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Biomedical subjects

T R Spitzer

Publications and source records attributed to T R Spitzer.

At least 37 records · Page 2Linked to original sources
PubMed1999

Late onset veno-occlusive disease following high-dose chemotherapy and stem cell transplantation.

The original definition of hepatic veno-occlusive disease (VOD), which is still widely accepted, includes onset of the clinical syndrome before day +20 following high-dose chemotherapy (HDC) and stem cell transplantation (SCT). We retrospectively identified four patients following HDC and SCT presenting with late onset VOD occurring at day +24, day +27, day +34 and day +42 post SCT. All patients had moderate VOD, with successful resolution of the VOD before day +100 with optimal supportive therapy. Common risk factors for VOD shared by all four patients included an older age (median age: 60 years), and use of a busulphan-containing regimen. Mean and maximum bilirubin levels for all patients during the VOD syndrome were 2.02, 1.76, 5.09, 2.87 mg/dl and 2.5, 2.2, 8.9 and 4.1 mg/dl, respectively, which correlated well with duration of VOD. All patients encountered platelet transfusion-dependent thrombocytopenia during VOD. Ursodeoxycholic acid was used as VOD prophylaxis beginning at a mean of 33 days prior to onset of VOD. As the cellular target of hepatic VOD is as yet unidentified, it is uncertain whether ursodiol or other common characteristics of patients with late onset VOD influence the pathogenesis and natural history of this disease. We believe that the uncommon clinical entity of late onset VOD, a potentially fatal regimen-related toxicity, should not be ignored as a diagnosis of liver disease after 3 or more weeks following HDC and SCT.

Aged↗
PubMed1998

Antiemetic strategies for high-dose chemoradiotherapy-induced nausea and vomiting.

The treatment of nausea and vomiting in patients receiving high doses of irradiation and/or chemotherapeutic agents as preparation for hematopoietic stem cell transplantation is discussed. Such patients have very high rates of both early and delayed emesis. Based on the available evidence it is recommended that 5-HT3 receptor antagonists be used to combat emesis in this setting. Continued research is also required to define the optimal antiemetic strategy for these patients.

Antiemetics↗
PubMed1998

Early vs delayed administration of G-CSF following autologous peripheral blood stem cell transplantation.

It is well established that recombinant human G-CSF accelerates neutrophil recovery following autologous peripheral blood stem cell transplantation (PBSCT). However, the optimal timing of G-CSF following transplantation remains unknown. We have conducted a retrospective analysis of patients treated with either early, day +1 (n = 42) or delayed, day +4 (n = 39) administration of G-CSF following autologous PBSCT for a variety of hematologic malignancies and solid tumors. G-CSF was given at a dose of 5 microg/kg/day i.v. as a 2 h infusion beginning either day +1 or day +4 following PBSC infusion and continued until the total white blood count (WBC) was >10 x 10(9)/l. The numbers of transplanted CD34+ cells were similar in each group. Treatment with early administration of G-CSF resulted in a significantly shorter time to an absolute neutrophil count (ANC) of >0.5 x 10(9)/l (8.5 vs 10.0 days, P < 0.0003) and shorter length of hospitalization (16.3 vs 18.6 days, P < 0.0008), a trend towards a reduced incidence of infection (53 vs 72%) and a significant decrease in the duration of non-prophylactic antibiotic (NPA) therapy for neutropenic fever (4.0 vs 7.5 days, P < 0.009) compared to day +4 administration. Despite the additional cost of G-CSF, the reduction in the hospitalization and NPA therapy with early G-CSF administration resulted in 11% cost savings overall per transplant at our institution.

Adolescent↗
PubMed1998

Outcomes of recipients of both bone marrow and solid organ transplants. A review.

In this review we examine the clinical outcomes of patients who have received both bone marrow transplantation (BMT) and solid organ transplantation (SOT) and discuss the possible immunologic consequences of the dual transplants. We collected cases through a comprehensive literature search (MEDLINE database, English literature only) covering the years 1990 through 1997 and correspondence with the International Bone Marrow Transplant Registry. Our study selected case reports of patients who have undergone both bone marrow and solid organ transplants; cases in which bone marrow transplantation was undertaken as an adjunct ot induce or augment donor-specific tolerance in a recipient to the transplanted organ were excluded. Clinical characteristics included patient's demographic information, underlying disorders for each transplant, source of donor organ or tissue, time between transplants, and immunosuppressive regimens used to prevent graft-versus-host disease (GVHD) or graft rejection. Clinical outcomes included patient survival, complications of transplantation, and donor-specific tolerance that was experienced in many cases. Twenty-one cases of SOT after BMT and 7 cases of BMT after SOT were reviewed. Solid organ transplantations included lung, liver, cardiac, and kidney for a variety of BMT-related complications including GVHD, hepatic veno-occlusive disease, chronic renal failure, end-stage pulmonary disease, and severe cardiomyopathy. Bone marrow transplants were performed following SOT for aplastic anemia and hematologic malignancies. Clinical outcomes for patients who received both BMT and SOT were variable and depended on transplant indication and degree of histocompatibility. Prior bone marrow transplantation may tolerize for a subsequent organ transplant from the same donor. Conversely, severe GVHD may follow BMT from human leukocyte antigen (HLA)-matched donors following SOT. The favorable survival in this high-risk group of patients may represent a literature review bias (that is, an undetermined number of unsuccessful cases may not have been reported). Nonetheless, dual transplantation is clearly feasible in selected cases.

Bone Marrow Transplantation↗
PubMed1997

Ursodiol to prevent hepatic venoocclusive disease.

VOD is an important cause of morbidity and mortality in patients following allogeneic bone marrow transplantation. Although VOD may improve in some patients, severe cases are often fatal. There is no established therapy to prevent progression to severe VOD; nor are there any conclusive or universally accepted methods for prevention of mortality associated with severe VOD. A treatment that could minimize hepatic damage and cause VOD to manifest as reversible liver damage rather than a progressive, fatal disease would indeed have a place in posttransplant therapy. Nontoxic ursodiol may play such a role by replacing hepatotoxic bile acids. Based on the limited available literature (2 studies), it is difficult to draw firm conclusions regarding the use of ursodiol to prevent VOD, although the preliminary results are promising. The studies, although small and not without weakness, suggested that ursodiol effectively reduces the incidence of VOD in allogeneic BMT patients. They do not, however, suggest that ursodiol is effective as treatment for existing VOD, as this was not studied. Also, conclusions were based on patients given busulfan and cyclophosphamide as conditioning therapy and thus might not apply to patients conditioned by other means such as total body irradiation. In summary, the available data do not definitively support the use of ursodiol; however, patients conditioned with busulfan and cyclophosphamide who are at risk for VOD (e.g., pretransplant liver disease, liver metastases) may be candidates for ursodiol prophylactic therapy. Larger, randomized clinical trials are warranted to further define the potential role of ursodiol for the prevention of venoocclusive disease of the liver in BMT patients.

Bone Marrow Transplantation↗
PubMed1997

Cellular modulation of acute graft-vs.-host disease.

Bone marrow transplantation (BMT) is a potentially curative therapy for a number of life-threatening hematologic malignancies; however, the subsequent development of severe graft-vs.-host disease (GVHD) remains a major obstacle, impeding its widespread application. Prevention and treatment of GVHD may involve modulating the host/donor cellular environment following BMT. Suspected mechanisms by which cells with immunoregulatory properties inhibit alloresponses include natural suppressor and veto activity. Cell phenotypes associated with suppressive activity in mice and humans include null cells, double negative T lymphocytes, and natural killer cells. Cellular-based therapies for the treatment of acute GVHD using autologous peripheral blood mononuclear or bone marrow cells have shown promise in reversing GVHD following allogeneic transplantation. In this review, we examine the considerable evidence supporting an immunoregulatory role for both host and donor cells in modulating acute GVHD.

Animals↗
PubMed1996

Allogeneic bone marrow transplantation in a patient with hypereosinophilic syndrome.

We describe a 32-year-old man with idiopathic hypereosinophilic syndrome (HES) who presented with pulmonary dysfunction, thrombocytopenia, lymphadenopathy, and hepatosplenomegaly. The patient developed progressive disease on prednisone and hydroxyurea therapy, and he underwent a successful allogeneic bone marrow transplantation (BMT). The patient is asymptomatic with no evidence of eosinophilia 30 months after transplantation. There is currently no cure for patients with HES, and BMT should be considered in selected patients.

Adult↗
PubMed1996

Antithymocyte immunoglobulin in severe aplastic anemia and bone marrow transplantation.

OBJECTIVE: To review antithymocyte immunoglobulin (ATG) and its current role in the treatment of severe aplastic anemia (SAA), focusing on ATG in immunosuppressive therapy compared with bone marrow transplantation (BMT). DATA SOURCES: A MEDLINE search (1966 to 1996) of English-language literature and human subjects pertaining to ATG and BMT therapy in SAA was performed. Additional literature was obtained from reference lists of pertinent articles identified through the search. STUDY SELECTION AND DATA EXTRACTION: All articles were considered for possible inclusion in the review. Pertinent information, as judged by the authors, was selected for discussion. DATA SYNTHESIS: The hallmark of SAA is pancytopenia and bone marrow hypoplasia. Although the etiology in a majority of cases remains unknown, current data implicate an immune-mediated destruction of stem cells. ATG is a potent immunosuppressive agent and has emerged as an important therapy for patients with SAA. The exact mechanism of immunosuppressive action is not fully understood, although ATG appears to disrupt cell-mediated immune responses resulting in inhibition or altered T-cell function. Numerous trials have evaluated the use of ATG both as monotherapy and in combination with other immunosuppressive agents. Treatment with ATG in SAA has demonstrated a 40-70% response rate. Data suggest that intensive immunosuppressive therapy with ATG in combination with cyclosporine may provide the optimal immunosuppressive treatment. Questions still remain concerning complications and long-term survival of the patients. Although more than a 2-year follow-up shows a decline in mortality, a plateau in the survival curve was not achieved. BMT is a potential treatment for SAA. Although there is a high initial mortality due to treatment-related toxicities, successful marrow engraftment provides a cure for SAA. Many patients (75-90%) experience long-term survival after allogenic BMT. Age, donor availability, and severity of disease limit the number of eligible patients. CONCLUSIONS: Due to excellent results with BMT, it has become the therapy of choice for selected patients with SAA. For patients who are not eligible for BMT, intensive immunosuppressive therapy with ATG and cyclosporine is recommended. Further study to better understand the pathogenesis of SAA and prevent treatment-related complications is essential to provide the best care to all patients.

Anemia, Aplastic↗
PubMed1996

Allogeneic peripheral blood stem cell transplantation.

The use of mobilized peripheral blood stem cells (PBSC) for hematopoietic reconstitution following myeloablative chemoradiotherapy has been well shown to be an effective and probably superior alternative to autologous bone marrow support. Early concerns of increased engraftment failure risk (owing to a decreased number of multipotential stem cells), increased graft vs. host disease risk (due to an excess of circulating T cells) and donor safety concerns, however, delayed efforts to use mobilized PBSC for allogeneic transplantation. Recent reports, however, have demonstrated excellent donor tolerance of G-CSF administration and yields of CD34+ progenitor cell collections. Engraftment with allogeneic peripheral blood stem cells has been rapid and sustained in several early clinical series. Surprisingly, no apparent increase in risk of moderate to severe acute graft versus host disease has occurred with unmanipulated mobilized PBSC. Despite this early promise, long-term safety concerns of administration of recombinant myeloid growth factors to normal donors have been raised. Long-term lymphohematopoietic engraftment also needs to be more conclusively demonstrated. Optimal mobilizing and collecting strategies also need to be defined to ensure donor safety and comfort. The possible roles of PBSC in the matched unrelated donor and mismatched related donor settings need to be defined before widespread adoption of mobilized PBSC as an alternative to bone marrow for allogeneic transplantation. Prospective randomized trials are recommended to definitively evaluate long term donor safety and recipient hematopoietic and immunologic reconstitution.

Clinical Trials as Topic↗
PubMed1996

Marrow engraftment and clinical manifestations of capillary leak syndrome.

A capillary leak syndrome occurs frequently in bone marrow transplant patients in addition to graft-versus-host-disease and infection. The underlying pathology is poorly understood but the clinical manifestations of excessive weight gain, ascites, and edema associated with kidney and liver abnormalities suggest a common injury to multiple organs. The clinical courses of 55 allogeneic and autologous marrow transplant recipients were retrospectively reviewed with regard to the presentation of a capillary leak syndrome (CLS). Twenty-nine patients (53%) developed non-cardiogenic pulmonary edema with or without concurrent pleural effusions; the incidence was comparable in allogeneic and autologous recipients. Pulmonary features were accompanied by hepatic dysfunction in 28, renal dysfunction in 22, and central nervous system abnormalities in 17. There was a strong correlation between time of engraftment and the first manifestations of CLS, both of which occurred earlier in allogeneic than in autologous transplant recipients. These data confirm that CLS occurs in both allogeneic and autologous transplant recipients and suggest a pivotal contribution by circulating leukocytes.

Bone Marrow Transplantation↗
PubMed1995

Phase I-II trial of high-dose cyclophosphamide, carboplatin and autologous bone marrow or peripheral blood stem cell rescue.

In an effort to evaluate the toxicities and anti-tumor efficacy of the combination of high-dose cyclophosphamide (CY) and carboplatin, we undertook a phase I-II trial with autologous bone marrow (BM) or peripheral blood stem cell (PBSC) rescue for patients with solid tumors. Forty three patients, 39 of whom had either high risk stage II or III or metastatic breast cancer were treated with escalating doses of carboplatin 1200-1800 mg/m2 and cyclophosphamide 4800-6000 mg/m2 over 3 days followed by autologous BM or PBSC infusion. No life-threatening or fatal toxicities were observed. Reversible congestive heart failure was seen in two patients. Transient hepatotoxicity, characterized primarily by elevation of transaminase levels, and nausea and vomiting, adequately managed with anti-emetic therapy, were seen in 39 and 40 of 43 patients, respectively. The 14 month post-transplant probability of relapse-free survival for 26 patients with high risk II-III breast cancer was 79%; for 13 patients with metastatic disease, the 22 month relapse-free survival probability was 23%. High-dose carboplatin and CY at maximally administered doses of 1800 mg/m2 and 6000 mg/m2 is a well tolerated preparative transplant regimen for autologous BM or PBSC transplantation. It appears to have similar anti-tumor activity and an improved safety profile when compared with other commonly employed transplant preparative regimens.

Adult↗
PubMed1994

Etoposide in combination with cyclophosphamide and total body irradiation or busulfan as conditioning for marrow transplantation in adults and children.

PURPOSE: In an attempt to intensify conditioning therapy for bone marrow transplantation of hematologic malignancies, a retrospective three center evaluation of escalating doses of etoposide added to cyclophosphamide and either total body irradiation or busulfan was undertaken. METHODS AND MATERIALS: Seventy-six patients who received etoposide (25-65 mg/kg) added to cyclophosphamide (60-120 mg/kg) and either total body irradiation (12.0-13.2 Gy) or busulfan (12-16 mg/kg) were evaluable for toxicity. Fifty-one of the evaluable patients received allogeneic transplants, while twenty-six received autologous transplants. A comparative analysis of toxicities according to conditioning regimen, donor source and etoposide dose was made. RESULTS: Similar toxicities were observed among the treatment groups with the exception of more frequent skin (p = 0.003) and life threatening hepatic toxicities (p = 0.01) in the busulfan treated patients. Life threatening or fatal toxicities were not influenced by donor source, either when analyzed by treatment group or etoposide dose. Etoposide at a dose of 60-65 mg/kg in combination with TBI and cyclophosphamide was associated with a significantly increased incidence of life threatening or fatal toxicities compared with a combination using a dose of 25-50 mg/kg (15 of 24 vs. 5 of 20; p = 0.013). The maximally tolerated dose of etoposide in combination with busulfan and cyclophosphamide cannot be definitively established in this analysis in part due to the heterogeneity of the patient population and treatment schemes. CONCLUSION: Although toxicities with bone marrow transplant preparative regimens containing etoposide in combination with cyclophosphamide and total body irradiation or busulfan were frequently severe, treatment related mortality risk was believed to be acceptably low.

Adolescent↗
PubMed1994

The impact of harvest center on quality of marrows collected from unrelated donors.

The total number and distribution of nucleated cells in harvested bone marrow are potentially important determinants of patient outcome following bone marrow transplantation. In order to assess whether marrows collected from predominantly unrelated donors at Georgetown University Medical Center (GUMC) were different in cellular content from marrows collected at harvest centers outside of GUMC, we compared the nucleated cell counts and mononuclear cell subset distribution (CD34, CD3, CD4, CD8, CD19 antigen-positive cell content) of 10 consecutive marrows harvested at GUMC to 10 unrelated donor marrows from outside harvest centers. Significantly higher nucleated cell counts and CD34 antigen-positive cell content and significantly lower CD3 and CD4 antigen-positive T-cell numbers were demonstrated among the marrows harvested at GUMC. These results confirmed significant variability in marrow collection practices between GUMC and 10 different outside harvest centers and suggest that strict adherence to a specific collection procedure, involving small volume marrow aspirations and multiple puncture sites, results in a product with a high number of early hematopoietic progenitor cells and minimal contamination by peripheral blood. These data further suggest the need for careful monitoring of individual unrelated donor marrow collection centers' practices to optimize the quality of the harvested marrow.

Academic Medical Centers↗
PubMed1994

Randomized double-blind, placebo-controlled evaluation of oral ondansetron in the prevention of nausea and vomiting associated with fractionated total-body irradiation.

PURPOSE: To evaluate oral ondansetron in the prevention of total-body irradiation (TBI)-induced nausea and vomiting. METHODS: Twenty patients who received 4 days of TBI as part of their preparative regimen before bone marrow transplantation were randomized to receive either 8-mg oral doses of ondansetron or placebo. Administration of drug was double-blinded. Initial rescue therapy consisted of intravenous (i.v.) ondansetron 0.15 mg/kg following two or more emetic episodes between successive fractions of TBI or five total emetic episodes during the 4 days of therapy. If, after receipt of i.v. ondansetron, patients had two or more emetic episodes between fractions of TBI or five total emetic episodes, additional antiemetics were administered. RESULTS: Patients who received oral ondansetron had significantly fewer emetic episodes compared with those who received placebo (P = .005) over the entire 4-day study period. Oral ondansetron was also significantly superior to placebo with respect to the time of onset of emesis or rescue (P = .003). Six of 10 patients treated with oral ondansetron completed the study without additional antiemetic therapy, while none of 10 patients who received placebo completed the study without rescue antiemetic therapy. Six placebo patients who received initial rescue therapy with i.v. ondansetron required no additional antiemetics. No relationships were apparent between peak ondansetron concentration (Cmax) or area under the concentration versus time curve (AUC) and number of emetic episodes. CONCLUSION: Oral ondansetron is an effective therapy for the prevention of emesis induced by TBI.

Administration, Oral↗
PubMed1993

Use of a licensed electrolyte solution as an alternative to tissue culture medium for bone marrow collection.

Bone marrow for transplantation is traditionally collected into tissue culture medium with heparin. A licensed electrolyte solution (Plasma-Lyte A [PLA]) was used as a substitute for tissue culture medium in the harvesting of 28 bone marrows, 17 autologous and 11 allogeneic, which were subsequently transplanted. Data that were analyzed from the 25 evaluable patients consisted of the numbers of cells and colony-forming units in the transplanted marrow as well as the time to neutrophil and platelet engraftment. These results were compared with those in the 30 (26 evaluable) preceding transplanted marrows that were collected into a tissue culture medium (RPMI-1640 [RPMI]). The autologous marrow transplant patients in both the PLA and RPMI groups reached a neutrophil count of > or = 0.5 x 10(9) per L a mean of 19 days following transplantation. The patients who underwent transplantation with allogeneic bone marrow collected in RPMI achieved > or = 0.5 x 10(9) per L of neutrophils an average of 20 days following transplantation, while those who received marrow collected in PLA achieved engraftment of neutrophils to that level in a mean of 21 days. Because in vitro and in vivo results with RPMI and PLA are similar in this study, further work using a licensed solution for clinical bone marrow transplantation is indicated.

Adolescent↗
PubMed1993

Bone marrow transplantation in miniature swine: IV. Development of myeloablative regimens that allow engraftment across major histocompatibility barriers.

Studies of the myeloablative regimens capable of permitting successful BMT across MHC barriers in miniature swine have been performed. To minimize graft-versus-host disease (GVHD), engraftment was studied in the F1-->P combination (i.e., MHC homozygous ["parental"] swine receiving bone marrow from one-haplotype matched MHC heterozygous ["F1"] donors). Animals given total body irradiation (TBI) up to 1100 cGy, 10 cGy/min, in a single dose failed to engraft. Increasing the dose rate led to unacceptable extramedullary toxicity without improving engraftment. Eleven different fractionated TBI regimens were tested in this F1-->parent model. At all of the dose rates tested, a total dose of less than 1000 cGy was insufficient for engraftment, and a total dose of 1400 cGy led to unacceptable toxicity. Between these extremes, a window was defined in which engraftment could be obtained without unacceptable extramedullary toxicity utilizing 2 equally divided fractions of TBI delivered 24 hr apart. The addition of 50 mg/kg cyclophosphamide i.v. to fractionated TBI (1150 cGy total dose [500 + 650]) also permitted engraftment, with decreased incidence of interstitial pneumonitis as compared to fractionated TBI (1300 cGy total dose [650 x 2]). Both of these regimens were also confirmed to permit engraftment between heterozygous donors and recipients sharing a single common haplotype ("F1-->F1"). The regimen of 1300 cGy (650 x 2) also permitted engraftment in completely MHC mismatched BMT, but with subsequent death from GVHD. These studies of the myeloablative regimens permitting engraftment across defined MHC barriers in miniature swine provide a basis for further studies of allogenic BMT and GVHD in this large animal preclinical model.

Animals↗