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Biomedical subjects

M Körbling

Publications and source records attributed to M Körbling.

At least 19 recordsLinked to original sources
PubMed2005

Umbilical cord blood-derived cells for tissue repair.

Hematopoietic tissue-derived cells, including stem cells, have been shown to generate solid organ tissue-specific cells. Besides bone marrow and peripheral blood, umbilical cord blood (UCB) has the advantage of being an easily accessible stem cell source provided as a banked cell product. Using the xenogeneic human into NOD/SCID mouse stem cell transplant model preliminary data suggest UCB-derived tissue-specific cells generated in liver, pancreas, CNS and endothelium. In a clinical sex-mismatched UCB transplant setting Y-positive, UCB-derived gastrointestinal epithelial cells and CNS-specific cells have been identified in female patients. The potential therapeutic use of UCB cells for tissue repair is, however, limited by a low total stem cell number available and by HLA-disparity.

Animals↗
PubMed2004

Circulating stem cells and tissue repair.

Stem cells are defined as cells that have clonogenic, self-renewing capacities and the capability to differentiate into multiple cell lineages. Whereas embryonic stem cells are derived from mammalian embryos in the blastocyst stage and can generate terminally differentiated cells of all 3 embryonic germ layers, adult human stem cells are capable of maintaining, generating, and replacing terminally differentiated cells within their own specific tissue as a consequence of physiologic cell turnover or tissue injury. The traditional idea of organ-restricted stem-cell differentiation is now being challenged by the suggestion that adult stem cells retain developmental plasticity. Preclinical and clinical studies described in this review provide evidence that within the blood circulate not only progenitor cells that differentiate into hematopoietic cells, but also stem/progenitor cells which can participate in the homeostasis, repair and replacement of solid organ tissues. In addition to the occurrence of cell fusion, there are 4 suggested mechanisms of adult stem cell differentiation into solid organ cells. Preclinical data support these models particularly that of transdifferentiation as the most likely model, allowing stem/progenitor cells to differentiate across lineage, tissue, and germ layer boundaries. There is increasing evidence that we can manipulate in vivo circulating adult stem cells to repair or regenerate solid organ tissue, which offers potential clinical benefit in the treatment of many hereditary and acquired diseases.

Animals↗
PubMed2003

Extracorporeal photopheresis therapy in the management of steroid-refractory or steroid-dependent cutaneous chronic graft-versus-host disease after allogeneic stem cell transplantation: feasibility and results.

We conducted a retrospective analysis of all allogeneic stem cell transplantation (ASCT) patients started on extracorporeal photopheresis (ECP) for the management of steroid-dependent (SD) or steroid-refractory (SR) cutaneous chronic graft-versus-host disease (cGVHD) following ASCT during a 36-month period (9/98-8/01). Only SD or SR patients who were treated by ECP after day 100 and who received at least 4 weeks of ECP were considered evaluable for this analysis. Out of 64 ASCT patients reviewed, 32 patients met the inclusion criteria. All 32 patients had been previously treated with systemic corticosteroids with 11 (34%) being SR and 21 (66%) SD. Cutaneous cGVHD was extensive in 28 patients (88%) and was accompanied by visceral (hepatic, gastrointestinal) cGVHD in 23 patients (72%). The 32 evaluated patients had received a median of three prior therapies before ECP, most commonly systemic corticosteroids, tacrolimus, and mycophenolate mofetil. Patients received a median of 36 ECP sessions (range 12-98) over a median of 5.3 months (range 1-28), with a median of six sessions per month. The complete response (CR) rate was 22% (n=7) and the partial response rate was 34% (n=11). In all, 28 patients were on systemic corticosteroid therapy at ECP initiation and 18 patients achieved 50% dose reduction while on ECP, yielding a 64% steroid-sparing response rate. Of seven CRs, five are ongoing. A total of 11 (34%) patients have died after ECP, with all cases due to visceral cGVHD or cGVHD-related infectious complications. All 21 surviving patients remain on at least some immunosuppressive cGVHD therapy (including ECP in eight). Overall, ECP displays a substantial response rate and, in particular, steroid-sparing activity in SR/SD extensive cutaneous cGVHD. However, most patients continue to require at least some chronic therapy and cGVHD-related morbidity and mortality remain high.

Adolescent↗
PubMed2003

Adult stem cells and tissue repair.

Recently, adult stem cells originating from bone marrow or peripheral blood have been suggested to contribute to repair and genesis of cells specific for liver, cardiac and skeletal muscle, gut, and brain tissue. The mechanism involved has been termed transdifferentiation, although other explanations including cell fusion have been postulated. Using adult stem cells to generate or repair solid organ tissue obviates the immunologic, ethical, and teratogenic issues that accompany embryonic stem cells.

Adult↗
PubMed2002

Long-term outcome in acute myelogenous leukemia autografted with mafosfamide-purged marrow in a single institution: adverse events and incidence of secondary myelodysplasia.

We have analyzed the long-term outcome and toxicities in 98 patients with high-risk acute myelogenous leukemia (AML) who were treated with autologous bone marrow transplantation (ABMT) and monitored for a median observation period of 11.67 years. Between 1983 and 1994, 98 patients in our institution in first or second and higher complete remission (CR) underwent total body irradiation and high-dose cyclophosphamide prior to ABMT purged with mafosfamide. Twenty-seven out of the 90 evaluable patients (30%) were alive and in continuous CR for a median of 11.67 years (range, 6.39-15.53) after ABMT and could be considered as 'cured'. Among the 90 patients, 39 were transplanted at first CR and had a significantly higher survival rate than those transplanted at > or = 2 CR. Younger patients (<40 years) had a better prognosis and patients with FAB M1-4 had a more favorable outcome than those with M5. Long-term complications included four patients with cardiac complications, two with renal insufficiency. Five developed HCV infections, four myelodysplastic syndrome. The incidence of cataract among the long-term survivors was 44.4%. Therefore, a significant number of adult patients with AML in first CR derived long-term benefit from ABMT, despite the risks of a few long-term complications and of MDS (4.4%).

Adolescent↗
PubMed2002

Long-term follow-up of normal peripheral blood progenitor cell donors treated with filgrastim: no evidence of increased risk of leukemia development.

Data on the long-term safety of filgrastim administration in peripheral blood progenitor cell (PBPC) donors are scarce. The main theoretical risk is believed to be the possible development of leukemia. We conducted a survey of filgrastim-treated related donors to determine the incidence of leukemia after PBPC donation. Of the 343 PBPC donors eligible for inclusion in the survey, 281 (82%) were interviewed by telephone between December 1998 and February 2000. The mean age at donation was 44 years. The median time elapsed after PBPC donation was 39 months, and in 278 (99%) of the interviewed donors it was at least 1 year. At the time of the interview none of the donors had been diagnosed with acute or chronic leukemia. Although the sample size is small and the follow-up duration is limited, these data suggest that exposure to filgrastim is not associated with any notable risk of leukemia development in PBPC donors.

Adolescent↗
PubMed2002

Risk of therapy-related myelodysplastic syndrome/acute leukemia following high-dose therapy and autologous bone marrow transplantation for non-Hodgkin's lymphoma.

BACKGROUND: Several recent reports have suggested that patients with non-Hodgkin's lymphomas (NHL) who undergo autologous stem cell transplantation (ASCT) are at increased risk of developing therapy-related myelodysplastic syndrome (tMDS) and acute myelogenous leukemia (tAML). PATIENTS AND METHODS: We analyzed 493 patients with NHL who underwent ASCT at The University of Texas M.D. Anderson Cancer Center between January 1990 and August 1999. RESULTS: With a median follow-up time of 21 months after HDT, 22 patients developed persistent cytopenia in at least one cell line with morphologic or cytogenetic evidence of tMDS or tAML. Univariate analysis identified prior fludarabine therapy, bone marrow involvement with lymphoma, and total body irradiation (TBI) as significant risk factors for the development of tMDS/tAML (P <0.05). Multiple logistic regression analysis showed that TBI was independently associated with an increased risk of developing tMDS/tAML (P <0.01). Further analysis of the patients who received TBI revealed that patients receiving TBI in combination with cyclophosphamide and etoposide were more likely to develop tMDS/tAML than those who received TBI with cyclophosphamide or thiotepa (P <0.01). The median survival of patients developing tMDS/tAML was 7.5 months (range 0-32 months). CONCLUSIONS: TBI, especially when used in combination with cyclophosphamide and etoposide as the pretransplant conditioning regimen, is a significant risk factor for the development of tMDS/tAML.

Acute Disease↗
PubMed2001

Peripheral blood stem cell versus bone marrow allotransplantation: does the source of hematopoietic stem cells matter?

Hematopoietic stem cells from 4 different sources have been or are being used for the reconstitution of lymphohematopoietic function after myeloablative, near-myeloablative, or nonmyeloablative treatment. Bone marrow (BM)-derived stem cells, introduced by E. D. Thomas in 1963, are considered the classical stem cell source. Fetal liver stem cell transplantation has been performed on a limited number of patients with aplastic anemia or acute leukemia, but only transient engraftment has been demonstrated. Peripheral blood as a stem cell source was introduced in 1981, and cord blood was introduced as a source in 1988. The various stem cell sources differ in their reconstitutive and immunogenic characteristics, which are based on the proportion of early pluripotent and self-renewing stem cells to lineage-committed late progenitor cells and on the number and characteristics of accompanying "accessory cells" contained in stem cell allografts.

Blood Cells↗
PubMed2001

Controlled trial of filgrastim for acceleration of neutrophil recovery after allogeneic blood stem cell transplantation from human leukocyte antigen-matched related donors.

The rapid recovery of hematopoiesis after allogeneic blood stem cell transplantation has been attributed to the quality and quantity of hematopoietic progenitors in the blood stem cell grafts from filgrastim-stimulated donors. To determine whether further stimulation with filgrastim after transplantation would affect hematopoietic recovery, a prospective, randomized, controlled study was performed. Forty-two adult recipients of allogeneic blood stem cells from human leukocyte antigen-matched related donors were randomized to receive 10 microg/kg per day filgrastim subcutaneously from day 1 through neutrophil recovery or no growth factor support after transplantation. There was no significant difference between the 2 groups in the number of CD34(+) cells infused (median, 4.8 vs 4.3 x 10(6)/kg). Graft-versus-host (GVHD) disease prophylaxis consisted of tacrolimus and steroids for 9 patients and tacrolimus and minimethotrexate for 33 patients. The group receiving filgrastim had a shorter time to neutrophil levels greater than 0.5 x 10(9)/L (day 12 vs day 15, P =.002) and to neutrophil levels greater than 1.0 x 10(9)/L (day 12 vs day 16, P =.01). The filgrastim group also had a trend for earlier discharge (day 16 vs 20, P =.05). There was no significant difference between the groups in time to platelet recovery, number of transfusions, regimen-related toxicity, infection, incidence of GVHD, relapse, survival, or hospital charges. It can be concluded that the administration of filgrastim after allogeneic blood stem cell transplantation shortens the time to neutrophil recovery. (Blood. 2001;97:3405-3410)

Adolescent↗
PubMed2001

Donor lymphocyte apheresis for adoptive immunotherapy compared with blood stem cell apheresis.

Donor lymphocyte transfusion has gained considerable interest as adoptive cellular immunotherapy for prevention or treatment of relapse after allogeneic stem cell transplantation. This study was designed to compare the yield of CD3(+), CD3(+)4(+), CD3(+)8(+), CD19(+), CD3(-)56(+)16(+), and CD34(+) cells contained in apheresis products from 61 consecutive non-cytokine treated, human leukocyte antigen (HLA)-matched donors for lymphocyte collection with the corresponding apheresis-derived cell yield from 112 consecutive, HLA-matched donors for blood stem cell collection who received recombinant human granulocyte colony stimulating factor (rhG-CSF, filgrastim) 6 microg/kg every 12 hours until cell collection was completed. Apheresis was started on day 4 or 5 of rhG-CSF treatment. The yield of lymphoid subsets was significantly different in the two sample groups, rhG-CSF treated product yields exceeding untreated product yields by a median of 2.1-fold (range: 1.3-2.6). However, the CD34(+) cell yield in rhG-CSF-treated apheresis products exceeded untreated products by 26-fold. A single untreated apheresis procedure was usually sufficient to collect a target dose of 1 x 10(8)/kg CD3(+) cells. Untreated apheresis products contained a median of 0.2 x 10(6)/kg CD34(+) cells. A potential engraftment dose of > or =0.5 x 10(6) CD34(+) cells per kg of recipient body weight was contained in 16% of 57 untreated apheresis products. One single apheresis performed in a normal, untreated donor provides a sufficient amount of CD3(+) cells for adoptive immunotherapy. Compared with that of an rhG-CSF stimulated apheresis product, the CD34(+) cell count is usually, but not always, below the engraftment dose range. RhG-CSF treatment has little effect on the yield of lymphoid subsets collected by apheresis but is highly selective of the release of CD34(+) cells. This report provides baseline data for studies that will show whether other cytokines such as granulocyte macrophage colony stimulating factor (GM-CSF) and/or Flt-3 Ligand can immunomodulate allotransfusates in vivo to improve the graft-vs.-leukemia (GVL) effect after allogeneic stem cell transplantation, while lowering the incidence and severity of graft-vs.-host disease (GVHD).

Adult↗
PubMed2001

Continuous complete remission in adult patients with acute lymphocytic leukaemia at a median observation of 12 years after autologous bone marrow transplantation.

We report our long-term experience with autologous bone marrow transplantation (ABMT) for 32 adult patients with acute lymphocytic leukaemia (ALL) in second or later remission (CR), or in first CR but with high-risk. Bone marrow was purged with mafosfamide (n = 25) or with immunomagnetic beads and monoclonal antibodies (n = 7). Retrospective analysis showed that 12 out of 32 patients were in continuous complete remission (CCR) at a median of 143 months (range 66-181 months). A plateau was reached at 50 months and the disease-free and overall survival rates were both 37.5%. It was notable that durable CCR could be achieved for patients in second (three out of nine) or third (one out of six) CR. ABMT could produce durable CCR and the long-term outcome compared favourably with those reported for allogeneic transplantation.

Adolescent↗
PubMed2000

Cryofibrinogenemia and skin necrosis in a patient with diffuse large cell lymphoma after high-dose chemotherapy and autologous stem cell transplantation.

A 34-year-old woman with diffuse mediastinal B cell large cell lymphoma presented 60 days after high-dose chemotherapy and autologous stem cell transplantation, and post-transplant immunotherapy with interleukin-2, with skin necrosis in the ears and extremities. Extensive work-up revealed the presence of cryofibrinogenemia and associated thrombotic vasculopathy. The patient was successfully treated with corticosteroids and therapeutic plasma exchange. However, she had recurrence of large cell lymphoma a few weeks later and died of progressive disease. Cryfibrinogenemia and skin necrosis may have occurred secondary to the imminent relapse, or as a rare complication of high-dose chemotherapy or treatment with interleukin-2.

Adult↗
PubMed2000

A comparative study of once-daily versus twice-daily filgrastim administration for the mobilization and collection of CD34+ peripheral blood progenitor cells in normal donors.

Eighty-one first-time normal donors underwent leukapheresis for peripheral blood progenitor cell (PBPC) collection after mobilization with filgrastim administered either twice-daily (6 microg/kg every 12 h; n = 40) or once-daily (12 microg/kg; n = 41) subcutaneously for 3 d. The groups were similar for age, donor blood volume and target CD34+ cell dose to be collected (>/= 4 x 106 CD34+ cells/kg recipient). There was no statistically significant difference in the apheresis yield of CD34+ PBPCs (x 106) per kg recipient weight (5.6 +/- 3.3 vs. 5.6 +/- 4.3; P = 0.94) and per litre of blood processed (30 +/- 17.2 vs. 30.4 +/- 19.5; P = 0.92).

Adult↗
PubMed2000

High CD34 cell doses do not worsen regimen-related toxicity or early mortality after autologous blood stem cell transplantation for breast cancer.

BACKGROUND: Some transplant-related complications, such as the engraftment syndrome, are thought to be mediated by cytokines released during expansion of hematopoietic progenitors at the time of neutrophil recovery. Since there is an inverse correlation between CD34(+) cell dose and time to neutrophil recovery, we sought to determine if peritransplant toxicity and early mortality were adversely affected by high CD34(+) cell doses. METHODS: The study group included 186 women with breast cancer who received high-dose cyclophosphamide, carmustine, thiotepa and an autologous PBSC transplant. The median CD34(+) cell dose was 5.9 x 10(6)/kg (1.0-154.7 x 10(6)/kg). Patients were categorized by CD34(+) cell dose (1.0-3.5, 3.6-5.9, 6.0-19.9, and 20.0-154.7 x 10(6)/kg) for assessment of outcomes. RESULTS: Grades 2-4 mucositis occurred in 49%, cardiac toxicity in 7%, pulmonary toxicity in 5%, cystitis in 4%, diarrhea in 3%, renal toxicity in 1%, and central nervous system toxicity in 1%. A Grade 2-4 regimen-related toxicity occurred in 109 patients (59%) and Grade 3-4 in eight patients (4%). Overall survival was 100% at Day 30, 96% at Day 90, and 89% at 1 year. Treatment-related mortality was 3.8%. In multivariate analyses that included prior chemotherapy, disease status, visceral metastases, prior chest radiation and age, CD34(+) cell dose group was not an independent risk factor for Grade 2-4 mucositis, Grade 2-4 maximum toxicity, Grade > or =3 cumulative toxicity, 90 day survival or 1 year survival. DISCUSSION: We conclude that CD34(+) cell doses >20 x 10(6)/kg do not affect transplant outcome in a negative or positive fashion.

Adult↗
PubMed1999

Risk factors for acute graft-versus-host disease after allogeneic blood stem cell transplantation.

We evaluated demographic characteristics and graft composition as risk factors for acute graft-versus-host disease (GVHD) in 160 adult recipients of HLA-identical allogeneic blood stem cell transplants. The patients received a median nucleated cell dose of 7.9 x 10(8)/kg and median C34(+) cell dose of 5.6 x 10(6)/kg. GVHD prophylaxis consisted of cyclosporine (CSA) and steroids, tacrolimus (FK506) and steroids, or FK506 and methotrexate. Grades 2 to 4 GVHD occurred in 31% (95% CI, 23% to 39%), and grades 3 to 4 GVHD in 14% (95% CI, 8% to 20%). In univariate analyses, GVHD prophylaxis with CSA and high CD34(+) cell doses were significant risk factors for grades 2 to 4 GVHD, but diagnosis, age, use of total body irradiation, donor sex, female donor for male recipient, donor parity, donor alloimmunization, viral serology, nucleated cell dose, CD3(+) cell dose, and CD56(+) cell dose did not alter the incidence of GVHD significantly. With a CD34(+) cell dose less than 8 x 10(6) CD34(+) cells/kg, the risk of grades 2 to 4 GVHD was significantly higher for those who received CSA (39%, 95% CI, 21% to 47%) in comparison with those on FK506 (18%, 95% CI, 10% to 26%) (P =.03), but GVHD prophylaxis regimen had less impact with a higher CD34(+) cell dose (overall grades 2 to 4 GVHD rate 52%, 95% CI, 37% to 67%). GVHD prophylaxis and CD34(+) cell dose are independent risk factors for acute GVHD after allogeneic blood stem cell transplantation.

Adolescent↗
PubMed1999

Thiotepa, busulfan and cyclophosphamide as a preparative regimen for allogeneic transplantation for advanced chronic myelogenous leukemia.

Thirty-six adults with chronic myelogenous leukemia (CML) in second or greater chronic phase, accelerated phase, or blast crisis underwent marrow or blood stem cell transplantation from an HLA-matched sibling using high-dose thiotepa, busulfan and cyclophosphamide (TBC) as the preparative regimen. All evaluable patients engrafted and had complete donor chimerism. One patient failed to clear meningeal leukemia, and one patient had one of 30 metaphases positive for the Philadelphia chromosome at 2 months post transplant. The remainder of the patients studied had eradication of CML documented by cytogenetics and/or Southern blot for BCR gene rearrangement, and 13 of 15 patients studied became negative for the BCR gene rearrangement by polymerase chain reaction. Three-year relapse rate is 42% (95% CI, 19-64%). The relapse rate was significantly lower for patients transplanted without blast crisis (9% vs 100%, P < 0.001). Eight (22%, 95% CI, 10-39%) patients had severe or fatal veno-occlusive disease (VOD). Elevated liver enzymes within 1 month prior to transplantation and transplantation using marrow were significantly associated with the occurrence of VOD. Three-year survival is 28% (95% CI, 13-43%). Survival was significantly higher for patients transplanted without blast crisis (45% vs 0%, P = 0.01). TBC is an effective preparative regimen for CML in accelerated phase but not refractory blast crisis, and it should be used with caution in patients with prior hepatopathy who have an increased risk of severe VOD.

Adult↗
PubMed1999

Tacrolimus and minidose methotrexate for prevention of acute graft-versus-host disease after HLA-mismatched marrow or blood stem cell transplantation.

Thirty adults with leukemia or lymphoma transplanted with marrow or blood stem cells from 1-antigen mismatched related donors received tacrolimus and minidose methotrexate to prevent acute graft-versus-host disease (GVHD). The group had a median age of 42 years (range 18-56 years). Twenty-seven patients had advanced disease, and 13 were resistant to conventional therapy. Tacrolimus was administered at 0.03 mg/kg/day i.v. by continuous infusion from day -2, converted to oral at four times the i.v. dose following engraftment, and continued to day 180 post-transplant. Methotrexate 5 mg/m2 was given i.v. on days 1, 3, 6 and 11. Mild nephrotoxicity was common before day 100; 69% of patients had a doubling of creatinine, 56% had a peak creatinine greater than 2 mg/dl, and two patients were dialyzed. Other toxicities prior to day 100 thought to be related to tacrolimus included hypertension (45%), hyperkalemia (17%), hyperglycemia (14%), seizures (13%), headache (3%) and hemolytic uremic syndrome (3%). Grades 2-4 GVHD occurred in 59% (95% CI, 38-70%), and grades 3-4 GVHD in 17% (95% CI, 1-32%). Overall survival at 1 year was 29% (95% CI, 12-45%). We conclude that tacrolimus and minidose methotrexate is active post-transplant immunosuppression for patients with 1-antigen mismatched donors.

Acute Disease↗