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Biomedical subjects

R Storb

Publications and source records attributed to R Storb.

At least 397 records · Page 22Linked to original sources
PubMed1989

High-dose cytosine arabinoside, total body irradiation and marrow transplantation for advanced malignant lymphoma.

Twenty-four patients with advanced malignant lymphoma including Hodgkin's disease (HD, n = 1), intermediate grade non-Hodgkin's lymphoma (IGL, n = 12) and high-grade non-Hodgkin's lymphoma (HGL, n = 11) were prepared for syngeneic (n = 2), allogeneic (n = 11) or autologous (n = 11) marrow transplantation with cytosine arabinoside, 3 g/m2 every 12h for 12 doses (HDAC) and total body irradiation, 200 cGy daily for 6 days (TBI) to determine toxicity and efficacy. Eight patients (33%) died from early regimen related toxicity and all eight had a Karnofsky performance score less than or equal to 80 at the start of treatment. The actuarial probability of disease-free survival was 17% with a 65% probability of relapse at 4 years after transplantation. Four patients are surviving 2-4 years post-transplant, three transplanted for IGL and one for HD. None of the patients transplanted for HGL survived. The result of this phase II study suggests that HDAC followed by TBI and marrow infusion offers no apparent advantage over cyclophosphamide + TBI for patients with relapsed advanced malignant lymphoma. Earlier transplantation currently is the only demonstrated method of achieving better results.

Adolescent↗
PubMed1989

Busulfan, cyclophosphamide and fractionated total body irradiation as a preparatory regimen for marrow transplantation in patients with advanced hematological malignancies: a phase I study.

Thirty-six patients with advanced hematologic malignancy were entered into a phase I study designed to define a tolerable dose of busulfan (BU) and cyclophosphamide (CY) combined with 12 Gy of fractionated total body irradiation (TBI) as preparation for marrow transplantation from HLA-identical siblings, 0-1 locus HLA-non-identical family members or autologous cryopreserved marrow. Five of 18 evaluable patients prepared with 8.7 mg/kg of BU and 69 mg/kg CY + TBI developed severe regimen related toxicity (RRT) while none of 15 patients treated with 6.9 mg/kg of BU and 47 mg/kg of CY + TBI developed severe RRT. Ten of the 15 evaluable patients treated on the lower dose level are alive, nine disease-free, 262-737 days (median, 547) post-transplant with a 87% and 67% actuarial probability of survival at 3 and 18 months respectively. Six of the 18 patients treated on the higher dose level are alive disease-free 273-1039 days (median, 668) post-transplant with a 56% and 27% actuarial probability of survival at 3 and 18 months respectively. Eighteen patients were transplanted with allogeneic marrow for chronic myelogenous leukemia beyond chronic phase and acute non-lymphocytic leukemia beyond first remission or in relapse other than first untreated relapse and only one has relapsed posttransplant. It was concluded that a transplant preparative regimen combining 6.9 mg/kg of BU with 47 mg/kg of CY followed by 12 Gy fractionated TBI is well tolerated. The high probability of surviving this regimen and the low early relapse rate in patients with advanced myeloid malignancies is encouraging.

Adult↗
PubMed1989

Long-term culture of canine bone marrow cells.

Conditions that allow the growth of canine marrow cells in long-term marrow culture are described. The quality of the culture conditions was evaluated based on the weekly number of granulocyte-macrophage colony-forming units (CFU-GM) in the nonadherent cell fraction. Using this parameter, the highest number of CFU-GM was obtained when marrow cells were incubated at 37 degrees C in RPMI-1640 or McCoy's 5A medium supplemented with 20% prescreened horse serum without addition of hydrocortisone. CFU-GM colonies could be regularly grown out of the nonadherent cell fraction for 20-31 weeks, after recharging the cultures with 1.5 X 10(7) mononuclear autologous marrow cells 1 week after establishing the stromal cell layer.

Animals↗
PubMed1989

Improved retroviral transfer of genes into canine hematopoietic progenitor cells kept in long-term marrow culture.

Amphotropic helper-free retroviral vectors containing either the bacterial neomycin phosphotransferase gene (NEO) or a mutant dihydrofolate reductase gene (DHFR*) were used to infect canine hematopoietic progenitor cells. In previous experiments, successful transfer and expression of both genes in canine CFU-GM were achieved after 24-hour cocultivation with virus-producing cells. The average rate of gene expression was 10% (6% to 16%) as measured by the number of CFU-GM resistant to either the aminoglycoside G418 or methotrexate. In an attempt to increase the efficiency of gene transfer, marrow was cocultured for 24 hours with either NEO or DHFR* virus-producing packaging cells and then kept in long-term marrow culture fed three times with virus-containing supernatant (2 to 5 x 10(6) CFU/mL). After six days, cells were harvested and cultured in CFU-GM assay with and without a selective agent. The average rate of gene expression in CFU-GM in five independent experiments was 46% and ranged from 19% to 87%. In conclusion, the efficiency of gene transfer into canine hematopoietic progenitor cells has been increased fourfold by combining cocultivation with long-term marrow culture as compared with results obtained with cocultivation only.

Animals↗
PubMed1989

Specific marrow localization of an 131I-labeled anti-myeloid antibody in normal dogs: effects of a "cold" antibody pretreatment dose on marrow localization.

Tumor recurrence and regimen-related toxicity remain major obstacles in the successful use of marrow transplantation as therapy for hematologic malignancies. By attaching radionuclides to monoclonal antibodies (MoAbs) targeted at myeloid-associated antigenic determinants, a more effective and directed delivery of therapy may be possible without increasing toxicity. We investigated the biodistribution over time of an anti-myeloid antibody (DM-5) labeled with trace amounts of 131I in normal dogs. This study demonstrates the ability to target marrow with a high degree of selectivity, achieving marrow/blood ratios of 25-30:1 with the greatest concentration in any other organ being a tissue/blood ratio of 1.4:1 for stomach at 48 h. A pretreatment dose of unlabeled antibody effectively reduced early hepatic uptake by 80%, resulting in improved marrow localization with an estimated 58.6% of the injected dose localized in marrow within 2 h following infusion, compared to 32.8% without pretreatment. The marrow concentration clearance curve for the radioimmunoconjugate revealed an initial short half-life (4.75 h), suggesting rapid internalization, digestion, and release of free iodine (dehalogenation). This view was supported by a corresponding rise in trichloroacetic acid-non-precipitable activity during this period. Methods aimed at decreasing dehalogenation may result in longer residence time of the radionuclide within the marrow space, resulting in more effective tumor cell kill. This approach may provide a way to improve upon the current results obtained with marrow transplantation as treatment for patients with leukemia and other hematologic malignancies.

Animals↗
PubMed1988

Transfer of allergen-specific IgE-mediated hypersensitivity with allogeneic bone marrow transplantation.

We investigated whether allergen-specific IgE-mediated hypersensitivity is transferred by bone marrow transplantation. Twelve patients, 14 to 47 years of age, undergoing allogeneic bone marrow transplantation for the treatment of hematologic cancer were selected, along with their donors, by a screening questionnaire for a history of atopy in the donor. We evaluated these donor-recipient pairs before transplantation and at several points afterward for immediate skin-test reactivity to 17 allergens. For allergens for which pretransplantation skin tests had been positive in the donors and negative in the recipients, 20 of 46 post-transplantation skin tests were positive in 8 of the 11 recipients who survived for more than one year after transplantation. For allergens for which both donors and recipients had had negative skin tests before transplantation, only 6 of 256 tests (2.3 percent) were positive in the recipients after transplantation. Long-term transfer of donor-derived mite-specific IgE was demonstrated by radioallergosorbent testing in two recipients. Seven recipients either acquired or had an exacerbation of allergic rhinitis, and two recipients without a history of asthma had asthma one year after transplantation. We conclude that allergen-specific IgE-mediated hypersensitivity is adoptively transferred by bone marrow transplantation from donor to recipient by B cells with allergen-specific memory.

Adolescent↗
PubMed1988

Retroviral transfer of genes into canine hematopoietic progenitor cells.

Amphotropic retroviral vectors containing either the bacterial neomycin phosphotransferase gene or a mutant dihydrofolate reductase gene (DHFR*) were used to infect canine hematopoietic progenitor cells. Successful transfer and expression of both genes in canine hematopoietic progenitor cells has been achieved as measured by the ability of the viruses to confer resistance to either methotrexate (MTX) or the aminoglycoside G418, respectively. Gene transfer was achieved using helper-free retroviral vectors. The rate of gene expression in canine granulocyte/macrophage colony-forming units (CFU-GM) after cocultivation for 24 hours with virus-producing packaging cells ranged from 6-25%. Autologous marrow cocultivated for 24 hours with virus-producing packaging cells was transplanted into six dogs after lethal total body irradiation. All dogs showed engraftment within two weeks and four dogs survived for 5-7 months without adverse effects. One dog that had been given marrow infected with a DHFR* virus and that received MTX as in vivo selection after marrow transplantation and survived, showed 0.1 and 0.03% MTX-resistant CFU-GM at weeks 3 and 5. The efficiency of gene transfer into canine CFU-GM has been increased threefold by culturing marrow cells for six days in long-term marrow culture after 24 hour cocultivation with virus producing packaging cells.

Animals↗
PubMed1988

Single dose or fractionated total body irradiation and autologous marrow transplantation in dogs: effects of exposure rate, fraction size, and fractionation interval on acute and delayed toxicity.

Dogs were given single dose or fractionated total body irradiation (TBI) and autologous marrow grafts to prevent death from myelosuppression. Acute and delayed non-marrow toxicities were compared. Fifty-six dogs were given single dose TBI at 2.1 (n = 13), 5 (n = 12), 10 (n = 15), or 20 (n = 16) cGy/min. Acute radiation toxicity and mortality was related to the exposure rate; radiation doses resulting in 50% mortality at 7 days (LD 50/7) at 2.1, 5, 10 and 20 cGy/min were 1,692, 1,499, 1,261, and 1,056 cGy respectively. Fifty-three dogs were given fractionated TBI, 200 cGy three times a day with 6-hour intervals at 2.1 (n = 13), 5 (n = 9), 10 (n = 13), or 20 (n = 18) cGy/min. The LD 50/7 at the four exposure rates were 1,628, 1,470, 1,184, and 1,320 respectively. Thus, for exposure rates of 2.1, 5, and 10 cGy/min, the tolerated doses were comparable for single dose and fractionated TBI. At 20 cGy/min dose fractionation appeared to offer some advantage, although this fractionation effect in part may have been due to random variation with small numbers of dog treated. Following recovery from the immediate TBI-related toxicity, eight dogs given single dose and four dogs given fractionated TBI died, generally from infections, 8-30 days following transplantation. There was a striking difference in regards to long-term survival dependent upon the TBI regimen. Among dogs given greater than or equal to 1,000 cGy of TBI and alive 30 days after transplant only 1 of 18 given single dose TBI became a long-term survivor compared to 19 of 22 given fractionated TBI. Causes of death included pancreatic fibrosis, malnutrition, hepatic failure, and a generalized wasting syndrome. All 5 dogs given a single dose of 800 cGy (at 20 cGy/min) became long-term survivors. Fourteen dogs were given increments of 150 cGy at 7 cGy/min every 3 hours for total doses of 1,500-2,400 cGy. The LD 50/7 was approximately 1,900 cGy. All 6 dogs alive at 30 days became healthy long-term survivors. Four dogs were given increments of 600 cGy at 2.1 cGy/min every 48 hours for a total dose of 1,800 cGy. All 4 dogs became long-term survivors. In conclusion, exposure rate and total dose are the most important parameters for acute toxicity associated with TBI. The effect of dose fractionation is minimal at low exposure rates and appears to be dependent also upon increment size and fractionation interval.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1988

Syndrome of idiopathic hyperammonemia after high-dose chemotherapy: review of nine cases.

PURPOSE: The syndrome of idiopathic hyperammonemia occurs in patients who have received high-dose cytoreductive therapy for the treatment of hematologic malignancy. It is characterized by abrupt alteration in mental status and respiratory alkalosis associated with markedly elevated plasma ammonium levels in the absence of any identifiable cause, and frequently results in intractable coma and death. Our goal was to survey clinical and pathologic manifestations of the disorder and discuss treatment options. PATIENTS AND METHODS: Plasma ammonium levels were measured in patients on the acute leukemia service or on the bone marrow transplant service at The Johns Hopkins Hospital, and a level more than twice normal was considered diagnostic of hyperammonemia. The syndrome was identified in nine patients; in eight, hyperammonemia occurred after administration of intensive cytoreductive therapy that resulted in profound leukopenia. The disorder occurred in the ninth patient two months after allogeneic bone marrow transplantation. RESULTS: Three of the nine patients survived an episode of idiopathic hyperammonemia; one patient subsequently died of leukemia and one of recurrent idiopathic hyperammonemia. The one long-term survivor is currently alive and well without neurologic sequelae 250 days after autologous bone marrow transplantation. CONCLUSION: Because neurologic function can deteriorate rapidly, early recognition of this disorder and close monitoring of the patient's neurologic status are critical.

Adolescent↗
PubMed1988

Treatment of acute graft-versus-host disease with anti-CD3 monoclonal antibodies.

A dose-escalation trial was carried out to determine the efficacy and safety of using an IgG2a anti-CD3 monoclonal antibody to treat acute graft-v-host disease (GVHD) in marrow transplant recipients. Two patients received the antibody as the initial treatment of GVHD, and 22 patients received the antibody after failure of initial treatment with corticosteroids, cyclosporine, antithymocyte globulin (ATG), or combined ATG and cyclosporine. Antibody was administered at four dose levels, beginning at approximately 0.015 mg/kg/d and increasing by threefold increments. The initial doses of antibody were nearly always associated with fever and chills, and treatment had to be discontinued in one patient because of intolerable side effects. Improvement in skin disease could be reliably achieved at a dose of 0.15 mg/kg/d, but threefold higher doses appeared to be necessary for improvement in the liver or gut. In no case was there complete resolution of all manifestations of disease, and all patients surviving after antibody treatment required additional immunosuppressive treatment. Four patients developed Epstein-Barr virus (EBV)-associated lymphoproliferative disorders within seven to 18 days after starting antibody therapy. The overall risk of this complication in patients not given anti-CD3 monoclonal antibody is less than 1%. Anti-CD3 antibody represents an effective immunosuppressive agent for treatment of acute GVHD, but this treatment is associated with a substantial risk of EBV-associated lymphoproliferative disorders.

Acute Disease↗
PubMed1988

Selective inhibition of the canine mixed lymphocyte response by HLA-DR and DP-reactive monoclonal antibodies.

Twenty-three of 37 anti-Ia McAb reactive with human B cells, as determined by indirect immunocytofluorescence, were shown to be reactive with canine peripheral blood mononuclear cells (PBMC). Using a panel of human B cell lines that differ in their expression of HLA-DR, -DP, and -DQ molecules, it was shown that 15 of these antibodies identify HLA-DR and DP molecules (i.e., broadly reactive), while 22 identify only HLA-DR molecules. Fourteen of the 15 broadly reactive McAb were reactive with canine PBMC while only 9 of the 22 HLA-DR-specific McAb reacted with canine PBMC, suggesting that broadly reactive anti-Ia McAb are much more likely to react with canine cells than narrowly reactive McAb. Ten of the canine reactive McAb that were shown to identify typical Ia bimolecular structures on canine cells using immune precipitation analysis were tested for blocking activity in the canine mixed lymphocyte culture (MLC). All four of the broadly reactive McAb (B1F6, J-70, 9-49, and HB10a) plus two of the six narrowly reactive McAbs (H81.98.21 and H40.164.3) blocked the canine MLC when added to culture wells on day 0, suggesting that inhibition may be related to the specificity of the anti-Ia McAb employed. Since the MLC may reflect cellular interactions occurring during graft-versus-host disease, this assay may be useful for screening functionally relevant broadly reactive McAb in experimental canine bone marrow transplantation studies. These data suggest that the dog may be a useful model to study anti-Ia immunotherapy.

Animals↗
PubMed1988

L-leucyl-L-leucine methyl ester treatment of canine marrow and peripheral blood cells. Inhibition of proliferative responses with maintenance of the capacity for autologous marrow engraftment.

Incubation of canine marrow and peripheral blood mononuclear cells with L-leucyl-L-leucine methyl ester resulted in the inhibition of mitogen- and alloantigen-induced blastogenesis, the elimination of allosensitized CTL and NK activity, and prevented the development of CTL from pCTL. The effects of these incubations were similar to those described in mice and humans. Additionally, in vitro CFU-GM growth from treated canine marrow was reduced, but could be regained when the Leu-Leu-OMe-treated marrow was cocultured with either untreated autologous peripheral blood mononuclear cells or monocyte-enriched PBMC but not with untreated monocyte-depleted PBMC. Six of seven dogs conditioned with 920 cGy total-body irradiation engrafted successfully after receiving autologous marrow that was incubated with Leu-Leu-OMe prior to infusion. These cumulative results indicate that incubation with Leu-Leu-OMe is a feasible method to deplete canine marrows of alloreactive and cytotoxic T cells prior to transplantation.

Animals↗
PubMed1988

Treatment of gold-induced aplastic anaemia with immunosuppressive therapy.

Between June 1978 and August 1985 12 patients with gold-induced aplastic anaemia were treated with immunosuppressive therapy. Median age was 38.5 years for the 11 females and one male. Treatment regimens varied, but all patients received 150-160 mg/kg horse anti-human thymocyte globulin (ATG) over 4-10 d. Five patients had complete recovery of peripheral counts and one patient had a partial response. Of the six nonresponders one had a spontaneous recovery a year later and five died 6-67 d after beginning treatment. Seven patients are alive 4.3-8.9 years later. Six patients remain haematologically stable and one patient has developed a myelodysplastic syndrome. This experience confirms earlier reports of patients recovering marrow function after receiving immunosuppressive therapy for gold-related aplasia.

Adolescent↗