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Biomedical subjects

C D Hillyer

Publications and source records attributed to C D Hillyer.

At least 37 records · Page 2Linked to original sources
PubMed1997

The outcome of unrelated donor bone marrow transplantation in patients with hematologic malignancies using tacrolimus (FK506) and low dose methotrexate for graft-versus-host disease prophylaxis.

Initial studies of FK506 combined with methotrexate (MTX) in patients receiving unrelated donor BMT have demonstrated a possible-decrease in the incidence of severe GVHD but high rates of severe stomatitis and nephrotoxicity. With this background, we undertook a pilot study evaluating FK506 in combination with a lower than usual dose of MTX in an attempt to improve the tolerability of this immunoprophylaxis regimen. Between July 1993 and October 1994, 26 consecutive adults receiving unrelated donor BMT at Emory University Hospital were enrolled on this study. All patients received FK506 intravenously at an initial dose of 0.03 mg/kg/day beginning day -1 and continuing until oral FK506 was tolerated. Patients also received MTX intravenously at 5 mg/m2 on days 1, 3, 6, and 11. The preparative regimen administered to all but one patient included cyclophosphamide at 200 mg/kg over 4 days followed by total body irradiation (TBI) at 1400 cGy in twice daily fractions over 4 days. The median age of patients was 31 years (range: 19 to 52). Sixteen donor/recipient pairs were matched for HLA-A, -B, and -DR by serology and molecular typing. Ten paris were minor mismatches at either class I or class II. Twenty-two of 26 patients (85%) completed four doses of MTX on schedule. Nephrotoxicity was the most common adverse event associated with the administration of FK506: 88% of patients experienced a doubling of their serum creatinine. One patient died of central nervous system hemorrhage prior to engraftment. Twenty-four of the remaining 25 patients (96%) engrafted. Fourteen of 24 patients (50%) evaluable developed grades 2-4 acute GVHD. The rate of severe (grades 3-4) acute GVHD was 25%. Chronic GVHD developed in 11 of 20 (55%) evaluable patients. At a median follow-up of 461 days, 14 patients (54%) are alive. All are relapse-free with a median Karnofsky performance status of 90% (range: 70-100%). The cumulative probability of 2-year disease-free survival is 50% (95% confidence interval [CI]: 0.33 to 0.77); for low risk patients 67% (95% CI: 0.47 to 0.95) and for high risk patients 23% (95% CI: 0.049 to 1.00). These preliminary data indicate that FK506-based immunosuppression following unrelated donor BMT is effective in preventing severe acute GVHD and warrants comparison to CSA-based regimens.

Adult↗
PubMed1996

Peripheral blood progenitor cells for marrow reconstitution: mobilization and collection strategies.

Previous studies of PBPC BMR have found evidence supporting its safety, feasibility, and efficacy when used in a wide range of patients. Although the optimal regimen for mobilization remains a focus of debate, data from the use of combinations of chemotherapy and cytokines suggest that there is more rapid white cell and platelet engraftment than with BMT, which leads to decreased transfusion requirements and, possibly, reduced patient care costs. Recent advances in the field include allogeneic PBPC BMR, negative selection of tumor cells to reduce contamination, and positive selection of CD34+ cells. These new strategies are anticipated to enhance the therapeutic effectiveness of PBPC BMR while minimizing toxicity. Still, the ultimate comparison of PBSC BMR and medullary BMT will depend on the results of well-designed, randomized, controlled clinical trials with long-term outcome analysis. However, the refinement and improvement of mobilization and collection techniques for PBPC BMR continue to add to the armamentarium of current therapeutic approaches for cancer and related nonmalignant conditions and will enable future strategies for ex vivo expansion of progenitor cells and use in gene transfer studies.

Animals↗
PubMed1996

Induction of autologous tumor-specific cytotoxic T-lymphocyte activity against a human renal carcinoma cell line by B7-1 (CD8O) costimulation.

Recently mouse models have shown that expression of costimulatory molecules such as B7-1 on tumor cells can induce tumor-specific immunity, suggesting that tumor cells modified to express costimulatory molecules can be a potential tumor vaccine. To investigate the importance of B7-1 co-stimulation in induction of autologous tumor immunity in humans, we established a renal carcinoma cell line, RCC-1, from a tumor resection and studied the patient's antitumor immune responses in vitro. The RCC-1 cell line constitutively expressed major histocompatibility complex (MHC) class I, intercellular adhesion molecule (ICAM)-1, and leukocyte function-associated antigen (LFA)-3 molecules, and MHC class II molecules were induced by interferon-gamma (IFN-gamma) treatment in vitro. However, neither RCC-1- nor IFN-gamma-treated RCC-1 cells expressed B7-1, and both failed to induce T-cell proliferative responses in mixed lymphocyte and tumor cell reaction (MLTR) assays, suggesting that the costimulatory signals provided by cell adhesion molecules such as ICAM-1 and LFA-3 were not sufficient to elicit an antitumor immune response. However, on transfection of the human B7-1 into RCC-1, these cells were able to induce a significant T-cell proliferation in MLTR assays. This T-cell response could be blocked by anti-B7 mAb treatment of the tumor cells. RCC-1B7 cells also induced the generation of tumor-specific cytolytic T lymphocytes to the parent RCC-1 cells in vitro, with little nonspecific cytolysis of an unrelated RCC line, A498, or autologous phytohemagglutinin (PHA) blasts. This specific cytotoxicity could be abrogated by anti-CD8 mAb and complement treatment. In summary, our study indicates that B7-1-CD28 interaction plays a critical role in induction of autologous tumor-specific cytotoxic T lymphocytes (CTLs) in humans, suggesting that the costimulatory molecule transfected tumor cells could be useful in expanding tumor-specific autologous CTL in vitro for adoptive tumor immunotherapy.

Antigens, Neoplasm↗
PubMed1996

Minimal toxicity and mortality in high-risk breast cancer patients receiving high-dose cyclophosphamide, thiotepa, and carboplatin plus autologous marrow/stem-cell transplantation and comprehensive supportive care.

PURPOSE: To assess the clinical toxicity and outcome associated with a comprehensive supportive care approach in poor-risk breast cancer (BrCA) patients with high-dose chemotherapy (HDC). PATIENTS AND METHODS: One hundred twenty-five consecutive patients with stages II, III or metastatic breast cancer received HDC between February 1992 and June 1994. Recipients received 4 days of continuous infusion of cyclophosphamide 1.5 g/m2/d, thiotepa 125 mg/m2/d, and carboplatin 200 mg/m2/d followed by infusion of bone marrow or peripheral-blood stem cells (PBSC) and recombinant human growth factor (rhu-GF) support. Patients received similar supportive care that included administration of prophylactic antibiotics, management of neutropenic fevers, and transfusion support. RESULTS: There were 38 women with stage II or III (27 patients with > or = 10 lymph nodes), four with stage IIIB, and 83 with metastatic breast cancer. The median age was 44 years (range, 27 to 61). Grade II or greater nonhematologic toxicities included diarrhea (66%), stomatitis (33%), hepatic venoocclusive disease (VOD) (5%), and pulmonary toxicity (4%). Myeloid and platelet engraftment was comparable between bone marrow and PBSC recipients (P > .1). Infectious complications were rare and consisted of gram-negative bacteremia (1.6%), gram-positive bacteremia (1.6%), fungemia (1.6%), and documented or suspected aspergillosis infection (3%). There was one treatment-related death secondary to severe VOD. CONCLUSION: A comprehensive supportive care approach was associated with a low treatment-related mortality rate of less than 1%. With the observed reduction in treatment-related mortality, it is reasonable to evaluate the efficacy of HDC in women with less than 10 positive nodes and stage II disease in well-designed clinical trials.

Actuarial Analysis↗
PubMed1996

Association of busulfan area under the curve with veno-occlusive disease following BMT.

Busulfan pharmacokinetics, specifically area under the concentration curve (AUC), have been correlated with the occurrence of veno-occlusive disease (VOD) following BMT. To evaluate the risk of VOD, we studied 66 patients who received pharmacotherapeutically monitored busulfan regimens in combination with CY, etoposide (VP16) and/or Ara-C in preparation for BMT. These patients received a total of 16 doses of busulfan dosed as 1 mg/kg/dose q 6 h beginning at 09.00 (n = 39), 18.00 (n = 2), 21.00 (n = 1) or 24.00 (n = 24) h. With the first dose, blood samples were obtained at baseline, every 15-30 min for 2 h, then every 1-2 h for 4 h. Blood was analyzed for busulfan concentration by high performance liquid chromatography and AUC calculated by the trapezoidal rule. Seventeen patients (25.8%) were not evaluable for AUC calculation due to slow absorption and/or elimination: 13 of 27 (48.1%) received the first dose between 18.00-24.00 vs four of 39 (10.2%) patients who received the first dose at 09.00 (P < 0.001). Eighteen of 51 (35.3%) evaluable patients had an AUC > 1500 mumol x min/l; 10 of whom received doses reduced proportionally to achieve an AUC = 1200 mumol x min/l starting with the 10th to 15th dose. Six of 18 (33.3%) patients with an initial AUC > 1500 mumol x min/l developed VOD vs one of 33 (3.0%) patients with an initial AUC < 1500 mumol x min/l (relative risk = 11.1; P = 0.0056). Other pharmacokinetic parameters, age, gender, type of BMT, previous therapy or pre-transplant liver function tests were not predictive of VOD. A higher incidence of VOD occurred in patients receiving BUCY (4 of 10) compared to those receiving BUCYAra-C (1 of 18) or BUCYVP16 (7 of 38), which could not be attributed to increased busulfan exposure in the BUCY patients. Routine pharmacotherapeutic monitoring of busulfan is recommended with further study to evaluate the impact of earlier and greater overall dose reduction in patients with high initial busulfan exposures.

Adolescent↗
PubMed1995

Chemotherapy-induced hemolytic uremic syndrome: description of a potential animal model.

Hemolytic uremic syndrome (HUS) is an uncommon complication of chemotherapy that contributes to the morbidity of oncology and bone marrow transplant patients. The pathogenesis is not well understood and no established clinical animal model exists. We studied four rhesus monkeys (RM) that developed fatal HUS following high-dose chemotherapy. Microangiopathic hemolytic anemia (pre-Hct 40% and day 5-8 Hct 31% (P < .05), increased BUN (168 mg/dl), creatinine (8.2 mg/dl), and lactate dehydrogenase (1458 IU/L) (mean day 5-8 measurements) were observed. Platelets counts decreased to 39 +/- 15 x 10(9)/l from a mean of 397 +/- 31 x 10(9)/L (P < .0001). vWF, ATIII, thrombin:anti-thrombin complex (T:AT) and prothrombin fragment F1.2 levels were not different from a control group (N = 2). The data presented describe chemotherapy-induced HUS with typical clinical and laboratory features which may provide an animal model for the study of this important syndrome.

Animals↗
PubMed1994

Effect of recombinant human interleukin-6 (rhIL-6) and rhIL-3 on hematopoietic regeneration as demonstrated in a nonhuman primate chemotherapy model.

Using a recently developed hepsulfam-induced pancytopenia model in rhesus macaques, we have studied the effects of recombinant human interleukin-6 (rhIL-6) and rhIL-3 on marrow regeneration. Control animals were given hepsulfam (1.5 g/m2 by a single 30-minute intravenous [i.v.] injection, n = 4), while study animals received hepsulfam followed by rhIL-6, rhIL-3, or a combination of rhIL-6 and rhIL-3 (n = 3 per study group). Each cytokine was administered by once-daily subcutaneous (SC) injection (15 micrograms/kg/d) for 3 weeks beginning the day after chemotherapy (days 2 through 22). Mean platelet counts in control animals were < 100,000/microL on days 15 through 24, with 50% of the counts < 50,000/microL and two of four animals requiring platelet transfusion. In the rhIL-6- and rhIL-6/rhIL-3-treated groups, the nadir mean platelet counts were 164,000 +/- 58,700/microL and 162,300 +/- 23,800/microL, respectively, and occurred on day 15. Platelet counts in the rhIL-3-treated group were similar to those in controls. Mean absolute neutrophil counts (ANCs) < 1,000/microL occurred on days 10 through 29 in control animals, days 8 through 15 in rhIL-6-treated animals, and days 6 through 8 and 13 in rhIL-6/rhIL-3-treated animals. The frequency of ANCs < 500/microL was significantly less in the rhIL-6- and rhIL-6/rhIL-3-treated groups versus control groups (2.7 +/- 0.6 and 2.0 +/- 1.0 vs 7.0 +/- 1.4 occurrences, respectively; P < .05). rhIL-3-treated animals had ANCs similar to those in controls; one animal died with septicemia on day 21. Monkeys receiving rhIL-6 were significantly more anemic during the cytokine administration period; however, the anemia resolved by day 24. Coadministration of rhIL-3 and rhIL-6 partially corrected the anemia. The data indicate that rhIL-6 prevents significant thrombocytopenia and shortens the neutropenic period in this chemotherapy model.

Animals↗
PubMed1994

Comparable safety of blood collection in "high-risk" autologous donors versus non-high-risk autologous and directed donors in a hospital setting.

The safety of autologous blood donation by "high-risk" patients (those with some preexisting medical conditions) has been questioned. The authors reviewed 1393 consecutive blood donation records (207 high-risk autologous [HRA], 665 non-high-risk autologous [NHRA], and 521 directed donors [DD]) to determine the safety and outcome of blood donation by HRA patients as compared with other donors at their center. The HRA group included patients with a history of significant coronary artery on cerebral vascular disease, recent seizures, cardiac arrhythmia, chronic heart failure, valvular or congenital heart disease, symptomatic dyspnea, insulin-dependent diabetes and/or current therapy with two or more antihypertensive medications. Those designated NHRA were all other autologous donors; DD met all criteria for homologous donation. Donor characteristics including predonation hematocrit, pre- and postdonation mean arterial pressure and heart rates were similar in all groups. Eight HRA donors (3.9%) had reactions, compared with 21 NHRA (3.2%) and 23 DD (4.4%), a difference that was without statistical significance. The reaction rate in all autologous donors (HRA and NHRA) was 3.4%. No differences in symptoms reported, hemodynamics or reaction severity were observed among the three groups (P > .05). A multiple logistic regression was performed within and among the groups with the risk factor categories listed above and medication classes including beta blockers, cardiac glycosides, calcium-channel blockers, antihypertensive agents, nitrates, and antiarrhythmic agents (chi 2 = 14.9; P = .0006). Only first-time donation (P = .0001) and cardiac glycoside usage (P = .04) were positively associated with an untoward reaction. The authors conclude that donation by HRA donors is at least as safe as that by donors who meet homologous donation criteria in their population and setting.

Adult↗
PubMed1993

CD34+ and CFU-GM progenitors are significantly decreased in SIVsmm9 infected rhesus macaques with minimal evidence of direct viral infection by polymerase chain reaction.

Hematologic abnormalities in the peripheral blood and bone marrow are associated with human immunodeficiency and simian immunodeficiency virus (HIV, SIV) infection. The reasons for these abnormalities remain unclear. Bone marrow specimens collected from uninfected animals (Group A, Controls) and from rhesus macaques experimentally infected with SIVsmm9 during the asymptomatic stage (Group B, SIV+ "well") and during the clinically ill stage (Group C, SIV+ "sick"), underwent a variety of in vitro assays of hematopoiesis. Colony forming unit-granulocyte/macrophage (CFU-GM) per plate growth was 46.7 +/- 7.7, 31.9 +/- 8.4 and 6.5 +/- 5.0 (mean +/- sd, P < .02 each mean compared to the others) in the 3 groups respectively. Burst forming unit-erythroid (BFU-E) growth was similarly decreased in bone marrow samples from the SIV+ animals. There was no change in the number of CFU-GM per plate with the removal of plastic adherent or T-cell mononuclear cell fractions. There was no increase in CFU-GM per plate growth with the addition of low dose GM-CSF (1 or 5 ng/mL) though there was a near 67% increase (48 to 80 CFU-GM per plate) with the addition of 100 ng/mL recombinant rhesus IL-3 and 100 ng/mL GM-CSF in SIV+ "sick" animals. Variation in frequency of CD34+ progenitor cells in SIV+ animals was seen, with 3.0% CD34+ cells in SIV- controls, 4.9% CD34+ cells in SIV+ "well" animals and 0.5% CD34+ progenitor cells in SIV+ "sick" monkeys (P < .01, each mean compared to the others). Finally, there was minimal evidence of SIV sequences by polymerase chain reaction in pooled cultured CFU-GM, and no evidence in flowcytometrically sorted CD34+ progenitor cells from selected animals. Thus, the SIV seropositive rhesus monkey appears to have similar hematopoietic aberrations as are found in HIV infected human subjects and may be an excellent model for studying the interaction of lentiviruses on the kinetics of blood formation.

Animals↗
PubMed1993

CD34+ progenitors and colony-forming units-granulocyte macrophage are recruited during large-volume leukapheresis and concentrated by counterflow centrifugal elutriation.

The recruitment of mononuclear cells (MNCs), colony-forming units-granulocyte macrophage (CFU-GM), lymphocyte subpopulations, and CD34+ progenitor cells was studied during large-volume (15-25 L blood processed) peripheral blood stem cell (PBSC) harvests. Normal donors (n = 13) underwent a 4-hour leukapheresis designed to maximize PBSC yield (blood flow rate, 85 mL/min). Mean (+/- SD) volume processed was 17.7 +/- 0.4 L, and yield was 2.4 +/- 0.7 x 10(10) white cells containing 99 percent MNCs and 1.3 mL red cells per L of blood processed. Postapheresis hematocrit, platelets, and MNCs were reduced from preapheresis values by 7, 35, and 23 percent, respectively (p < 0.05). In nine donors, the component was collected as four 1-hour samples, and culturing of CFU-GM and flow cytometric analysis of lymphocyte subpopulations and CD34+/HLA-DR+ cells were done in individual samples. Total CFU-GM were 2.4 +/- 1.4 x 10(6) (3.0 +/- 1.8 x 10(4) CFU-GM/kg) and lymphocytes were 20.8 x 10(9), with 75 percent CD3+ T cells, 10 percent CD19/CD20+ B cells, and 17 percent natural killer cells. A more than twofold increase in CFU-GM and CD34+ cells was noted over the course of the 4-hour procedure (p < 0.05). In four donors, the leukapheresis component underwent counterflow centrifugal elutriation (CCE), which separated it into four fractions in an attempt to concentrate CD34+ and CFU-GM progenitors and to deplete T-lymphocytes on a large scale. There was a 1.8-, 4.6-, 3.9-, and 0.32-fold increase in CFU-GM in the four fractions relative to the unseparated component.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

Alternative sources of hematopoietic stem cells for bone marrow transplantation and rescue.

Hematopoietic stem cells from sources other than medullary bone marrow are being used for experimental and clinical rescue following myeloablative therapy. In this paper we review the cells capable of bone marrow engraftment and the use of orthotopic, cadaveric, peripheral blood, umbilical cord blood, and fetal liver derived stem cells in transplantation.

Blood Cells↗
PubMed1993

Large volume leukapheresis to maximize peripheral blood stem cell collection.

Large volume leukapheresis, defined as the processing of greater than three volumes of blood at one sitting, can be safely and easily performed using a variety of cell separators in a range of patients. This paper describes the history, technique, outcome, complications, and proposed uses for this procedure.

Animals↗
PubMed1993

Multifactorial etiology of anemia in SIV-infected rhesus macaques: decreased BFU-E formation, serologic evidence of autoimmune hemolysis, and an exuberant erythropoietin response.

We attempted to define the etiology of anemia in SIV-infected rhesus macaques. Bone marrow culture showed significantly decreased (75% reduction) burst forming unit-erythroid (BFU-E) growth in end-stage SIV+ "sick" animals. Direct antiglobulin tests (DAT) were positive in nine of 35 SIV+ "well" and 14 of 14 SIV+ "sick" monkeys (0 of 25 control animals had positive DATs). In animals with a positive DAT, moderate to severe anemia was observed, as was increased LDH and spherocytosis. Erythropoietin was measured in four control, eight SIV+ "well" and five SIV+ "sick" animals with mean levels of 4.0, 15.4, and 1176 mU/mL (r = .94) in the three groups. These data suggest that the cause of anemia in the SIV-infected rhesus macaque is multifactorial, that there may be a defect in erythropoiesis, and that, serologically, an IgG mediated autoimmune hemolytic anemia is also present.

Anemia↗
PubMed1993

Peripheral blood stem cell acquisition by large-volume leukapheresis in growth factor-stimulated and unstimulated rhesus monkeys: development of an animal model.

Twelve (eight unstimulated [UNS], four growth factor-stimulated [ST]) anesthetized adult male rhesus monkeys underwent a single large-volume leukapheresis (> 3 blood volumes processed) in an attempt to define an animal model for use in future peripheral blood stem cell (PBSC) transplantation studies. The cell separator was primed with autologous blood and saline and set according to the manufacturer's mononuclear cell (MNC) protocol using the granulocyte separation and small volume collection chambers with additional modifications. Stimulated animals received 5 micrograms/kg recombinant human interleukin-3 (rhIL-3) on days -12 to -5, 5 micrograms/kg granulocyte-macrophage colony-stimulating factor (GM-CSF) on days -4 to -1, and large-volume leukapheresis on day 0. UNS animals did not receive growth factors. Vascular access was via a triple lumen intra-aortic catheter; blood pressure was monitored via the third lumen. Pre- and post-apheresis blood counts were determined and product hematocrit (Hct), MNC, colony-forming units-granulocyte/macrophage (CFU-GM), CD34+, and lymphocyte subsets were studied. During the 100-minute large-volume leukapheresis with mean flow rate 26.4 +/- 3.9 mL/min, the pre- and post-Hct were 36.6 +/- 2.6 and 32.3 +/- 7.0%, platelets 447 +/- 305 and 154 +/- 77 x 10(9)/L, and MNC 2.7 +/- 0.9 and 1.9 +/- 1.4 x 10(9)/L (all p < .05) in UNS animals. In ST animals, the pre- and post-Hct were 39.0 +/- 5.6 and 34.9 +/- 3.7%, platelets 507 +/- 100 and 150 +/- 9 x 10(9)/L (p < .05), and MNC 4.9 +/- 1.6 and 2.8 +/- 0.7 x 10(9)/L (p < .05). The product contained 98.5 +/- 1.4% MNC, 4.1 +/- 4.1% Hct, 1.9 +/- 0.6 x 10(9) MNC, 9.2 +/- 7.3 x 10(4) CFU-GM, and 3.5 +/- 2.1 x 10(6) CD34+ cells in UNS animals. In ST monkeys, the product contained 49.5 +/- 32% MNC, 6.4 +/- 4.4% Hct, 3.6 +/- 1.8 x 10(9) MNC, 49.3 +/- 39 x 10(4) CFU-GM, and 9.1 +/- 5.5 x 10(6) CD34+ cells. Greater than 75% of the product MNC were CD2+ T cells in ST and UNS animals. Large-volume leukapheresis in rhesus monkeys was tolerated well. Herein we characterize an animal model for large-volume leukapheresis in UNS monkeys that is similar to that of human PBSC leukapheresis. In ST animals there is more than a five-fold increase in CFU-GM collected and an increase in circulating CFU-GM/MNC.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1992

Induction of endonuclease-mediated apoptosis in tumor cells by C-nitroso-substituted ligands of poly(ADP-ribose) polymerase.

6-Nitroso-1,2-benzopyrone and 3-nitrosobenzamide, two C-nitroso compounds that inactivate the eukaryotic nuclear protein poly(ADP-ribose) polymerase [NAD+:poly(adenosine diphosphate D-ribose) ADP-D-ribosyltransferase, ADPRT, EC 2.4.2.30] at one zinc-finger site, completely suppressed the proliferation of leukemic and other malignant human cells and subsequently produced cell death. Tumoricidal concentrations of the drugs were relatively harmless to normal bone marrow progenitor cells and to superoxide formation by neutrophil granulocytes. The cellular mechanism elicited by the C-nitroso compounds consists of apoptosis due to DNA degradation by the nuclear calcium/magnesium-dependent endonuclease. This endonuclease is maintained in a latent form by poly(ADP-ribosyl)ation, but inactivation of ADPRT by C-nitroso drugs derepresses the DNA-degrading activity. ADPRT is thus identified as a critical regulatory enzyme component of a DNA-binding multiprotein system that plays a central function in defining DNA structures in the intact cell.

Animals↗