analog of protegrin-1, a naturally occurring peptide with broad-spectrum microbicidal activity. A randomized, double-blind, placebo-controlled study was conducted to evaluate the efficacy and safety of iseganan in preventing UOM after stomatotoxic therapy. Patients received an oral rinse, consisting of iseganan 9mg or placebo, to be swished/swallowed six times daily, starting with stomatotoxic therapy and continuing up to 21 days. Patients were assessed for stomatitis and UOM, and administered a questionnaire evaluating mouth pain and difficulty swallowing thrice weekly. The primary study efficacy endpoint was the proportion of patients who did not have peak stomatitis NCI-CTC grade >or=2. Between November 2001 and June 2002, 502 patients were randomized to receive iseganan (251) or placebo (251). Equivalent numbers of patients in both cohorts received bone marrow or peripheral blood allogeneic or autologous stem cell transplantation (SCT). Forty-three percent and 37% of iseganan and placebo patients, respectively, did not have peak stomatitis grade =2 (P = 0.182). There was no significant difference between the cohorts in stomatitis severity, incidence of UOM, peak mouth pain, peak difficulty swallowing, amount of opiate analgesics used, or adverse event type or incidence. A major impact of Iseganan on reducing stomatitis, UOM, or its clinical sequelae in patients receiving stomatotoxic therapy was not detected on this study.

Antimicrobial Cationic Peptides↗
PubMed2004

Supportive care.

To optimize treatment outcomes for hematologic malignancies, minimizing the consequences of treatment complications requires as much skill as the choice of the treatment itself. Myelosuppression and immunosuppression are frequent complications and have potentially serious infectious consequences. Invasive fungal infections and infections from respiratory viruses are increasing in frequency and have life-threatening potential. Damage to vital organs, especially the liver, is another important concern. In this chapter, the scope of invasive fungal and respiratory viral infections, recent insights into the pathogenesis of hepatic sinusoidal injury, and recent developments that impact prevention and treatment approaches for these complications are described. In Section I, Dr. John Wingard describes the advantages and disadvantages of various treatment options for invasive infections by the two chief fungal pathogens, Candida and Aspergillus. Adjunctive therapies and practical considerations that clinicians should weigh in choosing one or another of the various agents are discussed. The studies that have evaluated antifungal prophylaxis and empirical treatment strategies are reviewed. Finally, new approaches such as combination therapy, new diagnostics, and efforts to bolster host immunity are considered. In Section II, Dr. W. Garrett Nichols describes the epidemiology of community-acquired respiratory viruses (CRV) in patients with hematologic malignancies. Risk factors, clinical syndromes, and possible indirect effects of CRV infections are discussed. Treatment and prevention options are reviewed. In Section III, Dr. George McDonald describes sinusoidal obstruction syndrome (once known as hepatic veno-occlusive disease). Recent insights into pathogenesis are described. Diagnostic criteria and the advantages and disadvantages of various diagnostic methods are reviewed and prognosis is considered. Prevention and treatment options are discussed.

Aspergillosis↗
PubMed2003

Evaluation of pain associated with oral mucositis during the acute period after administration of high-dose chemotherapy.

BACKGROUND: No single oral mucositis (OM) assessment scale is universally accepted; the most commonly used scales are deficient because they combine subjective and objective measures and do not capture the patient's perspective. Because pain is the hallmark symptom of OM, the authors sought to determine whether a simple measure of patient-reported pain was correlated with objective, physician-assessed measures of OM. The findings of the current study may provide a clinical context for understanding the relation between objective indicators and patients' perceptions of OM. METHODS: Three hundred twenty-three patients receiving stomatotoxic chemotherapy and randomized to receive either iseganan or placebo for treatment of OM underwent periodic objective and subjective evaluations of OM. Objective measures included clinician scoring of stomatitis and dysphagia using the National Cancer Institute Common Toxicity Criteria scales. A subjective measure was obtained by having patients complete a questionnaire (with questions based on an 11-point numeric scale) regarding oral pain. RESULTS: More than 90% of scheduled oral assessments were obtained. Mouth pain scores were closely related to stomatitis and dysphagia; peak mouth pain coincided with peak stomatitis and dysphagia. Analgesic use increased by 0.7 days for each unit rise on the pain scale. Patients receiving iseganan had a significantly lower level of peak mouth pain than did patients receiving placebo (P=0.041). CONCLUSIONS: A separate measurement of patient-reported pain was useful for capturing the patient's perspective on OM and was correlated with the physician's objective assessment. These findings support the use of a simple, patient-reported rating of mouth pain as a clinically relevant and responsive endpoint in clinical trials. This rating system also may provide a straightforward method of following OM in clinical practice.

Adolescent↗
PubMed2003

Access to stem cell transplantation: do women fare as well as men?

Women have less access to certain types of expensive treatments including renal transplantation, cardiac catheterization and diagnostic studies for lung cancer. Whether women have less access to stem cell transplantation (SCT) is not known. We evaluated allogeneic SCT data from the International Bone Marrow Transplant Registry (IBMTR) and compared them with disease incidence data from the Surveillance and Epidemiologic End Results (SEER) database. We estimated the ratio of males to females among transplanted patients with acute lymphoblastic (ALL), acute myelogenous (AML) and chronic myelogenous (CML) leukemia, diseases for which SCT is often done and compared them to male/female ratios of disease incidence. The association between gender and SCT was estimated as odds ratios (OR) with 95% confidence intervals (CI). There was no association between gender (male vs female) and the rates of SCT for individuals with AML (OR = 0.95, 95% CI = 0.89-1.02), or CML (OR = 1.0; CI = 0.90-1.1). Among patients with newly diagnosed ALL, more males underwent SCT than females (OR = 1.30, CI = 1.18-1.44). Because children with newly diagnosed ALL usually have a favorable prognosis, SCT is not generally a frontline therapy. Therefore, when we compared SCT rates to a population of children with relapsed ALL, the gender differences disappeared (OR = 1.09, CI = 0.94-1.25). We conclude that for the diagnoses where SCT is commonly used, there is no significant bias towards use in males compared to females. While boys with ALL appear to receive SCT at a higher rate, this difference is likely attributable to biological rather than social reasons.

Adult↗
PubMed2003

Busulfan, cyclophosphamide, and etoposide as conditioning for autologous stem cell transplantation in multiple myeloma.

Autologous stem cell transplantation (ASCT) has enabled the use of high-dose alkylating agents either as a single agent or in combination with other cytotoxic agents and/or total body irradiation (TBI) for the treatment of multiple myeloma. Despite improved complete remission rates, relapse and regimen-related toxicities remain challenging. In an effort to increase event-free survival and decrease the high incidence of regimen-related toxicity, we have studied the use of etoposide in combination with reduced-dose busulfan and cyclophosphamide as a conditioning regimen for ASCT in a group of 26 patients with advanced multiple myeloma. Median follow-up for the group was 30 months. There was no early treatment-related mortality. The main toxicity was mucositis. Otherwise, there was 1 case of reversible, clinically diagnosed hepatic veno-occlusive disease. Post-engraftment, 10 patients (38%) achieved CR, 15 (58%) patients achieved PR or SD, and 1 patient developed progressive disease (4%). Five patients in PR and 1 with progressive disease before transplant attained a CR post-transplant. The median times for event-free survival and overall survival after transplantation were 24 and 43 months, respectively. In conclusion, conditioning with busulfan, cyclophosphamide, and etoposide followed by ASCT is a safe regimen with comparable effectiveness to other previously used preparative regimens, thus providing another approach of non-TBI containing high-dose chemotherapy for patients with multiple myeloma.

Adult↗