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R Storb

Publications and source records attributed to R Storb.

At least 361 records · Page 20Linked to original sources
PubMed1990

Bone marrow transplantation in canine GM1 gangliosidosis.

Allogeneic bone marrow transplantation was carried out in an 81-day-old Portuguese water dog with GM1 gangliosidosis using a DLA identical sibling as donor. Engraftment was complete and beta-galactosidase activity in leukocytes of the transplanted dog were similar to those in the donor. Over the next 2.5 months neurological deterioration in the transplanted dog was similar to that in untreated dogs with GM1 gangliosidosis. Cerebral ganglioside GM1 concentrations were not diminished by bone marrow transplantation and cerebral beta-galactosidase activity was negligible. We conclude that allogeneic bone marrow transplantation early in life is ineffective in canine GM1 gangliosidosis.

Animals↗
PubMed1990

Batten's disease: failure of allogeneic bone marrow transplantation to arrest disease progression in a canine model.

We investigated whether the course of canine ceroid lipofuscinosis (CCL), a model of Batten's disease in man, was affected by allogeneic bone marrow transplantation. Four English setters with CCL, 4 1/2 months of age, were given 9.2 Gy of total body irradiation, followed by the infusion of bone marrow cells from healthy DLA identical sibling donors. All transplanted dogs had complete hematologic reconstitution. However, at 12-13 months posttransplant, all dogs developed characteristic and progressive signs of CCL. Autopsies revealed cerebral atrophy and findings of ceroid storage not different from those in non-transplanted controls. These findings suggest that bone marrow cells do not contain or release the gene product(s) necessary to correct the disease. It appears unlikely that with our current knowledge, allogeneic marrow transplantation would be beneficial in the treatment of Batten's disease.

Animals↗
PubMed1990

Autologous marrow transplantation for malignant lymphoma: a report of 101 cases from Seattle.

Between October 1979 and January 1988, 101 patients with malignant lymphoma who failed initial induction treatment or relapsed received high-dose combination chemotherapy or chemoradiotherapy followed by infusion of autologous bone marrow. Twenty-eight of the 101 patients survive, 18 of whom are disease-free for a median of 26 (range, 12 to 66) months. The 5-year actuarial probabilities of survival, event-free survival (EFS), and relapse from transplantation were 20%, 11%, and 84%, respectively. Multivariate analysis showed that the likelihood of EFS was decreased among patients transplanted with a Karnofsky score of less than 80%. Recurrent lymphoma after transplant was the most important cause of treatment failure with 36 of 62 relapses occurring within 100 days from marrow infusion. Early, but not late relapse, was more frequent in patients transplanted for advanced lymphoma, and both early and late relapses were increased among patients with impaired pretransplant clinical performance or high-grade histology of lymphoma. Ten patients who relapsed post-transplant are alive, seven in remission. Further improvement of these results will require earlier transplantation, improved preparative regimens, or early posttransplant therapy.

Adolescent↗
PubMed1990

Cytomegalovirus infection after marrow transplantation for aplastic anemia.

Data from 137 patients who underwent allogeneic marrow transplantation for aplastic anemia and who had sufficient virologic and serologic surveillance data were reviewed for risk factors for cytomegalovirus (CMV) infection and associations between CMV infection and acute or chronic graft-versus-host disease (GVHD). Total CMV infection (i.e. excretion or seroconversion) occurred in 58% of the patients. Twelve patients (9%) developed CMV pneumonia. Among seropositive patients occurrence of acute GVHD was associated with increased risk of total CMV infection and CMV excretion, but not of seroconversion. Acute GVHD did not influence the likelihood of total CMV infection, excretion, or seroconversion in seronegative patients. Among seronegative patients marrow donor seropositivity, buffy coat infusions, and granulocyte transfusions were significant risk factors for total CMV infection and seroconversion, but not for CMV excretion. No influence of either total CMV infection or the patient's or donor's serologic status for CMV was found on the risk of developing chronic GVHD in this homogeneous group of patients who underwent allogeneic marrow transplantation for aplastic anemia.

Adolescent↗
PubMed1990

Canine models of bone marrow transplantation.

Progress in experimental bone marrow transplantation in dogs has provided for the direct transfer of research data to the clinical setting and the therapeutic application of marrow grafting to a variety of human diseases. Animal models of total body irradiation, engraftment and graft-versus-host disease are still needed to solve the existing clinical problems of marrow transplantation. Therefore, work in various canine model systems continues to be of interest. Pet dogs with spontaneously occurring lymphomas are used to study the clinical parameters necessary for applying the technique of transplanting their own marrow (autologous), in conjunction with high dose radiation and/or chemotherapy, to human patients with cancer. A major consideration in the successful transplantation of donor bone marrow (allogeneic) is overcoming histocompatibility barriers to assure engraftment and the prevention of graft-versus-host disease, a major limiting aspect of clinical marrow transplantation. Chemicals, radiation, radiotherapeutic techniques, antisera and monoclonal antibodies have been and continue to be developed in laboratory bred dogs. These approaches suppress the immune system either nonspecifically by ablation of immune reactive tissue, or specifically by affecting certain types of immune reactive cells. Parameters such as clinical effectiveness (engraftment or prevention of graft-versus-host disease), immune reconstitution and undesirable side affects in long-term survivors are all used to determine whether new technology can be transferred from preclinical canine studies to human bone marrow transplantation protocols.

Animals↗
PubMed1990

Treatment of aplastic anemia.

Survival of patients with aplastic anemia after immunosuppressive therapy with ATG/ALG ranges from 35% to 60%. However, long-term follow-up on these patients has indicated a high frequency of hematologic complications, including PNH, myelodysplasia, ANL, and recurrent aplasia. In contrast to immunosuppressive therapy, allogeneic marrow transplantation results in cure of aplasia. Problems initially limiting the success of HLA-matched allogeneic marrow transplants included graft rejection and complications associated with acute and chronic GVHD. Infusion of donor buffy coat cells along with marrow or alternatively more intensive immunosuppressive regimens containing irradiation have substantially decreased the risk of rejection. However, buffy coat infusion increases the incidence of chronic GVHD and irradiation treatment adds to toxicity of the conditioning regimen as well as producing long-term complications. The incidence and severity of acute GVHD have been significantly decreased by the use of MTX/CSP as GVHD prophylaxis; however, this regimen has had no impact on the incidence of chronic GVHD. Long-term survival in multiply transfused patients after HLA-identical marrow transplantation is on the order of 60% to 70%; survival in untransfused patients approximates 80%. Patients less than age 18 transplanted on protocols currently active in Seattle have greater than 90% survival. Further increases in survival must come from improvement in preventing and treating chronic GVHD. Patients diagnosed with aplastic anemia should have rapid HLA typing performed to identify possible marrow donors. Transfusions from prospective marrow donors should be avoided and the patient referred to a major treatment center. We continue to recommend allogeneic marrow transplantation for patients with severe aplastic anemia who are less than 40 years old and who have HLA-identical related donors. Immunosuppressive therapy should be tried first in patients without HLA-matched donors and for patients over the age of 40. HLA-mismatched marrow transplantation and use of unrelated marrow donors for severe aplastic anemia remain areas of active research.

Anemia, Aplastic↗
PubMed1990

Transfusion of autologous cytotoxic cells leads to failure of unrelated, DLA-nonidentical marrow grafts.

Dogs conditioned with 9.2 Gy total body irradiation (TBI) and given histoincompatible marrow transplants have a high rate of graft failure. Engraftment can be achieved by using 18 Gy fractionated TBI as preparative regimen. In this study, we tested the effects of infusing, at the time of histoincompatible marrow transplantation, autologous cells that had been stored before beginning high-dose (18 Gy) TBI. Our aim was to identify the peripheral blood mononuclear cells (PBMC) that contribute to failure of marrow grafts. Marrow graft failure was observed in three of three dogs receiving a mean of 2.1 x 10(8) unfractionated autologous PBMC/kg body weight as well as in two of two dogs receiving a mean dose of 0.075 x 10(8) PBMC/kg. When the dose of PBMC was decreased to 0.01 x 10(8)/kg, engraftment was seen in two of two dogs. These experiments thus established a cell dose response for causing marrow graft failure; further studies evaluated which subset of cells mediated this effect. Infusion of 0.09 x 10(8) nylon wool-nonadherent, plastic-nonadherent PBMC/kg was effective in causing marrow graft failure in three of three dogs. In contrast, infusion of 0.03 x 10(8) autologous monocytes/kg, enriched threefold above the number contained in the lower dose of PBMC causing graft failure, was associated with engraftment in four of six dogs. Infusion of 0.13 x 10(8) PBMC/kg treated with L-leucyl-L-leucine methyl ester (Leu-Leu-OMe), a drug that depletes canine cytotoxic T-lymphocytes (CTL), natural killer (NK) cells, and monocytes, permitted engraftment in three of four dogs. These data suggest that cytotoxic lymphocytes mediate failure of histoincompatible marrow grafts.

Animals↗
PubMed1990

Failure of anti-MHC antibodies to prevent GVHD in DLA mismatched unrelated canine marrow recipients.

Gene products of the major histocompatibility complex (MHC) have been shown to elicit lethal graft-versus-host disease (GVHD) in experimental animals. Antibodies specific for MHC cell surface determinants might therefore be expected to overcome histocompatibility barriers and influence survival of marrow graft recipients. GVHD can be consistently induced in dogs by transplanting donor marrow cells into lethally irradiated, unrelated, mismatched recipients. Three anti-Ia monoclonal antibodies were administered to five canine recipients, each at a dose of 0.2 mg/kg body weight per day intravenously for 10 days, beginning on day 0, the day of transplantation. Eight canine recipients were treated with antidog alloantiserum 10 ml/kg body weight per day intravenously on days -2 to day +20, in addition to receiving postgrafting methotrexate. The antiserum was generated by immunizing a matched littermate of the donor with peripheral blood cells of the recipient before transplantation. Survival was no different in the two groups of dogs, compared with historical controls without antibody treatment. A possible explanation for the failure of anti-MHC antibodies to modify acute GVHD in the dog is the inability of antibody to reach critical tissue sites targeted in GVHD.

Animals↗
PubMed1990

Gynecological abnormalities following allogeneic bone marrow transplantation.

Forty-four post-pubertal women were studied 261-4628 days after allogeneic transplantation to determine the nature and degree of gynecological abnormalities following bone marrow transplantation. Evaluations included pelvic examinations, exfoliative cytology, serum gonadotropin levels, direct preparations for micro-organisms, and microbial cultures. Pelvic abnormalities were detected in 35 of 44 (80%) women and resembled atrophic changes known to occur after ovarian failure. Findings included reduced vaginal elasticity and rugal folds, pale tissues, small vaginal, uterine and cervical size, atrophic vulvovaginitis, introital stenosis, and loss of pubic hair. Atrophic abnormalities were noted in 33 of 36 recipients of total body irradiation (TBI) compared to two of eight women not prepared with TBI (p = 0.02). Vasomotor symptoms were reported in 67% of TBI recipients compared to 38% of those not given TBI. Elevated serum gonadotropin levels suggested that TBI had caused the ovarian failure. Recognition of these gynecological abnormalities can lead to earlier hormone replacement, alleviating unnecessary discomfort and improving the well-being of the marrow transplant recipient.

Adolescent↗
PubMed1989

Prevention of transfusion-induced graft-versus-host disease in dogs by ultraviolet irradiation.

Ten dogs were given 9.2 Gy of total body irradiation and autologous bone marrow infusion followed by ten daily transfusions of leukocytes for a total of 11.5 to 36.2 (median, 18.8) x 10(8)/kg obtained via leukapheresis from histoincompatible unrelated donors. Four dogs were given unirradiated leukocytes, and all developed graft-versus-host disease (GVHD). In contrast, only two of three dogs given leukocytes irradiated with 20 mJ/cm2 of ultraviolet (UV) light (200 to 300 nm), and none of three dogs given leukocytes irradiated with 1,000 mJ/cm2 developed GVHD. These data indicate that UV irradiation abrogates the alloreactive potential of transfused leukocytes, and suggest that UV irradiation can be used to prevent the development of transfusion-induced GVHD.

Animals↗
PubMed1989

Secondary cancers after bone marrow transplantation for leukemia or aplastic anemia.

To determine the incidence of secondary cancers after bone marrow transplantation, we reviewed the records of all patients at our center who received allogeneic, syngeneic, or autologous transplants for leukemia (n = 1926) or aplastic anemia (n = 320). Thirty-five patients were given a diagnosis of secondary cancer between 1.5 months and 13.9 years (median, 1.0 year) after transplantation. Sixteen patients had non-Hodgkin's lymphomas, 6 had leukemias, and 13 had solid tumors (including 3 each with glioblastoma, melanoma, and squamous-cell carcinoma). There were 1.2 secondary cancers per 100 exposure-years during the first year after transplantation (95 percent confidence interval, 0.7 to 2.0). The rate declined to 0.4 (95 percent confidence interval, 0.2 to 0.7) after one year. The age-adjusted incidence of secondary cancer was 6.69 times higher than that of primary cancer in the general population. In a multivariate model, the predictors (and relative risks) of any type of secondary cancer were acute graft-versus-host disease treated with either antithymocyte globulin (relative risk, 4.2) or an anti-CD3 monoclonal antibody (13.6) and total-body irradiation (3.9). Two additional factors were associated with secondary non-Hodgkin's lymphomas: T-lymphocyte depletion of donor marrow (12.4) and HLA mismatch (3.8). We conclude that recipients of bone marrow transplantation have a low but significant risk of a secondary cancer, particularly non-Hodgkin's lymphoma.

Adolescent↗
PubMed1989

Comparison of fractionated to single-dose total body irradiation in conditioning canine littermates for DLA-identical marrow grafts.

We explored the ability of fractionated total body irradiation (TBI) given at a rate of 7 cGy/min from opposing dual 60Co sources at otherwise lethal doses of 450, 600, 700, 800, and 920 cGy to condition dogs for marrow grafts from DLA-identical littermates. Results were compared with those of a previously reported study using single-dose TBI administered under otherwise identical conditions. Fractionated TBI was less immunosuppressive than single-dose TBI, as evidenced by a significantly higher rate of graft rejection (P = .001). Specifically, sustained allogeneic engraftment was observed in only two of 18 (11%) dogs that received 600 to 800 cGy fractionated TBI as compared with 11 of 17 (65%) dogs that received comparable doses of single-dose TBI. Only at 450 cGy (none of the ten dogs studied had sustained engraftment) and at 920 cGy (four of five dogs that received fractionated and 20 of 21 dogs that received single-dose TBI engrafted) were we unable to find differences between the two modes of radiation. Most dogs that rejected their graft survived with autologous recovery (13 of 22 that received fractionated and eight of 12 that received single-dose TBI; P = .49), presumably the result of extended support provided by the transient allogeneic grafts. We conclude that at equivalent doses fractionated TBI is significantly less effective than single-dose TBI to condition DLA-identical littermate dogs for marrow transplantation. These findings have implications for the design of conditioning programs in clinical transplantation, especially when T-cell-depleted marrow grafts are used.

Animals↗
PubMed1989

Influence of acute and chronic graft-versus-host disease on relapse and survival after bone marrow transplantation from HLA-identical siblings as treatment of acute and chronic leukemia.

To assess the influence of graft-versus-host disease (GVHD) on recurrent leukemia and survival after allogeneic marrow transplantation, we studied 1,202 patients with acute nonlymphocytic leukemia (ANL), acute lymphocytic leukemia (ALL), and chronic myelogenous leukemia (CML) given unmodified marrow grafts from HLA-identical siblings. Proportional hazards regression models using acute GVHD and chronic GVHD as time-dependent covariates demonstrated a significant association of GVHD with a decreased relative risk (RR, 0.33 to 0.42) of relapse in patients with ANL, ALL, and CML transplanted in advanced disease. Among patients developing either acute or chronic GVHD, treatment failure (that is, mortality or relapse) was decreased in patients with ALL transplanted in relapse (RR = 0.70, P less than .033) and CML in blast crisis (RR = 0.37, P less than .009). This effect was independent of age, sex, preparative regimen, GVHD prophylaxis, or length of follow-up. Five-year actuarial estimates were derived for the subset of 657 patients who survived in remission 150 days after transplant and were at risk for development of chronic GVHD. Among patients with ANL in first remission or CML in chronic phase, GVHD had an adverse effect on survival and no apparent influence on relapse. Among patients with ANL and ALL transplanted in relapse, the probability of relapse after day 150 was 74% without [corrected] GVHD, 45% with acute and chronic GVHD, 35% with [corrected] only acute GVHD, and 34% with only chronic GVHD (P less than .001). Actuarial survival in these four GVHD groups was 25%, 34%, 59%, and 62%, respectively (P less than .009). Among patients with CML in acceleration or blast crisis, the probability of relapse after day 150 was 65% without GVHD and 36% with acute and/or chronic GVHD (P less than .017). We conclude that acute and chronic GVHD were associated with a durable antileukemic effect and improved survival in patients transplanted in advanced stages of ALL and CML.

Bone Marrow Transplantation↗