Biomedical subjects

Craig A Mullen

Publications and source records attributed to Craig A Mullen.

12 recordsLinked to original sources

PubMed2007

Medical and non-medical barriers to outpatient treatment of fever and neutropenia in children with cancer.

BACKGROUND: A number of clinical trials have employed clinical criteria that can identify pediatric patients at low-risk for complicated episodes of fever and neutropenia (F&N) and have successfully treated low-risk patients in the outpatient setting. Despite this, inpatient management remains the standard of care. This trial tested the hypothesis that a strategy of initial hospitalization followed by continuation of therapy in the outpatient setting could be practically implemented in the majority of episodes. PROCEDURE: Patients presenting with F&N were initially evaluated to determine if they had high-risk clinical criteria that would exclude them from this approach. Eligible patients were then hospitalized and treated with iv antibiotics. On subsequent days the attending physician determined whether the patient had exhibited improvement and could continue therapy in the outpatient setting with oral antibiotics. Outpatients were seen three times weekly and continued antibiotics until recovery from F&N. RESULTS: Outpatient oral antibiotic therapy was practically implemented in less than one-quarter of episodes of pediatric F&N. Forty-nine percent of episodes were excluded from study by medical and social protocol exclusion criteria. One hundred five episodes were enrolled and among these 59 episodes included outpatient management. Common barriers to outpatient care included serious medical comorbidities, non-medical barriers including language and distance of residence from the medical center, and lack of interest. The average duration of outpatient care was 3.6 days following an average of 3.5 days of hospitalization. Ninety percent did not require rehospitalization. They experienced no complications. CONCLUSIONS: In only a minority of episodes can outpatient antibiotic management be implemented. Medical comorbidities and social barriers can make the transition to outpatient care difficult. However, initial hospitalization followed by oral antibiotic outpatient management appears safe and effective for low-risk patients who exhibit good responses to initial antibiotic therapy in hospital.

Administration, Oral↗

PubMed2007

Hematopoietic stem cell recipients do not develop post-transplantation immune tolerance to antigens present on minimal residual disease.

The immune environment present after allogeneic hematopoietic stem cell transplantation (HSCT) contributes to the control of leukemia. Our laboratory has demonstrated in a murine model that vaccination of recipients after transplantation with recipient tumor vaccines does not exacerbate graft-versus-host disease but does induce meaningful graft-versus-tumor effects. We previously demonstrated that part of the reason for the lack of graft-versus-host disease from post-transplantation vaccination is due to gradual acquisition of tolerance or unresponsiveness to recipient immunodominant minor histocompatibility antigens that are ubiquitously expressed in the recipient. However, our prior studies have not critically addressed the question of whether a similar process of acquisition of unresponsiveness to or tolerance of antigens present on minimal residual disease also occurs. The present study tested the hypothesis that unresponsiveness to antigens present on minimal residual disease present at the time of HSCT would also occur. The answer to this question would have a significant effect on the potential efficacy of post-transplantation tumor vaccines. In a murine model of major histocompatibility complex matched, minor histocompatibility antigen mismatched HSCT (C3.SW female donors and C57BL/6 female recipients), we tested whether transplant recipients would acquire unresponsiveness to antigens present on small numbers of residual leukemia/lymphoma cells. We employed a male C57BL/6 lymphoid malignancy with an immunoglobulin/c-myc oncogene in these studies using as a model of tumor-restricted antigen the well-characterized male (HY) antigen system present only on the tumor but not present as ubiquitous minor antigens in the recipient. After HSCT, recipients did not mount immune responses to the ubiquitously distributed immunodominant recipient strain H7 minor histocompatibility antigen, but did retain the capacity to mount significant T cell responses to HY antigens present on small numbers of HY+ tumor cells present at transplantation. Additional studies using small numbers of nonmalignant recipient male B cells or dendritic cells as models of minimal residual disease also demonstrated that the transplant recipients retained their capacity to mount anti-HY T cell responses. After HSCT, recipients may retain the capacity to mount effective T cell responses to antigens present on minimal residual disease and still acquire relative tolerance to ubiquitously distributed immunodominant minor antigens that are related to graft-versus-host disease.

Animals↗

PubMed2005

Bacterial infections in low-risk, febrile neutropenic patients.

BACKGROUND: Accurate identification of low-risk, febrile neutropenic patients has become possible only recently. Many such patients are treated with oral antibiotics without hospitalization. To the authors' knowledge, data concerning the spectrum of bacterial infections in these patients are scarce, and collecting such data may have an impact on the choice of empiric oral regimen(s). METHODS: Using the same risk-prediction and eligibility criteria, four studies of empiric therapy in low-risk, febrile neutropenic patients were conducted at the authors' institution. Based on that experience, patients also were entered on clinical pathways for outpatient therapy. For the current study, microbiologic data were pooled from those trials and clinical pathways (757 episodes) to describe the nature and spectrum of infections seen in this setting. RESULTS: Unexplained fever occurred most often (58% of episodes), and both clinically documented and microbiologically documented infections were seen with equal frequency (21% of episodes, respectively). The most common clinical sites of infection were the upper respiratory tract, skin, and skin structure. Among microbiologically documented infections, monomicrobial, gram-positive infections accounted for 49% (with coagulase-negative staphylococci the most frequent); monomicrobial, gram-negative infections accounted for 36% (with Escherichia coli the most frequent); and 15% of infections were polymicrobial. CONCLUSIONS: In this description of the spectrum of infections in the largest cohort of low-risk febrile neutropenic patients to date, episodes of unexplained fever were predominant, but gram-positive, gram-negative, and polymicrobial infections also were documented. Although these patients were at low risk for complications, they required broad-spectrum antibiotic therapy when they developed neutropenic fever.

Anti-Bacterial Agents↗

PubMed2005

Cellular tumor vaccines administered after T cell-depleted allogeneic bone marrow transplantation induce effective anti-tumor immune responses.

In allogeneic hematopoietic stem cell (HSC) transplantation, graft vs. tumor (GVT) activity contributes to the cancer cure. It is closely associated with graft vs. host disease (GVHD), an immune response initiated by transplanted donor T-cell responses against host minor histocompatibility antigens (mHAgs). GVHD is prevented by T-cell depletion of the donor graft, but T-cell depletion also abrogates curative GVT. We wished to test the hypothesis that cellular tumor vaccines administered after T cell-depleted HSC transplant can induce significant GVT effects, despite the absence of transplanted mature donor T cells. In this investigation, a murine model of major histocompatibility complex (MHC)-matched, mHAg-mismatched allogeneic HSC transplant was studied. T cell-depleted or normal T cell-containing grafts were given to myeloablated recipients. Following reconstitution the recipients were vaccinated with tumor vaccines. GVT responses were measured in vitro by T-cell function assays and flow cytometry, and in vivo by tumor burden or survival. Post-transplant tumor vaccines induced effective anti-tumor responses in recipients of T cell-depleted transplants, producing cytolytic and cytokine responses, reduced tumor burden and prolonged survival. Recipients of T cell-depleted transplants that still have significant thymic function may be suitable subjects for post-transplant vaccine therapy.

Animals↗

PubMed2004

Pharmacokinetics and individualized dose adjustment of intravenous busulfan in children with advanced hematologic malignancies undergoing allogeneic stem cell transplantation.

We investigated the pharmacokinetics (PK) of a recently approved intravenous busulfan (IVBU) formulation as a part of the preparative regimen in 20 children with advanced hematologic malignancies undergoing allogeneic hematopoietic stem cell transplantation. Seventeen patients received a thiotepa, IVBU, and cyclophosphamide-based regimen, and 3 patients received an IVBU and cyclophosphamide-based regimen. All patients received IVBU 0.8 mg/kg for the first 2 doses; thereafter, the IVBU dose was modified, if required, to achieve a final area under the concentration-time curve (AUC) at steady state of 1150 micromol/L/min per dose (range, 1000-1300 micromol/L/min per dose; SD +/-13%) based on the first-dose PK determination. PK studies were repeated on subsequent doses to verify the final AUC. Initial mean IVBU clearance and half-life were 3.96 mL/min/kg and 1.98 hours, respectively. Sixteen (80%) of the 20 patients received dose adjustments: 14 patients required dose escalations, and 2 required dose reductions. Overall, thirteen (72%) of 18 available sample sets at final follow-up PK analysis showed the IVBU exposure to be within the targeted range. IVBU PK was linear, and interpatient variability was much lower than that observed with oral busulfan. IVBU was well tolerated, and no case of hepatic veno-occlusive disease was encountered. Mild and transient hyperbilirubinemia was observed in 7 patients. Thirteen of the 20 patients were alive at a median follow-up of 651 days (range, 386-1555 days). We conclude that a standardized IVBU dose of 0.8 mg/kg in children does not always result in an AUC within the reference range defined in this study. Therapeutic drug monitoring with dose adjustment based on first-dose PK can optimize the systemic busulfan exposure for children undergoing allogeneic hematopoietic stem cell transplantation.

Adolescent↗

PubMed2003

Fludarabine and once-daily intravenous busulfan for allogeneic bone marrow transplantation for Chediak-Higashi syndrome.

An HLA-identical sibling bone marrow transplant was done for a patient with Chediak-Higashi syndrome. The preparative regimen included intravenous fludarabine (40 mg/m2/dx4) and busulfan (130 mg/m2/dx4). Busulfan was given once daily. Pharmacokinetic studies showed the area under the concentration-time curve of the once-daily intravenous busulfan was similar to that seen with the total daily dose administered with an every-6-hourly regimen. Toxicity was minimal. Myeloid engraftment occurred on day +17 and donor chimerism was complete. Fludarabine and once-daily intravenous busulfan is well tolerated and is adequate for engraftment of sibling transplant in Chediak-Higashi syndrome.

Bone Marrow Transplantation↗

PubMed2003

Ciprofloxacin in treatment of fever and neutropenia in pediatric cancer patients.

This article reviews clinical trials of outpatient management of fever and neutropenia in pediatric cancer patients. The syndrome of fever and neutropenia is discussed, and strategies of identifying patients at low risk for complex or fatal infections are described. A number of clinical trials in a wide range of clinical settings and countries have demonstrated that low risk pediatric cancer patients with fever and neutropenia can be prospectively identified and safely treated as outpatients. In addition outpatient management has been shown to be less costly than conventional intravenous therapy in hospitalized patients. Oral fluoroquinolones, including ciprofloxacin, have been used as a component of therapy in several trials because of their ease of administration and their activity against the majority of pathogenic bacteria causing illness in this group. The article also discusses the role of antibiotic prophylaxis of fever and neutropenia in certain high risk settings, such as hematopoietic stem cell transplantation. In selected high risk patients, prophylactic use of limited spectrum fluoroquinolones such as ciprofloxacin may reduce the incidence of Gram-negative bacteremias. Use of fluoroquinolone therapy as prophylaxis, however, is controversial because of concerns about an emergence of resistant organisms. Prudent use of fluoroquinolones as therapy and prophylaxis is essential to prolonging the benefits of this class of compounds.

Ambulatory Care↗

PubMed2002

Suicide gene therapy using E. coli beta-galactosidase.

PURPOSE: Suicide gene therapy offers the potential to increase the selective toxicity of antitumor agents by intratumoral expression of exogenous enzymes that convert nontoxic prodrugs to toxic products. The use of herpes simplex virus thymidine kinase with ganciclovir, and E. coli cytosine deaminase with 5-fluorocytosine are well-known examples of this approach. The purpose of this study was to investigate a novel suicide gene therapy using E. coli beta-galactosidase (beta-gal) as the prodrug-activating enzyme. Advantages of this approach include: (1) the ability to use prodrugs that are cleaved by beta-gal to agents that are known to possess activity against human solid tumors, and (2) the extensive experience gained with targeting beta-gal to specific tumors in experimental animals and in humans. METHODS: Two different structural types of anthracycline prodrugs, N-[4"-(beta- D-galactopyranosyl)-3"-nitrobenzyloxycarbonyl]daunomycin (Daun02) and N-[(4" R,S)-4"-ethoxy-4"-(1"'- O-beta- D-galactopyranosyl)butyl]daunorubicin (gal-DNC4) were investigated. The prodrugs were evaluated as substrates for beta-gal. Cytotoxicity studies of Daun02 were conducted against a murine tumor (Panc02), two human breast tumors (MCF-7 and T47D), and three human prostate tumors (PC3, DU145 and LNCAP) that had been transduced to express beta-gal. Antitumor studies of Daun02 were conducted against mouse tumor Panc02 xenografts implanted subcutaneously. RESULTS: Daun02 was a good substrate for beta-gal. By comparison, gal-DCN4 was a poor substrate. Except for PC3, the beta-gal-transduced tumors showed 3- to 60-fold increased sensitivity to Daun02 compared with mock-transduced control cells. Daunomycin was formed from Daun02 in tissue culture medium containing beta-gal-transduced cell lines but was not observed in the medium from mock-transduced controls. In vivo therapeutic studies of Daun02 against the Panc02 tumor in athymic mice showed no significant inhibition of tumor growth. Pharmacokinetic studies showed limited distribution of the prodrug beyond the vascular space. CONCLUSIONS: E. coli beta-gal may be useful as a prodrug-activating enzyme in suicide gene therapy and has the potential to increase the selective toxicity of conventional antitumor agents. Although this approach worked well against tumor cells in vitro, it was not effective against a xenograft model in vivo, apparently because of poor drug-tissue distribution.

Animals↗

PubMed2002

Down-regulation of antihost alloreactivity after bone marrow transplant permits relapse of hematological malignancy.

Relapse of leukemia remains a common event after allogeneic bone marrow transplantation, despite potential donor antihost alloreactivity present in most transplants. This work examined posttransplant relapse of the DBA/2 P815 mastocytoma in a murine model of MHC-matched, minor histocompatibility antigen (mHAg)-mismatched bone marrow transplantation (BALB/c donors into DBA/2 recipients). Antihost alloreactivity was associated with reduction of posttransplant tumor burden and prolongation of survival, but posttransplant relapse commonly occurred. No evidence of acquired resistance to immune control was found in 12 relapse reisolates. Relapse tumors remained sensitive to donor antihost CTLs in vitro, suggesting continued expression of mHAgs. Reisolates also continued to express Fas. However, loss of posttransplant alloreactivity was observed at 3 weeks. This was temporally associated with the time of relapse. Antihost alloreactivity could be reactivated in stable graft-versus-host disease-free recipients by immunization with host cells. The results of this study suggest that one mechanism for relapse after bone marrow transplant is acquired tolerance of allogeneic minor histocompatibility antigens and that posttransplant immunotherapy directed against mHAgs may induce antitumor activity.

Animals↗

PubMed2002

Fever and neutropenia in children with solid tumors is similar in severity and outcome to that in children with leukemia.

There is growing interest in developing criteria that will allow efficient prospective discrimination between cancer patients at high and at low risk for complex fever and neutropenia. The objective of this study was to determine whether there were differences in patterns of documented infections and outcome of episodes of fever and neutropenia in pediatric patients with leukemia and those with solid tumors, a potential risk factor. A total of 283 febrile neutropenia episodes in pediatric cancer patients at a single center were retrospectively reviewed; 38% of the patients concerned had leukemia and 62% had solid tumors. Fever of unexplained origin was seen in 73% and 74% of episodes in patients with leukemia and solid tumor, respectively. Bacteremia occurred in 18% and 16% of patients in these respective groups. There was no difference in the type of microorganisms that were isolated in the groups, with gram positives predominating in both. The median duration of fever was 2 days in both groups. The depth of neutropenia was similar, with 75% of leukemia patients and 70% of solid tumor patients presenting with ANC of 100 cells/microl or lower. The median duration of neutropenia was 9 days in patients with leukemia and 6 days in solid tumor patients. The median duration of antibiotic treatment was 9 days and 7.5 days in the same respective groups. Antibiotic modification occurred in 25% episodes of febrile neutropenia in leukemia patients and in 11% of episodes in solid tumor patients. No deaths occurred in either group. Subgroup analysis of leukemic patients suggested that patients in the induction phase of therapy have a higher rate of bacteremia and pneumonia. No substantial difference in course or outcome was seen between the leukemia and solid tumor groups, possibly because of the intensive treatment administered to pediatric patients with solid tumors. Risk assessment strategies based on chemotherapy dose intensity and patient comorbidities rather than underlying malignancy should be prospectively studied.

Adolescent↗

PubMed2002

Treatment of leukemia relapse with recombinant granulocyte-macrophage colony stimulating factor (rhGM-CSF) following unrelated umbilical cord blood transplant: Induction of graft-vs.-leukemia.

An infant with congenital leukemia in complete remission (CR1) received an unrelated donor umbilical cord blood cell transplant from a one-HLA disparate donor. The conditioning regimen consisted of thiotepa, busulfan and cyclophosphamide. GVHD prophylaxis consisted of tacrolimus and mini-methotrexate. Engraftment occurred and a bone marrow aspirate obtained on day 28 showed 100% donor cells. The post-transplant course was complicated by skin and liver GVHD, grade III, that responded to therapy with methylprednisolone, anti-thymocyte globulin and daclizumab (Zenapax), in addition to tacrolimus. A bone marrow aspirate obtained on day 187 showed relapse, with 17% blasts. The patient was then treated for 30 days with recombinant human granulocyte-macrophage colony-stimulating factor treatment (rhGM-CSF). A bone marrow aspirate obtained 17 days after the initiation of rhGM-CSF treatment showed 2% blasts. Ascites was the predominant side-effect of the rhGM-CSF treatment. The patient remains in complete remission 24 months after relapse and 30 months after transplantation. This case documents that rhGM-CSF and withdrawal of immunosuppression can induce a durable complete remission after relapse following an unrelated donor cord blood transplant.

Cord Blood Stem Cell Transplantation↗

PubMed2002

Influence of tumor vaccines on graft versus tumor activity and graft versus host disease in allogeneic bone marrow transplantation.

Powerful immunologically-mediated antitumor efforts can be observed in allogeneic hematopoietic stem cell transplantation. In the absence of specific immune interventions, this graft versus tumor effect is closely associated with graft versus host disease. In the work summarized here, the influence of cellular tumor vaccines on graft versus tumor activity and graft versus host disease is examined in a murine model of MHC-matched, minor histocompatibility antigen-mismatched bone marrow transplantation. The experiments have generated the following conclusions. First, complex cellular vaccines, which include recipient minor histocompatibility antigens, when administered to allogeneic donors generate powerful graft versus tumor effects but also induce unacceptable exacerbations of graft versus host disease. Second, cellular tumor vaccines, which contain recipient minor histocompatibility antigens, can be administered to transplant recipients after transplant without significant exacerbation of GVHD and with retention of clinically significant graft versus tumor effects. Third, immunization of donors with molecularly defined tumor-associated antigens, which are not recipient minor histocompatibility antigens, can be coupled with post-transplant immunization of recipients with cellular vaccines without exacerbation of GVHD.

Animals↗