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Biomedical subjects

J R Wingard

Publications and source records attributed to J R Wingard.

At least 37 records · Page 2Linked to original sources
PubMed2001

Infection and mucosal injury in cancer treatment.

The oral and gastrointestinal mucosa acts as an important mechanical barrier that prevents local or systemic invasion by microorganisms. Cytotoxic chemotherapy-induced mucosal injury (MI) of oral cavity and intestinal epithelium occurs in many patients treated for malignancy. Compromise of the mucosal barrier can contribute to local invasion by colonizing microorganisms and, subsequently, to systemic infection. Historically, gram-negative bacteremia has been the most problematic bacterial infection in neutropenic patients, but its incidence has reduced over time because of the use of prophylactic antibiotics. There has been a shift in the type of infecting organisms responsible for bacteremia in these patients, from predominantly gram-negative organisms to gram-positive cocci. The viridans group of streptococci is composed of the most frequent bacterial pathogens associated with MI. When speciated, oral colonizers such as Streptococcus mitis, Streptococcus oralis, and Streptococcus sangulis II are the most frequently identified pathogens. Other systemic infections caused by vancomycin-resistant enterococci, Stenotrophomonas maltophilia, and Candida species have also been associated with MI after cancer treatment. Infection can also exacerbate MI after cancer treatment. The best recognized example is herpes simplex virus type 1 (HSV-1). Latent virus is frequently reactivated in HSV-seropositive patients; this reactivation leads to stomatitis, which can be indistinguishable from MI caused by cytoreductive therapies. Antiviral prophylaxis or treatment can control the virus-induced MI and bring about overall amelioration of MI. Recognition of this infectious cause of MI is important in order for clinicians to anticipate and minimize oral toxicity and to facilitate optimal delivery of the antineoplastic regimen.

Antineoplastic Agents↗
PubMed2001

Empiric antifungal therapy for the neutropenic patient.

One of the major challenges facing oncologists today is invasive fungal infection. Difficult to diagnose and deadly when missed, invasive fungal infection--primarily by Candida and Aspergillus organisms--is the major infectious cause of death associated with chemotherapy-induced myelosuppression. In this review, the problem will be described and evidence-based approaches to management, including assessment for risk factors and empiric antifungal therapy, will be discussed. Finally, the future of diagnostic and therapeutic strategies for protecting the immunocompromised patient will be considered.

Antifungal Agents↗
PubMed2000

A randomized, double-blind comparative trial evaluating the safety of liposomal amphotericin B versus amphotericin B lipid complex in the empirical treatment of febrile neutropenia. L Amph/ABLC Collaborative Study Group.

In this double-blind study to compare safety of 2 lipid formulations of amphotericin B, neutropenic patients with unresolved fever after 3 days of antibacterial therapy were randomized (1:1:1) to receive amphotericin B lipid complex (ABLC) at a dose of 5 mg/kg/d (n=78), liposomal amphotericin B (L Amph) at a dose of 3 mg/kg/d (n=85), or L Amph at a dose of 5 mg/kg/d (n=81). L Amph (3 mg/kg/d and 5 mg/kg/d) had lower rates of fever (23.5% and 19.8% vs. 57.7% on day 1; P<.001), chills/rigors (18.8% and 23.5% vs. 79.5% on day 1; P<.001), nephrotoxicity (14.1% and 14.8% vs. 42.3%; P<.01), and toxicity-related discontinuations of therapy (12.9% and 12.3% vs. 32.1%; P=.004). After day 1, infusional reactions were less frequent with ABLC, but chills/rigors were still higher (21.0% and 24.3% vs. 50.7%; P<.001). Therapeutic success was similar in all 3 groups.

Adolescent↗
PubMed2000

Status of high-dose chemotherapy for breast cancer: a review.

The purpose of this review is to analyze the current status of high-dose chemotherapy (HDCT) with autologous stem cell transplantation for patients with breast cancer. Current results from the major prospective phase 2 and phase 3 trials in metastatic breast cancer (MBC) and high-risk primary breast cancer (HRPBC) are reviewed. Prognostic factors and future research directions are also discussed. The encouraging results of phase 2 trials suggested a benefit for HDCT in HRPBC and some categories of patients with MBC. Some investigators have argued that patient selection might have been a critical factor in those studies. Recently reported randomized trials in patients with chemosensitive MBC have included only small numbers of patients in complete remission and thus have not adequately addressed the relative value of HDCT versus maintenance standard-dose chemotherapy in this patient subset. Although initial results of 2 studies have been reported, most randomized phase 3 studies of HDCT in HRPBC require longer follow-up before definitive conclusions can be made about its efficacy in this setting. We conclude that the role of HDCT for HRPBC or MBC patients has not yet been fully defined. Longer follow-up of the ongoing randomized trials is necessary, and their mature results will help clarify this important question. In the meantime, it is imperative that research continues, to enhance the efficacy of the procedure. This may come through incorporating more active drugs into HDCT regimens and combining HDCT with novel strategies aimed at eradication of posttransplantation minimal residual disease.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2000

Acquiescence to adjunctive experimental therapies may relate to psychological distress: pilot data from a bone marrow transplant center.

Use of alternative therapy for breast cancer outside of the hospital setting has been identified as a marker of psychological distress. Whether acquiescence to experimental therapies within the medical setting might also be a sign of psychological distress is not well known. We therefore evaluated patients with breast cancer undergoing bone marrow transplantation (BMT), an experimental method for treatment, to determine if acquiescence to further adjunctive experimental therapy related to psychological distress. In order to do this, we studied psychological test results of 42 breast cancer patients undergoing BMT at the University of Florida between January and December 1997. These tests included the Medical Outcomes Short Form Health Survey, the Beck Depression Inventory, the State-Trait Anxiety Inventory and the Medical Coping Modes Questionnaire. Women who accepted adjunctive experimental therapy had significantly higher trait anxiety and poorer role functioning compared to women who did not (both P < 0.001). These findings suggest that psychological distress may be a factor in medical decision-making even within the medical setting and that prospective research in this area is warranted.

Adult↗
PubMed2000

Subcutaneous phaeohyphomycosis in transplant recipients: review of the literature and demonstration of in vitro synergy between antifungal agents.

Infection of subcutaneous tissue by black fungi (subcutaneous phaeohyphomycosis) has only been reported in six transplant patients, all of whom were solid organ recipients. These patients presented with indolent, localized infections at least 1 year after transplant, while on maintenance immunosuppressive regimens. They were cured by surgical resection, either alone or in conjunction with antifungal agents. We report a case of subcutaneous phaeohyphomycosis occurring in a bone marrow transplant recipient receiving high doses of immunosuppressive agents, in whom widespread subcutaneous infection due to Exophiala jeanselmei was not eradicated by repeated resections and therapy with amphotericin B and flucytosine. The infection was eventually cured after addition of itraconazole to the therapeutic regimen. Results of in vitro testing of the isolate for susceptibility to a combination of amphotericin B, flucytosine and itraconazole confirmed the potential role of combination antifungal therapy in the setting of refractory infection.

Amphotericin B↗
PubMed2000

Invasive aspergillosis. Disease spectrum, treatment practices, and outcomes. I3 Aspergillus Study Group.

A review of representative cases of invasive aspergillosis was conducted to describe current treatment practices and outcomes. Eighty-nine physicians experienced with aspergillosis completed case forms on 595 patients with proven or probable invasive aspergillosis diagnosed using modifications of the Mycoses Study Group criteria. Pulmonary disease was present in 56%, with disseminated infection in 19%. The major risk factors for aspergillosis were bone marrow transplantation (32%) and hematologic malignancy (29%), but patients had a variety of underlying conditions including solid organ transplants (9%), AIDS (8%), and pulmonary diseases (9%). Overall, high antifungal failure rates occurred (36%), and complete antifungal responses were noted in only 27%. Treatment practices revealed that amphotericin B alone (187 patients) was used in most severely immunosuppressed patients while itraconazole alone (58 patients) or sequential amphotericin B followed by itraconazole (93 patients) was used in patients who were less immunosuppressed than patients receiving amphotericin B alone. Response rate for patients receiving amphotericin B alone was poor, with complete responses noted in only 25% and death due to or with aspergillosis in 65%. In contrast, patients receiving itraconazole alone or following amphotericin B had death due to or with Aspergillus in 26% and 36%, respectively. These results confirm that mortality from invasive aspergillosis in severely immunosuppressed patients remains high even with standard amphotericin B. Improved responses were seen in the less immunosuppressed patients receiving sequential amphotericin B followed by itraconazole and those receiving itraconazole alone. New approaches and new therapies are needed to improve the outcome of invasive aspergillosis in high-risk patients.

Adolescent↗
PubMed2000

Characterization and outcome of "hard to mobilize"' lymphoma patients undergoing autologous stem cell transplantation.

A "hard to mobilize" patient was defined as one in whom >or= 1x10(6) CD 34+ cells/kg cannot be obtained after two consecutive large volume aphereses. Forty-four consecutive Hodgkin's and non-Hodgkin's lymphoma patients who underwent autologous peripheral blood stem cell (PBSC) transplant treatment between June 1996 and June 1998 were included in this study. Twenty-one patients (48%) met the definition of "hard to mobilize" (Group I). All the rest of the patients (n=23) were the good mobilizers (Group II). The initial mobilization protocol for most patients was 10 microg/kg of G-CSF alone for both groups. For Group I, 7/21 (33%) patients were unable to achieve a minimal dose of >or= 1x10(6) CD34+ cells/kg even after a second mobilization attempt and/or bone marrow (BM) harvest (n=5). Overall, 11/21 (52%) required an additional mobilization and/or BM harvest. Only 3/21 (14%) patients were able to meet the target cell dose of >or= 2.5x10(6) CD34+ cells/kg (median of 4 apheresis). In contrast, 87% of Group II achieved the target dose with a median of 2 aphereses. Predictors of poor mobilization were greater than two prior treatment regimens (p=0.038) and the WBC count (<25,000/microL) on the first day of apheresis (p=0.053). Nineteen patients in Group I and all Group II completed treatment with a median time to engraftment of ANC>500/microl of 12 and 11 days, and platelet >20x10(3)/microl of 31 and 13 days, respectively. Outcome analysis revealed that 6/19 patients in Group I died of relapse within one year from transplant compared with only 2/23 of Group II who died of relapse (p=0.005, log rank test). There were no treatment related deaths in either group. Independent predictive features for "hard to mobilize" patients are a lack of significant increase in WBC count on the first day of apheresis and the number of prior treatment regimens. Poor mobilization appears to predict a worse outcome after autografting for lymphoma patients.

Actuarial Analysis↗
PubMed1999

Long-term survival and late deaths after allogeneic bone marrow transplantation. Late Effects Working Committee of the International Bone Marrow Transplant Registry.

BACKGROUND AND METHODS: It is uncertain whether mortality rates among patients who have undergone bone marrow transplantation return to the level of the mortality rates of the general population. We analyzed the characteristics of 6691 patients listed in the International Bone Marrow Transplant Registry. All the patients were free of their original disease two years after allogeneic bone marrow transplantation. Mortality rates in this cohort were compared with those of an age-, sex-, and nationality-matched general population. Cox proportional-hazards regression was used to identify risk factors for death more than two years after transplantation (late death). RESULTS: Among patients who were free of disease two years after transplantation, the probability of living for five more years was 89 percent (95 percent confidence interval, 88 to 90 percent). Among patients who underwent transplantation for aplastic anemia, the risk of death by the sixth year after transplantation did not differ significantly from that of a normal population. Mortality remained significantly higher than normal throughout the study among patients who underwent transplantation for acute lymphoblastic leukemia or chronic myelogenous leukemia and through the ninth year among those who underwent transplantation for acute myelogenous leukemia. Recurrent leukemia was the chief cause of death among patients who received a transplant for leukemia, whereas chronic graft-versus-host disease was the chief cause among those who received a transplant for aplastic anemia. Advanced, long-standing disease before transplantation and active chronic graft-versus-host disease were important risk factors for late death. CONCLUSIONS: In patients who receive an allogeneic bone marrow transplant as treatment for acute myelogenous or lymphoblastic leukemia, chronic myelogenous leukemia, or aplastic anemia and who are free of their original disease two years later, the disease is probably cured. However, for many years after transplantation, the mortality among these patients is higher than that in a normal population.

Adolescent↗
PubMed1999

Opportunistic infections after blood and marrow transplantation.

Opportunistic infections are major causes of morbidity and mortality following bone marrow transplantation. Technological advances in stem cell procurement, the introduction of hematologic growth factors to speed engraftment, the development of new immunosuppressive regimens to control graft-versus-host disease (GVHD), the development of technology to perform graft engineering with removal of T lymphocytes in toto or subpopulations of T lymphocytes, the use of molecular techniques to optimize donor and recipient matching, advances in blood banking, and development of international donor registries, are among the various factors that have led to tremendous changes in transplant practices. Because of such changes in transplant practices, along with the advent of new antimicrobial agents, and development of infection control measures affecting pathogen exposure, alterations in the interplay between host and potential pathogens have occurred. Shifts in the incidence and types of opportunistic pathogens are taking place. Several historically important infectious syndromes are today well controlled; others have diminished in importance early after transplant but are more problematic at a later time; new emerging pathogens are being recognized due to selection pressures from antimicrobial usage and new hosts, such as recipients of alternate donor allogeneic transplant procedures, with even more profound and prolonged immune suppression. Such shifts and new syndromes pose continuing new challenges to the transplant clinician.

Blood Transfusion↗
PubMed1999

Increased clearance of tacrolimus in children: need for higher doses and earlier initiation prior to bone marrow transplantation.

The pharmacokinetics of tacrolimus have been studied in healthy volunteers and in adults undergoing bone marrow transplantation. However, there is little information on the pharmacokinetics of tacrolimus in children undergoing BMT. We studied pharmacokinetics of tacrolimus in seven patients (age 8-17 years) undergoing allogeneic stem cell transplantation. Four patients received matched unrelated donor (MUD) transplants, two underwent HLA-matched related donor transplants, and one underwent an umbilical cord blood donor transplant. All patients received tacrolimus by continuous infusion at 0.03-0.04 mg/kg/day beginning on the day prior to transplant. Tacrolimus whole blood concentrations were monitored by microparticle enzyme immunoassay. Our goal was to maintain a blood tacrolimus level of 10-20 microg/ml. Once patients were tolerating oral medications, tacrolimus infusion was converted to oral dosing using a 4:1 conversion. Dose of tacrolimus and resulting tacrolimus concentrations were recorded and the total body clearance of tacrolimus was calculated retrospectively. The mean clearance, based on first steady-state tacrolimus concentrations necessary for achieving a therapeutic level (10-20 microg/ml), was 108.1 ml/h/kg (range 79.7-142.0 ml/h/kg), greater than that reported in adult BMT patients (71 +/- 34 ml/h/kg). The average dose required to achieve that therapeutic range was 0.0354 mg/kg/day as an intravenous continuous infusion. Over the entire course of intravenous tacrolimus, mean clearance was 97.0 ml/h/kg (range 33.4-153.3 ml/h/kg). In six of the seven patients, clearance values dropped after 2-4 weeks of therapy by an average of 32.5 ml/h/kg. In two patients, sharp drops in clearance were temporally related to changes in liver function tests. Three of the seven patients died of severe acute GVHD; all these had undergone matched unrelated donor transplantation, and two of these three had initial clearance levels over 120 ml/h/kg. Thus, children appear to have more rapid tacrolimus clearance than adults and may need to begin therapy earlier in order to obtain stable and optimal levels. More studies are needed to confirm these preliminary results.

Adolescent↗
PubMed1999

Fungal infections after bone marrow transplant.

With improved control of cytomegalovirus infection, invasive fungal infections have become the leading cause of infectious mortality after bone marrow transplantation (BMT). A number of changes in transplant practices have led to changes in patterns of fungal infections: neutropenic episodes have been shortened through the use of hematopoietic growth factors and peripheral blood as a source of stem cells. More potent immunosuppressive regimens, including T-cell depletion techniques, have encouraged the use of alternate donor sources with greater numbers of transplant recipients experiencing more prolonged and more profound immunodeficiency following engraftment. The advent of new antifungal agents has led to a decline in Candida infections, but has encouraged the emergence of other less susceptible fungal pathogens. The development of molecular techniques to distinguish different fungal strains has led to identification of nosocomial transmission as an unexpected means for the spread of fungal infections in BMT units. These shifts in fungal infection patterns emphasize the need for infection control monitoring. The development of more accurate diagnostic tools and the incorporation of new antifungal agents into practice are needed to further improve outcomes.

Antifungal Agents↗
PubMed1999

Relationship of tacrolimus whole blood levels to efficacy and safety outcomes after unrelated donor marrow transplantation.

Tacrolimus has proved effective for preventing acute graft-vs.-host disease (GVHD) after unrelated donor marrow transplantation, but the therapeutic window is apparently narrow. Therapeutic drug monitoring could potentially be used to guide dose modifications, but the optimal target range of tacrolimus blood concentrations is unknown. We determined whether acute GVHD and renal dysfunction correlated with tacrolimus whole blood levels as measured by the IMx assay. Data were analyzed for 97 adults treated in a multicenter trial of tacrolimus and methotrexate or methylprednisolone as GVHD prophylaxis after unrelated donor marrow transplantation. The rate of grades II-IV GVHD was 49%; 81% of patients had a doubling of the serum creatinine; and 61% had a serum creatinine <2 mg/dL. The initial tacrolimus target range for the clinical trial was 10-60 ng/mL. Tacrolimus blood levels were averaged over a 14-day period, and Cox models were used with averaged blood levels as a time-dependent covariate. No significant change was observed in the risks of acute GVHD, doubling of creatinine, need for dialysis, or death over a tacrolimus blood level range of 5-40 ng/mL, but there was a direct correlation between risk of developing a creatinine <2 mg/dL and increasing tacrolimus blood levels (4.7% increased risk for each 1 ng/mL increase in blood concentration, p < 0.001). When the tacrolimus level exceeded 20 ng/mL, there was a 2.2-fold increase in the rate of renal toxicity (p < 0.001), a trend for an increase in mortality (relative risk 3.9, p=0.08), and no impact on the risk of GVHD. This analysis supports 10-20 ng/mL as the therapeutic range of tacrolimus whole blood steady state or trough levels for unrelated donor marrow transplantation.

Adolescent↗
PubMed1999

Tacrolimus vs. cyclosporine immunosuppression: results in advanced-stage disease compared with historical controls treated exclusively with cyclosporine.

A phase HI comparative trial of tacrolimus- vs. cyclosporine-based graft-vs.-host disease (GVHD) prophylaxis for human leukocyte antigen (HLA)-identical sibling bone marrow transplantation showed less GVHD but poorer survival in the tacrolimus arm. To test the comparability of the two treatment arms with respect to baseline survival prognosis, a matched control study using exclusively cyclosporine-treated patients from the International Bone Marrow Transplant Registry (IBMTR) database was performed. Controls were matched (2:1) based on age (within 5 years), disease, and pretransplant disease status. Two-year survival for tacrolimus-treated clinical trial patients was similar to that of their cyclosporine-treated matched controls (27 and 24%, respectively), and 2-year survival of the cyclosporine-treated clinical trial patients was similar to that of their cyclosporine-treated matched IBMTR controls (42 and 45%, respectively). Consistent with the clinical trial results, the cyclosporine-treated IBMTR controls matched to the tacrolimus group had significantly poorer 2-year survival than the cyclosporine-treated IBMTR controls matched to the cyclosporine group (24 and 45%, respectively; p < 0.01). No significant difference was seen in GVHD between the cyclosporine-treated clinical trial patients and their matched controls; however, the tacrolimus-treated clinical trial patients had significantly less GVHD than their cyclosporine-treated IBMTR controls (p < 0.01). These results support the hypothesis that the survival difference in the phase III trial resulted from an imbalance in the underlying risk factors for death in the two groups rather than from the randomized immunosuppressive regimen.

Adolescent↗